Publications

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.

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.

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.

Subjective xerostomia is a common side-effect following radiotherapy for the treatment of head-and-neck cancer. Standard mean dose models previously used to model xerostomia only that partially predict the occurrence of xerostomia. Studies in animal models have suggested that there are regional variations in the radiosensitivity of the parotid glands. In this work we tested the hypothesis that this is also true for the human parotid gland.

Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone.

Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia.

Background: Recruitment to randomised controlled trials (RCTs) with very different treatment arms is often difficult. The ProtecT (Prostate testing for cancer and Treatment) study successfully used qualitative research methods to improve recruitment and these methods were replicated in five other RCTs facing recruitment difficulties. A similar qualitative recruitment investigation was undertaken in the SPARE (Selective bladder Preservation Against Radical Excision) feasibility study to explore reasons for low recruitment and attempt to improve recruitment rates by implementing changes suggested by qualitative findings.Methods: In Phase I of the investigation, reasons for low levels of recruitment were explored through content analysis of RCT documents, thematic analysis of interviews with trial staff and recruiters, and conversation analysis of audio-recordings of recruitment appointments. Findings were presented to the trial management group and a plan of action was agreed. In Phase II, changes to design and conduct were implemented, with training and feedback provided for recruitment staff.Results: Five key challenges to trial recruitment were identified in Phase I: (a) Investigators and recruiters had considerable difficulty articulating the trial design in simple terms; (b) The recruitment pathway was complicated, involving staff across different specialties/centres and communication often broke down; (c) Recruiters inadvertently used 'loaded' terminology such as 'gold standard' in study information, leading to unbalanced presentation; (d) Fewer eligible patients were identified than had been anticipated; (e) Strong treatment preferences were expressed by potential participants and trial staff in some centres. In Phase II, study information (patient information sheet and flowchart) was simplified, the recruitment pathway was focused around lead recruiters, and training sessions and 'tips' were provided for recruiters. Issues of patient eligibility were insurmountable, however, and the independent Trial Steering Committee advised closure of the SPARE trial in February 2010.Conclusions: The qualitative investigation identified the key aspects of trial design and conduct that were hindering recruitment, and a plan of action that was acceptable to trial investigators and recruiters was implemented. Qualitative investigations can thus be used to elucidate challenges to recruitment in trials with very different treatment arms, but require sufficient time to be undertaken successfully.

Background: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen.Patients and methods: Sonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the IntergroupExemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2-3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation.Results: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67).Conclusion: Switching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration.

Human epidermal growth factor receptor 2 (HER-2) expression is associated with increased risk of high-grade disease, nodal metastasis, and absence of estrogen receptors (ERs) in early breast cancer. We tested interactions between ER and HER-2 to determine if they may modulate breast cancer nodal metastasis and proliferation.

Background Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer.Methods Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN11883920.Findings Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p < 0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p < 0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p < 0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003).Interpretation These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

Background Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival.Methods 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920.Results After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded.Conclusions Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

Background: Selenium is known to be important to the brain. Three small, published studies have suggested an effect of selenium supplementation or deprivation on mood in healthy volunteers. We investigated these findings on a much larger scale.Methods: In this double-blind, placebo-controlled intervention, 501 UK participants aged 60-74 were randomly allocated to receive 100, 200 or 300 mu g selenium/d as high-selenium yeast or placebo yeast. Mood (Profile of Moods States - Bipolar Form, [POMS-BI] questionnaire), "quality of life" (Short Form 36 [SF-36] questionnaire) and plasma selenium were measured at baseline and six months.Results: Supplementation significantly increased plasma selenium above baseline values: from an overall mean (SD) of 90(19) ng/g to 9.1(26), 144(27), 191(41) and 227(53) ng/g in the placebo, 100, 200, 300 mu g selenium groups respectively (p < .001). Four hundred forty-eight participants completed the POMS-BI questionnaires at both time points, with no significant differences in total mood or mood-subscale scores seen between doses. After six months of supplementation, mean (SD) total mood scores for the four doses were 163(36), 161(37), 162(33), 162(34), F-3,F-443 = .25, p = .86. Quality of life was similarly unaffected.Conclusions: There was no evidence that selenium supplementation benefited mood or quality of life in these elderly volunteers. Though Though this is at odds with some previous results, our robust study design, much larger sample size and longer supplementation period, together with the evidence that the brain is a privileged site for selenium retention, suggest that Ibis is a reliable finding.

Background: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil + adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm.Patients and methods: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial.Results: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P = 0.87) or OS (hazards ratio: 0.98, P = 0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively.Conclusion: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.

Background and purpose: Tissue hardness (induration), pain and tenderness are common late adverse effects of curative radiotherapy for early breast cancer. The purpose of this study was to test the efficacy of IH636 grape seed proanthocyanidin extract (GSPE) in patients with tissue induration after high-dose radiotherapy for early breast cancer in a double-blind placebo-controlled randomised phase II trial.Patients and methods: Sixty-six eligible research volunteers with moderate or marked breast induration at a mean 10.8 years since radiotherapy for early breast cancer were randomised to active drug (n = 44) or placebo (n = 22). All patients were given grape seed proanthocyanidin extract (GSPE) 100 mg three times a day orally, or corresponding placebo capsules, for 6 months. The primary endpoint was percentage change in surface area (cm(2)) of palpable breast induration measured at the skin surface 12 months after randomisation. Secondary endpoints included change in photographic breast appearance and patient self-assessment of breast hardness, pain and tenderness.Results: At 12 months post-randomisation, >= 50% reduction in surface area (cm) of breast induration was recorded in 13/44 (29.5%) GSPE and 6/22 (27%) placebo group patients (NS). At 12 months post-randomisation, there was no significant difference between treatment and control groups in terms of external assessments of tissue hardness, breast appearance or patient self-assessments of breast hardness, pain or tenderness.Conclusions: The study failed to show efficacy of orally-adminstered GSPE in patients with breast induration following radiotherapy for breast cancer. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

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.

We have previously developed a quantitative PCR (QPCR) technique for the detection of cytokeratin 19 (CK19) transcripts in blood and bone marrow and compared this to immunocytochemistry (ICC). Together, both have shown promise for monitoring therapeutic efficacy in patients with metastatic breast cancer. The aim of this study was to determine the feasibility and value of these assays for minimal residual disease (MRD) in monitoring efficacy of adjuvant therapy following surgery for primary breast cancer. Bone marrow aspirates and peripheral blood samples were taken at the time of surgery from patients with primary breast cancer and no evidence of metastases on conventional scans. These were tested for the presence of CK19 mRNA transcripts and cytokeratin positive cells. Follow-up bone marrow aspirates were taken at 3, 6, 12, 24, 36 and 48 months. Prior to surgery, 51% of patients displayed evidence of disseminated cancer cells in the bone marrow by either or both QPCR and ICC. Of 91 patients who had repeat samples assayed, 87% and 65% had positive results at some time using QPCR and ICC, respectively. All patients received adjuvant systemic therapy and in 44 cases where there was a positive result in either the pretreatment or 3-month aspirate, 32/44 (73%) showed a fall in CK19:ARL ratio (QPCR) and 15/24 (63%) showed a reduction in the number of cytokeratin-positive cells (ICC) during follow-up. These results indicate that MRD persists despite adjuvant therapy in a majority of patients with primary breast cancer up to 4 years following surgery. (C) 2004 Wiley-Liss, Inc.

Background and purpose: Radiation-induced tissue fibrosis is a common adverse effect of curative treatment for pelvic cancer. Pilot studies testing alpha-tocopherol and pentoxifylline provide evidence of clinical regression of superficial radiation fibrosis after radiotherapy.Patients and methods: Twenty-seven eligible research volunteers with a minimum of one grade 3 or 4 disability (LENT SOMA) due to previous radiotherapy were entered into the study. Volunteers were given dl-alpha tocopheryl acetate 500 mg twice a day orally plus pentoxifylline 400 mg twice a day orally over a period of 6 months. Clinical assessment of late side effects recorded using LENT SOMA scales was selected as the primary endpoint, taken at baseline and at 6 and 12 months post-registration. Patient self-assessment of function and quality of life was assessed as a secondary endpoint using the EORTC QLQ-C30 core questionnaire and the EORTC QLQ-CR38 pelvic module. Magnetic resonance imaging was undertaken in 13/23 evaluable volunteers before and after 6 months of therapy.Results: At 12 months post-registration there were 4 out of 23 responders. At 6 months post-registration there was a statistically significant improvement (i.e. reduction) in the median of the LENT SOMA summed scores in all areas assessed apart from 'male sexual dysfunction', 'vulva' and 'vagina' which were unchanged at 6 months. The median total LENT SOMA score at baseline and 6 months was 49 and 34, respectively, with a median change in total LENT SOMA score between baseline and 6 months of 9 (IQR 7-18) (P<0.001). The maximum LENT SOMA scores improved over the study period, with a total number of 82 maximum grade 3 or 4 normal tissue scores at baseline (median of four complications per person) reduced to a total number of 67 maximum grade 3 or 4 scores at 6 months post-registration (median of 3 complications per person), i.e. a median reduction in severe complications of one per person. LENT SOMA scores at 12 months were similar to those observed at 6 month suggesting no further improvement nor deterioration in late side effects. These findings were, however, not reflected in the patient self-assessment of function and quality of life, raising question about the possibility of observer bias in recording LENT SOMA scores. No significant changes were reported on magnetic resonance images at 6 months from baseline.Conclusions: Despite only seeing four a priori defined responders in this pilot study testing dl-alpha tocopheryl acetate plus pentoxifylline in patients suffering complications of pelvic radiotherapy, changes in LENT SOMA scores suggest beneficial effects. However, we are not convinced that these effects are real, since no significant changes in symptoms and functional status were recorded by detailed prospective patient self-assessments. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects.Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors.Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials.For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, >= 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis.These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments.For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes.Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.

BACKGROUND:Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.METHODS:We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival.RESULTS:Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported -- 183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04).CONCLUSIONS:Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

Background: Radiation-induced arm lymphoedema is a common and distressing complication of curative treatment for early breast cancer. Hyperbaric oxygen (HBO2) therapy promotes healing in bone rendered ischaemic by radiotherapy, and may help some soft-tissue injuries too, but is untested in arm lymphoedema.Methods: Twenty-one eligible research volunteers with a minimum 30% increase in arm volume in the years after axillary/supraclavicular radiotherapy (axillary surgery in 18/21 cases) were treated with HBO2. The volunteers breathed 100% oxygen at 2.4 ATA for 100 min in a multiplace hyperbaric chamber on 30 occasions over a period of 6 weeks. The volume of the ipsilateral limb, measured opto-electronically by a perometer and expressed as a percentage of contralateral limb volume, was selected as the primary endpoint. A secondary endpoint was local lymph drainage expressed as fractional removal rate of radioisotopic tracer, measured using lymphoscintigraphy.Results: Three out of 19 evaluable patients experienced > 20% reduction in arm volume at 12 months. Six out of 13 evaluable patients experienced a > 25% improvement in Tc-99-nanocolloid clearance rate from the ipsilatieral forearm measured by quantitative lymphoscintigraphy at 12 months. Overall, there was a statistically significant, but clinically modest, reduction in ipsilateral arm volume at 12 months follow-up compared with baseline (P = 0.005). The mean percentage reduction in arm volume from baseline at 12 months was 7.51. Moderate or marked lessening of induration in the irradiated breast, pectoral fold and/or supraclavicular fossa was recorded clinically in 8/15 evaluable patients. Twelve out of 19 evaluable patients volunteered that their arms felt softer, and six reported improvements in shoulder mobility at 12 months. No significant improvements were noted in patient self-assessments of quality of life.Conclusion: Interpretation is limited by the absence of a control group. However, measurement of limb volume by perometry is reportedly reliable. and lymphoscintigraphy is assumed to be operator-independent. Taking all data into account, there is sufficient evidence to justify a double-blind randomised controlled trial of hyperbaric oxygen in this group of patients. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Background and purpose: Treatinent-induced arm lymphoedema is a common and distressing complication of curative surgery and radiotherapy for early breast cancer. A number of studies testing alpha-tocopherol (vitamin E) and pentoxifylline suggest evidence of clinical regression of superficial radiation-induced fibrosis but there is only very limited evidence from randomised trials. Ann lymphoedema after lymphatic radiotherapy and surgery has been used in the present study as a clinical system for testing these drugs in a double-blind placebo-controlled randomised phase 11 trial.Patients and methods: Sixty-eight eligible research volunteers with a minimum 20% increase in ann volume at a median 15.5 years (range 2-41) after axillary/supraclavicular radiotherapy (plus axillary surgery in 51/68 (75%) cases) were randomised to active drugs or placebo. All volunteers were given dl-alpha tocopheryl acetate 500 mg twice a day orally plus pentoxifylline 400 mg twice a day orally, or corresponding placebos. for 6 months. The primary endpoint was volume of the ipsilateral limb measured opto-electronically using a perometer and expressed as a percentage of the contralateral limb volume.Results: At 12 months post-randomisation, there was no significant difference between treatment and control groups in terms of arm volume. Absolute change in arm volume at 12 months was 2.5% (95% Cl - 0.40 to 5.3) in the treatment group compared to 1.2% (95% CI - 2.8 to 5.1) in the placebo group. The difference in mean volume change between randomisation groups at 12 months was not statistically significant (P = 0.6), - 1.3% (95% Cl - 6.1 to 3.5), nor was there a significant difference in response at 6 months (P = 0.7), where mean change in arm volume from baseline in the treatment and placebo groups was -2.3% (95% Cl - 7.9 to 3.4) and - 1.1% (95% Cl - 3.9 to 1.7), respectively. There were no significant differences between randomised groups in terms of secondary endpoints, including tissue induration (fibrosis) in the irradiated breast or chest wall, pectoral fold or supraclavicular fossa, change in photographic breast/chest wall appearance or patient self-assessment of function and Quality of Life at either 6 or 12 months.Conclusions: The study fails to demonstrate efficacy of dl-alpha tocopheryl acetate plus pentoxifylline in patients with arm lymphoedema following axillary surgery and lymphatic radiotherapy, nor does it suggest any benefits of these drugs in radiation-induced induration (fibrosis) in the breast, chest wall, pectoral fold, axilla or supraclavicular fossa. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Background: Radiation-induced brachial plexopathy (RIBP) is an untreatable complication of curative radiotherapy for early breast cancer, characterized by chronic neuropathic pain and limb paralysis. Hyperbaric oxygen (HBO2) therapy is known to promote healing of tissue rendered ischaemic by radiotherapy, but is untested in RIBP.Methods: Thirty four eligible research volunteers suffering from RIBP were randomized to HBO2 or control group. The HBO2 group breathed 100% oxygen for 100 min in a multiplace hyperbaric chamber on 30 occasions over a period of 6 weeks. The control group accompanied the HBO2 group and breathed a gas mixture equivalent to breathing 100% oxygen at surface pressure. All volunteers and investigators, except the operators of the hyperbaric chamber and the trial statistician, were blind to treatment assignments. The warm sensory threshold, which measures the function of small sensory fibres, was selected as the primary endpoint.Findings: Pre-treatment neurophysiological tests were grossly abnormal in the affected hand compared to the unaffected hand in both HBO2 and control groups, as expected, but no statistically significant differences were noted in either group at any time up to 12 months posttreatment. However, normalization of the warm sensory threshold in two of the HBO2 group was reliably recorded. Two cases with marked chronic arm lymphoedema reported major and persistent improvements in arm volume for at least 12 months after treatment with HBO2.Interpretation: There is no reliable evidence to support the hypothesis that HBO2 therapy slows or reverses RIBP in a substantial proportion of affected individuals, although improvements in warm sensory threshold offer some suggestion of therapeutic effect. Improvement in long-standing arm lymphoedema was not anticipated, and justifies further investigation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

We describe the psychometric analysis of a supplementary quality of life measure (MRC/EORTC QLQ-LEU) for evaluating long term sequelae of leukaemia treatments. The questionnaire under development was administered to 388 patients entered into the EORTC-GIMEMA AML 8A and the MRC AML10 clinical trials who were in complete remission for at least one year after completion of treatment on these trials. Results indicated a measure which is useful in evaluating the long-term effects of treatment in relation to chronic graft-vs-host disease and infection susceptibility. The performance of this measure in terms of its sensitivity and specificity between treatment arms was established by comparisons between the three treatment modalities in the above-mentioned trials and is the subject of further investigation. The new Leukaemia Module can be recommended for use alongside generic QOL instruments as a measure of long-term quality of life in leukaemia trials.