Publications

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four genome-wide association studies (GWAS) including 5,953 cases of aggressive PrCa and 11,463 controls (men without PrCa). We computed association tests for ~2.6M SNPs and followed up the most significant SNPs by genotyping 49,121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa (OR=1.12 (95% CI 1.03-1.21), P=1.4x10(-8)). This report describes a genetic variant which is associated with aggressive prostate cancer, which is a type of prostate cancer associated with a poorer prognosis.

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.

BACKGROUND AND PURPOSE: The Normal Tissue Complication Probability (NTCP) for rectum is usually defined for late rectal bleeding. This study calculates NTCP parameter values for additional rectal toxicity endpoints observed in clinical practise. MATERIALS AND METHODS: 388 patients from the multicentre MRC-RT01 prostate conformal radiotherapy trial (ISRCTN 47772397) were used to derive independent Lyman Kutcher Burman model (LKB) parameters for five late rectal toxicity endpoints: rectal bleeding, proctitis, stool frequency, loose stools and rectal urgency. The parameters were derived using maximum likelihood estimation. Bootstrap and leave-one-out methods were employed to test the generalisability of the results for use in a general population. RESULTS: A consistent pattern of increasing value of TD50(1) for Grade 2 toxicity only compared to Grades 1 and 2 toxicity was observed for all endpoints. Parameter values varied between endpoints (particularly for the volume parameter n). TD50(1), m and n were 68.5Gy (95% CI)(66.8-70.8), 0.15 (0.13-0.17) and 0.13 (0.10-0.17), respectively, for G2 rectal bleeding. Bootstrap and leave-one-out results showed that the rectal bleeding and proctitis parameter fits were extremely robust. CONCLUSIONS: The variation between the values derived for different endpoints may indicate different patho-physiological responses of the rectum to radiation. Therefore different parameter sets would be required to predict specific rectal toxicity endpoints.

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. METHODS: We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3-6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. FINDINGS: 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5-61·3), six (4·3%; 95% CI 1·6-9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2-8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2-5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5-6·2) of 138 men, three (2·2%; 0·5-6·3) of 137, and none (0·0%; 97·5% CI 0·0-2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. INTERPRETATION: Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. FUNDING: Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

BACKGROUND: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. METHODS: 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. FINDINGS: None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. INTERPRETATION: We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. FUNDING: Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.

The objectives of our study were to establish the apparent diffusion coefficients (ADCs) of tumor and nontumor irradiated tissues in patients with suspected postradiation recurrence of prostate cancer and to determine the sensitivity and specificity of a combination of T2-weighted and diffusion-weighted imaging (DWI) for detecting local recurrence.

INTRODUCTION: 3-Hydroxy-methylglutaryl coenzyme-A reductase inhibitors (statins) improve survival following pelvic irradiation for cancer. Large studies suggest that patients with hypertension may have reduced gastrointestinal (GI) toxicity. Animal data suggest that statins and ACE inhibitors (ACEi) may protect against normal tissue injury. Their efficacy in humans has not been reported. AIMS/METHODS: To evaluate the impact of statins and ACEi on normal tissue toxicity during radical pelvic radiotherapy. GI symptomatology was recorded prospectively before radiotherapy, weekly during treatment and 1 year later using the Inflammatory Bowel Disease Questionnaire - Bowel (IBDQ-B) subset. Cumulative acute toxicity (IBDQ-B AUC) and worst score were determined. Dose, brand and duration of statin and/or ACEi usage were obtained from General Practitioners. RESULTS: Of 308 patients recruited, 237 had evaluable acute drug and toxicity data and 164 had data at 1year. Acutely, 38 patients (16%) were taking statins, 39 patients (16.5%) were taking ACEi and 18 patients (7.6%) were taking statin+ACEi. Mean changes in acute scores were 7.3 points (non-statin users), 7.3 (non-ACEi users) and 7.0 (non-statin+ACEi users) compared to 4.8 points (statin users), 5.0 points (ACEi users) and 4.9 points (statin+ACEi users). Statin use (p=0.04) and combined statin+ACEi use (p=0.008) were associated with reduced acute IBDQ-B AUC after controlling for baseline scores (ANOVA). At 1 year, users maintained higher IBDQ-B scores than non-users in all user subgroups. CONCLUSION: Use of statin or statin+ACEi medication during radical pelvic radiotherapy significantly reduces acute gastrointestinal symptoms scores and also appears to provide longer-term sustained protection.

BACKGROUND: Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE-an international, open-label, randomised controlled trial-uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). METHODS: Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. FINDINGS: 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90-1·06). 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. INTERPRETATION: Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. FUNDING: Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK).

Wedlake L.J., McGough C., Shaw C., Klopper T., Thomas K., Lalji A., Dearnaley D.P., Blake P., Tait D., Khoo V.S. & Andreyev H.J.N. (2012) Clinical trial: efficacy of a low or modified fat diet for the prevention of gastrointestinal toxicity in patients receiving radiotherapy treatment for pelvic malignancies. J Hum Nutr Diet. ABSTRACT: Background:  Inflammatory responses to pelvic radiotherapy can result in severe changes to normal gastrointestinal function with potentially severe long-term effects. Reduced or modified fat diets may confer benefit. Methods:  This randomised controlled trial recruited patients with gynaecological, urological or lower gastrointestinal malignancy due to receive radical radiotherapy. Patients were randomised to a low fat (20% total energy from long chain triglycerides), modified fat (20% from long chain triglycerides and 20% from medium chain triglycerides) or normal fat diet (40% total energy from long chain triglycerides). The primary outcome was a difference in change in Inflammatory Bowel Disease Questionnaire - Bowel (IBDQ-B) score, from the start to end of radiotherapy. Results:  A total of 117 patients with pelvic tumours (48% urological; 32% gastrointestinal; 20% gynaecological), with mean (SD) age: 65 (11.0) years, male : female ratio: 79 : 38, were randomised. The mean (SE) fall in paired IBDQ-B score was -7.3 (0.9) points, indicating a worsening toxicity. Differences between groups were not significant: P = 0.914 (low versus modified fat), P = 0.793 (low versus normal fat) and P = 0.890 (modified versus normal fat). The difference in fat intake between low and normal fat groups was 29.5 g [1109 kJ (265 kcal)] amounting to 11% (of total energy intake) compared to the planned 20% differential. Full compliance with fat prescription was only 9% in the normal fat group compared to 93% in the low fat group. Conclusions:  A low or modified fat diet during pelvic radiotherapy did not improve gastrointestinal symptom scores compared to a normal fat intake. An inadequate differential in fat intake between the groups may have confounded the results.

PURPOSE: Most studies investigating the dose-response of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal-sphincter region and radiation-induced side-effects were quantified. MATERIALS AND METHODS: Dose-surface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397). RESULTS: Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53Gy (p=0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface. CONCLUSIONS: The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model.

We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.

Purpose: To investigate the effects of an endorectal device during prostate radiotherapy on the spatial distribution of dose to the ano-rectal region and quantify implications for normal-tissue-complication probabilities. Methods: Twenty-three patients with localised prostate cancer, referred for external beam radiotherapy had 2 CT scans acquired, without and with the rectal obturator (ProSpare) in-situ. For each patient two dose distributions were generated, based on both CT scans. Dose-surface maps for the rectal surface and the anal surface were generated and mean dose as well as a spatial measure (circumference of the dose distribution) were determined for all patients, with and without ProSpare. Using previously published NTCP models, the effect of ProSpare on NTCP was investigated for rectal bleeding and subjective sphincter control. Results: In a previous study subjective sphincter control correlated strongest with mean dose and lateral extent at 53 Gy. The use of ProSpare resulted in a highly significant reduction of the lateral extent at 53 Gy (p=0.006), mean dose (p=0.0009) and NTCP according to the LKB model (p=0.002 for grade 2 and p=0.001 for grade >=1). In a previous study we reported that rectal bleeding correlated most strongly with the lateral extent at 55 Gy and presented the constraint that it should not exceed 42% of the circumference. Using ProSpare resulted in a significant reduction of the lateral extent at 55 Gy (p=0.001) and significantly more patients met that proposed constraint (p=0.047). ProSpare resulted in a significant reduction of NTCP for grade-2 rectal bleeding (p=0.007) and a reduction for rectal bleeding grade >=1 (p=0.053). Conclusions: ProSpare resulted in a significant reduction of mean dose to the anal sphincter and a significant reduction of the lateral extent at 55 Gy. This corresponded to a significant reduction in the predicted risk of reporting subjective sphincter control and grade-2 rectal bleeding.

Background Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. Methods We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. Results Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). Conclusions Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653 .).

ABSTRACT: BACKGROUND: Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial. METHODS: STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate 'activity' stages (focus: failure-free survival), and a final 'efficacy' stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims. RESULTS: (1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies. CONCLUSIONS: The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.Trial registrationISRCTN78818544, NCT00268476First patient into trial: 17 October 2005First patient into abiraterone comparison: 15 November 2011.

PURPOSE: Intensity modulated radiation therapy (IMRT) is a significant therapeutic advance in prostate cancer, allowing increased tumor dose delivery and increased sparing of normal tissues. IMRT planning uses strict dose constraints to nearby organs to limit toxicity. Bile acid malabsorption (BAM) is a treatable disorder of the terminal ileum (TI) that presents with symptoms similar to radiation therapy toxicity. It has not been described in patients receiving RT for prostate cancer in the contemporary era. We describe new-onset BAM in men after IMRT for prostate cancer. METHODS AND MATERIALS: Diagnosis of new-onset BAM was established after typical symptoms developed, selenium-75 homocholic acid taurine (SeHCAT) scanning showed 7-day retention of <15%, and patients' symptoms unequivocally responded to a bile acid sequestrant. The TI was identified on the original radiation therapy plan, and the radiation dose delivered was calculated and compared with accepted dose-volume constraints. RESULTS: Five of 423 men treated in a prospective series of high-dose prostate and pelvic IMRT were identified with new onset BAM (median age, 65 years old). All reported having normal bowel habits before RT. The volume of TI ranged from 26-141 cc. The radiation dose received by the TI varied between 11.4 Gy and 62.1 Gy (uncorrected). Three of 5 patients had TI treated in excess of 45 Gy (equivalent dose calculated in 2-Gy fractions, using an α/β ratio of 3) with volumes ranging from 1.6 cc-49.0 cc. One patient had mild BAM (SeHCAT retention, 10%-15%), 2 had moderate BAM (SeHCAT retention, 5%-10%), and 2 had severe BAM (SeHCAT retention, <5%). The 3 patients whose TI received ≥45 Gy developed moderate to severe BAM, whereas those whose TI received <45 Gy had only mild to moderate BAM. CONCLUSIONS: Radiation delivered to the TI during IMRT may cause BAM. Identification of the TI from unenhanced RT planning computed tomography scans is difficult and may impede accurate dosimetric evaluation. Thorough toxicity assessment and close liaison between oncologist and gastroenterologist allow timely diagnosis and treatment.

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Diethylstilbestrol (DES) was the first hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past. Over 200 elderly men with castration-resistant prostate cancer were treated with 1-3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a significant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a significant analgesic benefit. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profile and offers a palliative benefit in frail elderly men who may not be fit for chemotherapy. OBJECTIVE: •  To assess the efficacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: •  A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000. •  The median pre-treatment prostate-specific antigen (PSA) level was 221 ng/mL. •  DES was used at a dose of 1-3 mg daily, with aspirin 75 mg. •  The primary endpoint was PSA response rate. RESULTS: •  The PSA response rate (using PSA Working Group criteria) was 28.9%. •  The median time to PSA progression was 4.6 months. •  Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score. •  Thromboembolic complications were seen in 9.9% of all patients. CONCLUSIONS: •  DES has significant activity in CRPC and can be of palliative benefit. •  DES has an acceptable toxicity profile in the management of patients with symptomatic CRPC when used at a dose of 1-3 mg, combined with aspirin and prophylactic breast bud radiotherapy.

Dose distributions for prostate radiotherapy are difficult to predict in patients with bilateral hip prostheses in situ, due to image distortions and difficulty in dose calculation. The feasibility of delivering curative doses to prostate using intensity-modulated radiotherapy (IMRT) in patients with bilateral hip prostheses was evaluated. Planning target volumes for prostate only (PTV1) and pelvic nodes (PTV2) were generated from data on 5 patients. PTV1 and PTV2 dose prescriptions were 70Gy and 60Gy, respectively, in 35 fractions, and an additional nodal boost of 65Gy was added for 1 plan. Rectum, bladder, and bowel were also delineated. Beam angles and segments were chosen to best avoid entering through the prostheses. Dose-volume data were assessed with respect to clinical objectives. The plans achieved the required prescription doses to the PTVs. Five-field IMRT plans were adequate for patients with relatively small prostheses (head volumes<60cm(3)) but 7-field plans were required for patients with larger prostheses. Bowel and bladder doses were clinically acceptable for all patients. Rectal doses were deemed clinically acceptable, although the V(50)(Gy) objective was not met for 4/5 patients. We describe an IMRT solution for patients with bilateral hip prostheses of varying size and shape, requiring either localized or whole pelvic radiotherapy for prostate cancer.

AIMS: A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. MATERIALS AND METHODS: Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. RESULTS: On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio=1.63, 95% confidence interval 1.18, 2.24; P=0.003) and increased stool frequency (hazard ratio=1.77, 95% confidence interval 1.27, 2.46; P=0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio=0.25, 95% confidence interval 0.09, 0.71; P=0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio=1.04 per year of age, 95% confidence interval 1.01, 1.08; P=0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio=2.09, 95% confidence interval 1.48, 2.95; P<0.0005), increased urinary incontinence (hazard ratio=4.22, 95% confidence interval 2.13, 8.35; P<0.0005) and decreased stream (hazard ratio=2.64, 95% confidence interval 1.62, 4.31; P<0.0005), after treatment and before the most recent follow-up assessment. CONCLUSIONS: In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed.

To examine patterns of bladder wall motion during high-dose hypofractionated bladder radiotherapy and to validate a novel adaptive planning method, A-POLO, to prevent subsequent geographic miss.

To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported.

The ratio of digit lengths is fixed in utero, and may be a proxy indicator for prenatal testosterone levels.

Background New or worsening bone lesions in patients responding to treatment, known as the flare phenomenon is well described on (99m)Tc-MDP bone scintigraphy, but to our knowledge has not previously been described on CT. The appearance of new or worsening bone sclerosis on CT in patients with prostate cancer may therefore be erroneously classified as disease progression. Purpose To assess the incidence of osteoblastic healing flare response at 3-month CT assessment in patients with castrate-resistant prostate cancer and to identify associated features that enable differentiation from progressive metastatic bone disease at 3 months. Material and Methods CT scans of 67 patients with castrate-resistant prostate cancer undergoing treatment were reviewed by a radiologist blinded to clinical outcome. Changes in number, size, and density of metastatic bone lesions were documented and Response Evaluation Criteria in Solid Tumours (RECIST) in soft tissue lesions, alkaline phosphatase, prostate specific antigen, and (99m)Tc-MDP bone scans were used for correlation. Results Of the 39 patients who had 3- and 6-month follow-up, eight patients (21%) demonstrated an increase in number, size, or density of sclerotic lesions on the 3-month CT scan despite improvement in PSA and soft tissue lesions. Three out of eight patients (8%) maintained partial response/remained stable at follow-up and were defined as showing a flare response: in this group bone metastases evident on CT showed a qualitative and quantitative increase in density and no lesions faded at 3 months. In contrast, in all patients who progressed at 3 months by PSA/RECIST criteria (n = 8) bone lesions showed a mixed pattern with some lesions increasing and others decreasing in density. Conclusion The incidence of flare response of metastatic bone disease evident at 3-month post-treatment CT in patients with prostate cancer undergoing systemic treatment is 8%. In patients with falling PSA and stable/responding soft tissue disease at 3 months an increase in bone sclerosis in the absence of fading bone metastases can be interpreted as flare and is likely to represent a response.

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) that are independently associated with small increments in risk of prostate cancer, opening up the possibility for using such variants in risk prediction. Using segregation analysis of population-based samples of 4,390 families of prostate cancer patients from the UK and Australia, and assuming all familial aggregation has genetic causes, we previously found that the best model for the genetic susceptibility to prostate cancer was a mixed model of inheritance that included both a recessive major gene component and a polygenic component (P) that represents the effect of a large number of genetic variants each of small effect, where . Based on published studies of 26 SNPs that are currently known to be associated with prostate cancer, we have extended our model to incorporate these SNPs by decomposing the polygenic component into two parts: a polygenic component due to the known susceptibility SNPs, , and the residual polygenic component due to the postulated but as yet unknown genetic variants, . The resulting algorithm can be used for predicting the probability of developing prostate cancer in the future based on both SNP profiles and explicit family history information. This approach can be applied to other diseases for which population-based family data and established risk variants exist. Genet. Epidemiol. 2011. © 2011 Wiley-Liss, Inc.

BACKGROUND AND PURPOSE: This pilot study investigates whether an individualized fluid and fibre prescription combined with a constant treatment can improve rectal filling consistency during radiotherapy. METHODS AND MATERIALS: Fibre, fluid intake and bowel function were assessed in 22 patients at a standard planning scan (SCT) and individualized dietary advice was prescribed to regularize bowel habit. Patients were requested to record frequency and type of bowel movements, fibre and fluid intake daily. Two subsequent CT scans were acquired at 7 (CCT1) and 10days (CCT2) after SCT at a similar time. Rectal volume and gas were measured planning CT's and 'on treatment' cone beam CT scans. We hypothesised that the difference in volume between CCT1 and CCT2 would be less than the difference between SCT and CCT1. RESULTS: The mean (SD) change in volume between SCT to CCT1 and CCT1 to CCT2 was 5.68cm(3) (26.2) and -8.6cm(3) (40.1), respectively (p=0.292). Of the 22 patients scanned 20 provided a complete record of dietary intake and bowel motion. The majority of patients either achieved or exceeded prescription. Change in rectal gas was the only correlation with change in rectal volume. CONCLUSION: Patient self reporting of bowel motion, fibre, fluid intake was achievable but consistency of rectal filling was not improved. Improved understanding of the aetiology and management of rectal gas is indicated.

Bone scintigraphy (BS) lacks sensitivity for detecting very early skeletal metastases (SM) in prostate cancer (PC) and is often limited by poor specificity. Also scintigraphic flare of SM can occur following effective treatment and mislead an early response assessment. We hypothesised that a flare reaction might amplify the signal from subclinical SM, increasing the sensitivity of BS and that the phenomenon may be specific for metastases.

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% CI 46-192), and a polygenic standard deviation of 2.01 (95% CI 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes.

Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important.

In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects.

Accurate reporting of complications following radiotherapy is an important part of the feedback loop to improve radiotherapy techniques. The definition of toxicity is normally regarded as the maximum or peak (P) grade of toxicity reported over the follow-up period. An alternative definition (integrated longitudinal toxicity (ILT)) is proposed which takes into account both the severity and the duration of the complication.

Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy.

Testicular cancer is curable in the majority of men, and persisting treatment toxicity is a concern. The authors report a cross-sectional study of the long-term effects of chemotherapy (C) on neurologic function and development of Raynaud phenomenon.

The aim of this study was to determine whether serum concentrations of micronutrients, antioxidants and vitamins predict rate of disease progression in untreated, localised prostate cancer. Patients with localised prostatic adenocarcinoma on a prospective study of active surveillance underwent monitoring with serial PSA levels and repeat prostate biopsies. Disease progression was defined as either adverse histology on repeat biopsy (primary Gleason grade >or=4 or >50% positive cores of total) or radical treatment for PSA velocity >1 ng ml(-1) year(-1). Time to disease progression was analysed with respect to baseline levels of alpha-tocopherol, gamma-tocopherol, alpha-carotene and beta-carotene, lycopene, retinol and selenium. One hundred four patients were evaluable, with a median follow-up of 2.5 years. Thirty-eight patients experienced disease progression, 13 biochemical and 25 histologic progression. Median time to disease progression was 2.62 years. No significant association was seen between time to disease progression and baseline serum levels of alpha-tocopherol (p = 0.86), gamma-tocopherol (p = 0.84), alpha-carotenoid (p = 0.66), beta-carotene (p = 0.65), lycopene (p = 0.0.15), retinol (p = 0.76) or selenium (p = 0.76). No significant association was seen between serum levels of the micronutrients, antioxidants or vitamins and either adverse histology on repeat biopsy or PSA velocity. Our data do not support the hypothesis that high serum concentrations of micronutrients, antioxidants and vitamins prevent disease progression in men with localised prostate cancer.

The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours.

Following orchidectomy patients with stage I seminoma of the testis may be managed by either surveillance or adjuvant treatment. In view of the very high cure rate, it is important to analyse long-term outcomes.

Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC).

Neurological deficit from malignant spinal cord compression (SCC) is a major complication of metastatic castration-resistant prostate cancer (CRPC). The aims of the present study were to determine the incidence of neurological deficit in metastatic prostate cancer patients and to determine the optimal frequency of screening magnetic resonance imaging (MRI) spine required to detect clinically occult radiological SCC (rSCC).

The UK incidence of prostate cancer has been increasing in men aged < 60 years. Migrant studies and global and secular variation in incidence suggest that modifiable factors, including a high-fat diet, may contribute to prostate cancer risk. The aim of the present study was to investigate the role of dietary fat intake and its derivatives on early-onset prostate cancer risk. During 1999-2004, a population-based case-control study with 512 cases and 838 controls was conducted. Cases were diagnosed with prostate cancer when < or = 60 years. Controls were sourced from UK GP practice registers. A self-administered FFQ collected data on typical past diet. A nutritional database was used to calculate daily fat intake. A positive, statistically significant risk estimate for the highest v. lowest quintile of intake of total fat, SFA, MUFA and PUFA was observed when adjusted for confounding variables: OR 2.53 (95 % CI 1.72, 3.74), OR 2.49 (95 % CI 1.69, 3.66), OR 2.69 (95 % CI 1.82, 3.96) and OR 2.34 (95 % CI 1.59, 3.46), respectively, with all P for trend < 0.001. In conclusion, there was a positive statistically significant association between prostate cancer risk and energy-adjusted intake of total fat and fat subtypes. These results potentially identify a modifiable risk factor for early-onset prostate cancer.

Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation.

The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).

There is a need to improve the outcomes for men with high-risk localised, nodal or metastatic prostate cancer, or with aggressively relapsing disease after initial therapy for local disease. This group of men is currently managed with long-term hormone therapy. Thus we aim to evaluate the toxicity and efficacy of three different systemic therapies (docetaxel, zoledronic acid and celecoxib) used alone or combined at the initiation of hormone manipulation for high-risk prostate cancer. A novel statistical design (multi-arm, multistage method) simultaneously tests multiple distinct strategies in parallel against a single control arm. The trial has several 'stages', from initial confirmation of safety to a phase III assessment of survival, with a series of intervening activity stages. This method provides a means of assessing several agents more quickly and efficiently, and allows inactive treatments to be dropped from further study at an early stage. STAMPEDE has been designed to address in parallel the activity and efficacy of these agents for this patient group. It is a flagship randomized clinical trial for academic research into prostate cancer in the UK. More than 500 patients have been recruited on schedule, confirming the acceptability of this complex trial design to patients and clinicians. The trial targets a population of approximately 3000 patients. STAMPEDE is a major new trial with a novel design applicable to the synchronous testing of several agents. It is hoped that the results will improve outcomes for patients with high-risk prostate cancer. The design could be applicable to the study of new therapies in other cancer types. Continued efforts are required by the urological cancer community to maintain the excellent recruitment shown to date.

Magnetic resonance imaging (MRI) is an effective method for evaluating the spine in patients with a high risk of metastatic disease. The aim of this study was to compare MRI spine with radionuclide bone scan in detecting spinal metastases for staging prostate cancer patients.

To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at < or = 60 years old.

There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment.

Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.

To determine the sensitivity of magnetic resonance imaging (MRI) in the detection of retroperitoneal lymph nodes in patients with testicular germ cell tumours (TGCT).

To identify predictive factors of adherence to medical advice, specifically the likelihood of attendance to a recommended follow-up regimen in patients with newly diagnosed testicular cancer. PATIENTS AND METHODS; This was a prospective study measuring initially not only aspects of the doctor-patient interview, but also a range of demographic, psychological, social, and medical factors, and then recording attendance behavior on follow-up. All 209 new patients with testicular cancer referred between June 1992 and May 1995 were approached, and 184 men consented and completed questionnaires. The nonadherence end point (nonattender) was two failures to attend an outpatient appointment at least 1 month apart, despite a written reminder.

The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.

Single-modality approaches to the treatment of high-risk prostate cancer, whether radical prostatectomy or external-beam radiotherapy, have yielded disappointing results. Treatment intensification has, thus, been the subject of considerable research activity in recent years. This review will discuss the evidence for neoadjuvant and adjuvant treatment approaches when surgery is chosen as the definitive therapy for high-risk prostate cancer. Particular emphasis will be placed on the randomized trials, both completed and in progress. Trials investigating adjuvant radiotherapy, androgen-deprivation therapy and chemotherapy will each be discussed in turn. Among these, only adjuvant radiotherapy has been shown to prolong survival after surgery, and the recently published evidence for this benefit will be discussed in detail.

Bisphosphonates might modulate the development of symptomatic bone metastases in men with prostate cancer. The Medical Research Council (MRC) PR05 and PR04 randomised controlled trials assessed the use of sodium clodronate, an oral, first-generation bisphosphonate. We report the final analyses of long-term survival data with additional follow-up in both trials.

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

Many studies have been performed to assess correlations between measures derived from dose-volume histograms and late rectal toxicities for radiotherapy of prostate cancer. The purpose of this study was to quantify correlations between measures describing the shape and location of the dose distribution and different outcomes. The dose to the rectal wall was projected on a two-dimensional map. In order to characterize the dose distribution, its centre of mass, longitudinal and lateral extent, and eccentricity were calculated at different dose levels. Furthermore, the dose-surface histogram (DSH) was determined. Correlations between these measures and seven clinically relevant rectal-toxicity endpoints were quantified by maximally selected standardized Wilcoxon rank statistics. The analysis was performed using data from the RT01 prostate radiotherapy trial. For some endpoints, the shape of the dose distribution is more strongly correlated with the outcome than simple DSHs. Rectal bleeding was most strongly correlated with the lateral extent of the dose distribution. For loose stools, the strongest correlations were found for longitudinal extent; proctitis was most strongly correlated with DSH. For the other endpoints no statistically significant correlations could be found. The strengths of the correlations between the shape of the dose distribution and outcome differed considerably between the different endpoints. Due to these significant correlations, it is desirable to use shape-based tools in order to assess the quality of a dose distribution.

Whole-body MRI is an effective method for evaluating the entire skeletal system in patients with metastatic disease. This study aimed to compare whole-body MRI and radionuclide bone scintigraph in the detection of skeletal metastases in patients with prostate cancer. Patients with prostate cancer at high risk of skeletal metastasis with (i) prostate-specific antigen of >= 50 ng/mL; (ii) composite Gleason score of >= 8 with prostate-specific antigen of >20 ng/mL; or (iii) node-positive disease were enrolled in this prospective study before systemic treatment was initiated. Whole-body MR images and bone scans of 39 patients were analysed. Seven patients had bone metastases on bone scans, while seven patients had skeletal metastases by whole-body MRI, with concordant findings only in four patients. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivity for both bone scans and MRI was 70%, and the specificity for both was 100%. Magnetic resonance imaging detected 26 individual lesions compared with 18 lesions on bone scans. Only eight lesions were positive on both. Bone scans detected more rib metastases, while MRI identified more metastatic lesions in the spine. Whole-body MRI and radionuclide bone scintigraphy have similar specificity and sensitivity and may be used as complementary investigations to detect skeletal metastases from prostate cancer.

It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.

The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with castration-resistant prostate cancer (CRPC).

Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate analysis, PSA density (P=0.001), Gleason score (P=0.001), clinical T stage (P=0.01), Ki-67 LI (P=0.02) and initial PSA (P=0.04) were associated with time to radical treatment. On multivariate analysis, PSA density (P=0.01), Ki-67 LI (P=0.03) and Gleason score (P=0.04) were independent determinants of progression to radical treatment. TMAs constructed from prostate needle biopsies can be used to assess immunohistochemical markers in localized prostate cancer managed by active surveillance. Ki-67 LI merits further study as a possible biomarker of early prostate cancer behaviour.

To compare the accuracy of prostate-specific antigen (PSA) velocity (PSAV) vs PSA doubling time (DT) for predicting the repeat biopsy results in men with localized prostate cancer on active surveillance (AS), as the utility of PSAV vs PSADT in untreated prostate cancer has not been well studied.

Fusion of the hormone-regulated gene TMPRSS2 with ERG occurs in 50-70% of prostate cancers; fusions of ETV1 with one of several partners occur in approximately 10% of prostate cancers. These two translocations are mutually exclusive. The presence of subclasses of these chromosomal rearrangements may indicate worse prognosis, with the subclass 2+Edel, which has duplication of TMPRSS2:ERG fusion sequences, indicating particularly poor survival. However as this case shows, significant heterogeneity can exist with ERG and ETV1 rearrangements occurring in both prostate intra-epithelial neoplasia and cancer in the same prostatectomy specimen and with adjacent cancer areas containing a single copy, duplication and even triplication of the rearranged locus. As the majority of ETS gene fusions are hormone regulated, they could explain the pathogenesis underlying exquisitely hormone-sensitive prostate cancer. This is exemplified by the case presented here of a patient diagnosed in 1991 who remains asymptomatic and chemotherapy-naïve after having long-lasting tumour responses to multiple lines of systemic hormonal treatments.

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n=48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.

Castration-resistant prostate cancer (CRPC) refers to patients who no longer respond to surgical or medical castration. Standard treatment options are limited.

We are evaluating the use of electroporation (EP) to deliver a novel DNA vaccine, p.DOM-PSMA(27). This vaccine encodes a domain (DOM) of fragment C of tetanus toxin to induce CD4(+) T cell help, fused to a tumor-derived epitope from prostate-specific membrane antigen (PSMA) for use in HLA-A2(+) patients with recurrent prostate cancer. We report on safety and tolerability and on antibody response to DOM as a first indication of the effect of EP in patients. In this open label phase I/II, two-arm, dose escalation trial DNA was delivered either by intramuscular injection or by intramuscular injection followed by EP (DNA+EP), with five patients per dose level. Three vaccinations were given at 0, 4, and 8 weeks,with booster doses at 24 and 48 weeks; here we allowed crossover between study arms if supported by the safety and immunological data. In the 20 patients in the first two dose cohorts we observed that beyond brief and acceptable pain at the injection site, EP did not appear to add toxicity to the vaccination. We evaluated humoral responses to DOM. Low anti-DOM IgG antibody responses were observed after intramuscular injection of DNA without EP (at week 12: mean 1.7- vs. 24.5-fold increase over baseline with DNA+EP). These could be boosted by delivery of DNA+EP at later time points. Delivery of DNA+EP at all five vaccinations yielded the highest levels of anti-DOM antibody. Responses persisted to 18 months of follow-up. These data establish EP as a potent method for stimulating humoral responses induced by DNA vaccination in humans.

To evaluate the prostate-specific antigen (PSA) response rate and duration of PSA response to dexamethasone in patients with castration-refractory prostate cancer (CRPC), as corticosteroids are frequently used as second-line hormonal treatment of CRPC and there is little published evidence concerning the efficacy of low-dose dexamethasone in this setting.

To evaluate the utility of intraprostatic markers in the treatment verification of prostate cancer radiotherapy. Specific aims were: to compare the effectiveness of offline correction protocols, either using gold markers or bony anatomy; to estimate the potential benefit of online correction protocol's using gold markers; to determine the presence and effect of intrafraction motion.

During commissioning of the Pinnacle (Philips) treatment planning system (TPS) the margining algorithm was investigated and was found to produce larger PTVs than Plato (Nucletron) for identical GTVs. Subsequent comparison of PTV volumes resulting from the QA outlining exercise for the CHHIP (Conventional or Hypofractionated High Dose IMRT for Prostate Ca.) trial confirmed that there were differences in TPS's margining algorithms. Margining and the clinical impact of the different PTVs in seven different planning and virtual simulation systems (Pinnacle, Plato, Prosoma (MedCom), Eclipse (7.3 and 7.5) (Varian), MasterPlan (Nucletron), Xio (CMS) and Advantage Windows (AW) (GE)) is investigated, and a simple test for 3D margining consistency is proposed.

A number of different prostate-specific antigen (PSA) assays are in common use. There has been little consideration of the possible clinical implications of interassay variation. The availability of two assays in the same laboratory provided an opportunity to audit the clinical implications of the interassay variation in PSA levels.

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at </=60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

This prospective randomised controlled study of 40 patients could not show a statistically significant advantage with 6 months of pentoxifylline compared with standard measures for late radiation-induced rectal bleeding. However, a modest benefit cannot be excluded and larger randomised placebo-controlled trials with longer durations of pentoxifylline treatment may be justified.

Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment.

Testicular germ cell tumours (TGCTs) are the most common cause of cancer in men between the ages of 15 and 40 years, and, overall, the majority of patients should expect to be cured. The European Germ Cell Cancer Consensus Group has provided clear guidelines for the primary treatment of both seminoma and nonseminomatous germ cell tumours. There is, however, no international consensus on how best to follow patients after their initial management. This must promptly and reliably identify relapses without causing further harm. The standardising of follow-up would result in optimising risk-benefit ratios for individual patients, while ensuring economic use of resources. We have identified the seven common scenarios in managing seminomas and nonseminomas of the various stages and discuss the pertinent issues around relapse and follow-up. We review the available literature and present our comprehensive TGCT follow-up guidelines. Our protocols provide a pragmatic, easily accessible user-friendly basis for other centres to use or to adapt to suit their needs. Furthermore, this should enable future trials to address specific issues around follow-up giving meaningful and useful results.

The MRC RT01 trial used conformal radiotherapy to the prostate, a method that reduces the volume of normal tissue treated by 40-50%. Because of the risk of geographical miss, the trial used portal imaging to examine whether treatment delivery was within the required accuracy.

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

Aims: To compare the radiotherapy planning techniques from two multicentre randomised external beam radiotherapy trials in the UK of conformal radiotherapy vs intensity-modulated radiotherapy (IMRT).Materials and methods: Sixteen sequential patients with histologically confirmed localised prostate cancer treated in the conventional or hypofractionated IMRT trial (CHHiP) were planned using both the CHHiP and Medical Research Council RT-01 planning protocols to 74 Gy in 37 daily fractions. The CHHiP plan used a single phase simple forward planned three-field IMRT plan for easy muiticentre adoption. The RT-01 plan used two phases: three-field conformal radiotherapy plan to 64 Gy followed by a six-field boost of 10 Gy. After coverage of the planning target volumes according to the respective trial protocols, the dose to the rectum and bladder was assessed for the two planning techniques.Results: There was acceptable planning target volume coverage by both the CHHiP and RT-01 plans. All CHHiP plans produced lower mean irradiated rectal volumes at ail measured dose levels compared with the RT-01 plans, particularly for irradiated rectal volumes at 50 and 70 Gy (P < 0.05). In the cases when a CHHiP plan failed to meet its own trial dose constraints, the volumes of irradiated rectum were less than if an RT-01 planning technique had been used. The CHHiP plans gave lower mean irradiated bladder volumes at both 50 and 60 Gy, but higher volumes at 74 Gy. These differences in irradiated bladder volumes were significant at the 60 and 74 Gy dose levels (P < 0.05) in favour of the CHHiP and RT-01 plans, respectively.Conclusion: The forward planned CHHiP IMRT planning solution gives more favourable rectal sparing than the RT-01 plan. This is important to limit any potential increase in late rectal toxicity for prostate cancer patients treated with high-dose conventional or hypofractionated schedules.

Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued.

To report the results of a prospective study of active surveillance of untreated prostate cancer, with a focus on baseline predictors of prostate-specific antigen (PSA) velocity, as PSA velocity before treatment is an important predictor of prostate cancer mortality, and patients on active surveillance are monitored for several years to estimate the PSA velocity and thus select patients for radical treatment.

Expression of intrinsic markers of tumour hypoxia and angiogenesis are important predictors of radiotherapeutic, and possibly surgical, outcome in several cancers. Extent of tumour hypoxia in localised prostate cancer is comparable to that in other cancers, but few data exist on the association of extent of tumour hypoxia with treatment outcome. We aimed to study the predictive value of intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer, both in patients treated with radiotherapy and in those treated surgically.

To determine whether urinary concentrations of phytoestrogens are associated with the rate of disease progression in men with untreated, localised prostate cancer.

Reliable, non-invasive biological markers of the severity of radiotherapy-induced damage to the gastrointestinal tract are not available. Clinicians continue to use symptom scores as surrogate indicators of toxicity.

To assess the hormonal effects of Fem7 (Merck, KGaA, Darmstadt, Germany) 100 microg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer.

The purpose of this study was to compare the apparent diffusion coefficient (ADC) of benign central gland (bCG), benign peripheral zone (bPZ) and cancer using diffusion-weighted MRI and whole mount specimens. 11 patients with biopsy-proven prostate cancer underwent diffusion-weighted MRI prior to radical prostatectomy. A single-shot echo planar image technique was used with b-values of 0 s mm(-2), 300 s mm(-2), 500 s mm(-2) and 800 s mm(-2). Whole mount specimens were compared with ADC maps. Areas of cancer, bCG and bPZ were identified, and regions of interest were drawn on ADC maps. Mean ADC values were recorded for all regions of interest, and paired t-tests were performed to compare mean values. Cancer was outlined in nine patients. In two patients, the tumours were too small to correlate with images; bCG was identified in 11 patients and bPZ was identified in 10 patients. Mean ADC values for bCG, bPZ and cancer were, 1.5 x 10(-3) mm(2) s(-1) (standard error (SE) = 0.04), 1.7 x 10(-3) mm(2) s(-1) (SE = 0.1), and 1.3 x 10(-3) mm(2) s(-1) (SE = 0.09), respectively. The most significant difference between benign tissue and cancer existed at b-values of 0-300 s mm(-2) (bCG vs cancer: mean difference = 0. 29, p = 0.001, 95% confidence interval (CI) = 0.17-0.41; bPZ vs cancer: mean difference = 0.34, p = 0.003, 95% CI = 0.18-0.61). In conclusion, we have confirmed, using whole mount verification, a significant difference in the ADC between benign tissue and cancer.

Exposure to ionising radiation is an established risk factor for many cancers. We conducted a case-control study to investigate whether exposure to low dose ionisation radiation from diagnostic x-ray procedures could be established as a risk factor for prostate cancer. In all 431 young-onset prostate cancer cases and 409 controls frequency matched by age were included. Exposures to barium meal, barium enema, hip x-rays, leg x-rays and intravenous pyelogram (IVP) were considered. Exposures to barium enema (adjusted odds ratio (OR) 2.06, 95% confidence interval (CI) 1.01-4.20) and hip x-rays (adjusted OR 2.23, 95% CI 1.42-3.49) at least 5 years before diagnosis were significantly associated with increased prostate cancer. For those with a family history of cancer, exposures to hip x-rays dating 10 or 20 years before diagnosis were associated with a significantly increased risk of prostate cancer: adjusted OR 5.01, 95% CI 1.64-15.31 and adjusted OR 14.23, 95% CI 1.83-110.74, respectively. Our findings show that exposure of the prostate gland to diagnostic radiological procedures may be associated with increased cancer risk. This effect seems to be modified by a positive family history of cancer suggesting that genetic factors may play a role in this risk association.

To explore patients' quality of life (QoL) during neoadjuvant hormone therapy (HT) using data from the Medical Research Council RT01 trial of standard- (64 Gy/32-fraction) and high- (74 Gy/37-fraction) dose radiotherapy (RT, both given conformally).

With a life expectancy similar to the general population, greater numbers of patients with Down's syndrome are being diagnosed with testicular cancer. Learning difficulties and medical co-morbidity are common in this patient population and may lead to non-standard oncological treatment. We aimed to identify and discuss management challenges in the treatment of these patients with chemotherapy and radiotherapy and report their clinical outcome.

Spinal cord compression (SCC) is the most significant complication due to skeletal metastasis from prostate cancer. The early detection of SCC is essential as the neurological status before treatment is the major determinant influencing outcome. The aim of this investigation was to determine the role of magnetic resonance imaging of the spine in detecting SCC or occult SCC in patients with metastatic prostate cancer with no functional neurological deficit (FND).

The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis-negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known.

To assess whether a long-term follow-up shows any reduction in the level of luteinizing hormone (LH) secretion, which could result in declining testosterone levels in men with localized prostate cancer, as most (96%) men have testosterone levels within the normal range by 1 year after treatment with a short course of LH-releasing hormone analogue (LHRHa) and radiotherapy, and LH and follicle stimulating hormone (FSH) remain high at 1 year after treatment, maintaining the testosterone levels.

To evaluate the utility of lactate dehydrogenase (LDH), a tumour marker that is frequently elevated at diagnosis and relapse of testicular germ cell tumours (TGCTs), in the follow-up of TGCTs for detecting tumour relapse, as it has role as a prognostic factor but its role in follow-up is less certain.

The aim of this work was to estimate tumor-absorbed doses delivered from the administration of fixed activities of (186)Re-HEDP for the treatment of bone metastases from prostate cancer. The variations and reproducibility in the estimated absorbed dose owing to the reconstruction algorithm used (OSEM vs. FBP) were also analysed. For this aim, correction methods for scatter and attenuation were kept identical, whereas the same calibration data and thresholding techniques were used to obtain quantification. This study was carried out in spinal and pelvic lesions of 7 patients. For comparison, the absorbed doses, based upon the maximum and the mean voxel count, were calculated, resulting in the absorbed dose (maximum): 60 Gy (sigma = 30 Gy) and 33 Gy (sigma = 15 Gy) for OSEM and FBP, respectively, and absorbed dose (mean): 26 Gy (sigma = 12 Gy) and 17 Gy (sigma = 7 Gy) with OSEM and FBP, respectively. We concluded that the administration of fixed activity resulted in a range of absorbed doses, and we showed that, despite using the same approach, the choice of the reconstruction algorithm can result in differences higher than 50% in the estimated tumor-absorbed doses. In conclusion, the need for a standardization of the methodology used for the calculations is emphasized by this work, especially when comparisons between patients and different centers are of interest.

There is considerable controversy surrounding target volume definition for parotid-sparing intensity modulated radiotherapy (IMRT) for head and neck cancer. The aim of this study was to evaluate the dosimetric and radiobiological predictors of outcome anticipated by application of the detailed target volume definition guidelines agreed for the UK multicentre randomised controlled trial of parotid-sparing IMRT (PARSPORT).

Intensity modulated radiotherapy (IMRT) allows the delivery of higher and more homogeneous radiation dose to head and neck tumours. This study aims to determine the safety of dose-escalated chemo-IMRT for larynx preservation in locally advanced head and neck cancer.

The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC).

This phase 1 study was designed to determine the toxicity of accelerated fractionation IMRT in locally advanced thyroid cancer.

The purpose of this study was to evaluate distortion-corrected MRI as a radiotherapy planning tool for prostate cancer and the resultant implications for dose sparing of organs at risk. 11 men who were to be treated with radical conformal radiotherapy for localized prostate cancer had an MRI scan under radiotherapy planning conditions, which was corrected for geometric distortion. Radiotherapy plans were created for planning target volumes derived from the MRI- and CT-defined prostate. Dose volume histograms were produced for the rectum, bladder and penile bulb. The mean volume of the prostate as defined on CT and MRI was 41 cm3 and 36 cm3, respectively (p = 0.009). The predicted percentage of the rectum treated to dose levels of 45-65 Gy was significantly lower for plans delineating the prostate with MRI than for those with CT. The rectal-sparing effect was confined to the lowermost 4 cm of the rectum (anal canal). There were no differences between the predicted doses to bladder or penile bulb (as defined using MRI) between plans. In conclusion, prostate radiotherapy planning based on distortion-corrected MRI is feasible and results in a smaller target volume than does CT. This leads to a lower predicted proportion of the rectum, in particular the lower rectum (anal canal), treated to a given dose than with CT.

To assess the feasibility of using cine-MR to study intra-fractional time-volume and volume-deformity patterns of the bladder during radiotherapy as initial methodology for Predictive Organ Localization (POLO).

Retrospective analysis in 150 patients with metastatic prostate cancer was conducted to determine whether early detection with MRI spine and treatment of clinically occult spinal cord compromise (SCC) facilitate preservation of neurologic function. Our results suggest that prophylactic radiotherapy for patients with back pain or radiological SCC without neurologic deficit may facilitate preservation of neurologic function. Thus MRI surveillance for SCC may be important for prostate cancer patients with bone metastases.

Background In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial.Methods The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397.Findings Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% Cl 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade 2:2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >= 2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score 2:30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade 2:2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade 2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score 2:30) scale (HR 1.05 [0.81-1.36]).Interpretation Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events.

Background: Five-year disease-free survival rates for localised prostate cancer following standard doses of conventional radical external beam radiotherapy are around 80%. Conformal radiotherapy (CFRT) raises the possibility that radiotherapy doses can be increased and long-term efficacy outcomes improved, with safety an important consideration.Methods: MRC RT01 is a randomised controlled trial of 862 men with localised prostate cancer comparing Standard CFRT (64 Gy/32 f) versus Escalated CFRT (74 Gy/37 f), both administered with neo-adjuvant androgen suppression. Early toxicity was measured using physician-reported instruments (RTOG, LENT/SOM, Royal Marsden Scales) and patient-reported questionnaires (MOS SF-36, UCLA Prostate Cancer Index, FACT-P).Results: Overall early radiotherapy toxicity was similar, apart from increased bladder, bowel and sexual toxicity, in the Escalated Group during a short immediate post-radiotherapy period. Toxicity in both groups had abated by week 12. Using RTOG Acute Toxicity scores, cumulative Grade >= 2 bladder and bowel toxicity was 38% and 30% for Standard Group and 39% and 33% in Escalated Group, respectively. Urinary frequency (Royal Marsden Scale) improved in both groups from pre-androgen suppression to 6 months post-radiotherapy (p < 0.001), but bowel and sexual functioning deteriorated. This pattern was supported by patient-completed assessments. Six months after starting radiotherapy the incidence of RTOG Grade >= 2 side-effects was low (< 1%); but there were six reports of rectal ulceration (6 Escalated Group), six haematuria (5 Escalated Group) and eight urethral stricture (6 Escalated Group).Conclusions: The two CFRT schedules with neo-adjuvant androgen suppression have broadly similar early toxicity profiles except for the immediate post-RT period. At 6 months and compared to before hormone therapy, bladder symptoms improved, whereas bowel and sexual symptoms worsened. These assessments of early treatment safety will be complemented by further follow-up to document late side-effects and efficacy. Crown Copyright (c) 2007 Published by Elsevier Ireland Ltd. All rights reserved.

Active surveillance for early prostate cancer is a policy of close monitoring with radical treatment targeted at cases with evidence of disease progression. There is no consensus on the need for or optimum timing of repeat biopsies as part of active surveillance.

To investigate, in a cross-sectional study, the prevalence of anxiety and depression in patients with localised prostate cancer managed by active surveillance, compared with those receiving immediate treatment, as active surveillance is a relatively new approach to managing this disease, designed to avoid 'unnecessary' treatment, but it is unclear whether the approach contributes to psychological distress, given that men are living with untreated cancer.A consecutive series of 764 patients with prostate cancer were approached in outpatient clinics. Of these, 329 men with localized disease (cT1/2, N0/NX, M0/MX) meeting the study entry criteria, completed the Hospital Anxiety and Depression Scale (HADS); 100 were on active surveillance, 81 were currently receiving radical treatment (radiotherapy + neoadjuvant hormone therapy) and 148 had previously received radical radiotherapy.Overall, 16% (51/329) of patients met the HADS criteria for anxiety and 6% (20/329) for depression. Analyses indicated that higher anxiety scores were significantly associated with younger age (P < 0.01) and a longer interval since diagnosis (P < 0.01), but not with management by active surveillance (P = 0.38). Higher depression scores were significantly associated with a longer interval since diagnosis (P < 0.05), but not with management by active surveillance (P = 0.83).Active surveillance for managing localized prostate cancer was not associated with greater psychological distress than more immediate treatment for prostate cancer.

To prospectively evaluate the time-course of recovery of serum testosterone levels after a short course of luteinizing hormone-releasing hormone analogue (LHRHa) and radical radiotherapy to the prostate.

To describe the distribution of enlarged lymph nodes by nodal group found radiologically in patients presenting with adenocarcinoma of the prostate. This will help to define which nodal groups should be treated during the pelvic radiotherapy of patients with less advanced disease.

We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of (186)Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC).

This study assesses the accuracy of NOMOS B-mode acquisition and targeting system (BAT) compared with computed tomography (CT) in localizing the prostate.

To investigate the potential for intensity-modulated radiotherapy (IMRT) to spare the bowel in rectal tumors.

Patients receiving radical radiotherapy to the prostate are requested to maintain a full bladder to displace the dome of the bladder and small bowel from the target volume. This study investigated patients' ability to consistently maintain a full bladder throughout planning and treatment before (Study 1) and after (Study 2) the introduction of a patient information sheet.

Within the UK RT01 trial the MRC also funded a quality assurance (QA) programme. This included a planning and dosimetry audit at participating centres using a purpose built phantom. Geometrical setup was visually assessed via field shaping around the phantom GTV (to within the order of 1 mm). Within the phantom, ion chamber positional uncertainties were estimated as 0.6 mm (95% CL, k=2). This was the basis for ion chamber measurements in a variety of dose gradients around the PTV closely simulating a patient case. The design provides a representative but reproducible system for QA in the prostate radiotherapy process, from CT scan to treatment. Setup errors are not eliminated, but minimised and estimated.

To estimate the rate of relapse in men with stage I nonseminomatous germ cell tumours (NSGCT) of the testis treated with one cycle of chemotherapy instead of the usual two cycles.

The radiation dose used to treat bladder cancer is limited by the risk of inducing severe late bladder toxicity. Retrospective data suggest that radiation tolerance is greater for partial rather than whole bladder irradiation. Limiting the high-dose region to a section of the bladder may reduce toxicity, opening the way for dose escalation. The aims of this study were to establish the efficacy and compare the late toxicity between (1) a two-phase technique limiting the high-dose area and (2) a conventional single-phase radiotherapy to the whole bladder.

To evaluate the relationship between erectile function and the radiation dose to the penile bulb and other proximal penile structures in men receiving conformal radiotherapy (CFRT) for prostate cancer (PCa).

The lead time and overdetection associated with prostate-specific antigen (PSA) screening, and generational improvements in all-cause mortality, make prostate cancer outcome studies from the pre-PSA era difficult to interpret in a contemporary setting. We developed a competing-risks hazard model to estimate the natural history of screen-detected prostate cancer, and the impact of radical treatment on overall survival. The model of hazard of mortality was fitted to clinical outcome data from the pre-PSA era, and the effects of screening, generational mortality improvements and radical treatment were incorporated. Sensitivities to the choice of baseline data and values of key parameters were assessed. Lead-time estimates in men diagnosed aged 55-59 years were 14.1, 9.3 and 5.0 years for men with Gleason scores < 7, 7 and > 7, respectively, assuming biennial screening with 100% attendance. Central estimates of 15-year prostate cancer mortality for conservative management of screen-detected prostate cancer ranged from 0 to 2% for Gleason scores < 7, 9 to 31% for Gleason score 7 and 28-72% for Gleason scores > 7. For men aged 55-59 years at diagnosis, the predicted absolute 15-year survival benefit from curative treatment was 0, 12 and 26% for men with Gleason scores < 7, 7 and > 7, respectively. Estimates of the survival benefit of radical treatment were relatively insensitive to values of key parameters. The case for curative treatment, rather than conservative management, of screen-detected localised prostate cancer is strongest in men with high-grade disease. This conclusion contrasts with current patterns of care.

This study examined factors that predict psychological morbidity and screening adherence in first-degree relatives (FDRs) taking part in a familial PSA screening study. Prostate cancer patients (index cases - ICs) who gave consent for their FDRs to be contacted for a familial PSA screening study to contact their FDRs were also asked permission to invite these FDRs into a linked psychosocial study. Participants were assessed on measures of psychological morbidity (including the General Health Questionnaire; Cancer Worry Scale; Health Anxiety Questionnaire; Impact of Events Scale); and perceived benefits and barriers, knowledge; perceived risk/susceptibility; family history; and socio-demographics. Of 255 ICs, 155 (61%) consented to their FDRs being contacted. Of 207 FDRs approached, 128 (62%) consented and completed questionnaires. Multivariate logistic regression revealed that health anxiety, perceived risk and subjective stress predicted higher cancer worry (P = 0.05). Measures of psychological morbidity did not predict screening adherence. Only past screening behaviour reliably predicted adherence to familial screening (P = 0.05). First-degree relatives entering the linked familial PSA screening programme do not, in general, have high levels of psychological morbidity. However, a small number of men exhibited psychological distress.

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age < or =65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45-69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were > or =4 ng ml(-1) and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied.

Clinical trials in early prostate cancer (EPC) have used a variety of outcome measures, including patient-reported outcomes (PROs) and physician-reported data. We review published studies and suggest a set of outcome measures and a portfolio of more detailed questionnaire options to produce a more homologous data set for future clinical trials.

Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3-6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58-81%) in the 74 Gy group vs 59% (95% CI 45-70%) in the 64 Gy group. There were 23 failures in the 74 Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38-1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53-77% vs 63%, 95% CI 50-74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50-1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent > or =Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG> or =2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade > or =3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade> or =1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis.

To investigate the dose distribution in active bone marrow of patients undergoing intensity-modulated radiotherapy (IMRT) for prostate cancer and compare it to the distribution in the same patients, if they had been treated using conformal plans, in order to develop criteria for optimization to minimize the estimated risk of secondary leukemia.

There is good evidence that radiation dose escalation in localised prostate cancer is associated with increased cell kill. The traditional two-dimensional (2D) technique of treatment planning and delivery is limited by normal tissue toxicity, such that the dose that can be safely delivered to the prostate by external beam radiotherapy is 65-70 Gy. Several technological advances over the last 20 years have enhanced the precision of external beam radiotherapy (EBRT), and have resulted in improved outcomes. The three-dimensional conformal radiotherapy (3D-CRT) approach reduces the dose-limiting late side-effect of proctitis and has allowed for dose escalation to the whole prostate to 78 Gy. More recently, intensity modulated radiotherapy (IMRT), an advanced form of conformal therapy, has resulted in reduced rectal toxicity when using doses greater than 80 Gy. In addition, IMRT can potentially escalate the dose to specific parts of the prostate where there are resistant subpopulations of tumour clonogens, or can be used to extend the high-dose region to pelvic lymph nodes. The addition of androgen deprivation to conventional radiotherapy has an impact on survival and local control. Initial hormone therapy causes cytoreduction of the prostate cancer allowing for a reduction in radiotherapy volume as well as an additive effect on cell kill. Long-term adjuvant androgen deprivation has been shown to improve overall survival in more advanced tumours. Prostate brachytherapy is now a recognised treatment for those with low-risk disease. It achieves similar long-term outcome to other treatment modalities. Brachytherapy can be used as monotherapy for localised disease, or as boost treatment following conventional EBRT for locally advanced disease. New techniques are available to improve the precision of both target definition and treatment verification. This so-called image-guided radiotherapy will help to enhance the accuracy of dose delivery by correcting both for inter-fraction positional variation and for intra-fraction movement of the prostate in real-time and will allow for tighter tumour margins and avoidance of normal tissues, thereby enhancing the safety of treatment.

Rectal bleeding after pelvic radiotherapy is often attributed to radiation proctitis and patients do not routinely undergo flexible endoscopy.

After radiotherapy for pelvic cancer, chronic gastrointestinal problems may affect quality of life (QOL) in 6-78% of patients. This variation may be due to true differences in outcome in different diseases, and may also represent the inadequacy of the scales used to measure radiotherapy-induced gastrointestinal side effects. The aim of this study was to assess whether outcome measures used for nonmalignant gastrointestinal disease are useful to detect gastrointestinal morbidity after radiotherapy. Results obtained from a Vaizey Incontinence questionnaire and a modified Inflammatory Bowel Disease questionnaire (IBDQ)--both patient completed--were compared to those from a staff administered Late Effects on Normal Tissue (LENT)--Subjective, Objective, Management and Analytic (SOMA) questionnaire in patients who had completed radiotherapy for a pelvic tumour at least 3 months previously. In all, 142 consecutive patients were recruited, 72 male and 70 female, median age 66 years (range 26-90 years), a median of 27 (range 3-258) months after radiotherapy. In total, 62 had been treated for a gynaecological, 58, a urological and 22, a gastrointestinal tract tumour. Of these, 21 had undergone previous gastrointestinal surgery and seven suffered chronic gastrointestinal disorders preceding their diagnosis of cancer. The Vaizey questionnaire suggested that 27% patients were incontinent for solid stools, 35% for liquid stools and 37% could not defer defaecation for 15 min. The IBDQ suggested that 89% had developed a chronic change in bowel habit and this change significantly affected 49% patients: 44% had more frequent or looser bowel movements, 30% were troubled by abdominal pain, 30% were troubled by bloating, 28% complained of tenesmus, 27% were troubled by their accidental soiling and 20% had rectal bleeding. At least 34% suffered emotional distress and 22% impairment of social function because of their bowels. The small intestine/colon SOMA median score was 0.1538 (range 0-1) and the rectal SOMA median score was 0.1428 (range 0-1). Pearson's correlations for the IBDQ score and small intestine/colon SOMA score was -0.630 (P<0.001), IBDQ and rectum SOMA -0.616 (P<0.001), IBDQ and Vaizey scores -0.599 (P<0.001), Vaizey and small intestine/colon SOMA 0.452 (P<0.001) and Vaizey and rectum SOMA 0.760 (P<0.001). After radiotherapy for a tumour in the pelvis, half of all patients develop gastrointestinal morbidity, which affects their QOL. A modified IBDQ and Vaizey questionnaire are reliable in assessing new gastrointestinal symptoms as well as overall QOL and are much easier to use than LENT SOMA.

To evaluate the benefit of using non-coplanar treatment plans for irradiation of two different clinical treatment volumes: prostate only (PO) and the prostate plus seminal vesicles (PSV).

To evaluate the prognostic significance of magnetic resonance imaging (MRI) tumour stage in clinically localised prostate cancer.

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.

Modern treatments cure most testicular cancer patients, so an important goal is to minimise toxicity. Fertility and sexual functioning are key issues for patients. We have evaluated these outcomes in a cross-sectional study of long-term survivors of testicular cancer. In total, 680 patients treated between 1982 and 1992 completed the EORTC Qly-C-30(qc30) questionnaire, the associated testicular cancer specific module and a general health and fertility questionnaire. Patients have been subdivided according to treatment received: orchidectomy either alone (surveillance, S n = 169), with chemotherapy (C, n = 272), radiotherapy (R, n = 158), or both chemotherapy and radiotherapy (C/RT n = 81). In the surveillance group, 6% of patients had an elevated LH, 41% an elevated FSH and 11% a low (< 10 nmol l(-1)) testosterone. Hormonal function deteriorated with additional treatment, but the effect in general was small. Low testosterone was more common in the C/RT group (37% P = 0.006), FSH abnormalities were more common after chemotherapy (C 49%, C/RT 71% both P < 0.005) and LH abnormalities after radiotherapy (11% P < 0.01) and chemotherapy (10%, P < 0.001). Baseline hormone data were available for 367 patients. After treatment, compared to baseline, patients receiving chemotherapy had significantly greater elevations of FSH (median rise of 6 (IQR 3-9.25) iu l(-1) compared to 3 (IQR 1-5) iu l(-1) for S; P < 0.001) and a fall (compared to a rise in the surveillance group) in median testosterone levels (-2 (IQR -8.0 to -1.5) vs 1.0. (IQR -4.0-4.0) P < 0.001). Patients with low testosterone (but not elevated FSH) had lower quality of life scores related to sexual functioning on the testicular cancer specific module and lower physical, social and role functioning on the EORTC Qly C-30. Patients with a low testosterone also had higher body mass index and blood pressure. Treatment was associated with reduction in sexual activity and patients receiving chemotherapy had more concerns about fathering children. In total, 207 (30%) patients reported attempting conception of whom 159 (77%) were successful and a further 10 patients were successful after infertility treatment with an overall success rate of 82%. There was a lower overall success rate after chemotherapy (C 71%; CRT 67% compared to S 85% (P = 0.028)). Elevated FSH levels were associated with reduced fertility (normal FSH 91% vs elevated 68% P < 0.001). In summary, gonadal dysfunction is common in patients with a history of testicular cancer even when managed by orchidectomy alone. Treatment with chemotherapy in particular can result in additional impairment. Gonadal dysfunction reduces quality of life and has an adverse effect on patient health. Most patients retain their fertility, but the risk of infertility is likely to be increased by chemotherapy. Screening for gonadal dysfunction should be considered in the follow-up of testicular cancer survivors.

Intensity modulated radiotherapy (IMRT) at the Royal Marsden Hospital London was introduced in July 2001. Treatment delivery was dynamic using a single-phase technique. Concerns were raised regarding increased clinical workload due to introduction of new technology. The potential increased use of resources was assessed.

Variants in the gene encoding the macrophage scavenger receptor 1 (MSR1(4)) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease.

To describe the preliminary clinical outcomes of active surveillance (AS), a new strategy aiming to individualize the management of early prostate cancer by selecting only those men with significant cancers for curative therapy, and illustrate the contrast with a policy of watchful waiting (WW).

To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging.

To evaluate the efficacy and toxicity of an accelerated fractionation regimen to treat localised muscle invasive bladder cancer.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

The aim of the current study was to determine the utility of routine digital rectal examination (DRE) after radical radiotherapy for prostate cancer.

Patients with skeletal metastases from hormone-refractory prostate cancer have shown variable responses to high-activity therapy with (186)Re-HEDP and peripheral stem cell support. In this paper, we report on the use of a novel technique to compare sequential planar images acquired post-(186)Re-HEDP therapy administration with pretherapy diagnostic (99m)Tc-MDP scans, to evaluate the turnover of the radiopharmaceutical in normal and abnormal bone. It was found that the activity in normal (i.e., disease-free) segments of the spine demonstrates a faster effective decay than that of the metastases, with the latter showing only physical decay. This study showed, for the first time, a detailed correlation in the behavior of the (99m)Tc-MDP and (186)Re-HEDP images, encouraging the possibility of using the pretherapy 99mTc-MDP scan for estimations of absorbed doses to be delivered by prescribed activities of (186)Re-HEDP.

The whole-body dose (WBD) is routinely calculated for targeted radionuclide therapy (TRT). The aim of this work was to investigate the feasibility of using spectral analysis (SA) for the automatic delineation of decay phases, and consequently, the calculation of the WBD given a whole-body (WB) time-activity curve (TAC). SA characterizes the TAC as an arbitrary sum of exponential functions determined by fitting the data with a non-negative least-squares (NNLS) algorithm. The cumulated activity (CA) is calculated analytically as the integral of the fitted curve while the number of phases describing the kinetics of the radiopharmaceutical and the half-lives of the phases can be determined from the spectrum. The uncertainty associated with the estimation of the WBD can be obtained using bootstrap techniques. SA was applied to WB TACs from (186)Re-HEDP and (131)I-mIBG therapies. The results were compared to results obtained using a semiempirical method and showed good agreement in the calculated WBDs. Bootstrapping with resampling on a subset of patients from the two therapies showed much larger coefficient-ofvariation (CV) for the (186)Re-HEDP TACs than for the (131)I-mIBG therapies. We concluded that SA provides a fast, accurate, and reproducible method to obtain WBDs and accurate estimates of the parameters describing the radiotracer kinetics. The method could be extended to other dosimetric applications.

To analyze the cause of GI symptoms after pelvic radiotherapy (RT) in a consecutive series of patients with symptoms beginning after RT. A striking lack of evidence is available concerning the optimal treatment for the 50% of patients who develop permanent changes in bowel habits affecting their quality of life after pelvic RT. As a result, in the UK, most such patients are never referred to a gastroenterologist.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.

Two systems have been developed for treating patients with locally advanced prostate cancer using intensity-modulated radiotherapy (IMRT): one using dynamic multi-leaf collimator delivery and the other using step-and-shoot. This paper describes the clinical implementation of these two techniques, and presents results from the first 14 patients treated in a clinical setting (nine dynamic, five step-and-shoot).

We studied the rate of response to palliative external beam radiation therapy (20 Gy/5 or 30 Gy/10 fractions) to the base of skull in 32 prostate cancer patients with cranial nerve dysfunction. Sixteen patients (50%; 95% CI, 34-66%) had a useful response to therapy. The median survival post-therapy was 3 months.

This paper discusses the application of artificial neural networks (ANN) in predicting biological outcomes following prostate radiotherapy. A number of model-based methods have been developed to correlate the dose distributions calculated for a patient receiving radiotherapy and the radiobiological effect this will produce. Most widely used are the normal tissue complication probability and tumour control probability models. An alternative method for predicting specific examples of tumour control and normal tissue complications is to use an ANN. One of the advantages of this method is that there is no need for a priori information regarding the relationship between the data being correlated.

The Grand Round was held at the Christie Hospital, Manchester, U.K., on 30 November 2002. It followed a presentation by Dr David Dearnaley from the Royal Marsden Hospital in Sutton on 'Novel approaches and trials in prostate cancer'. Controversies in the management of locally advanced prostate cancer were illustrated by a case presentation and followed by a discussion on the evaluation of disease extent, and the roles of radiotherapy and hormone ablation.

As the trend towards more conformal treatment continues, the accuracy of treatment delivery becomes more important. Conventionally, treatment set-up for prostate cancer patients is verified in relation to the bony anatomy. However, there can be prostate movement independent of bony anatomy. This study tested the feasibility of using Beam cath to enable online correction of treatment set-up in relation to the prostate position, and to assess inter-fraction and intra-fraction prostate movement.

Radiotherapy is the most frequently used treatment for men with localised prostate cancer. Conformal radiotherapy (CFRT) is a relatively new development. MRC RT01 was set-up to explore optimum CFRT dose.

Full inverse planned intensity modulated radiotherapy (IMRT) may be indicated to treat concave targets like prostate and pelvic nodes, because concave dose distributions cannot be generated with conformal radiotherapy (CRT). We investigated whether this concave dose distribution can be produced using simplified forward planned multi segment radiotherapy (MSRT).

In order to ensure the validity of the outcome of the Medical Research Council's 'RTO1 trial' of dose escalation in conformal radiotherapy for prostate cancer it was considered important that the quality of treatment delivery should meet an adequate standard across all contributing centres. A questionnaire was therefore devised to ensure that all aspects of the planning and delivery process were adequately covered.

A series of three dose escalating studies were conducted to investigate the ability of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate, to cause maximum suppression of testosterone synthesis when delivered to castrate and noncastrate males with prostate cancer. Study A was a single dose study in castrate males. Study B was a single dose study in noncastrate males and study C was a multiple dose study in noncastrate males. The drug was given orally in a once-daily dose and blood samples taken to assess pharmacokinetic (PK) parameters and hormone levels in all patients. The study drug was well tolerated with some variability in PKs. Suppression of testosterone levels to <0.14 nmol l(-1) was seen in four out of six castrate males treated with a single dose of 500 mg. At 800 mg given days 1-12 in noncastrate males, target suppression was achieved in three out of three patients, but a two- to three-fold increase of Luteinising Hormone (LH) levels in two out of three patients overcame suppression within 3 days. All patients in the multiple dose study developed an abnormal response to a short Synacthen test by day 11, although baseline cortisol levels remained normal. This is the first report of the use of a specific 17alpha-hydroxylase/(17,20)-lyase inhibitor in humans. Repeated treatment of men with intact gonadal function with abiraterone acetate at a dose of 800 mg can successfully suppress testosterone levels to the castrate range. However, this level of suppression may not be sustained in all patients due to compensatory hypersecretion of LH. The enhanced testosterone suppression achieved in castrate men merits further clinical study as a second-line hormonal treatment for prostate cancer. Adrenocortical suppression may necessitate concomitant administration of replacement glucocorticoid.

Serum hemoglobin level (Hb) is a significant determinant of treatment outcome after radical radiotherapy (RT) for several cancer types, but its importance in prostate cancer is not well established.

The role of postoperative radiotherapy and hormone treatment after radical prostatectomy is uncertain, with no good evidence base to guide practice. In particular, it is not known whether a blanket policy of adjuvant therapy offers any advantage over a selective approach using salvage treatment in people who develop biochemical failure. Furthermore the technique for postoperative radiotherapy to the prostate bed has not been well described. We surveyed the opinion of UK clinical oncologists to describe current practice, with a view to informing the design of clinical trials in this setting.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.

E2F transcription factors, including EM, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of EM-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer.

Broadley, K. E. Edmonds, P. M. Patel, S.

Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were </=55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer-susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.

Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure.

To determine a class solution coplanar plan from comparisons of three-field (3F), four-field (4F), and six-field (6F) plans in conformal non-intensity-modulated prostate radiotherapy.

Despite a high cure rate in patients with testicular cancer, there remain patients in the poor prognosis group who have a less favorable outcome. Intensive induction chemotherapy using a regimen consisting of carboplatin, bleomycin, vincristine, and cisplatin, followed by bleomycin, etoposide, and cisplatin (CBOP/BEP), developed at the Royal Marsden Hospital, is designed to overcome the rapid proliferation seen in germ cell tumors. This study assesses the outcome of patients with poor-prognosis nonseminomatous germ cell tumors (NSGCT) treated with CBOP/BEP.

To assess the risk of cardiovascular morbidity and cardiac risk factors in long-term survivors of testicular cancer according to treatment received.

In high-activity rhenium-186 hydroxyethylidene diphosphonate ((186)Re-HEDP) treatment of bone metastatic disease from prostate cancer the dose-limiting factor is haematological toxicity. In this study, we examined the correlation of the injected activity and the whole-body absorbed dose with treatment toxicity and response. Since the best response is likely to be related to the maximum possible injected activity limited by the whole-body absorbed dose, the relationship between pre-therapy biochemical and physiological parameters and the whole-body absorbed dose was studied to derive an algorithm to predict the whole-body absorbed dose prior to injection of the radionuclide. The whole-body retention of radioactivity was measured at several time points after injection in a cohort of patients receiving activities ranging between 2,468 MBq and 5,497 MBq. The whole-body absorbed dose was calculated by fitting a sequential series of exponential phases to the whole-body time-activity data and by integrating this fit over time to obtain the whole-body cumulated activity. This was then converted to absorbed dose using the Medical Internal Radiation Dose (MIRD) committee methodology. Treatment toxicity was estimated by the relative decrease in white cell (WC) and platelet (Plt) counts after the injection of the radionuclide, and by their absolute nadir values. The criterion for a treatment response was a 50% or greater decrease in prostate-specific antigen (PSA) value lasting for 4 weeks. Alkaline phosphatase (AlkPh), chromium-51 ethylene diamine tetra-acetate ((51)Cr-EDTA) clearance rate and weight were measured before injection of the radionuclide. The whole-body absorbed dose showed a significant correlation with WC and Plt toxicity ( P=0.005 and 0.003 for the relative decrease and P=0.006 and 0.003 for the nadir values of WC and Plt counts respectively) in a multivariate analysis which included injected activity, whole-body absorbed dose, pre-treatment WC and Plt baseline counts, PSA and AlkPh values, and the pre-treatment Soloway score. The injected activity did not show any correlation with WC or Plt toxicity, but it did correlate with PSA response ( P=0.005). These results suggest that the administration of higher activities would be likely to generate a better response, but that the quantity of activity that can be administered is limited by the whole-body absorbed dose. We have derived and evaluated a model that estimates the whole-body absorbed dose on an individual patient basis prior to injection. This model uses the level of injected activity and pre-injection measurements of AlkPh, weight and (51)Cr-EDTA clearance. It gave good estimates of the whole-body absorbed dose, with an average difference between predicted and measured values of 15%. Furthermore, the whole-body absorbed dose predicted using this algorithm correlated with treatment toxicity. It could therefore be used to administer levels of activity on a patient-specific basis, which would help in the optimisation of targeted radionuclide therapy. We believe that algorithms of this kind, which use pre-injection biochemical and physiological measurements, could assist in the design of escalation trials based on a toxicity-limiting whole-body absorbed dose, rather than using the more conventional activity escalation approach.

External beam radiotherapy is one of the curative treatment options for localised prostate cancer. This article will describe recent advances in prostate radiotherapy, focussing on the results of randomised trials which have addressed the role of radiation dose escalation and of adjuvant hormone therapy. Current controversies will then be considered, including the merits of radiotherapy in comparison with alternative approaches to early prostate cancer, and the possible role of adjuvant radiation following surgery. Finally, future developments will be described, including hypofractionation and dose individualisation, which have the potential to further improve the outcome of external beam radiotherapy for prostate cancer.

To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism.

The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression-free survival (BPFS) times among men with bone metastases from prostate cancer.

Biologically targeted radiotherapy optimization requires accurate dose estimation, from macroscopic to cellular/subcellular dimensions. In particular, dose perturbations produced at interfaces between dissimilar media could affect therapy outcome. The magnitude of these perturbations depends on a complex set of parameters. This study investigates perturbations on electron dose for materials with atomic numbers (Z) up to 79 (79Au) at their interface with water as a function of Z, energy, distance from interface and geometry. A Monte-Carlo method that produces absorbed dose distributions in a voxel geometry has been developed using EGSnrc transport routines. Heterogeneous media and activity distributions can be input into this code. The backscatter dose factor (BSDF), which quantifies interface dose perturbations, was estimated using this code. The BSDF magnitude ranged from approximately 3% to approximately 50%, depending on source energy and Z. The BSDF decreased with increasing energy and showed a logarithmic dependence on Z. Empirical functions were fit to the results, that could be used to correct dose calculations performed using dose-point-kernels estimated in water, to cases involving different scattering materials. The BSDF was found to be highly dependent on interface geometry and scoring volume; thus it is vital that BSDFs are used only in geometry conditions that are similar to those in which they were originally produced.

To determine if it is possible to exclude staging bone scans in a greater proportion of patients if more consideration is given to T stage and Gleason score, as recent guidelines from the National Institute of Clinical Excellence state that routine staging bone scans for prostate cancer are unnecessary in patients with a prostate specific antigen level (PSA) of < 10 ng/mL and Gleason scores of < 8.

Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer.

Approximately 13,000 patients undergo pelvic radiotherapy annually in the UK. It is not clear how frequently patients develop a permanent change in bowel habit after pelvic radiotherapy that affects their quality of life because the measures of gastrointestinal toxicity used in trials in the past have generally been inadequate. It has been suggested that patients who are symptomatic are only rarely referred to a gastroenterologist and it is not known how patients manage their symptoms.

While there are numerous uncertainties surrounding prostate cancer's detection and treatment, more research focusing on the psychological needs of prostate patients is required. This study investigated the support and psychological care needs of men with prostate cancer. Patients were approached during urological oncology clinics and asked to complete the: Support Care Needs Survey (SCNS), Support Care Preferences Questionnaire, EORTC QLQ-C30 (Version 3) Measure plus Prostate Module, and the Hospital Anxiety and Depression Scale (HADS). Of the 249 patients meeting study entry criteria, there was an 89% response rate resulting in a cohort of 210 patients. The data showed that significant unmet need exists across a number of domains in the areas of psychological and health system/information. The more commonly reported needs were 'fears about cancer spreading (44%),' 'concerns about the worries of those close to you (43%),' and 'changes in sexual feelings (41%).' Half of all patients reported some need in the domain of sexuality, especially men younger than 65 years. Needs were being well met in the domain of patient care and support. A significant number of patients reported having used or desiring support services, such as information about their illness, brochures about services and benefits for patients with cancer (55%), a series of talks by staff members about aspects of prostate cancer (44%), and one-on-one counselling (48%). Quality of life (QoL) was most negatively impacted in those who: were < or =65 years old, had been diagnosed within one year, or had metastatic disease. Men < or =65 had decreased social functioning, greater pain, increased sleep disturbance, and were more likely to be uncomfortable about being sexually intimate. Patients recently diagnosed had increased fatigue, more frequent urination, greater disturbance of sleep, and were more likely to have hot flushes. Those with advanced disease scored lower on 12 out of 15 QoL categories. PSA level had no effect on QoL or anxiety/depression scores. Men with advanced disease had greater levels of depression and those < or =65 years old were more likely to be anxious. Although most men with prostate cancer seem to function quite well, a substantial minority report areas of unmet need that may be targets for improving care.

BACKGROUND. The aggregation of prostate cancer within families suggests a major inherited component to the disease. Genetic linkage studies have identified several chromosomal regions that may contain prostate cancer susceptibility loci, but none has been definitively implicated.METHODS. We performed a genome-wide linkage search based on 64 families, 63 with at least 3 cases of prostate cancer, ascertained in five countries. The majority of cases from these centers presented with clinically detected disease. Four hundred and one polymorphic markers were typed in 268 individuals. Multipoint heterogeneity analysis was conducted under three models of susceptibility; non-parametric analyses were also performed.RESULTS. Some weak evidence of linkage, under at least one of the genetic models, was observed to markers on chromosomes 2 (heterogeneity LOD (HLOD) = 1.15, P = 0.021), 3 (HLOD = 1.25, P = 0.016), 4 (HLOD = 1.28, P = 0.015), 5 (HLOD = 1.20, P = 0.019), 6 (HLOD = 1.41, P = 0.011), and 11 (HLOD = 1.24, P = 0.018), and in two regions on chromosome 18 (HLOD = 1.40, P = 0.011 and HLOD = 1.34, P = 0.013). There were no HLOD scores greater than 1.5 under any model, and no locus would be predicted to explain more than half of the genetic effect. No evidence in favor of linkage to previously suggested regions on chromosomes 1, 8,17, 20, or X was found.CONCLUSIONS. Genetic susceptibility to prostate cancer is likely to be controlled by many loci, with no single gene explaining a large fraction of the familial risk. Pooling of results from all available genome scans is likely to be required to obtain definitive linkage results.

The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose-volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7-31.2% depending on the alpha/beta ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4-27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.

A mass may persist in the para-aortic region after patients undergo chemotherapy for metastatic, nonseminomatous germ cell tumor of the testis (NSGCT). Retroperitoneal lymphadenectomy removes the mass, which may contain residual active malignancy, and allows histologic assessment of the effectiveness of the chemotherapy. Whereas some have favored early, elective removal of such masses, others have chosen to observe them, reserving salvage surgery for patients who experience disease recurrence. A retrospective analysis was undertaken to define the outcome in these two groups of patients.

Polymorphisms in the promoter regions of cytokine genes may influence prostate cancer (PC) development via regulation of the antitumor immune response and/or pathways of tumor angiogenesis. PC patients (247) and 263 controls were genotyped for interleukin (IL)-1beta-511, IL-8-251, IL-10-1082, tumor necrosis factor-alpha-308, and vascular endothelial growth factor (VEGF)-1154 single nucleotide polymorphisms. Patient control comparisons revealed that IL-8 TT and VEGF AA genotypes were decreased in patients compared with controls [23.9 versus 32.3%; P = 0.04, odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.44-0.99 and 6.3 versus 12.9%; P = 0.01, OR = 0.45, 95% CI 0.24-0.86, respectively], whereas the IL-10 AA genotype was significantly increased in patients compared with controls (31.6 versus 20.6%; P = 0.01, OR = 1.78, 95% CI 1.14-2.77). Stratification according to prognostic indicators showed association between IL-8 genotype and log prostate-specific antigen level (P = 0.05). These results suggest that single nucleotide polymorphisms associated with differential production of IL-8, IL-10, and VEGF are risk factors for PC, possibly acting via their influence on angiogenesis.

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.

Testicular germ cell tumors are highly curable. However, 10-30% of patients have recurrence after initial treatment. The time-course of recurrence has implications for the duration of follow-up. This study was undertaken to assess the risk and time-course of recurrence and to identify patients at higher risk of late recurrence.

The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed <or=55 years) and 469 UK, population based control individuals with no family history of cancer. We found no significant difference in the frequencies of Thr541-containing genotypes between cases and controls (OR=1.41, 95% CI 0.79-2.50). The association remained non-significant when the analysis was restricted to cases divided by age of onset into those diagnosed <or=55 years (OR=1.50, 95% CI 0.79-2.85) or to patients diagnosed >55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.

Dynamic intensity modulated radiation therapy (IMRT) to treat prostate and pelvic nodes using the Varian 120-leaf Millennium multileaf collimator (MLC) has been implemented in our clinic. This paper describes the procedures that have been undertaken to achieve this, including some of the commissioning aspects of Helios, verification of the dynamic dose delivery, and quality assurance (QA) of the dose delivered to the patient. Commissioning of Helios included measurements of transmission through the 120-leaf MLC, which were found to be 1.7% for 6 mV and 1.8% for 10 MV. The rounded leaf edge effect, known as the dosimetric separation, was also determined using two independent methods. Values of 1.05 and 1.65 mm were obtained for 6 and 10 MV beams. Five test patients were planned for prostate and pelvic node irradiation to 70 and 50 Gy, respectively. Dose and fluence verification were carried out on specially designed phantoms and dose points in the prostate were measured to be within 2.0% (mean 0.9%, s.d. 0.6%) of the calculated dose and in the nodes within 3.0% (mean 1.6%, s.d. 1.1%). Following the results of this commissioning and implementation study, we have started to treat men with a target Volume including the prostate and pelvic nodes using Helios optimized dynamic IMRT delivery in a dose escalation protocol.

Epidemiological studies have suggested an association between low selenium levels and the development of prostate cancer. Human cellular glutathione peroxidase I (hGPX1) is a selenium-dependent enzyme that protects against oxidative damage and its peroxidase activity is a plausible mechanism for cancer prevention by selenium. The GPX1 gene has a GCG repeat polymorphism in exon 1, coding for a polyalanine tract of five to seven alanine residues. To test if the GPX1 GCG repeat polymorphism associates with the risk of young-onset prostate cancer we conducted a case-control study. The GPX1Ala genotypes were determined for 267 prostate cancer cases and 260 control individuals using polymerase chain reaction (PCR) amplification with fluorescently labelled primers and an ABI 377 automated genotyper. Associations between specific genotypes and the risk of prostate cancer were examined by logistic regression. We found no significant association between the GPX1 genotypes and prostate cancer. There was however an increased frequency of the GPX1Ala6/Ala6 genotype in the prostate cancer cases compared to controls (OR: 1.67; 95% CI: 0.97-2.87). The result of this study suggests that the GPX1 genotype is unlikely to be associated with the risk of developing prostate cancer.

Phase III studies have demonstrated the clinical benefit of adding neo-adjuvant androgen deprivation to radical radiotherapy for clinically localised prostate cancer, We have developed a nomogram to describe the probability of PSA control for patients treated in this way, Five hundred and seventeen men with clinically localised prostate cancer were treated with 3 - 6 months of neo-adjuvant androgen deprivation and radical radiotherapy (64 Gy in 32#) between 1988 and 1998. Median presenting PSA was 20 ng ml(-1), and 56% of patients had T3/4 disease. Multivariate analysis of pre-treatment factors was performed, and a nomogram developed to describe PSA-failure-free survival probability. At a median follow-up of 44 months, 233 men had developed PSA failure, Presenting PSA. histological grade and clinical T stage were all highly predictive of PSA failure on multivariate analysis The nomogram score for an individual patient is given by the summation of PSA (< 10=0, 10-19=16, 20-49=44, greater than or equal to50=100), grade (Gleason 2-4=0, 5-7=44, 8-10=81) and T stage (T1/2=0, T3/4=35). For a nomogram score of 0, 50 100 and 150 points the 2 year PSA control rate was 9 3, 87, 75 and 54%. and the 5 year PSA control rate was 82, 67, 44 and 18%. These results are comparable to those using surgery or higher doses of radical radiotherapy alone. The nomogram illustrates the results of multivariate analysis in a visually-striking way, and facilitates comparisons with other treatment methods, (C) 2002 Cancer Research UK.

To assess magnetic resonance (MR) measures of vascular permeability of prostate cancer treated with androgen deprivation and to correlate these with morphologic appearances and serum prostate-specific antigen (PSA) levels.

In a randomized trial, the incidence of rectal bleeding among patients treated for prostate cancer using conformal radiotherapy was significantly lower (p = 0.002) than that among those treated conventionally. Here the relationship between rectal dose distributions and incidences of bleeding is assessed.

The aim of this paper is to illustrate the potential gain in tumor control probability (TCP) of prostate cancer patients by individualizing the prescription dose according to both normal-tissue (N-T) dose-volume and radiosensitivity data.

To assess the results of treatment in 33 patients with stage IIA/B seminoma who were treated with carboplatin and radiotherapy (RT) between January 1989 and December 1996.

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).

To compare external beam radiotherapy techniques for parotid gland tumours using conventional radiotherapy (RT), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT). To optimise the IMRT techniques, and to produce an IMRT class solution.

External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated.

To evaluate an alternative treatment for advanced or metastatic urothelial cancers, a dose-intensive combination chemotherapy regimen using carboplatin, methotrexate, vincristine and cisplatin was given to 60 patients over a 3-year period (1990 to 1993). There were 26 patients with locally advanced disease and 34 with metastatic disease; 49 patients were evaluable for response. A complete response was noted in four patients (8%) and a partial response in 15 (31%), for an overall response rate of 39%. The median survival was 12 months. Two- and 5-year survival rates were 25.5% (95% confidence interval CI) 15.2-37.0) and 7.3% (95% CI 2.2-16.4) respectively. Failure-free survival was 15.3% (95% CI 7.5-25.6) at 2 years and 5.9% (95% CI 1.6-14.4) at 5 years, with a median of 8 months. For the responders, the median duration of response was 14 months, with a range of 2-59+ months. Toxicity included myelosuppression (28% grade 4/5 neutropenia, 19% grade 4 thrombocytopenia), peripheral neuropathy (54% grade 1 and 23% grade 2/3) and ototoxicity (21% grade 1, 19% grade 2). This schedule of dose-intensified platinum-based chemotherapy for bladder cancer resulted in significant neurotoxicity without evidence of enhanced response rates or survival. Regimens such as methotrexate, vinblastine, doxorubicin and cisplatin should remain standard. Accelerated regimens may be useful in situations were it is necessary to administer chemotherapy over a short time (e.g. as part of combined modality treatment).

This study was carried out to evaluate the possible long-term endocrine effect of short-term neoadjuvant leuteinizing hormone-releasing hormone analogue (LHRHa) administration in localized prostate cancer. A total of 419 men were treated for 3-6 months at The Royal Marsden NHS Trust by neoadjuvant androgen suppression using monthly depot injections of LHRHa before radical radiotherapy. Serum testosterone (852 measurements), leuteinizing hormone (LH) (799 measurements), and follicle-stimulating hormone (FSH) levels (801 measurements) were grouped according to their timing in relation to hormonal treatment and then analysed. Suppression of pituitary gonadotrophins and testosterone after the administration of LHRHa and their recovery after cessation of the drug was clearly observed. Median serum testosterone levels decreased from 16 nmol/l to 14 nmol/l when comparing prehormonal and follow-up phases. The same comparison showed an increase in median serum LH and FSH levels, with the median LH rising from 5 u/l to 8 u/l and the median serum FSH rising from 6 u/l to 20 u/l. On long-term follow-up, three of 256 men have remained with testosterone levels in the castrate range. Similar highly significant results were seen in subgroup of 103 men who had both pre-LHRHa and follow-up hormone levels analysed (P=0.012, P<0.001, P<0.001 for testosterone, LH and FSH respectively). Our data suggest the possibility of residual gonadal dysfunction after short-term LHRHa administration and radical radiotherapy in localized prostate cancer. Serum testosterone levels are restored to normal levels in the majority of patients, with a compensatory increase in serum levels of LH.

To assess 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) techniques to see whether doses to critical structures could be reduced while maintaining planning target volume (PTV) coverage in patients receiving conventional radiotherapy (RT) for carcinoma of the maxillary sinus because of the risk of radiation-induced complications, particularly visual loss.

To investigate the potential of intensity-modulated radiotherapy (IMRT) to reduce lung irradiation in the treatment of oesophageal carcinoma with radical radiotherapy.

The aim of this study was to determine the optimal co-planar beam arrangement from a variety of three-field (3F), four-field (4F) and six-field (6F) plans for the boost phase of a dose escalated conformal radiotherapy schedule. Three selected plans (3F 0 degrees, 90 degrees, 270 degrees plan, 4F 45 degrees, 90 degrees, 270 degrees, 315 degrees plan and 6F 40 degrees, 90 degrees, 115 degrees, 245 degrees, 270 degrees, 320 degrees plan) were compared with reference plans (3F 0 degrees, 120 degrees, 240 degrees plan, 4F 0 degrees, 90 degrees, 180 degrees, 270 degrees plan, 6F 55 degrees, 90 degrees, 125 degrees, 235 degrees, 270 degrees, 305 degrees plan and 6F 50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees plan) in 10 patients. Doses of 64 Gy and 74 Gy were prescribed to the isocentre using 6 MV photons. The boost planning target volume comprised the prostate gland alone without a margin. Plans were compared by means of rectal volumes irradiated to >50% (V50), >80% (V80) and >90% (V90) of the prescribed dose. Irradiated volumes were also measured for the bladder (V90) and the femoral heads (V70). All optimal 3F, 4F and 6F plans gave lower irradiated rectal V80 and V90 levels than their corresponding reference plan. The 3F (0 degrees, 90 degrees, 270 degrees) plan consistently provided lower irradiated rectal levels at V50 to V90, with acceptable bladder and femoral head doses compared with the other plans in the study. When the 6F (50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees) plan used at our institution for the boost phase was compared with the 3F (0 degrees, 90 degrees, 270 degrees) plan, the rectal V50 was reduced from 20.8+/-5.2%, to 12.6+/-5.1%, the rectal V80 was reduced from 8.7+/-2.9% to 6.5+/-3.1% and the rectal V90 was reduced from 5.5+/-2.1% to 3.9+/-2.0% (all p<0.001). The bladder V90 and the femoral heads V70 levels were equivalent. For the boost phase when escalating the dose from 64 Gy to 74 Gy, the co-planar plan that allowed optimal rectal sparing was a 3F beam arrangement using gantry angles of 0 degrees, 90 degrees and 270 degrees. This 3F plan provided improved rectal sparing compared with the 6F (50 degrees, 90 degrees, 130 degrees, 230 degrees, 270 degrees, 310 degrees) beam arrangement currently used at our institution, with equivalent and acceptable bladder and femoral head doses.

This study reports results from a randomised controlled trial of nurse-led care and was designed to determine whether nurse-led follow up improved patients morbidity and satisfaction with care in men treated with radical radiotherapy for prostate and bladder cancer. The aim was to compare outcomes in terms of toxicity, symptoms experienced, quality of life, satisfaction with care and health care costs, between those receiving nurse-led care and a group receiving standard care. The study population was of men prescribed radical radiotherapy (greater than 60 Gy). Participants completed self-assessment questionnaires for symptoms and quality of life within the first week of radiotherapy treatment, at week 3, 6 and 12 weeks from start of radiotherapy. Satisfaction with clinical care was also assessed at 12 weeks post-treatment. Observer-rated RTOG toxicity scores were recorded pre-treatment, weeks 1, 3, 6 and 12 weeks from start of radiotherapy. The results presented in this paper are on 115 of 132 (87%) of eligible men who agreed to enter the randomised trial. 6 men (4%) refused and 11 (8%) were missed for inclusion in the study. Data were analysed as a comparison at cross-sectional time points and as a general linear model using multiple regression. There was no significant difference in maximum symptom scores over the time of the trial between nurse-led follow-up care and conventional medical care. Differences were seen in scores in the initial self assessment of symptoms (week 1) that may have been as a result of early nursing intervention. Those men who had received nurse-led care were significantly more satisfied (P < 0.002) at 12 weeks and valued the continuity of the service provided. There were also significant (P < 0.001) cost benefits, with a 31% reduction in costs with nurse-led, compared to medically led care. Evidence from this study suggests that a specialist nurse is able to provide safe follow up for men undergoing radiotherapy. The intervention focused on coping with symptoms, and provided continuity of care and telephone support. Further work is required to improve the management of patients during and after radiotherapy.

To determine the optimal coplanar treatment technique for six-field conformal radiotherapy of prostate only (PO) or prostate plus seminal vesicles (PSV).

To quantify MRI enhancement characteristics of normal and abnormal prostatic tissues and to correlate these with tumour stage, histological grade and tumour markers.

To evaluate the impact of a customized immobilisation system on field placement accuracy, simulation and treatment delivery time, radiographer convenience and patient acceptability.

A series of coplanar three-field configurations for two different clinical treatment volumes, prostate only (PO) and prostate plus seminal vesicles (PSV) were studied to determine the optimal three-field plan arrangement for prostate radiotherapy.

In patients with advanced bladder cancer receiving chemotherapy, early assessment of response can avoid unnecessary toxicity. The aim of this study was to assess the role of tumour markers in monitoring response. Serum levels of one or more of markers beta human chorionic gonadotrophin (betahCG), carcinoembryomic antigen (CEA), CA125 and CA19.9 were measured in 74 patients with advanced bladder cancer receiving chemotherapy from 1992 to 1997. Forty-three of 74 (58%) of patients had at least one raised marker (1.5 times upper limit of normal range). This was more common in patients with extra-pelvic disease than in those with disease confined to the pelvis (P = 0.002). Thirty-eight of 78 (49%) assessable patients had a radiological response. Neither clinical response (P = 0.81) nor survival (P = 0.16) differed between marker-negative and marker-positive patients. Clinical response was strongly related to marker response in the 35 comparable patients (P = 0.0001). No patient had a clinical response without response of at least one marker. Ninety per cent of patients who achieved a marker response had done so by 8 weeks. Monitoring of tumour markers in patients with advanced bladder cancer can help predict the response to chemotherapy.

Intensity modulated radiotherapy represents a significant advance in conformal radiotherapy. In particular, it allows the delivery of dose distributions with concave isodose profiles such that radiosensitive normal tissue close to, or even within a concavity of, a tumour may be spared from radiation injury. This article reviews the clinical application of this technique to date, and discusses the practical issues of treatment planning and delivery from the clinician's perspective.

To assess the impact on patterns of recurrence of adjuvant chemotherapy in patients with stage 1 nonseminomatous germ cell tumours (NSGCT) of the testis, who have a high likelihood of relapse on surveillance if certain risk factors are identified in the orchidectomy specimen, and thus the theoretical need for retroperitoneal lymph node dissection (RPLND).

Image distortion is an important consideration in the use of magnetic resonance (MR) images for radiotherapy planning. The distortion is a consequence of system distortion (arising from main magnetic field inhomogeneity and nonlinearities in the applied magnetic field gradients) and of effects arising from the object/patient being imaged. A two stage protocol has been developed to correct both system and object-induced distortion in pelvic images which incorporates measures to maintain the quality, accuracy and consistency of the imaging and correction procedures. The first stage of the correction procedure is described here and involves the removal of system distortion. Object- (patient-) induced effects will be described in a subsequent work. Images are acquired with the patient lying on a flat rigid bed, which reproduces treatment conditions. A frame of marker tubes surrounding the patient and attached to the bed provides quality assurance data in each image. System distortions in the three orthogonal planes are mapped using a separate phantom, which fits closely within the quality control frame. Software has been written which automates the measurement and checking of the many marker positions which the test objects generate and which ensures that patient data are acquired using a consistent imaging protocol. Results are presented which show that the scanner and the phantoms used in measuring distortion give highly reproducible results with mean changes of the order of 0.1 mm between repeated measurements of marker positions in the same imaging session. Effective correction for in plane components of system distortion is demonstrated.

To investigate the role of intensity-modulated radiation therapy (IMRT) to irradiate the prostate gland and pelvic lymph nodes while sparing critical pelvic organs, and to optimize the number of beams required.

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m(2)to be corrected for glomerular filtration rate outside the range 81-120 ml min(-1)and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60-82%) in patients allocated C and 81% (71-90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was - 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32-1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75-92%) in those allocated C, and 89% (81-96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35-2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germline mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was less than or equal to 67 years at diagnosis, No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (less than or equal to 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 Sears, and the other is a 2-bp deletion at base 5531 (ex:on 11) in a man who had prostate cancer at 56 years, In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

There is evidence for genetic predisposition to prostate cancer. However, prostate cancer genes have been more difficult to find than genes for some of the other common cancers, such as breast and colon cancer. The reasons for this are discussed in this article and it is now becoming clear that prostate cancer is probably due to multiple genes, many of which are moderate or low penetrance. The advances in the Human Genome Project and technology, especially that of robotics, will help to overcome these problems. Prostate Cancer and Prostatic Diseases (2000) 3, 241-247

Prior to randomization of patients into the UK Medical Research Council multicentre randomized trial (RT-01) of conformal radiotherapy (CFRT) in prostate cancer, clinicians at participating centres were required to complete a quality assurance (QA) clinical planning exercise to enable an investigation of inter-observer variability in gross target volume (GTV) and normal structure outlining.

To evaluate the dynamic interrelationship between rectal distension and rectal movements, and to determine the effect of rectal movement on the position of the prostatic gland using cine magnetic resonance imaging (MRI).

Conformal radiotherapy of the prostate is an increasingly common technique, but the optimal choice of beam configuration remains unclear. This study systematically compares a number of coplanar treatment plans for four-field irradiation of two different clinical treatment volumes: prostate only (PO) and the prostate plus seminal vesicles (PSV).

Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)n coding for polyglutamine and (GGC)n coding for polyglycine, may be associated with prostate cancer risk; but no study has investigated their association with disease progression. We present here a study of both hAR trinucleotide repeat polymorphisms not only as they relate to the initial diagnosis but also as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 control individuals were genotyped by PCR for the (CAG)n and (GGC)n polymorphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors associated with disease-free survival (DFS) and overall survival (OS). The relative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1. 08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjusting for stage and grade, GGC effects remained but were not significant (RR(DFS)= 1.60, p = 0.052; RR(OS)= 1.65, p = 0.088). The greatest effects were in stage T1-T2 (RR(DFS)= 3.56, 95% CI 1.13-11.21) and grade 1 (RR(DFS)= 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele distributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant trends with stage and grade were found in the proportion of short GGC alleles. The (GGC)n polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumours, this marker may help forecast aggressive behaviour and could be used to identify those patients meriting more radical treatment.

When adding laminar or 2-D margins to the clinical target volume (CTV), additional borders are required superiorly and inferiorly. Two common strategies for adding these margins, the cylindrical method (CYL) and the chamfer method (CHR), are discussed, and improved 2-D methods are presented. The improved cylindrical method (ICYL) extends the PTV superiorly and inferiorly, but the uppermost and lowermost PTV outlines are limited laterally to the extent of the CTV. If the required 3-D margin is M, the improved chamfer method (ICHR) constructs a transaxial margin of the square root of M2-d2 on a CT plane which is a distance d above the most superior CTV outline. For a theoretical tumor, CYL and CHR overestimate and underestimate the superior target margin by 8.1 cm3 and 9.6 cm3, respectively, whereas ICYL overestimates by only 2.2 cm3 and ICHR provides the desired margin. For eight esophageal tumors (specified margin 20 mm), CHR systematically underestimates the margin on the slice immediately inferior to the CTV by 7 mm (median, range 7-27 mm, p<0.01), while CYL overestimates the margin two slices inferior to the CTV by 20 mm in all cases. ICYL removes the overestimation of CYL, but retains an overestimation of 3 (-17-3) mm (p<0.01) on the first slice inferior to the CTV. ICHR performs most accurately, the margin width being equal to that of a true 3-D margin, except for occasional underestimations (0-33 mm, p<0.01). Similar results are demonstrated for eight prostatic tumors (specified margin 10 or 15 mm), but with the more irregular tumor shape causing all 2-D methods to underestimate the margin, most notably by 4.5 (0-21) mm (p<0.01) on the inferior CTV slice for a 15-mm margin. In general, both improved 2-D methods produce significantly more accurate margins than the conventional methods, the margin produced by the improved chamfer method most closely approximating a true 3-D margin.

This feasibility study was performed to evaluate the suitability of MRI in defining appropriate pelvic radiotherapy treatment volumes, and to compare MRI sequences with CT for prostate cancer radiotherapy. Five patients with localized prostate cancer, imaged with four MRI sequences (spin echo (SE) T1, turbo SE (TSE) T2, high resolution TSE (HR) T2, and FLASH 3D (F3D)), compared with their corresponding CT planning scans. Segmentation ability of the following pelvic structures: prostatic apex (PA), prostate, rectum, bladder and seminal vesicles (SV), were evaluated by three independent observers. They used a five point grading scale based on the anatomical definition of the organ boundary, tissue contrast and multiplanar display. Results were averaged for the group and for each sequence. There was no significant interobserver variation in the assessed scores (p > 0.1). The average scores (+/- 1 SD) for all pelvic structures assessed by each imaging sequence were CT 1.3 +/- 0.6; SE T1 2.4 +/- 0.9; TSE T2 2.4 +/- 0.7; HR T2 2.2 +/- 0.7 and F3D 3.4 +/- 0.6. Compared with CT, the average MR score for each assessed pelvic structure was higher with a trend for all transaxial MR sequences to provide improved segmentation of the PA and rectum. The F3D sequence scored highest as it provided multiplanar views and avoided the problem of partial volume averaging. MRI, compared with CT, appears to provide improved definition of pelvic treatment volumes but further work is required to confirm this and to address the issues of MRI associated distortion and dosimetry before MRI can be used routinely for pelvic radiotherapy planning.

In order to develop a low toxicity regimen of bladder radiotherapy for the palliation of patients with poor performance status we carried out a Phase II study of weekly 6 Gy fractions to a maximum dose of 30-36 Gy in 65 patients with T(2)-T(4) bladder cancer (median age 81 years). A complete response was obtained in 23/37 (62%) assessable patients at cystoscopy. Local control was achieved in 16/65 (25%) patients. The median survival of all 65 patients was 35 weeks, and the 2-year actuarial survival 21%. The main acute toxicity was urinary frequency as often as hourly at the peak of the reaction (Radiation Therapy Oncology Group (RTOG) grade 3) in seven patients, and urinary obstruction (RTOG grade 4) in one. The reactions may have been compounded by the effects of locally advanced tumour. Late bladder toxicity amongst the 16 patients who were evaluable after 1 year included four patients with persisting frequency, one with severe haematuria (RTOG grade), and one with a bladder capacity <100 ml (RTOG grade 4). One patient experienced RTOG grade 4 late bowel and bladder morbidity. Weekly 6 Gy fractions to a total dose of 30-36 Gy is a satisfactory palliative regimen for patients with advanced bladder cancer who cannot tolerate standard radical radiotherapy, but it may produce significant late bladder morbidity.

As more and more patients with prostate cancer are cured and survive with only minor chronic morbidity, other potentially treatment related morbidity, in particular second cancers, becomes an urgent problem which may influence decisions on treatment strategy and treatment plan optimisation. Epidemiological data suggest a radiotherapy associated risk of AML in prostate cancer patients of approximately 0.1% in 10 years. The aim of the study was to determine the range of bone marrow doses from different treatment plans and in different patients in order to develop criteria for optimisation of treatment plans in conformal radiotherapy of prostate cancer to further minimise the small risk of secondary leukaemia.

Pelvic lymph node involvement is an adverse prognostic factor in clinically localized prostate cancer, and a knowledge of nodal status is important for patient management. Whereas nodal disease has been widely regarded as incurable, evidence is now accumulating that some men with lymph node involvement may benefit from radical multimodality treatment approaches. Pelvic nodal status may be assessed by predictive nomograms, by imaging studies and by surgery. The pros and cons of each method are discussed together with the prospects for future development. Optimal strategies combining the different diagnostic approaches for the detection of lymph node metastases are considered in the context of the changing therapeutic implications of nodal disease.

Radical radiotherapy is commonly used to treat localised prostate cancer. Late chronic side-effects limit the dose that can be given, and may be linked to the volume of normal tissues irradiated. Conformal radiotherapy allows a smaller amount of rectum and bladder to be treated, by shaping the high-dose volume to the prostate. We assessed the ability of this new technology to lessen the risk of radiation-related effects in a randomised controlled trial of conformal versus conventional radiotherapy.

There is some evidence to support the proposition that early diagnosis and treatment of prostate cancer may be beneficial and could reduce the mortality from the disease. Despite this, the introduction of a screening programme similar to those in place for breast and cervical cancer cannot be justified on current evidence, In the absence of alternative strategies to reduce mortality from prostate cancer, early diagnosis in appropriate circumstances should be encouraged. The establishment and Funding of adequate programmes to test the validity of population screening should be sought by BAUS and such programmes should he supported by all urologists, Opportunist screening, without prior consent of the patient, by general practitioners (GPs), as part of health-check protocols, hospital admission investigations, etc. should be discouraged. Patients requesting PSA testing should be considered sympathetically, but PSA testing should only be performed after full counselling. It is reasonable to comply with a patient's request if based on such information. Similar counselling should be given to patients with a family history or other risk factors if they seer; diagnostic testing. There is no evidence to support opportunist screening of such men, but men with a family history will seek advice and this should be available. It is recommended that all prostate assessment clinic protocols are reviewed and as a minimum, patients given written information that a PSA test is included in the protocol and an opportunity to opt out of the test if ther wish. Patients over 75 years old (or of an age to be agreed in local protocols) and those with conditions severely affecting life expectation, should only hare their PSA measured if there is clear clinical evidence that they may hare prostate cancer for which treatment will be needed. Urologists must agree with their referring GPs and with their hospital colleagues on protocols of PSA use. Transrectal ultrasonography and prostatic biopsy must be carried out in units with adequate equipment and expertise. Clear criteria for biopsy must be agreed between those referring patients and those performing biopsies, be they radiologist or urologist. ii protocol for further follow-up of men with raised PSA levels after a negative biopsy must be agreed, to minimize anxiety and allow early discharge. The BAUS Section of Oncology must establish criteria for designating prostate cancer clinics where patients being considered for radical prostatectomy or other active treatment can be counselled. Urologists performing radical prostatectomy ideally should be attached to such centres, and should participate in audit as laid down by the Oncology Section, and contribute to appropriate national trials.

Aim: To compare a single fraction of 8 Gy with a course of multifraction radiotherapy in terms of long-term benefits and short-term side effects in patients with painful skeletal metastases.Methods: Seven hundred and sixty-five patients with painful skeletal metastases requiring palliative radiotherapy were entered into a prospective randomised clinical trial comparing 8 Gy single fraction with a multifraction regimen (20 Gy/5 fractions or 30 Gy/10 fractions). Patients recorded pain severity and analgesic requirements on self-assessment questionnaires before treatment, at 2 weeks and at 1,2, 3, 4, 5, 6, 8, 10 and 12 months after radiotherapy. Pain relief was the primary endpoint of treatment benefit. Short-term side-effects were compared in a subset of 133 consecutive patients who graded nausea, vomiting and antiemetic usage prior to treatment and at daily intervals from days 1 to 14.Results: Overall survival at 12 months was 44%, with no statistically significant difference apparent between randomised groups. There were no differences in the time to first improvement in pain, time to complete pain relief or in time to first increase in pain at any time up to 12 months from randomisation, nor in the class of analgesic used. Retreatment was twice as common after 8 Gy than after multifraction radiotherapy, although retreatment for residual or recurrent pain did not reflect a difference between randomised groups in the probability of pain relief. The difference in the rate of retreatment is thought to reflect a greater readiness to prescribe radiotherapy after a single fraction, not a greater need. There were no significant differences in the incidence of nausea, vomiting, spinal cord compression or pathological fracture between the two groups.Conclusions: A single fraction of 8 Gy is as safe and effective as a multifraction regimen for the palliation of metastatic bone pain for at least 12 months. The greater convenience and lower cost make 8 Gy single fraction the treatment of choice for the majority of patients. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

An asymptomatic rising serum prostate-specific antigen (PSA) level is the most common form of failure after radical radiotherapy for localized prostate cancer, but there is no consensus as to how it should be managed. This review addresses the following three questions concerning men with PSA failure after radiotherapy: (i) what is the course of the disease without further intervention?; (ii) what is the role of radical treatment, such as salvage prostatectomy?; and (iii) should androgen deprivation be started immediately or should it be delayed until clinical progression occurs? An algorithm for the management of PSA failure after radical radiotherapy for localized prostate cancer is proposed.

The use of escalated radiation doses to improve local control in conformal radiotherapy of prostatic cancer is becoming the focus of many centers. There are, however, increased side effects associated with increased radiotherapy doses that are believed to be dependent on the volume of normal tissue irradiated. For this reason, accurate patient positioning, CT planning with 3D reconstruction of volumes of interest, clear definition of treatment margins and verification of treatment fields are necessary components of the quality control for these procedures. In this study electronic portal images are used to (a) evaluate the magnitude and effect of the setup errors encountered in patient positioning techniques, and (b) verify the multileaf collimator (MLC) field patterns for each of the treatment fields.

To assess the feasibility of intermittent hormone therapy for metastatic prostate cancer.

To evaluate the adequacy of tumor volume coverage using a three-dimensional (3D) margin-growing algorithm compared to a two-dimensional (2D) margin-growing algorithm in the conformal radiotherapy planning of prostate cancer.

A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (27/160) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic lose in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046). Int. J. Cancer 78:1-7, 1998. (C) 1998 Wiley-Liss, Inc.

Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease.

To analyze the probability of recovery of spermatogenesis after orchidectomy and cisplatin-based chemotherapy (CT) for testicular germ cell cancer.

The residual mass so frequently found after chemotherapy of advanced seminoma may consist entirely of benign tissue or may contain residual disease amenable to adjuvant therapy.

A prospective, randomized clinical trial to assess the effect of reducing the volume of irradiated normal tissue on acute reactions in pelvic radiotherapy accured 266 evaluable patients between 1988 and 1993.

The emerging utilisation of conformal radiotherapy (RT) planning requires sophisticated imaging modalities. Magnetic resonance imaging (MRI) has introduced several added imaging benefits that may confer an advantage over the use of computed tomography (CT) in RT planning such as improved soft tissue definition, unrestricted multiplannar and volumetric imaging as well as physiological and biochemical information with magnetic resonance (MR) angiography and spectroscopy. However, MRI has not yet seriously challenged CT for RT planning in most sites. The reasons for this include: (1) the poor imaging of bone and the lack of electron density information from MRI required for dosimetry calculations; (2) the presence of intrinsic system-related and object-induced MR image distortions; (3) the paucity of widely available computer software to accurately and reliably integrate and manipulate MR images within existing RT planning systems. In this review, the basic principals of MRI with its present potential and limitations for RT planning as well as possible solutions will be examined. Methods of MRI data acquisition and processing including image segmentation and registration to allow its application in RT planning will be discussed. Despite the difficulties listed, MRI has complemented CT-based RT planning and in some regions of the body especially the brain, it has been used alone with some success. Recent work with doped gel compounds allow the MRI mapping of dose distributions thus potentially providing a quality assurance tool and in a manner analogous to CT, the production of dose-response information in the form of dose volume histograms. However, despite the promise of MRI, much development research remains before its full potential and cost-effectiveness can be assessed.

This prospective randomized multicenter trial was designed to evaluate the efficacy of carboplatin plus etoposide and bleomycin (CEB) versus cisplatin plus etoposide and bleomycin (BEP) in first-line chemotherapy of patients with good-risk nonseminomatous germ cell tumors.

To assess the role of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) in evaluating suspected occlusion of the inferior vena cava (i.v.c.) in patients with abdominal nodal metastases from non-seminomatous germ cell tumours, thus giving information that may be helpful in planning surgery and for determining the need for anticoagulant therapy.

The purpose of this pilot study was to evaluate the acute gastrointestinal morbidity of adjuvant radiotherapy (RT) for Stage I seminoma of the testis. Ten Stage I patients receiving para-aortic and ipsilateral pelvic nodal (dog-leg) RT provided a toxicity baseline (group A). Twenty Stage I patients, randomized to dog-leg RT or para-aortic RT (10 per group) were further randomized to received prophylactic ondansetron or expectant therapy with metoclopramide (group B). Daily patient-completed questionnaires evaluated acute toxicity. In group A (n = 10), nausea, vomiting, diarrhoea and abdominal discomfort were experienced in 90%, 80%, 70% and 90% respectively. Antiemetic and antidiarrhoeal agents were required in 70% and 10% respectively, with good response. For group B (n = 20), the overall incidences of nausea, vomiting diarrhoea and abdominal discomfort were 80%, 45%, 60% and 80% respectively. The ondansetron group experienced less nausea (P = 0.02) and less vomiting (P = 0.06). Both reduced field size and ondansetron groups appeared to have less diarrhoea (P = 0.06). The use of antiemetics in the expectant therapy groups resulted in at least a two-level reduction of toxicity grade in 86% of patients. A high incidence of lethargy, anorexia and headaches was noted for all groups. The incidence of headaches was not increased with ondansetron. Dog-leg RT for Stage I seminomas is associated with readily demonstrable gastrointestinal tract (GIT) toxicity. The number of patients in this study is too small to produce definitive results, but there appears to be reduced GIT toxicity with prophylactic antiemetics. The effect of reduced RT fields has been assessed further in the MRC randomized trial of field sizes (TE10).

A multileaf collimator (MLC) can be used in parallel opposed techniques as a direct replacement for standard-shaped beam blocks. However, improved shielding is possible if the MLC field is designed to fit a target rather than to mimic a straight-edged block. This study has compared the treatment areas produced by the MLC and by conventionally blocked fields with the target area for 43 parallel opposed treatments. It was found in every case that the MLC treated less than 10% excess tissue, and, in over 70% of patients, the excess was less than 5%. The conventional fields, however, treated more than 10% excess tissue in 70% of patients. The effect of MLC orientation and the benefits of using an MLC are discussed.

Spinal cord compression (SCC) is an important complication of metastatic prostate cancer. We have analysed patients treated at the Royal Marsden Hospital to assess treatment outcome and prognostic factors in this patients group.

Radiotherapy is an effective treatment for localized prostate cancer. A dose response relationship has been demonstrated for both local tumor control and complications. Reducing the volume of normal tissue treated may allow dose escalation without an increase in RT induced side effects. Androgen blockade before RT could, by reducing tumor volume, increase local control, disease-free (DFS) and overall survival in patients (pts) with prostatic adenocarcinoma. A total of 79 patients with T2-T4 prostate cancer have been treated initially with LHRH agonists and cyproterone acetate followed by radical irradiation between 1988 and 1993. The first cohort of 22 patients were monitored intensively by transrectal ultrasound and computed tomography. For each patient conformal photon beam radiotherapy and conventional treatment plans were produced and dose volume histograms compared for total volume, rectal volume, and bladder volume. Overall mean reduction of prostate volume was about 50%, and radiotherapy target volume was reduced by 37%. 53 further patients without clinical evidence of regional or distant metastases were given 3 months preradiotherapeutic hormonal cytoreduction with a short course of cyproterone acetate and LHRH. PSA level fell rapidly in most patients and after 3 months treatment the median PSA level was 1 ng/ml and 83% had PSA level 10 ng/ml. At 18 months PSA levels continued to be < 2 ng/ml in 70% of the patients. Combined modality treatment with the neoadjuvant or adjuvant androgen deprivation and conformal therapy show considerable promise as novel methods to improve the therapeutic ratio. This treatment approach may be used to explore the possibility of dose escalation in prostate cancer to enhance local control, and therapeutic randomised studies are underway to test these approaches.

There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility.

The application of conservative surgery has been established in the treatment of transitional cell tumors of the renal pelvis. We reviewed retrospectively the long-term outcome after percutaneous treatment of select patients referred to a tertiary center with transitional cell tumors of the renal pelvis.

The aim of this study was to assess the accuracy of pelvic radiotherapy during a trial of blocked radiotherapy at the Royal Marsden Hospital, UK. Prospective evaluation was performed on 90 patients receiving CT planned pelvic radiotherapy using weekly anterior-posterior and lateral portal films. Field placement errors (FPEs) were calculated by comparing field centres of each film with a designated point of interest. Data was evaluated to calculate the overall treatment simulator differences, the number of error free treatments, and mean treatment-simulator position and to evaluate the role of systematic versus random errors. Age, weight, disease site, position of treatment, fractionation, blocked versus conventional techniques were assessed for their effect on treatment accuracy. The mean absolute error between treatment and simulator films was anterior right-left (ARL) 0.25 cm, anterior superior-inferior (ASI) 0.32 cm, lateral anterior-posterior (LAP) 0.42 cm, and lateral superior-inferior (LSI) 0.28 cm. On average the field centre was displaced by 0.66 cm (standard deviation, S.D. = 0.34) from that intended. On each treatment day 29% of anterior films and 45% of lateral films had at least one 0.5 cm error. Overall 59% of treatments had at least one 0.5 cm error and 9% a 1.0 cm error. The field centre was more than 0.5 cm from the position intended in 66% of treatments and over 1 cm for 14% of treatments. Analysis of variance showed that both random and systematic errors occurred in all directions. Though random errors were of similar magnitude in all direction (variance sigma 2 = 0.06-0.09 cm2); systematic errors showed a 4-fold variation being greatest in the LAP direction (sigma 2 = 0.19 cm2) and least the ARL direction (sigma 2 = 0.048 cm2). No factor consistently predicted for worse outcome in all directions. Hypofractionated treatments were less accurate in the LSI direction (P > 0.05). Systematic errors were associated in the ARL direction with hypofractionation (P < 0.01) and, in the LSI direction with weight (P < 0.03) and age (P < 0.05). We conclude that significant random and systematic errors can occur during pelvic radiotherapy especially in the LAP direction. These results suggest that in the absence of a customised immobilisation device, to cover 95% of errors, margins of 0.6 cm for RL and SI directions and 0.9 cm for AP direction should be allowed between the planning and clinical target volumes. However, ideally, each centre should determine their own margin requirements according to local clinical practice.

Spermatocytic seminoma is an uncommon variety of testicular neoplasm, differing from its classical counterpart at both clinical and pathological levels and having a low propensity to metastasize. This is a retrospective review of ten patients with pathologically confirmed and reviewed disease who were seen at the Royal Marsden Hospital. All patients presented as Stage I. Five were treated with radiotherapy and five have undergone surveillance. The median age was 56.5 years. The median follow-up is 8 years and no patient has relapsed. Two have died of intercurrent disease. Our series supports others of a similar size in the literature with respect to both the rarity and the good prognosis of spermatocytic seminoma. With only one case of relapse confirmed in the literature, this is a subgroup of patients in whom radiotherapy can safely be omitted.

We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance (530 in total) post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma (P = 0.01, log-rank test, chi-square test P = 0.001). The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome.

The aim of the present retrospective study was to assess long-term survival after cisplatin-based chemotherapy in 398 patients with advanced urothelial transitional cell carcinoma (TCC) treated at seven international oncological units. Various combinations of cisplatin, methotrexate, vinblastine (or vincristine) and doxorubicin were used. The complete response rate according to the WHO criteria was 17%. Partial responses were obtained in 42% of the patients. The overall cancer-related 2 year and 5 year survival rates were 21% and 11% respectively. Based on multivariate analyses, a good prognosis group could be identified comprising patients with a good performance status with disease confined to lymph nodes (14%) or patients with T4b disease only. These patients had a 28% 5 year survival rate, which, in part, has to be related to post-chemotherapy consolidation treatment in patients with pelvis-confined disease (radiotherapy, 26%; total cystectomy, 11%). Fifteen patients died of chemotherapy-related complications and in 16% of the patients toxicity led to discontinuation of treatment. Modern cisplatin-based chemotherapy leads to long-term survival and cure of selected patients with advanced urothelial transitional cancer. In routine clinical practice, chemotherapy should be offered to good prognosis patients; those presenting with a good performance status and a non-metastasising T4b tumour or with metastases confined to lymph nodes. Post-chemotherapy consolidation treatment by surgery or radiotherapy should always be considered. Such chemotherapy requires oncological expertise in order to avoid unnecessary toxicity.

To determine whether the initial regression rates of serum tumor marker concentration (alpha-fetoprotein [AFP] and beta-human chorionic gonadotrophin [HCG]) were important prognostic factors after chemotherapy for germ cell tumors.

A portal imaging system has been used, in conjunction with a movie measurement technique to measure set-up errors for 15 patients treated with radiotherapy of the pelvis and for 12 patients treated with radiotherapy of the brain. The pelvic patients were treated without fixation devices and the brain patients were treated with individually-moulded plastic shells. As would be expected the brain treatments were found to be more accurate than the pelvic treatments. Results are presented in terms of five error types: random error from treatment to treatment, error between mean treatment position and simulation position, random simulation error, systematic simulator-to-treatment errors and total treatment error. For the brain patients the simulation-to-treatment error predominates and random treatment errors were small (95% < or = 3 mm, 77% < or = 1.5 mm). Vector components of the systematic simulation-to-treatment errors were 1-2 mm with maximal random simulation error of +/- 5 mm (2 S.D.). There is much interest in the number of verification films necessary to evaluate treatment accuracy. These results indicate that one check film performed at the first treatment is likely to be sufficient for set-up evaluation. For the pelvis the random treatment error is larger (95% < or = 4.5 mm, 87% < or = 3 mm). The systematic simulation-to-treatment error is up to 3 mm and the maximal random simulation error is +/- 6 mm (2 S.D.). Thus corrections made solely on the basis of a first day check film may not be sufficient for adequate set-up evaluation.

We evaluated high-dose carboplatin and etoposide with autologous bone marrow stem cell support in the salvage treatment of patients with metastatic germ cell tumours who had failed previous chemotherapy. The treatment programme comprised initial conventional dose chemotherapy. 23 patients received a first cycle of high-dose treatment, and 12 who showed no evidence of progression had a second cycle 2-3 months later. 8 of the 23 patients treated with high-dose chemotherapy are alive in remission 4-29 months from the start of high-dose treatment. 3 of these 8 required further treatment for recurrence. In the initial part of the study, the dose of carboplatin was escalated in successive patients. Grade 3/4 treatment-related toxicity occurred in 4 of 18 patients (1 fatal) who received carboplatin doses to give a AUC (area under the serum concentration/time curve) of 30 mg.min/ml or less and 3 of 5 patients (2 fatal) who received higher doses. We, therefore, recommend 30 mg.min/ml for further evaluation in chemotherapy sensitive patients.

Radical radiotherapy has been established as an effective modality for eradicating localised prostate cancer. No satisfactory comparisons have been made with patients treated by total prostatectomy, but in surgically staged patients with negative lymph nodes survival after radiotherapy exceeds that of an aged matched population, cancer deaths occurring in only 6-15% of patients and 85% remaining free of local recurrence after 10 years. Results are predictably less satisfactory in surgically unstaged cases and for more advanced localised presentations. Nevertheless, radical radiotherapy achieves local control of disease in the majority of patients. Improved local control may be obtained by increasing radiation dose but at the expense of increased radiation-induced side-effects. Conformal radiotherapy and combined modality treatment with the neoadjuvant or adjuvant androgen deprivation show considerable promise as novel methods to improve the therapeutic ratio, and prospective randomised studies are underway to test these approaches.

A multileaf collimator (MLC) can be used as a replacement for conventional blocks as well as for conformal radiotherapy. This study has assessed the possibility of using a Philips MLC for 218 patients treated with conventionally blocked fields. It was found that MLC field shaping would have been appropriate for over 94% of such patients. The facility to treat large blocked fields has been found to be particularly useful. Use of the predefined shapes stored in the Regular Shape Library provided by Philips was evaluated and it was found that an appropriate shape was available in 52% of cases. The application of MLC fields to the treatment of different anatomical sites is discussed.

The aim of this study was to evaluate the relative merits of the coplanar field arrangements most frequently used for conformal radiotherapy of the prostate using dose-volume histograms and normal tissue complication probabilities (NTCPs). Twelve patients with early prostate cancer underwent a planning CT scan of the pelvis. Isocentric plans for each patient were devised using three, four, six and eight conformal fields and beam-weights optimised using fast simulated annealing to give a dose homogeneity across the planning target volume of +/- 5% or better while minimising irradiation of the relevant organs at risk. The plans were then evaluated using dose-volume histograms of the organs at risk (bladder, rectum and both femoral heads) and the Lyman model of normal tissue complication probability for the rectum. Analysis of dose-volume histogram data averaged over the 12 patients indicates an advantage for six (p = 0.002) and eight (p = 0.0001) fields with respect to the percentage volume of the femoral heads receiving > 50% of the prescribed dose compared with three fields. There was a similar advantage for six (p = 0.0007) and eight (p = 0.0001) fields compared with four fields. Ranking of the treatment techniques indicates that the four-field technique is the worst with respect to femoral head irradiation but the best with respect to reducing rectal irradiation. A higher dose can be prescribed to the isocentre with the four-field technique for a 5% rectal NTCP. The six-field technique led to sparing of the bladder when the different treatment techniques were ranked using bladder dose-volume histogram data. We conclude that none of the techniques studied consistently proved to be superior when applied to this sample of patients with prostate cancer with respect to sparing all the organs at risk. The absolute differences between techniques are small and would be very difficult to detect with respect to clinically relevant endpoints.

Percutaneous nephrostomy can be used to resect transitional cell carcinoma (TCC) from the renal pelvis, to avoid nephrectomy in selected patients. This procedure carries a potential risk of tumour seeding along the nephrostomy track, which it is our policy to irradiate prophylactically. A total of 25 procedures on 23 patients have been carried out since 1982. The 18 males and five females had a median age of 64 years (range 46-81) at the time of treatment. Of the ten patients with only one functioning kidney, nine had undergone contralateral nephroureterectomy, seven for TCC, one for a non-functioning kidney, and one for renal tuberculosis; one patient had received radical radiotherapy for an inoperable contralateral renal tumour. The other 13 patients had asked for a conservative treatment approach to be adopted. From 1982-1989, low dose rate 192Ir wire was used in 13 patients to deliver a median dose of 45 Gy (range 40-50) to the full length of the track at the surface of nephrostomy tube. Since 1989, we have used a high dose rate (HDR) 192Ir microSelectron to treat 12 patients with a single fraction of 10-12 Gy, including two who had undergone previously 192Ir wire track irradiation of the same kidney. One patient required a nephroureterectomy after developing a non-healing renal pelvis leak following combined modality treatment. Otherwise, no early or late radiation-related morbidity has been seen, and no nephrostomy track recurrences have occurred during a median follow-up of 5 years (range 1-9). The HDR microSelection has enabled us to deliver this treatment quickly and simply during the standard postoperative stay in hospital following percutaneous nephrostomy.

From 1988 to 1991, 284 patients with prostatic cancer and painful bone metastases were treated with either radiotherapy or strontium-89 (200 MBq). Patients were first stratified according to suitability for local or hemibody radiotherapy, then randomly allocated that form of treatment or strontium-89 (i.v. injection). After 4, 8 and 12 weeks pain sites were mapped, toxicity monitored, and all additional palliative treatments recorded. There was no significant difference in median survival (after > 80% had died); 33 weeks following strontium-89 and 28 weeks following radiotherapy (p = 0.1). All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the comparable strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05). Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect. Platelets and leukocytes fell by an average 30-40% after strontium-89 but sequelae were uncommon, and other symptoms rare.

A pilot study has been completed of an innovative dose intensive chemotherapy schedule for poor prognosis patients with metastatic germ cell tumours referred to the Royal Marsden Hospital between August 1989 and January 1992. The rationale underlying the regimen was the use of an extremely short intercycle interval in order to counteract the potential of these tumours for rapid proliferation. The drug combination in the first phase incorporated a combination of cisplatin and carboplatin, infusional bleomycin and vincristine and this was followed by three cycles of bleomycin, etoposide and cisplatin (C-BOP/BEP). 21 patients with adverse presentations were treated with C-BOP/BEP. The median follow-up of surviving patients is 36 months (range 18-52 months). 1 patient died of disease, 1 died of a treatment complication while in remission and 1 further patient relapsed, and is in remission after radiotherapy and surgery. The 2-year overall survival rate was 90% [95% confidence interval (CI) = 77-100%]. We conclude that this approach may represent an improvement over standard chemotherapy and should be assessed in a multicentre setting.

Proton beams are already being employed for radiation therapy in 15 centres worldwide and over a dozen more are planned. Good clinical results have been reported in uveal melanomas and in sarcomas of the skull base. Calculated dose distributions for the treatment of brain, lung, head and neck and pelvic tumours predict an improvement relative to multiple-field or conformal photon radiotherapy. Protons may well provide high-precision radiotherapy that will lead to improved treatment of certain tumours in specific anatomical locations.

Twenty-one patients with Stage IIA or B seminoma have been treated post orchidectomy by a single course of carboplatin prior to conventional radiotherapy in either the Royal Marsden Hospital or the Norwegian Radium Hospital during 1989-1993. Follow-up ranged from 8 months to 51 months with a mean of 36 months and median 34 months. All patients achieved complete remission and remain disease free. The main side-effects were nausea and vomiting while haematological toxicity was slight. There was no symptomatic peripheral neuropathy, ototoxicity or deterioration of renal function. This combined modality approach is rational, feasible, and effective, although a larger number of patients with longer term follow-up are needed for reasonable comparison with the use of infradiaphragmatic radiotherapy alone.

Conformal radiotherapy seeks to allow increased intensity of radiation by reducing the volume of normal tissues within the treatment volume. Techniques have developed secondary to improvements in three-dimensional imaging and accessible treatment technology is based on computer-controlled multileaf collimators to create an irregular radiation beam shape. Preliminary clinical work in the Royal Marsden Hospital seeks to quantify the toxicity reduction achievable by conformal techniques in the context of a prospective randomized pelvic radiotherapy trial which has now recruited 240 patients. The data accumulated during this trial will allow comparison of conformal and conventional radiotherapy and also analysis of the impact of dose and volume of a particular organ on both acute and late toxicity. Assessments have revealed that conformal techniques reduced significantly the treatment volume of normal tissues, e.g. by a mean of 54% for rectum and 42% for bladder. However, a relationship between volume and acute toxicity has not been established. Late toxicity is currently being analysed. Dose escalation trials in thoracic and in pelvic tumours are planned.

To determine whether the clinical course of patients with testicular teratoma differentiated (TD) and those with testicular teratoma undifferentiated justify a different follow-up protocol.

Effectiveness of radiotherapy is dependent on the accuracy of beam alignment. Recent developments in megavoltage imaging allow real-time monitoring of beam placement. Maximum gains from this new technology can only be made if the information is utilised to correct patient positioning prospectively before the majority of a treatment fraction is delivered. We have developed and utilised an integrated megavoltage imaging system to perform a randomised trial demonstrating significant improvements in accuracy using treatment intervention techniques for pelvic radiotherapy. The mean field-placement accuracy improved from 4.3 mm to 2 mm and the proportion of treatments given with a field-placement error of > or = 5 mm decreased from 69% to 7%. This improvement in accuracy may enable smaller margins around the target volume to be chosen whilst ensuring complete target coverage at each treatment fraction.

To assess whether the 'oestrogen effect' of vacuolation in treated prostatic cancer cells is seen after luteinizing hormone releasing hormone (LHRH) analogue therapy.

Between 1979 and 1989, 122 patients with clinical stage II testicular nonseminoma were treated with primary platinum-based combination chemotherapy following orchiectomy. Of the patients 58 had Royal Marsden Hospital stage IIA (nodes less than 2 cm. in diameter) and the other 64 had stage IIB (nodes 2 to 5 cm. diameter) disease. With a median followup after chemotherapy of 5.5 years, 118 patients (97%) were disease-free. Two patients died of progressive germ cell tumors, 1 of bleomycin toxicity and 1 of coincidental disease. The 5-year actuarial survival probability was 95% (95% confidence intervals 91 to 99%) and the 5-year failure-free survival probability was 92% (95% confidence intervals 88 to 97%). Tumor substage was not predictive of relapse but did indicate the probability of lymphadenectomy for a post-chemotherapy residual mass since this was performed in 17% of the patients with stage IIA disease and 39% with stage IIB disease (p < 0.05). Resected specimens contained mature teratoma (29), necrosis alone (5) or embryonal carcinoma (1). We conclude that for these clinical stages primary chemotherapy was as effective as primary lymph node dissection and a major operation was avoided in 68% of the cases.

Transforming growth factor beta-1 (TGF-beta 1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-beta 1 confirmed that the source of the stromal TGF-beta 1 was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-beta expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-beta 1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-beta 1, TGF-beta 2 or TGF-beta 3. These data illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-beta 1.

Prostate cancer presents a growing health problem in Western societies as longevity increases. It is characteristically a disease of elderly men associated with the development of osteoblastic bone metastases and initial hormone responsiveness to androgen deprivation. Previously regarded as a Cinderella of cancers, there is currently more controversy concerning the detection and management of both localised and metastatic disease than for any other common malignancy. A balance needs to be drawn between the potential gains of more aggressive management and the disadvantages in terms of increased treatment side effects and cost, taking into account both the natural course of the disease and the life expectancy of patients.

Conformal photon and proton therapy plans for prostate cancer have been compared in an attempt to quantify the potential advantages of using protons. Two X-ray plans (3-field, 6-field) and a 2-field proton plan were made and compared for each of 20 T3 prostate patients with the aid of the 3D planning system VOXELPLAN. Dose distributions were analysed in terms of dose-volume histograms (DVH). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were computed using our own and the Lyman-Kutcher-Burman models, respectively. The study shows that on average the proton technique results in the best dose distribution, giving the lowest rectal complication probability, and also that the 3-field X-ray technique is more effective than the 6-field X-ray technique in sparing the rectum. At 5% rectal NTCP, the predicted proton average TCP for the 20 patients is 2% (in absolute terms) greater than that obtained using 3-field X-ray therapy. For 7 of the patients the gain in TCP is more than 3%. For the same rectal NTCP as the 3-field X-ray plan with a 64 Gy mean target dose, the use of protons increases the TCP by 2% on average, but for 5 of the patients the increases are greater than 4%. The result is in general positive towards the use of protons but a few patients do not benefit from it and this indicates the importance of patient selection for maximum clinical benefit.

A scanning megavoltage imaging detector, with associated image storage and analysis facilities has been developed. This produces images of the treatment portals in under 10 seconds, in a digital format, facilitating rapid, quantitative image analysis. Image quality is comparable to, and at some sites improves upon, that available from film. Clinical problems in the use of megavoltage imaging include limited field of view, loss of information at the field edge due to penumbra effects, degradation of the image by bowel gas, and difficulties in the detection of soft tissue-air interfaces. Possible solutions to these problems are discussed. The imaging system has been used to assess the random errors occurring during routine para-aortic nodal irradiation. The errors detected are small, with over 95% of set-ups lying within +/- 4.5 mm of the mean daily position. No differences were detected in the magnitude of random errors between anterior and posterior treatment fields.

During the last 3 years the Royal Marsden Hospital (RMH) has conducted a prospective randomised trial of conformal pelvic radiotherapy in which dose/volume data and acute toxicity scores have been determined prospectively. Pending completion of the trial, a preliminary analysis has been undertaken of the volume reductions achieved, and of some of the symptom scores. The average symptom score increased during radiotherapy, more markedly for bowel than bladder symptoms. In comparing total doses of 30-38 Gy with 56-65 Gy, watery bowel motions were more frequent with the higher doses (p = 0.013) but in the high-dose group neither this symptom nor tenesmus correlated with volume of rectum treated to at least 90% of the prescribed dose. We conclude that the assessment of the impact of volume on the level of acute symptoms in pelvic radiotherapy is complex, and requires analysis of a range of symptoms, dose levels and normal-tissue volumes. The degree of symptom reduction from conformal radiotherapy will emerge from the RMH randomised trial within the next 12 months.

Between 1976 and 1990, 231 patients had excision of para-aortic lymph node masses remaining after chemotherapy for metastatic non-seminomatous germ cell tumours. The overall 5-year survival rate was 80%. Multivariate analysis of survival after surgery was performed and the following were found to be independent prognostic variables: completeness of surgical excision, pathology of excised mass, timing of surgery after chemotherapy (elective versus salvage) and year of treatment (before or after 1984). Para-aortic lymphadenectomy provided both therapeutic benefit and histological information of prognostic value in planning future treatment and follow-up. Size of mass and serum markers at the time of surgery were of no additional prognostic value once completeness of excision and pathology were taken into account. We therefore recommend that all residual masses should be removed soon after completion of chemotherapy.

A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.

Review of 26 patients presenting with metastatic non-seminomatous germ cell tumours (NSGCT) associated with serum human chorionic gonadotrophin (HCG) >100,000 IU/1 between 1980 and 1990 suggested that this syndrome merits discrete recognition within the spectrum of germ cell tumours. All had lung metastases and in 23 these were very bulky by Medical Research Council (UK) criteria. Other features included gynaecomastia, rapid growth, and multi-system involvement. Following chemotherapy, there was initially a risk of tumour flare (4 patients). The time course of radiological tumour clearance was slow. The overall prognosis was 50% probability of 2-year survival and prognosis was worse with delayed presentation or presentation with brain metastases. It is therefore important to recognise this syndrome early and to proceed immediately with intensive combination chemotherapy.

The overall cure rate of patients with metastatic non-seminoma of the testis is high and a recent survey of 795 patients by the Medical Research Council indicated that 85% were alive 3 years after the start of chemotherapy. Two major categories of patients can be identified with a poorer prognosis. First are those with adverse prognostic factors at presentation defined by presence of one of the following factors: high tumour markers, more than 20 lung metastases, liver bone or brain metastases, mediastinal mass more than 5 cm. In these patients, the RMH is investigating accelerated chemotherapy employing a 7 day cycle, combined carboplatin and cisplatin and infusional bleomycin (C-BOP regimen). Of 21 patients followed for a median of 18 months, 18 (85%) have remained continuously disease free. The second adverse group are patients who have already failed first line chemotherapy. A multivariate prognostic factor analysis on 105 patients treated at the Royal Marsden Hospital indicates that adverse factors for salvage chemotherapy are the disease-free interval and the extent of disease at relapse. Our approach to patients with disseminated relapse includes high dose carboplatin and etoposide with autologous bone marrow support. With follow-up from 3-24 months, 7 of 11 patients treated with high dose chemotherapy remain continuously free from progressive disease. The need for an alkylating agent in the high dose combination is questionable.

This randomised, double-blind, parallel-group study was carried out to compare the efficacy and safety profile of ondansetron plus dexamethasone and metoclopramide plus dexamethasone in patients receiving fractionated cisplatin (20-25 mg/m2/day) chemotherapy for the treatment of testicular cancer. An interim analysis of 95 patients showed that the ondansetron regimen was significantly superior compared to the metoclopramide regimen (p < 0.001). According to the study protocol the study was terminated at this stage. At the time the decision to stop the study was taken, a total of 113 patients had been enrolled and were evaluable on an 'intention to treat' basis. Fifty-six of these had received ondansetron (32 mg i.v. single dose/day) plus dexamethasone (20 mg i.v. single dose/day) and 57 were given metoclopramide (2 mg/kg or 1 mg/kg i.v. twice a day) plus dexamethasone (20 mg i.v. single dose/day). The ondansetron regimen was significantly superior in the control of emesis and nausea. Seventy-one percent of patients experienced 2 or fewer emetic episodes over the entire 5-day study period compared with 26% of patients given metoclopramide (p < 0.001). Seventy-nine percent of patients in the ondansetron group experienced 'none' or only 'mild' nausea compared with 39% of patients in the metoclopramide group (p < 0.001). The dose of metoclopramide had to be reduced during the study from 2 mg/kg i.v. twice daily to 1 mg/kg i.v. twice daily because 4 of the first 8 patients randomised to this treatment experienced extrapyramidal reactions. Ondansetron was well tolerated and it did not induce any extrapyramidal reactions. The results of this study show that ondansetron plus dexamethasone represents a very effective treatment option for patients receiving fractionated cisplatin chemotherapy for testicular cancer.

The antiemetic efficacy and safety of granisetron (40 mug/kg), a selective and potent 5-hydroxytryptamine (serotonin) antagonist, was compared with that of metoclopramide (7 mg/kg) plus dexamethasone (12 mg) in patients receiving fractionated chemotherapy. Patients receiving cisplatin at doses of at least 15 mg/m2 or etoposide at least 120 mg/m2 or ifosfamide at least 1.2 g/m2 on each of 5 consecutive days were eligible. A total of 143 patients received granisetron and 141 received the comparator regimen. The 5-day complete response rate (no vomiting, no worse than mild nausea) for granisetron (46.8%) was equivalent to that for metoclopramide plus dexamethasone (43.9%). The overall 5-day response profile was superior for granisetron (P = 0.013) because of fewer failures in this group. The overall incidence of adverse experiences was significantly lower in the granisetron group (60.8% versus 77.3%, P = 0.003). Headache and constipation, more prevalent in the granisetron group, are recognized side-effects of serotonin antagonists. Extrapyramidal syndrome, not seen in any granisetron patients, occurred in 20.6% of comparator patients (P<0.0001). The majority of granisetron patients only required a single prophylactic dose of the drug on each treatment day (at least 82%). In conclusion, granisetron showed at least equivalent efficacy to metoclopramide plus dexamethasone in patients receiving 5-day fractionated chemotherapy. In addition it offered a simple and convenient dosing regimen and a safer side-effect profile.

The high cure rate among young men with metastatic testicular germ cell tumors heightens the issue of late treatment toxicity. Conventional combination chemotherapy based on cisplatin can be expected to cure 85% to 90% of patients with metastatic disease; however the cost of this success includes severe treatment side effects, including irreversible renal damage and the risk of neurotoxicity and ototoxicity. Carboplatin was investigated as a replacement for cisplatin in the treatment of these tumors because of its reduced toxicity. The Royal Marsden Hospital pilot studies have included 76 patients treated for metastatic nonseminoma with the combination carboplatin/etoposide/bleomycin between 1984 and 1988. The median follow-up at time of analysis was 24 months. The complete remission rate was 95% and the overall cause-specific survival was 98.5%. Also, 33 patients treated with single-agent carboplatin for advanced metastatic seminoma were followed for a median of 36 months. The actuarial progression-free survival was 79%, and 91% of patients were alive and disease-free. The results of these studies indicate that carboplatin has activity equivalent to cisplatin in germ cell tumors of the testis and is less toxic.

The palliation of bone pain is a common clinical problem once metastatic prostate cancer has escaped from hormonal control. This retrospective study compares the results of treatment using hemibody irradiation (HBI) at the Royal Marsden Hospital (27 cases) with isotope therapy using the bone-seeking isotope strontium-89 (89Sr) at Southampton General Hospital (51 cases). Prior to analysis patients were matched for potential prognostic factors (performance status, bone scan extent of disease, age, histology and duration of hormone response) to minimize the effect of treatment selection bias. Pain control assessed at 3 months was similar for HBI and matched 89Sr cases, with 63% and 52% respectively showing some benefit. Median survival was similar for these groups at 20 and 21 weeks respectively. The unmatched 89Sr group, which had more favourable prognostic factors, had a better outcome with 96% showing improvement in pain and with a median survival of 59 weeks. Subsequent univariate analysis demonstrated that performance status and extent of disease on bone scan were of overriding importance in determining outcome. Transfusion requirements were higher for the HBI group than for the matched 89Sr group (50% and 25% respectively) but other bone marrow toxicity was similar. Despite routine anti-emetic therapy 37% of patients treated with HBI had some nausea or vomiting. Although expensive, 89Sr appears as effective a treatment option as HBI. Response is most likely with either approach when patients have a good performance status and a limited extent of disease.

Between 1982 and 1990, 70 patients with advanced metastatic seminoma were treated with 4-6 courses of single-agent carboplatin (SAC) administered at 400 mg/m2 every 3-4 weeks. Treatment was of low toxicity and no patients suffered neurotoxicity, ototoxicity or significant renal damage. There was only one episode of neutropenic sepsis and no thrombocytopenic bleeding. The median follow-up of surviving patients was 3 years. 16 patients have relapsed and 4 of these 16 have died, thus the actuarial 3-year relapse-free survival was 77% (95% CI 65-86%), cause-specific survival was 94% (95% CI 82-99%) and overall survival was 91% (95% CI 80-96%). The risk of relapse was reduced by post-chemotherapy irradiation (PCRT) to involved nodes, occurring in 1/20 patients treated with PCRT compared with 11/31 who could have been treated but were not (P = 0.04). Of the 16 patients who relapsed, 12(75%) have been salvaged with combination chemotherapy and remain free from further relapse with a median follow-up of 18 months. Though this level of survival is equivalent to that obtained with initial cisplatin-based combination chemotherapy, the recurrence rate indicates that SAC remains an investigative treatment, except for unfit patients.

We report the effect on prostatic volume of the administration of the luteinising hormone-releasing hormone (LHRH) analogue goserelin in 22 patients with locally advanced carcinoma of the prostate; 20 achieved a significant reduction in volume, the median volume being 66 ml before treatment (range 40-130) and 30 ml after 17 weeks (range 13-47). If used before external beam radiotherapy (RT), volume reduction will permit smaller boost fields and thus potentially reduce adverse radiotherapy effects. In addition, reducing tumour volume before RT may lead to an increase in local control. We discuss the possible role of hormonal volume reduction in the management of prostatic cancer.

An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% (95% confidence intervals, 74%-88%). No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol.

In 224 consecutive patients with hormone-resistant prostatic cancer referred to 2 European Cancer Centres for palliation of painful bone metastases the one year survival for all patients was 24% (2-year survival: 7%). The median survival was 8 months. In univariate analyses the following prognostic factors were identified: performance status, serum creatinine, alkaline phosphatase, duration of response to primary hormone treatment, degree of bone scan involvement and hemoglobin. Multivariate analyses confirmed the four first parameters to be independent factors. A prognostic model was established (no or one risk factors vs 2 risk factors vs 3 or 4 risk factors) based on performance status, creatinine, alkaline phosphatase and hormone response duration. The median survival of these groups was 10 months, 6 months and 3 months, respectively. This model proved to be discriminative in an external data set of 214 patients with hormone-resistant prostatic cancer entered in two prospective trials. The above differences in outcome between readily and simply defined prognostic groups are greater than the differences one can realistically hope to produce using new treatment strategies. These prognostic factors should be taken into account both in the design and interpretation of clinical studies dealing with the treatment of hormone-resistant progressing prostatic cancer and painful bone metastases.

The combination of carboplatin, etoposide, and bleomycin (CEB) was evaluated as initial chemotherapy in 76 patients with good-prognosis metastatic nonseminomatous germ cell tumors (NSGCT) between 1984 and 1988. The classification of eligible patients included Royal Marsden Hospital (RMH) stages IM, IIA, IIB, IIC, IIIA, IIIB, IV0ABCL1, and IV0ABL2. Four courses of combination chemotherapy were administered in a 21-day cycle, and surgical excision of residual mass was performed in 27 cases (23 laparotomies and four thoracotomies). At the time of analysis, median follow-up was 24 months from start of chemotherapy (range, 6 to 54 months). The 2-year cause-specific survival probability was 98.5%, the single cause-related mortality being caused by bleomycin pneumonitis. Five patients failed CEB chemotherapy, but all have been successfully salvaged with a combination of surgery and intensive chemotherapy, follow-up from completion of all treatment being 35 to 44 months. The toxicity of CEB included bone marrow suppression and alopecia in all patients but no significant neurotoxicity or ototoxicity, and minimal renal toxicity. Only four (5%) patients had a decrease in the glomerular filtration rate greater than 15%. In 51% of patients, the hemoglobin fell below 10 g/dL. The WBC count nadir was less than 1,500/microL in 11% of treatment cycles and in 16% the platelet nadir fell below 50,000/microL. Decreases in the WBC and platelet counts were of very brief duration. Only one of 310 CEB cycles was complicated by neutropenic sepsis, and there were no episodes of thrombocytopenic purpura or bleeding. We conclude that the CEB combination represents an effective alternative to cisplatin-based chemotherapy in good-prognosis NSGCT and that the replacement of cisplatin by carboplatin leads to reduced toxicity.

127 men with previously untreated non-seminomatous germ cell tumours (NSGCT) of the testis were given BEP chemotherapy (bleomycin, etoposide and cisplatin) between 1979-1986. Long-term follow-up (median 65 months) has shown an overall 5 year survival of 87.2% (95% confidence limits 81.1%-93.3%). Outcome was related to both tumour volume and serum marker levels of alpha-fetoprotein (alpha FP) and beta human chorionic gonadotropin (HCG), with 5 year actuarial survivals of 97.8%, 72.2% and 26.7% respectively for small, large and very large volume disease defined by Medical Research Council criteria, and 91.2% and 60.8%, respectively, for men with low (alpha FP less than or equal to 500 kU/l and HCG less than or equal to 1000 iU/l) or high serum marker levels. 79 men (62%) had a complete radiological and serum marker response to chemotherapy alone; residual masses postchemotheraphy were resected in 39 patients (31%), showing undifferentiated tumour in only 6 (15%). 23 of the 127 patients (18%) failed to respond or developed recurrent disease after BEP; only 5 were successfully salvaged. Myelotoxicity of treatment was mild with grade 4 toxicity in 2% of chemotherapy courses and 3 episodes of neutropenic sepsis. Mean glomerular filtration rates fell by 15.6% between courses 1 and 4 of BEP. Bleomycin pneumonitis developed in 13% of cases with 1 fatality. So far 21 men have had children following chemotherapy, but semen analysis 12 months or more (median 36 months) after treatment showed azoospermia in 11 out of 54 (20%) men tested. BEP chemotherapy can be regarded as standard treatment for patients with metastatic NSGCT in low-risk categories, but more intensive therapy is required for advanced presentations. Strategies to develop "risk related" treatment are under investigation.

Metastatic tumour of the sphenoid sinus from distant primary sites are rare. If sphenoid involvement from adjacent structures is excluded there have been 26 reported cases of metastatic sphenoid sinus tumours. Seminoma metastatizing to other paranasal sinuses has been reported but a careful literature search did not reveal this occurring previously in the sphenoid sinus.

"Micrometastases" can be identified in the bone marrow of patients with apparently localised breast cancer using an immunocytochemical stain for epithelial membrane antigen (EMA). Of 39 women who had marrow samples examined at the time of initial presentation (37), or with locally recurrent disease (2), 13 (33%) had samples which contained small numbers of EMA positive cells. 10 out of 23 (44%) lymph-node positive patients were marrow positive, compared to 1 out of 14 (7%) lymph node negative cases (P = 0.03). Long-term follow-up (median 9.5 years) has shown that 11 out of 13 (85%) patients with micrometastases have developed metastatic disease compared to 8 out of 26 (31%) with negative bone marrow aspirates (P less than 0.05). The small number of EMA positive cells detected in bone marrow samples probably reflects the high metastatic potential of primary or recurrent cancers rather than established microscopic deposits; it is not yet clear whether the finding of such micrometastases will act as an independent variable compared to established prognostic factors.

One hundred and forty nine patients with carcinoma of the tongue or floor of mouth were treated with interstitial irradiation (+/- external beam therapy) using caesium needles or iridium wires between 1970 and 1986. Multivariate analysis showed the main predictors of outcome to be tumour stage, site and histology. Caesium and iridium techniques gave similarly good local control rates of 90% at 5 years for T1 and T2 tumours when used as the standard departmental method. Local failure was shown to have a major impact on the risk of dying from disease and elective neck irradiation (ENI) conferred a favourable benefit on neck control and survival provided the primary site was controlled. Patients less than 40 years of age appeared to have an unfavourable prognosis. Radical irradiation including interstitial techniques gives excellent results in early oral cancer and is the treatment of choice for T2 tumours. We recommend elective neck irradiation in patients at high risk of developing lymph node metastases.

Using an antiserum to epithelial membrane antigen we have screened multiple bone marrow aspirates from 350 patients with primary breast cancer taken at the time of initial surgery. 89 (25%) patients were found to have micrometastases and their presence was related to pathological size (P less than 0.01), the presence of peritumoral vascular invasion (P less than 0.001), and positive lymph nodes (P less than 0.005) but not menopausal status. At a median follow-up of 76 months (range 34-108) 107 patients had relapsed with distant metastases. 48% (43 of 89) of these patients had micrometastases initially compared with 25% (64 of 261) who did not (P less than 0.005). The test predicts for relapse in bone (P less than 0.01) and other distant sites excluding bone (P less than 0.001) and is associated with a shorter overall survival (P less than 0.005). We conclude that the detection of micrometastases signals a high likelihood of early relapse and decreased survival in breast cancer.

Del Favero A and members of the Multi-day Cisplatin Emesis Study Group (Arechevala E, Aulitzky W, Boeckmann W, Dearnaley D P, Droz J-P, Fossa S D, Henricksson R, Jones W G, Rath U, Upadhyay B K, Weissbach L)

Between 1983 and 1988, 113 patients with Stage I seminoma were managed after orchidectomy by surveillance rather than adjuvant radiotherapy. The actuarial risk of relapse at 3 years was 15.8% (95% confidence interval, 7.8% to 23.8%). All 13 patients who experienced a relapse are currently in remission (4 to 45 months after salvage therapy), although 5 suffered second relapses requiring further treatment. Close surveillance is a safe alternative to adjuvant radiotherapy in Stage I seminoma. However, the policy requires prolonged observation of patients with intensive use of resources. Therefore, adjuvant radiotherapy should be considered the treatment of choice.

A retrospective analysis has been made of all patients with pineal and CNS germ cell tumors who were treated at The Royal Marsden Hospital between 1962-1987. A total of 67 new cases were seen: 17 had initial histological verification of tumor type and the remainder were tested for radiosensitivity with a dose of 20 Gy following a shunting procedure. Patients with germ cell or radiosensitive tumors were treated with a uniform policy of whole neuraxis radiotherapy giving 50 Gy to the local tumor and 30 Gy to the remaining brain and spinal cord. Nonresponding lesions continued with local fields to a dose of 50 Gy. Patients were divided into three groups (a) germinoma and radiosensitive tumours, 34 cases; (b) malignant teratoma, 12 cases; (c) non-germ cell, 21 cases. Median follow-up is 83 months (range 2-246 months). Overall and cause specific actuarial 5/10 year survival were for group 1, 81.7%/69.4% and 86.5%;/86.5%; group 2, 18.2%/18.2% and 18.2%/18.2%, and group 3, 64.3%/46.8% and 64.3%/52.6%, respectively. No patient in group 1 treated during the last 12 years has recurred. Univariate analysis of factors at presentation, showed that neurological performance status (p less than .001) as well as tumor type (p less than .001) correlated with outcome. Recurrence was confined to the primary site in only 1 of 4 patients in group 1 compared to 6 of 9 patients in group 2 and 9 of 10 patients in group 3. No isolated spinal recurrence occurred in group 1 patients. A total of eight patients have received platinum containing chemotherapy for recurrence (6 cases) or adjuvant therapy (4 cases). Germinomas appear to respond better than teratomas, all of which have recurred rapidly following initial partial response. Shunting and radiosensitivity testing remains the treatment of choice for tumors compatible with germinoma. Craniospinal irradiation is associated with low morbidity providing spinal growth is complete and is recommended in older patients as salvage following spinal recurrence is unsatisfactory. Aggressive combined modality approaches with surgery, radiotherapy and chemotherapy need to be investigated to improve results in CNS teratoma.

Between 1986 and 1988 10 patients with primary cerebral lymphoma (PCL) were treated with initial MACOP-B chemotherapy followed by radiotherapy. All demonstrated radiological response to chemotherapy but this did not predict final clinical outcome. The overall median survival was 14 months. Patients with poor MRC neurological performance status (NPS) 2-4 had a median survival of 5 months. Three of 7 patients with NPS 0-1 died and the median survival is 18 months with a median follow-up of 13 months (10-35 months). The results were compared to 25 patients with primary cerebral lymphoma treated between 1963 and 1986 with radiotherapy as the main treatment modality. The overall median survival was 16 months. Patients presenting with poor NPS (2 and 3) had worse survival (median survival 8 months) compared to patients with good NPS (median survival 22 months; p less than 0.025). Patients diagnosed and treated from 1982 to 1986 also had significantly worse prognosis when compared to earlier treated patients. The preliminary results of combined modality therapy are so far not significantly different when compared to historical series and we have to await long-term outcome before recommending combined modality therapy as the treatment of choice.

Between 1982 and 1986, 34 patients with advanced metastatic seminoma were treated with four to six courses of single-agent carboplatin administered at 400 mg/m2 every 4 weeks either on an outpatient basis or during 24-hour admissions. Patients with raised serum alphafetoprotein (AFP) or with multiple (more than three) lung metastases were excluded since these features may indicate a nonseminomatous component. In this series 20 patients were previously untreated except for orchiectomy, and 14 patients had received prior radiotherapy restricted to infradiaphragmatic nodal areas. Treatment was extremely well tolerated. No patient suffered renal damage, neurotoxicity, or ototoxicity, and there were no episodes of neutropenic septicemia, thrombocytopenic hemorrhage, or bruising. The actuarial 2-year survival was 94% (95% confidence intervals, 83% to 100%) with follow-up of 12 to 46 months from completion of carboplatin (mean, 26 months). The actuarial chance of remaining alive and free from progressive disease at 2 years was 80% (95% confidence intervals, 66% to 94%). Of six patients who relapsed, five are currently in remission 9 to 18 months after completion of salvage treatment. This level of antitumor activity is equivalent to that seen with aggressive combination regimens. Single-agent carboplatin should be considered the treatment of choice for advanced stages of malignant seminoma when limitation of toxicity is considered important; however, the rarity, especially of extranodal metastases from seminoma, leads to the need for further investigation using this approach.

An increase in initial chemotherapy intensity was evaluated in 29 patients with high risk metastatic non-seminomatous germ cell tumours (NSGCT) of the testis, defined by the presence of multiple large lung metastases, liver, bone or brain metastases, or the combination of large abdominal mass with high serum concentration of the tumour markers alpha-foetoprotein (AFP) or beta subunit of human chorionic gonadotrophin (HCG) (AFP greater than 500 ku/l or HCG greater than 1000 iu/l). Four courses of bleomycin, vincristine and cisplatin (BOP) were given at 7 day intervals, followed by three courses of etoposide, cisplatin with or without bleomycin (BEP or EP) at 21 day intervals for a total of 13 weeks of chemotherapy. Twenty-three (85%) of 27 evaluable patients have remained continuously free from disease progression at a median of 24 months (range 14-38 months) from chemotherapy and the actuarial 2 year freedom from progression rate is 86% (95% CI = 73-99%). Three patients died from non-malignant causes, two of bleomycin pneumonitis and one from complications of cystic fibrosis. Thus cause specific overall survival in the total population of treated patients is 79%. With appropriate limitation of bleomycin dosage, this approach is well tolerated and results compare favourably with less intensive induction schedules based on initial 21-28 day cycles.

In a series of 22 patients, high dose BCNU (800-1,000mg m-2) with autologous bone marrow transplantation was given as the first post-surgical treatment for grade IV astrocytoma and followed by full dose radiotherapy. When compared to historical experience and matched to control patients in national studies, there appeared to be a small prolongation of survival but no increase in the proportion of long survivors. Acute myelosuppression was mild but toxicity to lung and liver was substantial and limited further dose escalation. Late bone marrow failure was seen in 4 patients. Pharmacokinetic studies were performed and suggested that the late marrow failure was due to persistence of BCNU at the time of marrow return. Despite the suggestion of a prolongation of survival this approach is not routinely recommended and a randomised trial is probably not justified.

The inability to remove all disease at the time of a radical neck dissection, or inoperable recurrent disease after a neck dissection, are both familiar problems for the head and neck surgeon. All too frequently the conventional treatment options have already been used, the patient having received external beam radiotherapy and possibly cytotoxic chemotherapy. In such circumstances, and provided that the primary tumour remains under control, a positive approach to the further management of the neck metastases should be adopted, given that the patient is in otherwise reasonable health and does not have gross distant metastatic disease. We describe our experience with postoperative interstitial irradiation (brachytherapy) using after-loaded iridium-192 (192Ir) wires positioned at the site of the tumour after its surgical exposure and debulking or clearance. All the treated patients had previously received external beam irradiation to the neck and in the first three cases local skin necrosis occurred as a sequel to interstitial implantation. Therefore, in the other five patients, cutaneous or myocutaneous flaps were used to resurface the area at the time of implant placement. This combination of techniques, which has not been described previously, provided local tumour control in four out of the five cases without irradiation necrosis occurring in any of them.

An immunocytochemical method was used to screen smears obtained at primary surgery from multiple bone-marrow sites in 110 patients with breast cancer; at this time other techniques did not reveal metastases. Tumour cells were detected in the bone-marrow of 31 (28%) patients. The number of cells detected ranged from 1 to greater than 500; none was detected in conventionally stained smears. Patients in whom conventional criteria indicated a very poor prognosis seemed more likely to have such micrometastases. A further follow-up period is required to determine whether patients with micrometastases relapse earlier than those in whom no tumour cells are demonstrable.

Single cells from mammary carcinoma infiltrating bone marrow can be detected in marrow aspirates using immunocytochemical stains for epithelial membrane antigen (EMA). This technique has been used to examine marrow aspirates taken from multiple sites from 24 patients at surgery for breast cancer. Ten of these patients had EMA-positive cells in their marrow, while 32 marrow samples from patients who did not have carcinoma were negative. These results have been combined with those obtained by taking aspirates from single sites from 47 breast patients without known skeletal deposits. Follow up showed that the patients with EMA-positive cells in their marrow developed bone metastases at a significantly faster rate.

We have investigated the role of biochemical markers in breast and lung cancer but have found that currently available tests have little role in management. In breast cancer, for example, we have found that the most sensitive method for routine screening for metastases is by using chest x-ray and clinical examination, liver function tests, and carcinoembryonic antigen measurements. We are now examining other methods for detecting metastases using immunocytochemistry in cytological preparations of bone marrow and attempting to raise monoclonal antibodies to breast cancer cells. In lung cancer, the major effort has been directed towards characterisation of large-molecular-weight ectopic hormones, particularly calcitonin.

The cytological distinction between reactive mesothelial and malignant cells frequently causes problems for the diagnostic cytologist. In order to determine whether an immunocytochemical method might help resolve these difficult cases, we have stained smears from 309 serous effusions from 246 patients for the Epithelial Membrane Antigen (EMA). The EMA staining was classified as strong, weak or negative. Carcinoma cells (as diagnosed by conventional cytology) stained strongly for EMA in 63 of the 116 positive smears (54%). Five out of 15 (33%) of cytologically suspicious smears from patients with known carcinomas gave a strong EMA stain. Of particular interest were three effusions in which malignant cells were not identified in conventionally stained smears and in which a small number of EMA positive cells were identified. The EMA positive cells were subsequently restained by the Papanicolaou method and identified as malignant on retrospective morphological examination.

Various methods have been evaluated for their ability to detect bone metastases in patients with breast cancer. Bone scanning and hydroxyproline measurements are insensitive and showed metastases in few patients with primary breast cancer despite the fact that most will develop bone metastases. We have therefore investigated the value of examining the bone marrow with immunocytochemical staining for breast carcinoma cells. Initial results in 68 patients with no evidence of bone metastases by conventional means indicated (a) that some patients have breast cancer cells in bone marrow despite having no evidence of dissemination using other tests, and (b) that patients with micrometastases relapse sooner than those patients with normal bone marrows.

We have developed a technique for the immunocytochemical staining of marrow smears using antiserum to epithelial membrane antigen (EMA). This membrane component is confined to, but widely distributed in, epithelial tissues and tumours derived from them, and is strongly expressed by infiltrating breast carcinoma cells. Marrow aspirates from patients with both early and metastatic breast cancer have been examined, and the results of immunocytochemical staining compared with conventional cytology and histology. Staining with antiserum to EMA enabled us to detect small numbers of carcinoma cells, and increased the yield of positive samples. Furthermore, using this technique, we found malignant cells in the marrow of patients with primary breast cancer with no other evidence of metastatic disease. Thus immunocytochemical staining for EMA may be of value in the detection of micrometastases in patients with primary breast carcinoma.

A new human antigen, designated epithelial membrane antigen (EMA), has recently been described on surface membranes of a wide variety of normal epithelium but not on connective tissue cells. The antigen is only weakly expressed on normal or reactive mesothelium. Increased expression of the antigen has been observed in most neoplasms of epithelial origin and in malignant mesothelioma. We have investigated the possibility of using this difference in the expression of the antigen to distinguish between mesothelial cells and malignant cells in cytological smears of serous effusions. This distinction cannot always be made on morphological grounds alone and problems of differential diagnosis are encountered in about 15% of all specimens of serous effusions sent for cytological examination. Using antisera to EMA we have applied an indirect immunoalkaline phosphatase technique to alcohol-fixed smears prepared from serous effusions and have found that intense staining of the antigen is confined to effusions from patients in whom there is either clinical or cytological evidence of malignancy. The technique proved to be especially useful in cytologically equivocal cases, where there were problems of differential diagnosis.

Computed tomography (CT) of the brain has been performed in 60 patients with breast cancer presenting with neurological symptoms suggestive of intracranial metastases, and the findings correlated with clinical features and Technetium (Tc) brain scan when available. Small size of the intracerebral metastases demonstrated by CT was clearly correlated with good clinical response to treatment, and CT was effective in detecting residual tumour. However, the varied CT appearance of intracerebral metastases did not allow differentiation from primary cerebral tumors in those patients with solitary lesions. Tc brain scan was abnormal in most patients with intracerebral metastases, but was less effective than CT in detecting multiple deposits; furthermore, skull deposits frequently made interpretation difficult. Neither test was effective in detecting meningeal infiltration. Careful CT examination of the skull overlying apparent superficial parenchymal lesions permitted the recognition of a group of patients with extradural extension of skull deposits. CT examination of brain increases diagnostic accuracy and provides important prognostic information in patients with intracranial metastases from breast cancer.

Cerebrospinal fluid (CSF) and plasma levels of carcinoembryonic antigen (CEA) have been measured in 39 patients with disseminated breast cancer, 22 of whom had metastases involving the central nervous system (CNS). CSF CEA was also measured in 13 patients without cancer who had non-malignant disorders. Thirteen of the 22 patients with CNS metastases had elevated CSF CEA, together with 4 of 17 patients with disseminated breast cancer without neurological involvement. These 4 patients were shown to have extensive dorso-lumbar spine deposits. CSF CEA was not detected in any of the 13 patients without cancer. Estimation of CEA in the cerebrospinal fluid may be a useful adjunct in the diagnosis of disseminated breast cancer involving the CNS, provided that spinal metastases are absent.

Danazol, an effective agent in the treatment of benign breast disease, has been administrated to 41 patients with advanced breast cancer. These patients were treated with danazol for periods ranging from 1 to 40 weeks and responses were seen in seven of 41 (17%) patients. No responses were seen in the four premenopausal patients treated. Side effects were seen in nine of 41 (22%) patients, but in most patients these stopped when the dose of danazol was reduced. This preliminary study indicates that danazol may be an effective form of hormone treatment in patients with advanced breast cancer.