Publications

A 3 week schedule of whole breast radiotherapy is firmly established in the UK and is becoming more accepted internationally, especially as accelerated partial breast radiotherapy regimens become more common. It seems that a 3 week schedule is unlikely to be the lower limit of whole breast hypofractionation and the partial breast may even be adequately treated with just a single treatment. It is, however, essential that these hypotheses are rigorously tested within well-designed trials to ensure the highest quality of radiotherapy. This overview will address the rationale for hypofractionation in breast cancer, discuss past trials and outline the design of current studies.

BACKGROUND AND PURPOSE: Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-β1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies. MATERIALS AND METHODS: TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment-related data, and clinically-assessed fibrosis (measured at least 2years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed. RESULTS: No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85-1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability. CONCLUSION: This meta-analysis has not confirmed previous reports of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium.

BACKGROUND AND PURPOSE: Identification of mechanisms of late normal tissue responses to curative radiotherapy that discriminate individuals with marked or mild responses would aid response prediction. This study aimed to identify differences in gene expression, apoptosis, residual DNA double strand breaks and chromosomal damage after in vitro irradiation of lymphocytes in a series of patients with marked (31 cases) or mild (28 controls) late adverse reaction to adjuvant breast radiotherapy. MATERIALS AND METHODS: Gene expression arrays, residual γH2AX, apoptosis, G2 chromosomal radiosensitivity and G0 micronucleus assay were used to compare case and control lymphocyte radiation responses. RESULTS: Five hundred and thirty genes were up-regulated and 819 down-regulated by ionising radiation. Irradiated samples were identified with an overall cross-validated error rate of 3.4%. Prediction analyses to classify cases and controls using unirradiated (0Gy), irradiated (4Gy) or radiation response (4-0Gy) expression profiles correctly identified samples with, respectively, 25%, 22% or 18.5% error rates. Significant inter-sample variation was observed for all cellular endpoints but cases and controls could not be distinguished. CONCLUSIONS: Variation in lymphocyte radiosensitivity does not necessarily correlate with normal tissue response to radiotherapy. Gene expression analysis can predict of radiation exposure and may in the future help prediction of normal tissue radiosensitivity.

Limited guidelines exist for breast cancer management in developing countries. In this context, the Women's Cancer Initiative - Tata Memorial Hospital (WCI-TMH) organised its 8(th) Annual Conference to update guidelines in breast cancer.

To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy (including cone beam CT verification) following breast conservation surgery for early breast cancer.

A molecular understanding of tissue sensitivity to radiotherapy fraction size is missing. Here, we test the hypothesis that sensitivity to fraction size is influenced by the DNA repair system activated in response to DNA double-strand breaks (DSB). Human epidermis was used as a model in which proliferation and DNA repair were correlated over 5 weeks of radiotherapy.

To examine the effect of UK breast radiotherapy trials on the adoption of new radiotherapy techniques over the last 15 years.

Linear quadratic models predict that hypofractionation increases the biological effect of physical dose inhomogeneity. The clinical significance of this effect was tested retrospectively in a trial of adjuvant breast hypofractionation.

Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results.

Cancer survivors previously treated with curative radiotherapy are at risk of developing long-term toxicities due to radiation-induced normal tissue injury. Radiation fibrosis is an important component of the spectrum of radiation injury and at the present time treatment for this condition is limited. Data from both studies of clinical intervention and from preclinical models support the idea that fibrosis is a dynamic process and may in part be reversible. Clinical therapeutic interventions for radiation fibrosis have included empirical treatments, such as antioxidant therapies using superoxide dismutase, or vitamin E and pentoxifylline, and although evidence for therapeutic efficacy exists, further randomised studies are required. Potential therapeutic strategies that have shown promise in preclinical models include targeting pro-fibrotic cytokines such as: (1) transforming growth factor beta 1, (2) platelet-derived growth factor and its receptor tyrosine kinase and (3) connective tissue growth factor and the Rho/ROCK intracellular signalling pathway. Progress in the understanding of stem cell biology and the involvement of stem cells in radiation injury has led to the investigation of their role as a therapeutic strategy for ameliorating this disease process by promoting organ regeneration and repair. In this review we discuss the clinical and pathological features of radiation fibrosis and present the available clinical data and laboratory data relevant to these approaches to therapeutic intervention.

The FAST (FASTer radiotherapy for breast radiotherapy) trial is a UK Phase 2 multicentre randomised clinical trial evaluating a five-fraction schedule of whole-breast radiotherapy following local excision of early breast cancer. The purpose of this quality assurance study was to analyse the radiotherapy planning data in order to confirm compliance with the trial protocol.

Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer.

To establish planning solutions for a concomitant three-level radiation dose distribution to the breast using linear accelerator- or tomotherapy-based intensity-modulated radiotherapy (IMRT), for the U.K. Intensity Modulated and Partial Organ (IMPORT) High trial.

To test a prone position against the international-standard supine position in women undergoing whole-breast-radiotherapy (WBRT) after wide-local-excision (WLE) of early breast cancer (BC) in terms of feasibility, set-up errors, and respiratory motion.

Large breast size is associated with an increased risk of late adverse effects after breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association.

We describe a feasibility study testing the use of gold seeds for the identification of post-operative tumour bed after breast conservation surgery (BCS).

Gene expression profiling of the transcriptional response of human dermal fibroblasts to in vitro radiation has shown promise as a predictive test of radiosensitivity. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer.

The aim of this study was to compare inter-individual and inter-cell type variation in DNA double-strand break (DSB) repair following in vivo irradiation of human skin.

To test the association of DNA double-strand break (DSB) repair and chromosomal radiosensitivity in ex vivo irradiated blood lymphocytes with late-onset normal tissue responses following breast radiotherapy.

The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs).

Background and purpose: Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen.Materials and methods: Women aged >= 50 years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50 Gy in 25 fractions versus 28.5 or 30 Gy in 5 once-weekly fractions of 5.7 or 6.0 Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance.Results: Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twentynine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p < 0.001) for 30 Gy and 1.15 (0.82-1.60, p = 0.489) for 28.5 Gy versus 50 Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%. p < 0.001) for 30 Gy and 11.1% (7.9-15.6%, p = 0.18) for 28.5 Gy compared with 9.5% (6.5-13.7%) after 50 Gy. With a median follow-up in survivors of 37.3 months, 2 local tumour relapses and 23 deaths have occurred.Conclusion: At 3 years median follow-up, 28.5 Gy in 5 fractions is comparable to 50 Gy in 25 fractions. and significantly milder than 30 Gy in 5 fractions, in terms of adverse effects in the breast. (c) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 100 (2011) 93-100

Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen.

Few trials of adjuvant breast radiotherapy have incorporated patient-reported breast symptoms and related areas of quality of life. We assessed these measures in a quality-of-life study that was part of the randomised START (Standardisation of Breast Radiotherapy) trials.

Deregulation of normal regenerative responses to physical, chemical and biological toxins in susceptible individuals leads to abnormal remodelling of extracellular matrix with pathological fibrosis. Processes deregulated after radiotherapy have much in common with processes associated with fibrotic diseases affecting the heart, skin, lungs, kidneys, gastro-intestinal tract and liver. Among the secreted factors driving fibrosis, transforming growth factor beta 1 (TGFβ1) produced by a wide range of inflammatory, mesenchymal and epithelial cells converts fibroblasts and other cell types into matrix-producing myofibroblasts. Even if required for the initiation of fibrosis, inflammation and the continued stimulus of TGFβ1 may not be needed to maintain it. After myofibroblast activation, collagen production can be perpetuated independently of TGFβ1 by autocrine induction of a cytokine called connective tissue growth factor. The role of inflammation, the origins and activation of myofibroblasts as biosynthetic cells and the downstream pathways of extracellular matrix synthesis in common fibrotic states are reviewed. Oxidative stress, hypoxia and microvascular damage are also considered, before examining the same processes in the context of radiotherapy. One of the main uncertainties is the relevance of very early events, including inflammatory responses in blood vessels, to fibrosis. Despite the power of animal models, including genetic systems, the potential contribution of research based on human tissue samples has never been greater. A closer interaction between scientists researching fibrosis and radiation oncologists holds enormous promise for therapeutic advances.

To compare partial-breast clinical target volumes generated using a standard 15 mm margin (CTV(standard)) with those generated using three-dimensional surgical excision margins (CTV(tailored 30)) in women who have undergone wide local excision (WLE) for breast cancer.

Partial breast irradiation (PBI) is currently under investigation in several phase III trials and, following a recent consensus statement, its use off-study may increase despite ongoing uncertainty regarding optimal target volume definition. We review the clinical, pathological and technical evidence for target volume definition in external beam partial breast irradiation (EB-PBI). The optimal method of tumour bed (TB) delineation requires X-ray CT imaging of implanted excision cavity wall markers. The definition of clinical target volume (CTV) as TB plus concentric 15 mm margins is based on the anatomical distribution of multifocal and multicentric disease around the primary tumour in mastectomy specimens, and the clinical locations of local tumour relapse (LR) after breast conservation surgery. If the majority of LR originate from foci of residual invasive and/or intraduct disease in the vicinity of the TB after complete microscopic resection, CTV margin logically takes account of the position of primary tumour within the surgical resection specimen. The uncertain significance of independent primary tumours as sources of preventable LR, and of wound healing responses in stimulating LR, increases the difficulties in defining optimal CTV. These uncertainties may resolve after long-term follow-up of current PBI trials. By contrast, a commonly used 10mm clinical to planning target volume (PTV) margin has a stronger evidence base, although departmental set-up errors need to be confirmed locally. A CTV-PTV margin >10mm may be required in women with larger breasts and/or large seromas, whilst the role of image-guided radiotherapy with or without TB markers in reducing CTV-PTV margins needs to be explored.

To compare non-target tissue (including left-anterior-descending coronary-artery (LAD)) dosimetry of prone versus supine whole (WBI) and partial-breast irradiation (PBI).

Randomised trials report no disadvantages for hypofractionation based on 2.67 Gy fractions of adjuvant whole breast radiotherapy in terms of local tumour control and late adverse effects. Current 15- or 16-fraction schedules may not represent the limits of this approach, and limited data suggest that fewer larger fractions can be delivered safely provided appropriate downward adjustments are made to the total dose. Therapeutic gain will be undermined if breast cancer proves to be, on average, significantly less sensitive to fraction size than the dose-limiting late reacting normal tissues. If so, shortening overall treatment time might wholly or partially offset these limitations, and these uncertainties are addressed in ongoing or planned trials. Meanwhile, the experience of accelerated partial breast irradiation suggests a strong volume effect for late normal tissue damage. Schedules that may be safe when delivered to small partial volumes cannot be assumed to be safe if delivered to larger partial volumes or to the whole breast. Based on current evidence, testing the effectiveness of a 5-fraction schedule of hypofractionated whole breast radiotherapy appears to be a realisable research objective.

Purpose: To test for association between single nucleotide polymorphisms at the TGF beta 1 locus and the risk of late normal tissue injury following whole breast radiotherapy.Methods: A retrospective study compared the number of variant alleles at -509 and codons 10 and 25 of the TGF beta 1 locus in women followed up in two prospective clinical trials who developed either marked radiotherapy adverse effects or no adverse effects after matching on fractionation schedule, breast size, surgical deficit, chemotherapy and length of follow up.Results: Median follow up in the two trials was 7.4 (maximum 15) years and 5.3 (maximum 5.3) years. 1237/1716 (72%) women with photographic assessments of radiotherapy adverse effects were alive and well, and 147/1237 (12%) potential cases with the most marked change in photographic change in breast appearance were matched to potential controls recording no change. In an unmatched analysis of 82 cases and 108 controls, no significant difference in the number of genetic variants was observed.Conclusions: No association was detected between sequence variations at the TGF beta 1 locus and the risk of late adverse effects of breast radiotherapy. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 15-18

Published results of randomised trials involving >7000 women confirm the safety and efficacy of hypofractionated schedules of adjuvant radiotherapy for women with early breast cancer using fraction sizes between 2 and 3 Gy assuming appropriate downward adjustments to total dose. Unnecessary concerns relating to heart tolerance, suboptimal dose distribution and duration of follow up need not discourage the routine adoption of 15- or 16-fraction schedules in women treated by breast conservation surgery for early breast cancer. Regardless of fractionation regimen, dose escalation to the index quadrant in high risk subgroups will result in a greater relative increase in late adverse effects than tumour control, a therapeutic disadvantage that can only be overcome by exploiting a marked dose-volume effect. A 15-fraction schedule of whole breast radiotherapy is unlikely to represent the lower limits of hypofractionation, and the preliminary results of a 5-fraction regimen are encouraging.

Background: A non-randomised phase II study suggested a therapeutic effect of hyperbaric oxygen (HBO) therapy on arm lymphoedema following adjuvant radiotherapy for early breast cancer, justifying further investigation in a randomised trial.Methods: Fifty-eight patients with >= 15% increase in arm volume after supraclavicular +/- axillary radiotherapy (axillary surgery in 52/58 patients) were randomised in a 2:1 ratio to HBO (n = 38) or to best standard care (n = 20). The HBO group breathed 100% oxygen at 2.4 atmospheres absolute for 100 min on 30 occasions over 6 weeks. Primary endpoint was ipsilateral limb volume expressed as a percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK SF-36 Health Survey Questionnaire.Findings: Of 53/58 (91.4%) patients with baseline assessments, 46 had 12-month assessments (86.8%). Median volume of ipsilateral limb (relative to contralateral) at baseline was 133.5% (IQR 126.0-152.3%) in the control group, and 135.5% (IQR 126.5-146.0%) in the treatment group. Twelve months after baseline the median (IQR) volume of the ipsilateral limb was 131.2% (IQR 122.7-151.5%) in the control group and 133.5% (IQR 122.3-144.9%) in the treatment group. Results for the secondary endpoints were similar between randomised groups.Interpretation: No evidence has been found of a beneficial effect of HBO in the treatment of arm lymphoedema following primary surgery and adjuvant radiotherapy for early breast cancer. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 97 (2010) 101-107

Despite the improvement in outcome for women with early breast cancer undergoing breast conservation surgery and radiotherapy, there are significant gaps in our understanding of local tumour relapse. In this Personal View, we propose two hypotheses: early-onset changes in breast-duct anatomy limit the degree of intraductal spread and explain much of the substantial age-related difference in risk of local tumour relapse; and wound-healing proteins stimulate the growth of cancer cells left behind after surgery. These mechanisms help to explain why generous surgical margins offer no greater protection against local tumour relapse than narrow margins after complete microscopic tumour excision.

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.

Rates of local tumour relapse after breast conservation treatment in women with early breast cancer are falling. Explanations for this decline are considered in this review including advances in breast cancer management and aging of the breast cancer population. Breast surgery has become more standardised following publication of practice guidelines and is mostly carried out by specialist surgeons. Systemic therapies (hormonal therapy and chemotherapy) are now more effective and are recommended to a higher proportion of patients than ever before. Radiotherapy techniques have also improved. The contributions of each factor are difficult to quantify precisely, but all are likely to be relevant. In order to identify a subgroup of women that might safely be spared radiotherapy, several factors are analysed, including the prognostic significance for local relapse of tumour characteristics (pathologic data, gene-expression profiles), patient characteristics and life expectancy (age and comorbidities).

To determine target volume changes by using volume and shape analysis for patients receiving radiotherapy after breast conservation surgery and to compare different methods of automatically identifying changes in target volume, position, size, and shape during radiotherapy for use in adaptive radiotherapy.

To compare tumor bed (TB) volumes delineated using magnetic resonance imaging plus computed tomography and clips (MRCT) with those delineated using CT and clips (CT/clips) alone in postlumpectomy breast cancer patients positioned prone and to determine the value of MRCT for planning partial breast irradiation (PBI).

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit; CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ERalpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor; CCN2) were increased. Further investigation revealed that c-Kit and ERalpha were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed 'cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for 'connective tissue disorders, dermatological diseases and conditions, genetic disorder' and 'cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occurring after radiotherapy for early breast cancer.

Seven randomised trials are currently testing accelerated partial breast irradiation against whole breast radiotherapy after breast conservation surgery. The trials are varied in the techniques used to deliver partial breast radiotherapy, reflecting the range of opportunities offered by advanced brachytherapy and teletherapy modalities. Dose schedules also vary between trials, but the most important point of difference between them reflects alternative concepts of clinical and planning target volumes. These are based mainly on the spatial pattern of relapse in retrospective and prospective studies, which report the majority of first local relapses close to the primary tumour site, and on the assumption that radiotherapy does not prevent the development of new primary tumours developing elsewhere in the breast. However, the pattern of ipsilateral breast tumour relapse is not accurately defined in the clinical literature and does not correspond closely to pathological findings. In addition, published data are consistent with a significant reduction in the rate of other quadrant relapse after whole breast radiotherapy. Regardless of the biological model of local tumour relapse and responsiveness to radiation, the ongoing trials will generate level I evidence for or against accelerated partial breast irradiation, provided patients are followed up long enough before the first reporting of results.

The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size.

The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy.

The purpose of this study was to investigate methods used to modulate dose distributions in radiotherapy planning, to determine the fundamental features of these and to establish the attainable dose uniformity. Published modulation methods were categorized, and a simple physical model devised to predict the weight of the wedged beam and the relative dose distribution for each category. Each technique was applied to patient data with planning target volume sizes ranging from below 500 cm(3) to 2200 cm(3). The spatial distribution of high-dose regions in the breast, and maximum dose for the heart and lung, were determined for each plan. The dose uniformity was analysed by evaluating the volume of the breast (V(I)) receiving <95% and <105% of the prescribed dose. The difference between V(105%) and V(95%) for each method for each patient data set was also calculated. The simple model predicted the trend in percentage weight of the wedge beam and the form of the dose distribution in the transverse plane with the modulation method. Improvements in the dose uniformity were seen for the majority of modulation methods. The magnitude of the change was between 5.6% and 11.1% (p<0.05) of the breast volume for breast sizes above 500 cm(3). Some modulation methods introduced high dose at the chest wall. In conclusion, the majority of the methods improved dose uniformity for breast sizes of 500 cm(3) or greater. No method showed a clear advantage over the others. The use of modulation methods should be governed by consideration of its effects relative to a simple wedge plan.

Serial photographs have been collected prospectively to evaluate the effect of radiotherapy on normal tissues in the breast. The aim of this study was to compare two methods of scoring radiation-induced changes.

Aims: A pilot study was undertaken with the aim of documenting acute skin reactions and 2-year late adverse effects of a five-fraction course of adjuvant whole breast radiotherapy delivered over 15 days after local tumour excision of early breast cancer.Materials and methods: Thirty women with early invasive breast cancer aged >= 50 years with a pathological tumour size < 3 cm, complete microscopic resection, negative axillary node status and no requirement for cytotoxic therapy were prescribed 30 Gy in five fractions over 15 days to the whole breast using tangential 6-10 MV X-ray beams and three-dimensional dose compensation with written informed consent. Post-surgical baseline photographs of the breasts were taken, and acute skin erythema and moist desquamation were each scored weekly for 7 weeks using four-point graded scales (grade 0 = none, 1 = mild, 2 = moderate, 3 = severe). This was followed by an annual clinical assessment, including repeat photographs at 2 years.Results: Nine patients (30%, 95% confidence interval 14.7-49.4%) developed grade 2 erythema, with the remaining 21 patients developing milder degrees of reaction. Four (13.3%, 95% confidence interval 3.7-30.7) patients developed moist desquamation, grade 1 in three women and grade 2 in the fourth. At 2 years after treatment, 23/30 (77%) patients scored no change in photographic breast appearance compared with the pre-treatment baseline; seven (23%, 95% confidence interval 9.9-42.3) scored a mild change in breast appearance, and none developed a marked change. After a mean follow-up of 3.1 years (standard deviation 0.37, range 2.1-3.9 years) there have been no ipsilateral local tumour relapses.Conclusions: Further evaluation of a five-fraction regimen of adjuvant whole breast radiotherapy in a phase III randomised trial is justified, including a regimen delivered in a total of 5 days.

Chronic tissue hypoxia may play a role in the pathogenesis of late radiation fibrosis. In order to investigate this hypothesis, the immunohistochemical distribution of pimonidazole hydrochloride (n = 14 patients) and carbonic anhydrase IX (CAIX) (n = 38 patients) was studied in samples of previously irradiated normal human tissue. One sample of irradiated breast tissue, which also showed marked histological features of radiation injury, stained positive for pimonidazole hydrochloride. No CAIX staining was seen in irradiated tissue other than some evidence of physiological hypoxia in the epidermis of two samples of irradiated skin; both were positive for pimonidazole and one was focally positive for CAIX. Pimonidazole hydrochloride staining of tissue with morphological changes of radiation injury could support a role for hypoxia in the pathogenesis of late normal tissue fibrosis in humans.

Background Substantial survival benefits exist for patients with early-stage breast cancer who undergo treatment with single-modality tamoxifen, ovarian ablation or suppression, or chemotherapy. To determine whether additional benefits exist with combined treatment, the Adjuvant Breast Cancer (ABC) Trials were undertaken.Methods The ABC Ovarian Ablation or Suppression Trial randomly assigned pre- and perimenopausal patients with early-stage breast cancer who were receiving prolonged (5 years) tamoxifen treatment with or without chemotherapy to ovarian ablation or suppression (by oophorectomy, ovarian irradiation, or treatment with luteinizing hormone-releasing hormone agonist) versus no ovarian ablation or suppression. Trial endpoints included relapse-free and overall survival. Hazard ratios (HRs) were derived from Cox models, and all statistical tests were two-sided.Results Between 1993 and 2000, 2144 (1063 ovarian ablation or suppression, 1081 no ovarian ablation or suppression) patients were randomly assigned. A total of 942 (89%) received ovarian ablation or suppression as allocated. Overall, no evidence of a benefit for ovarian ablation or suppression was observed for relapse-free survival (relapse in the ovarian ablation/suppression versus no ovarian ablation/suppression group, 290 events versus 306 events, HR = 0.95, 95% confidence interval [CI] = 0.81 to 1.12; P=.56) or overall survival (death from any cause in the ovarian ablation or suppression versus no ovarian ablation/suppression group, 215 events versus 230 events, HR = 0.94, 95% Cl = 0.78 to 1.13; P=.44), nor were differences seen after adjustment for age, nodal status, or estrogen receptor (ER) status.Conclusion Overall, no added effect of ovarian ablation or suppression was seen on relapse-free survival or overall survival of premenopausal women who were treated for early-stage breast cancer. However, the role of ovarian ablation or suppression in young (< 40 years) women with ER-positive tumors, especially those not receiving chemotherapy, requires further study.

Radiation dose distributions created by two dimensional (2D) treatment planning are responsible for partial volumes receiving >107% of the prescribed dose in a proportion of patients prescribed whole breast radiotherapy after tumour excision of early breast cancer. These may contribute to clinically significant late radiation adverse effects.

Standard curative schedules of radiotherapy to the breast deliver 25 fractions of 2.0 Gy over 5 weeks. In a randomised trial, we tested whether fewer, larger fractions were at least as safe and as effective as standard regimens. In this analysis, we assessed the long-term results of tumour control in the same population.

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.

Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom.Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points.Results: No increase in clinically significant late toxicity was seen in the mutation carriers.Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

Purpose: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003.Experimental Design: All participants were interviewed by one of two researchers using Standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent; but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers.Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02).Conclusions: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.

Advances in molecular and cellular biology are transforming our understanding of breast cancer and promise the same for radiotherapy over the next few years. At the clinical level, the molecular basis of fractionation dependency and other tumour and normal tissue responses are likely to become clearer. More importantly, they will become useful in the clinic, where molecular characterisation of the patient and tumour will start to determine therapeutic options. Although many of the fundamental processes are only amenable to study in laboratory systems, the power of array-based technologies makes it possibly to address highly relevant questions in the clinic, using functional imaging and/or tissue biopsies. To help clinical oncologists exploit these opportunities in translational research, some aspects of the molecular and cellular basis of radiotherapy are described below in their relation to breast cancer.

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 in early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995.Methods Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17 000 women; >10%, 25 000 women).Findings About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25 000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%,SE 0.8, 2p<0.00001).These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1 % (reduction 5.4%, S E 1.3, 2p=0.0002; overall mortality reduction 4.4%, S E 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large.To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0 06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004).Interpretation In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

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.

Recent studies suggest that normal tissue radiosensitivity is influenced by single nucleotide polymorphisms (SNPs) in certain genes. In order to seek a confirmation of these findings, this study investigated SNPs in genes TGFB1 (position - 509, codon 10 and codon 25), SOD2 (codon 16), XRCC1 (codon 399), XRCC3 (codon 241), APEX (codon 148) and ATM (codon 1853) in 26 breast cancer patients with marked changes in breast appearance after radiotherapy and 26 matched controls. Statistically significant associations were found between the TGFB1 codon 10 Pro allele (P = 0.005) as welt as the TGFB1 position -509 T allele (P = 0.018) and increased risk of altered breast appearance. No significant associations were found for the remaining SNPs. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Background and purpose: Unlike squamous carcinomas, breast adenocarcinoma may be as sensitive to fraction size as late dose-limiting normal tissues. If so, fewer larger fractions would be as safe and effective as regimens based on 2.0 Gy fractions. The first step is to test the effects of radiotherapy fractions > 2.0 Gy on late normal tissue responses in the breast after tumour excision and radiotherapy for early breast cancer.Patients and methods: One thousand four-hundred and ten women with T1-3 N0-1 M0 invasive breast cancer were randomised between 1986-98 into one of three radiotherapy regimens after local tumour excision of early stage breast cancer; 50 Gy in 25 fractions (F) vs two dose levels of a test schedule giving 39 or 42.9 Gy in 13 F over 5 weeks. Fraction sizes were 2.0, 3.0 and 3.3 Gy, respectively. The primary endpoint was late change in breast appearance compared to post-surgical appearance scored from annual photographs blinded to treatment allocation. Secondary endpoints included palpable breast induration (fibrosis) and ipsilateral tumour recurrence.Results: After a minimum 5-year follow up, the risk of scoring any change in breast appearance after 50 Gy/25 F, 39 Gy/13 F and 42.9 Gy/13 F was 39.6, 30.3 and 45.7%, from which an alpha/beta value of 3.6 Gy (95% CI 1.8-5.4) is estimated. The alpha/beta value for palpable breast induration was 3.1 Gy (95% CI 1.8-4.4).Conclusions: An alpha/beta value of around 3 Gy for late normal tissue changes in the breast is derived from the estimated equivalence of 41.6 Gy in 13 fractions and 50 Gy in 25 fractions over 5 weeks, in line with trial predictions. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

To determine (1) if the lower border of a standard anterior radiotherapy field to the supraclavicular fossa matches the upper limit of level II/III axillary dissection; and (2) whether standard lung blocks in patients prescribed axillary radiotherapy shield target axillary tissue in women with breast cancer.

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.

To evaluate functional microvascular characteristics of breast induration several years after radiation treatment using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques.

The causes of induration (hardness) in the breast many years after tumour excision and whole breast radiotherapy for early stage breast cancer are not well established. The purpose of this study is to describe morphological magnetic resonance imaging (MRI) appearances and MRI-derived microvascular functional characteristics of the indurated breast several years post-treatment.

The aim of this work was to evaluate the positional distribution of dose in a concise manner and to analyse dose-histogram results in tangential breast radiotherapy in 300 patients, randomized to standard wedged or intensity modulated radiotherapy (IMRT), for future correlation with clinical outcome data. A simple method for analysing the dose-position relationship in the treatment volume was used to compare the spatial distribution of dose in patients. The breast was divided into equal thirds (upper, middle and lower) and dose was assessed using three dose bands; 95-105%, >105-110% and >110% of the prescription dose. The effect of using IMRT on the dosimetry was assessed from dose-volume histogram data using the following parameters: percentage of the target volume receiving a dose less than 95%, greater than 105%, either less than 95% or greater than 105% of that prescribed; the mean dose; and the maximum dose. Doses greater than 105% were predominantly in the upper and lower regions of the breast in the standard wedged treatment. 96% of these patients received doses greater than 105% in the upper region of the breast and 70% received doses greater than 105% in the lower breast. Only 4% of patients allocated IMRT received doses greater than 105% in either region. Analysis of dose-volume histogram data showed that IMRT reduced the volume receiving a dose greater than 105% by a mean of 10.7% (p= or <0.001); the mean change in the volume receiving a dose less than 95% was 0.2% (p=0.63). Average mean plan dose was 101.6% for standard treatment and 99.6% for IMRT (p<0.001 for each compared with 100.0% ideal). The mean value of maximum dose was reduced from 111% to 106% in the group of patients randomized to IMRT. A simple method for describing the relationship between dose and position in the breast, which is helpful for the effective correlation of dosimetry and clinical effects, is reported. Further, application of IMRT to the tangential field irradiation of the breast has been demonstrated to reduce high dose regions in both volume and dose level without compromising either minimum dose coverage or mean dose delivered to the breast.

Small proportions of patients receiving radiotherapy develop marked long-term radiation damage. It is thought that this is due, at least in part, to intrinsic differences in cellular radiosensitivity, but the underlying mechanism is unknown. Reactive oxygen species are involved in cellular radiation damage, hence inter-individual differences in free radical detoxification may be related to radiosensitivity. Within mitochondria manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species. MnSOD has been linked to expression of malignant phenotype and apoptosis and polymorphic variation in the gene, SOD2 to risk of breast cancer.

To evaluate radiation-induced defects in myocardial perfusion imaging in early breast cancer patients treated with modern technique radiotherapy.

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.

A method that uses electronic portal imaging to design intensity-modulated beams for compensation in breast radiotherapy was implemented using multiple static fields in a planning study. We present the results of the study to verify the algorithm, and to assess improvements to the dosimetry.

Urinary markers of bone resorption, pyridinoline and deoxypyridinoline were measured before and at 4 weeks after radiotherapy for metastatic bone pain. An association was shown between relief of metastatic skeletal pain by radiotherapy and low marker concentrations before and after treatment, lending support to the hypothesis that relief of metastatic bone pain by radiotherapy relates to an effect on bone, rather than tumour physiology.

Fibrosis in normal tissues is a common and dose-limiting late complication of radiotherapy at many cancer sites, but its pathogenesis is poorly understood. We undertook a controlled study of the effect of irradiation on the collagen production of fibroblasts cultured from skin biopsies taken from patients undergoing radiotherapy treatment. Eight weeks after a single 8 Gy fraction using 300 kV X-rays, five patients treated at the Royal Marsden Hospital underwent biopsy of the irradiated site and of the contralateral, unirradiated body site. Fibroblasts from irradiated and control, unirradiated sites were cultured in vitro, and collagen production rates were measured during a 48-hour incubation under standardized conditions and in the presence and absence of transforming growth factor beta(1)(TGF beta(1)), 1 ng/ml, using HPLC. Collagen production was elevated in cells cultured from irradiated skin; median collagen production rates 61.16 pmoles hydroxyproline/10(5)cells/hour in irradiated cells, 39.78 pmoles hydroxyproline/10(5)cells/hour in unirradiated cells, P = 0.016 (Mann-Whitney U-test). In fibroblasts from unirradiated sites, collagen production rates were increased by the addition of TGF beta(1); however, in three of the cell lines cultured from irradiated sites this effect of TGF beta(1)on collagen production was not observed.

To develop a method of using a multileaf collimator (MLC) to deliver intensity modulated radiotherapy (IMRT) for tangential breast fields, using an MLC to deliver a set of multiple static fields (MSFs).

To test for an association between in vitro fibroblast radiosensitivity and complication risk in a case-control study of breast cancer patients treated under standard conditions in a clinical trial of radiotherapy dose fractionation.

The determination of the depth of the tumour bed within the breast requiring an electron therapy boost dose is generally judged clinically and can be inconsistent between individual radiotherapists. High frequency ultrasound provides a reproducible, safe and quick method of measuring this depth. In order to improve current working practice at the Royal Marsden NHS Trust the routine use of ultrasound when planning breast boost radiotherapy was established. Fifty-three early stage postoperative breast cancer patients had both clinical and ultrasound assessments of boost depth performed. These measurements were converted into electron energy and compared. Measurements ranged from 0.8 cm to 4.9 cm and electron energy from 4 MeV to 15 MeV. As a direct result of the ultrasound measurements taken, 60% of patients had their electron energy changed from that chosen by the clinically assessed measurement. Overall, the energy was as likely to be increased as decreased. Breast size did not influence the need for change but patients with small breasts never required an increase in the energy from that chosen clinically. It was concluded that the use of ultrasound, once integrated into the planning process, can improve accuracy when selecting electron energy for patients receiving breast boost irradiation.

The aim of this study was to review the ability to control symptoms of regional lymphatic relapse in women with early breast cancer. A retrospective study was made of 759 consecutive women presenting with stage 1 or 2 breast cancer treated by breast conserving surgery and radiotherapy between June 1984 and December 1994, 291 (38.3%) of whom were managed by a policy of observation on the lymphatic pathways. Patterns of lymphatic relapse, relapse management and morbidity caused by recurrent malignancy were reviewed from the case notes. The overall rate of relapse in the ipsilateral axilla and/or supraclavicular fossa was 76/759 (10%) at any time prior to death or last follow-up. 34 of 65 patients who relapsed in the axilla did so despite prior axillary surgery and/or radiotherapy. 41 of 76 patients with regional recurrence presented with symptoms, including lymphoedema, arm pain or sensory motor changes. These symptoms were poorly controlled by palliative surgery, radiotherapy or systemic therapy in 23 cases, including 12 who progressed to arm paralysis. Symptomatic control of patients with regional lymphatic relapse can be very difficult, even in women under regular surveillance in a multidisciplinary breast cancer clinic.

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.

Until recently, elective treatment of the lymphatic pathways in women with early invasive breast cancer was assumed to impact on quality of life rather than on overall survival. In a multidisciplinary breast clinic these considerations underpinned a policy of observation of the lymphatic pathways if axillary lymph nodes were not palpably enlarged and if recommendations for adjuvant systemic therapy did not depend on knowledge of pathological node status. This paper evaluates the long-term outcome of the observation policy in terms of lymphatic morbidity due to cancer recurrence.

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.

A method of using electronic portal imaging to design compensators for tangential breast irradiation has been developed. We describe how this has been implemented.

The study aimed to identify the proportion of patients with relapse or a contralateral breast tumour who are diagnosed as a consequence of regular follow-up in a specialist breast clinic after breast conserving surgery and radiotherapy for early breast cancer. A retrospective review was undertaken of 490 consecutive patients entered into a randomized clinical trial of radiotherapy fractionation at a single institution. As part of the trial, patients were reviewed in a multidisciplinary breast clinic 3-monthly for the first 3 years, 6-monthly between 3 and 5 years and annually thereafter, with biennial mammography. For this study, information was retrieved from hospital records to ascertain: (a) whether patients were symptomatic at the time of relapse or contralateral breast tumour; and (b) whether they presented at a scheduled appointment or brought their appointment dates forward. The subsequent management of patients with relapse was reviewed to determine whether or not this may have been influenced favourably by a policy of regular follow-up. Twenty-one (44%) of the 48 patients with locoregional relapse were asymptomatic. Of these, 17 were detected by clinical examination (that is, directly as a result of a routine clinic attendance), while four were detected by routine mammography. Ten of the 17 patients diagnosed by clinical examination had successful surgery for locoregional relapse and all have remained disease free. Five of 17 developed distant metastases within 6 months and two others had skin nodules on the breast excised. Only three of the 67 patients with distant relapses were asymptomatic. Two of the 11 patients with contralateral breast tumours were asymptomatic and were diagnosed on routine mammography. The benefits and cost-effectiveness of less rigid approaches to follow-up of breast cancer patients needs to be evaluated in large prospective randomized trials.

The radiosensitivity of skin fibroblasts derived from patients as measured in vitro by a clonogenic survival assay appears to correlate with the risk of developing severe late reactions to radiation. Unfortunately, these assays are clinically impractical as a predictive test for radiosensitivity. The purpose of this study was to assess the utility of two possible surrogate assays for radiosensitivity, pulsed-field gel electrophoresis (PFGE) and single-cell gel electrophoresis (comet assay), both of which can be used to measure DNA double-strand breaks. Twenty-three nontransformed human fibroblast cell lines exhibiting a range of radiosensitivities were studied with both of these assays. The results were correlated with measurements of radiosensitivity obtained as part of a larger study examining the correlation between cellular radiosensitivity and clinical response. [2-(14)C]Thymidine-labeled confluent cultures were irradiated at 1.0 Gy/min with doses of 0 to 150 Gy. After allowing 4 h for repair at 37 degrees C, cells were trypsinized and aliquots were used for preparing slides for the comet assay. After neutral lysis and electrophoresis, the slides were stained with ethidium bromide and 50 comet moments were measured for each dose. The remainder of the cells were formed into agarose plugs and, after neutral lysis, were subjected to PFGE. The fraction of activity released (FAR) from the well was measured by scintillation counting of appropriate segments of each gel lane. Cellular radiosensitivity was measured with a standard clonogenic assay at a low dose rate of 1.2 cGy/min, and the dose that resulted in a surviving fraction of 0.01 (D0.01) was calculated. The slope of the plot of comet moment as a function of dose for each cell line did not correlate with D0.01 (R = 0.36, P > 0.1). In contrast, the slope of the FAR as a function of dose had a weak inverse correlation with D0.01 (R = 0.43 and P = 0.05) such that the more radiosensitive cell lines exhibited a steeper dose response for FAR. Although the correlation between the slope of the dose response for FAR and D0.01 was weak, refinement of the PFGE technique may provide a potentially useful predictive assay for radiosensitivity.

Of patients being treated by radiotherapy for cancer, a small proportion develop marked long-term radiation damage. It is believed that this is due, at least in part, to intrinsic individual differences in radiosensitivity, but the underlying mechanism is unknown. Individuals affected by the recessive disease ataxia telangiectasia (AT) exhibit extreme sensitivity to ionizing radiation. Cells from such individuals are also radiosensitive in in vitro assays, and cells from AT heterozygotes are reported to show in vitro radiosensitivity at an intermediate level between homozygotes and control subjects. In order to examine the possibility that a defect in the ATM gene may account for a proportion of radiotherapy complications, 41 breast cancer patients developing marked changes in breast appearance after radiotherapy and 39 control subjects who showed no clinically detectable reaction after radiotherapy were screened for mutations in the ATM gene. One out of 41 cases showing adverse reactions was heterozygous for a mutation (insertion A at NT 898) that is predicted to generate a truncated protein of 251 amino acids. No truncating mutations were detected in the control subjects. On the basis of this result, the estimated percentage (95% confidence interval) of AT heterozygous patients in radiosensitive cases was 2.4% (0.1-12.9%) and in control subjects (0-9.0%). We conclude that ATM gene defects are not the major cause of radiotherapy complications in women with breast cancer.

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.

Electronic portal images may be used to design the compensation required to maximise dose uniformity in the breast from opposed tangential beams.

Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung cancer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with limited-stage SCLC who had had a complete response to induction therapy. Initially, patients were randomised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regimen versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29-0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58-0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66-1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fractionation and to clarify the effect on survival. Patients with SCLC achieving a complete response to induction therapy should be offered PCI.

Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung cancer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with Limited-stage SCLC who had had a complete response to induction therapy. Initially, patients were randomised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regimen versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29-0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58-0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66-1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fractionation and to clarify the effect on survival. Patients with SCLC achieving a complete response to induction therapy should be offered PCI. (C) 1997 Elsevier Science Ltd.

Advances have been made in unravelling the molecular chains of cause and effect that determine cellular responses to radiotherapy, including cell cycle arrest, DNA repair and apoptosis. To begin with, cells must have mechanisms that enable them to sense DNA damage. Little was known about this until recently, when a DNA-protein kinase (DNA-PK) system for detecting radiation-induced strand breaks was described. The ataxia telangiectasia (ATM) gene has amino acid sequence similarities to DNA-PK, raising the possibility that the ATM protein also functions in some way as a sensor of DNA damage. However, just knowing the DNA damage is present is not enough. Signals must be transmitted via afferent biochemical pathways to proteins, such as p53, that determine which cellular responses are activated. The responses include cell cycle arrest, apoptosis and DNA repair, all of which relate closely to loss of clonogenic capacity and the outcome of treatment in our patients.

The aim of this study was to evaluate the central lung distance (CLD) as a surrogate for the volume of lung irradiated during tangential breast radiotherapy. 20 women underwent a planning computed tomography (CT) scan and three-dimensional (3D) treatment planning for both breasts. The field size was perturbed in a systematic manner to give a number of plans with the CLD increasing from 0 to 30 mm. The volume of lung irradiated was determined directly using dose-volume histograms of the lung and correlated with the known CLD. The results indicate that absolute and percentage lung volumes increase with increasing CLD according to a quadratic relationship which is different for both left and right lungs. It is concluded that while there is no substitute for a 3D plan and a lung dose-volume histogram calculation, CLD may be used as a guide to the volume of lung included within the tangential fields used for breast radiotherapy.

The aim of this study was to evaluate the effect of breast size on dose heterogeneity. Twenty women underwent a planning CT scan of the thorax. A three-dimensional treatment plan was devised for each patient using a standard technique of isocentric medial and lateral wedged tangential fields. Three-dimensional dose distributions were derived using an equivalent path length (EPL) inhomogeneity correction and cumulative dose-volume histogram (DVH) data calculated for the breast. Analysis of the DVHs for each patient reveals that 0.2-23.8% of the breast received an absorbed dose outside the desired 95-105% of that prescribed at the isocentre. The degree of dose heterogeneity was most strongly correlated with breast volume (r = 0.70, 95% confidence interval (C.I.) 0.37-0.87). There was also a positive correlation for breast dose heterogeneity versus brassière (bra) cup size (Spearman rank correlation rho = 0.62), breast area (r = 0.39, 95% C.I. -0.06-0.71) and chest wall separation (r = 0.31, 95% C.I. -0.15-0.66). We conclude that breast size is an important determinant of dose heterogeneity within the breast.

A novel method of designing intensity modulated beams (IMBs) to achieve compensation in external beam radiotherapy of the breast, without the need for CT scans, is presented. The design method comprises three parts: (1) an electronic portal image is used to generate a map of radiological thickness; (2) this map is then used to obtain an estimate of the breast and lung outline; (3) a TMR-based dose calculation algorithm is then used to determine the optimum beam profile to achieve the best dose distribution. The dose distributions calculated for IMBs were compared with those calculated for the use of simple wedges. The results for two patients studied indicate that the dose inhomogeneity for IMBs is +/- 5%, compared with a value of +/- 10% for a wedged plan. The uncertainty in radiological thickness measurement corresponds to a dosimetric error of +/- 2%. Other errors associated with outline estimation are typically less than 2%, with a largest value of +5% for one of the patients who had a large and highly asymmetrical breast. The results for the two patients studied suggest that the uncertainties in the method are significantly smaller than the improvement in dose uniformity produced.

This paper reports on the delivery of radiotherapy to the primary site and lymphatic pathways in the management of early stage breast cancer. Radiotherapists were clear that their aim of locoregional radiotherapy was to reduce local recurrence. However, variation in policies for delivery were seen: 80% of radiotherapists did not always give radiotherapy routinely following wide local excision as part of breast conserving management; instead they withheld it selectively for a number of reasons. Only 66% routinely used breast boosts. There was a range of indications for giving radiotherapy to the lymphatic pathways; there was also variation in the management of incompletely or marginally excised primary tumours. Most sources of variation in the practice of radiotherapy in the management of women with early stage breast cancer appeared to arise from scientific uncertainty. However, organizational issues influenced many decisions. These scientific uncertainties and organizational issues are best addressed in the context of multidisciplinary breast clinics.

A national survey of British radiotherapy schedules used in women with early breast cancer was undertaken to document variation in treatment practices and to consider its clinical significance. Although the variation is considerable, the analysis suggests that the majority of schedules in use are very similar in terms of treatment intensity when allowance is made for fraction size and overall time. Half the respondents used one of three dosage schedules, which probably differ very little in terms of late normal-tissue effects and tumour control from a conventional schedule giving 50 Gy in daily 2 Gy fractions. Eighty-two percent of respondents were using schedules that are equivalent to a dose of between 45 Gy and 50 Gy in 2 Gy fractions. The study suggests that the protocols in use by a minority of respondents may be unduly conservative or aggressive, and it leads to the proposal that oncologists should set up trials comparing commonly used schedules as a matter of urgency.

A prospective assessment of late changes in breast appearance in 559 patients after tumour excision and radiotherapy for early breast cancer noted a strong association with breast size. Only 3/48 (6%) patients with small breasts developed moderate or severe late changes compared with 94/423 (22%) with medium sized breasts and 34/88 (39%) patients with large breasts (p < 0.001). One possibility is that greater radiation changes are related to greater dose inhomogeneity in women with large breasts. To explore this hypothesis, radiation dose distributions were assessed in a separate group of 37 women in whom three-level transverse computer tomographic images of the breast in the treatment position were available. A significant correlation was found between breast size and dose inhomogeneity which may account for the marked changes in breast appearance reported in women with large breasts.

There is a wide variation in normal tissue reactions to radiotherapy and in many situations the severity of these reactions limits radiotherapy dose. Clinical fractionation studies carried out in Gothenburg have demonstrated that a large part of the spectrum of normal tissue reactions is due to differences in individual normal tissue sensitivity. If this variation in normal tissue reactions is due to differences in intrinsic cellular radiosensitivity, it should be possible to predict tissue response based on measurement of cellular sensitivity. Here we report the initial results of a study aimed at establishing whether a direct relationship exists between cellular radiosensitivity and tissue response. Ten fibroblasts strains, including four duplicates, were established from a group of patients in the Gothenburg fractionation trials who had received radiotherapy following mastectomy. Skin doses were measured and both acute and late skin changes were observed following radiotherapy. Right and left parasternal areas were treated with different dose fractionation schedules. Clonogenic assays were used to assess intrinsic cellular radiosensitivity, and all experiments were carried out without prior knowledge of the clinical response, or which strains were duplicates. Irradiation was carried out using 60Co gamma-rays at high dose-rate (HDR) of 1-2 Gy/min and low dose-rate (LDR) of 1 cGy/min. A spectrum of sensitivity was seen, with SF2 values of 0.17-0.28 at HDR and 0.25-0.34 at LDR, and values of D0.01 of 5.07-6.38 Gy at HDR and 6.43-8.12 Gy at LDR. Comparison of the in vitro results with the clinical normal tissue effects shows a correlation between cellular sensitivity and late tissue reactions, which is highly significant with p = 0.02. A correlation between cellular sensitivity and acute effects was noted in the left-sided parasternal fields, but not the right. This is thought to be coincidental, and without biological significance. Our results suggest that cellular sensitivity might form the basis for the development of an assay system capable of predicting late normal tissue effects to curative radiotherapy, which might allow dose escalation in some patients. Increased local control and cure, with unchanged or improved normal tissue complications, could result from such individualised radiotherapy prescriptions.

Ultrasound has been used in 30 patients to measure breast thickness as a means of selecting the most appropriate electron energy for the boost in breast conservation radiotherapy. When compared with electron energies selected on the basis of clinical examination, the target volume was underdosed in 21/30 patients. A major problem in the placement of an electron boost is the demarcation of the target volume.

In recent years there have been great advances and innovations in all technical aspects of radiotherapy, including three dimensional (3D) computer planning, patient immobilization, radiation delivery and treatment verification. Despite this progress, the technique of tangential breast irradiation has changed little over this period and has not exploited these advances. There is increasing evidence that dose inhomogeneity within the breast is greater than at other anatomical sites, especially in women with large breasts. This paper is a review of the factors contributing to poor dosimetry in the breast, the clinical consequences of an inhomogeneous dose distribution, and how breast dosimetry could be improved by considering each of the stages from planning to accurate treatment delivery. It also highlights the particular problem of women with large breasts who may be more likely to have a poorer cosmetic outcome after a fractionated course of radiotherapy than women with small/medium-sized breasts, and supports the clinical impression that such women are also more likely to have greater dose inhomogeneity when 3D treatment plans are examined. Preliminary data from our current computed tomography (CT) planning study are presented to support these observations.

To evaluate the relationship between radiation-induced cell survival and DNA damage in primary human fibroblasts to decide whether the initial or residual DNA damage levels are the more predictive of normal tissue cellular radiosensitivity.

In recent years there have been great advances and innovations in all technical aspects of radiotherapy, including three dimensional (3D) computer planning, patient immobilization, radiation delivery and treatment verification, Despite this progress, the technique of tangential breast irradiation has changed little over this period and has not exploited these advances. There is increasing evidence that dose inhomogeneity within the breast is greater than at other anatomical sites, especially in women with large breasts. This paper is a review of the factors contributing to poor dosimetry in the breast, the clinical consequences of an inhomogeneous dose distribution, and how breast dosimetry could be improved by considering each of the stages from planning to accurate treatment delivery. It also highlights the particular problem of women with large breasts who may be more likely to have a poorer cosmetic outcome after a fractionated course of radiotherapy than women with small/medium-sized breasts, and supports the clinical impression that such women are also more likely to have greater dose inhomogeneity when 3D treatment plans are examined. Preliminary data from our current computed tomography (CT) planning study are presented to support these observations.

We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

The success of radiotherapy depends on the total radiation dose, which is limited by the tolerance of surrounding normal tissues. Since there is substantial variation among patients in normal-tissue radiosensitivity, we have tested the hypothesis that in-vitro cellular radiosensitivity is correlated with in-vitro normal-tissue responses. We exposed skin fibroblast cell lines from six radiation-treated patients to various doses of radiation and measured the proportions surviving. There was a strong relation between fibroblast sensitivity in vitro and normal-tissue reactions, especially acute effects. Assessment of radiosensitivity could lead to improved tumour cure rates by enabling radiation doses to be tailored to the individual.

270 patients with painful bone metastases requiring palliative radiotherapy were randomised to receive single fractions of 4 Gy or 8 Gy in a randomised trial. Pain scores and analgesic usage were recorded before treatment and at 2, 4, 8 and 12 weeks. Pain was assessed by patients on a 4 point graded scale using pain charts administered by a central trials office. Response was defined as an improved rating compared to the pretreatment value. Compliance with the pain chart was 72% at 4 weeks. At 4 weeks, the actual response rates were 69% for 8 Gy and 44% for 4 Gy (p less than 0.001), but there was no difference in complete response (no pain) rates at 4 weeks or duration of response between the two arms. It is concluded that 8 Gy gives a higher probability of pain relief than 4 Gy, but that 4 Gy can be an effective alternative in situations of reduced tolerance.

As radiotherapy following surgery for early breast cancer carries morbidity, financial cost, and potential mortality we have sought to select characteristics that will allow these risks to be minimised. The causes of increased mortality shown in the overview of mature trials of radiotherapy have been studied in a single large randomised trial. This has identified patients with large, poorly differentiated tumours to be most likely to benefit from the reduction in incidence of local recurrence achieved by radiotherapy while remaining at the lowest risk from suffering the increased mortality associated with the treatment. Much of the morbidity of radiotherapy is due to routine irradiation of lymphatic pathways. Three hundred and seven patients treated by breast-conserving surgery and breast radiotherapy have been evaluated. None received irradiation to their axilla or internal mammary lymphatics. Relapse in locoregional lymphatics (axilla or supraclavicular fossa) occurred in 15 patients. Only 4 had persisting symptoms from this relapse following further treatment.

Changes in body weight have been studied in 92 consecutive patients with primary breast cancer from the time of initial diagnosis and treatment. Sixty patients receiving tamoxifen were compared with 32 controls receiving no hormone treatment. Weight gain was seen in both groups, but was greater in the group receiving tamoxifen. Premenopausal women receiving tamoxifen had greater weight gain than postmenopausal women on tamoxifen therapy.

In view of the morbidity and potential mortality associated with routine post-operative lymph node radiotherapy in women with early stage breast cancer, an attempt has been made to select patients in whom radiotherapy can be withheld. Three hundred and forty-seven consecutive patients treated wide local excision plus or minus axillary surgery have been evaluated. Only 20% were subsequently given radiotherapy to regional nodes. Relapse in the axilla, the supraclavicular fossa or at both these sites have occurred in 16 patients so far, 12 of whom were successfully treated. Systemic relapse was seen in eight of these patients occurring with one exception before or within 3 months of node relapse. Only four have persisting symptoms as a result of nodal relapse. So far, a policy involving selective lymphatic radiotherapy in women treated for early breast cancer appears justified.

The cosmetic and functional results of breast conserving therapy were evaluated in a sample of 76 patients with early stage breast cancer, treated by wide local excision, axillary dissection and postoperative radiotherapy between 1975 and 1985. A comparison was made between patients' ratings, independent ratings by two observers (an oncology nurse and a radiation oncologist) and objective measurements. In approximately 40% of the cases, moderate to large differences in the appearance of the treated versus the untreated breast were reported by patients and clinical observers alike. When evaluated on an individual level, the observers' ratings showed relatively high inter-rater agreement (kappa = 0.64), but low levels of concordance were found between the patients' and observers' ratings (kappa < 0.10). Approximately half of the patients reported limited arm or shoulder function, generally mild in nature. Compared to the patients', the observers' ratings of arm edema were significantly lower, indicating 20% mild and 5% more severe swelling. Objective measures of cosmesis and function correlated moderately with the observers' and patients' ratings. Both cosmetic and functional results were found to be significantly related to time elapsed since treatment, with patients treated longer ago exhibiting more problems. The cosmetic and functional outcomes were not related to the patients' age. The results suggest that the patients' opinion can provide important additional information in the evaluation of cosmetic and functional results of breast conserving treatment.

The relationship between cosmetic and functional results of breast conserving therapy and psychosocial functioning was examined in a sample of 76 patients with early stage breast cancer, who received treatment between 1975 and 1985. The patients were interviewed at their homes regarding breast cosmesis, arm functioning and psychosocial health, and subsequently attended the hospital for independent assessment of cosmetic and functional outcomes by clinical observers. High levels of psychological distress, disturbance of body image, and decreased sexual functioning were noted in approximately one-quarter of the study sample. About half of the patients expressed heightened concern with disease recurrence and their future health. Psychosocial problems were only modestly associated with treatment-related cosmetic and functional outcomes, as determined by clinical ratings and objective assessments. The patients' own ratings of breast cosmesis and arm functioning exhibited somewhat higher correlations with self-reported psychosocial functioning. In particular, a significant association was noted between the patients' ratings of overall cosmesis and arm edema and their body image (r = 0.48 and r = 0.43, respectively). The association between cosmetic and functional results and self-reported psychosocial health was strongest among those patients younger in age and treated longer ago. These findings suggest that, in order to evaluate the impact of breast conserving therapy on the patients' quality of life, the patients' own assessments of cosmetic and functional outcomes should be used as a primary source of information.

Some of the cellular changes underlying the presentation of cancer in a patient can already be understood in terms of mutations affecting specific gene functions. So far, only a few of the mutated genes responsible for carcinogenesis have been identified and these are chiefly involved in deregulation of cell growth rather than with the processes of invasion and metastasis. Proto-oncogenes are important cellular genes which can acquire gain in function mutations as random events in somatic cells. In their mutated, activated forms they are called cellular oncogenes or c-oncs. This distinguishes them from homologous DNA sequences captured by viruses from host cells in the course of retroviral evolution that cause cancers in animal hosts (viral oncogenes or v-oncs). In recent years, loss of function mutations have been identified in regulatory genes that normally serve to constrain cell growth. These are called tumour suppressor genes. Loss of function mutations may be transmitted in the germline, as in hereditary retinoblastoma, or arise de novo in somatic cells. The normal molecular mechanisms disrupted by mutations in tumour suppressor genes include processes regulating progression through the cell cycle.

Thirty-six patients with small cell lung cancer have been treated using chemotherapy comprising carboplatin, ifosphamide and etoposide. A total of six cycles of chemotherapy were given. In 15 patients with limited disease intercalated radio-chemotherapy was used in which two 5-day courses of hyperfractionated radiotherapy were given to the thorax after the first and second cycles of chemotherapy. Each course of thoracic radiotherapy delivered 15 Gy in 15 fractions over 5 days. Oesophagitis occurred in 7 patients (40%), in 5 of whom this was severe (WHO grade 3). Radiological pneumonitis developed in 6 patients (40%) with subsequent fibrosis in 2 patients. These effects are greater than would be expected with this dose of radiation alone and reflect marked enhancement of normal tissue toxicity.

Large randomized clinical trials have redefined patterns of spread which have major implications for treatment options and outcomes in early stage breast cancer. Trials comparing mastectomy plus radiotherapy with mastectomy alone in women with T1-2 N0-1 M0 disease show clearly that the probability of developing distant metastases is unaffected by treatment of the lymphatic pathways. The inference is that, for the vast majority of women presenting with early stage disease, the cancer is either confined to the breast or else disseminated via vascular and lymphatic channels more or less simultaneously. Breast cancer is almost unique in that distant metastases may remain occult for several decades before becoming clinically apparent by mechanisms which remain unclear. The probability of haematogenous dissemination correlates closely with tumour size and this observation is the basis of population-based screening programmes discussed elsewhere in this issue. By identifying tumours earlier in their evolution, effective treatment of the primary disease is expected to be curative in a greater proportion of women. The implications for breast conserving management of women with early stage breast cancer are that initial surgery and radiotherapy must be of a high quality and promptly delivered if the expected reductions in breast cancer mortality are to materialize.

The improvements achievable by introducing individual tissue compensators in photon therapy of the breast were assessed. In 37 patients the dose ranged from +15% to -10% of the mid target dose using combinations of wedge filters and beam weights alone. With a tissue compensator the dose ranged from +4% to -11% provided that allowance was made for lung attenuation. A megavoltage imaging system is a potential source of the X-ray transmission data which can provide a basis for the calculation of thickness of the compensator.

Fifteen women undergoing breast radiotherapy following wide local excision of an early stage breast cancer were submitted to repeated measurements of surface landmarks to check the reproducibility of patient positioning, and to portal imaging using a megavoltage imaging device. When the patient is being set-up the mean rise and fall of a lateral skin mark (tattoo) was within 4 mm in 95 observations of 15 patients. At the end of the lateral field exposure, the mean displacement of the lateral tattoo was close to zero, with only 15/95 (16%) observations falling outside the range +/- 2 mm. The daily measurements of lung thickness fell above and below the simulated lung thickness, consistent with random fluctuations. Eighty-eight percent of lung thickness measurements were within +/- 5 mm of the simulator position. A tentative conclusion is made that more sophisticated immobilisation and imaging devices may be unnecessary for breast irradiation with a high degree of reproducibility.

A consensus on a quality assurance programme of the treatment of early breast cancer was reached in a multidisciplinary meeting of surgeons, pathologists, radiotherapists, physicists and radiographers. Guidelines for treatment preparation and execution have been set up, including careful location and excision with marking of the primary tumour. The target volumes for irradiation of the whole breast and boost area have been defined. Radiation dose prescription rules, specification and checking procedures are given, together with measures to achieve a homogeneous dose within the target volume. The rules for a quality assurance programme in each clinic are designed for checking equipment and treatment method.

A recent trial by the MRC Lung Cancer Working Party used physician assessments to compare two palliative schedules of radiotherapy in lung cancer. A prospective study has been undertaken on a subset of these trial patients to see how physician assessments of symptomatic relief and general condition correlate with patient perception of therapeutic response. In 40 patients followed up monthly from presentation until close to death, good agreement was found between doctors and patients on change in specific physical symptoms and overall physical condition. Doctors were poor judges of life quality at presentation but appeared able to identify relative improvement or deterioration in overall quality of life. In conclusion, physician assessments may constitute valid end-points for radiotherapy trials comparing palliative schedules in lung cancer.

Thirty-two previously untreated, fit patients with small-cell lung carcinoma (SCLC) were treated with an intensive combination chemotherapy regimen, with the aim of prolonging survival, as follows: carboplatin 400 mg/m2 intravenously (IV) day 1, ifosfamide 5 g/m2 IV day 1 in a 24-hour infusion with mesna, and etoposide 100 mg/m2 IV days 1 to 3, repeating at 28-day intervals for six courses. Limited-disease (LD) patients were given concurrent hyperfractionated radiotherapy for the first two courses, and all patients achieving a complete remission (CR) were offered prophylactic cranial irradiation (PCI). For 18 LD patients, the overall response was 94% with 72% CRs. For 14 extensive-disease (ED) patients the overall response was 100% with 29% CRs. Median response duration for LD patients was 11.5 months and for ED patients 7.5 months. Median survival for LD patients was 19 months with a predicted 24% 2-year survival and for ED patients 9.5 months with a predicted 14% 2-year survival. Hematologic toxicity was severe with 100% developing World Health Organization (WHO) grade 3-4 neutropenia and 94% WHO grade 3-4 thrombocytopenia during treatment. Seventy-two percent of patients required a dose reduction at some stage during treatment because of neutropenic infection or thrombocytopenia requiring platelet transfusions. Despite very high response rates, this intensive regimen achieves survival results only modestly better, if at all, than those reported for less toxic conventional regimens.

Single fraction radiotherapy can be used effectively to palliate painful bone metastases. The optimal single dose of radiotherapy required for pain relief is unknown. Twenty-six patients have been treated with a single fraction of 4 Gy to the site of the bone pain. Partial pain relief was seen in 9/21 (5%). Response occurred within 3 weeks of radiotherapy. These results question the mechanism of pain relief following radiotherapy and suggest a method of pain control using single repeatable low dose treatments.

Carboplatin (JM8) and etoposide (VP16) have demonstrated activity against a range of solid tumours. A retrospective study has looked for evidence of enhanced radiation pneumonitis when these drugs are employed in conjunction with irradiation. Twenty-nine patients with limited disease small cell lung cancer (S.C.L.C.) received JM8 (300 mg/m2) and VP16 (300 mg/m2) at intervals of 3-4 weeks for 4 cycles followed by thoracic irradiation. Twenty-one were evaluated and compared with 21 matched non-S.C.L.C. patients treated by radiotherapy alone. Patients were stratified into three groups according to the radiation dose schedule normalised using Wara's modification of Ellis' formula (n = 0.38, t = 0.06) [28]. Group 1 received less than 1014 rets, Group 2 1015-1250 rets and Group 3 greater than 1250 rets. Radiological pneumonitis was observed in 57% (12/21) of patients receiving combined modality treatment compared to 71% (15/21) of patients receiving radiation alone with evidence of a radiation dose-response relationship for the appearance of pneumonitis in both groups of patients (p greater than 0.1). In conclusion, no enhancement of radiation pneumonitis by carboplatin (JM8) or etoposide (VP16) has been observed.

One hundred patients with breast recurrence have been identified from patients at the Royal Marsden Hospital, treated by local excision +/- radiotherapy for early stage primary invasive breast cancer between 1961 and 1985. The mean follow-up was 58 months (range 1 month - 19 years). In 74/100 patients, breast recurrence occurred within the breast parenchyma, was not associated with systemic relapse and carried a relatively good prognosis with a median survival of 77 months from the time of breast relapse. In 67 patients with parenchymal relapse in whom the site of relapse could be reliably compared with that of the original tumour, 60 (90%) patients developed recurrent tumours at or close to the primary site. In 24/100 patients, breast recurrence occurred in the overlying skin and in only two of these patients (2% of total) did recurrence actually occur within the scar tissue. Skin relapse was associated with systemic relapse and carried a relatively poor prognosis with a median survival of 36 months from the time of recurrence. The pattern of breast relapse was similar in irradiated and unirradiated patients. Skin relapse appears to be a manifestation of metastatic disease while parenchymal relapse may represent regrowth of primary tumour. This pattern of breast relapse questions the requirement for radiotherapy to the whole breast after local excision for early stage breast cancer.

In 20 patients with invasive bladder cancer suitable for radical radiotherapy, a simple conformal planning technique has been compared with conventional beam arrangements in terms of normal tissue sparing. The median treatment volume for the group was reduced from 2275 to 1416 cm3 by the introduction of conformal planning. More specifically, in 13/20 patients (65%) the percentage volume of rectum irradiated to 90% of the isocentric dose was reduced by more than 30%, although the extent of rectal sparing varied greatly between patients. Overall, conformal planning appeared to be less successful at reducing the volume of large and small bowel irradiated to high dose. However, the data suggest that considerable benefit can be expected for those patients most at risk of morbidity by virtue of high bowel volumes included within the treatment length. A randomised trial is now being set up to determine the clinical impact of this planning technique in terms of reduced bowel morbidity.

Fifty-two previously untreated patients with small-cell lung carcinoma (SCLC) were treated with a combination of carboplatin 300 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on days 1 through 3 every 28 days for four courses. Patients with limited disease (LD) subsequently received thoracic radiotherapy; no prophylactic cranial radiotherapy was used. Forty-four patients (85%) achieved an objective response, including 82% (29% complete remissions) of LD patients and 88% (13% complete remissions) of extensive-disease (ED) patients. Median response duration for LD patients was 7 months and 5.5 months for ED patients. Median survival for both LD and ED patients was 9.5 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3/4 leucopenia occurring in 44% of patients. There was one (2%) treatment-related neutropenic death. Treatment was otherwise well tolerated, and in particular no renal toxicity, neurotoxicity, or ototoxicity was seen. This new combination is highly active in terms of response rate, but response duration and survival is disappointing, and might be improved by prolonged treatment or by the use of additional drugs in combination.

A retrospective study has been undertaken to test the NSD formula as a predictor of isoeffective schedules in women treated after mastectomy by parasternal radiotherapy using fraction sizes of 2-3 Gy. Forty three women were identified who have been treated on the same orthovoltage unit 8-18 years previously and the severity of overall skin changes and telangiectasia were assessed by three observers using a 4-point categorical scale. At each level of skin damage, radiotherapy schedules delivered using fraction sizes of 250 R or 300 R were associated with lower TDF values than schedules using 225 R fraction. The difference between TDF factors for isoeffective regimes using small (225 R) and large (250 R and 300 R) fraction sizes is highly significant for both overall skin damage and telangiectasia (p = 0.004 by rank sum test). Care should be exercised when using current empirical formulae to calculate regimes isoeffective for late skin damage, even when modest changes in fraction size from 2 to 3 Gy are contemplated.

The result of conservative management of breast cancer is strongly dependent on the homogeneity of the dose delivered a schedule of post-surgical radiotherapy. In addition to improvements in local control, late normal-tissue effects should be minimised by achieving a good dose homogeneity. The Royal Marsden Hospital prototype CT simulator has been used to image patients in the treatment position. With the CT data incorporated into the planning process a quantitative measure of the dose homogeneity was made. There are strong indications that unless tissue compensators are used and/or conformation therapy is performed, the dose inhomogeneity in a widely used treatment geometry is too large to be clinically acceptable.

Three hundred and twenty-two postmenopausal patients with primary breast cancer and ipsilateral axillary node involvement were randomized to receive aminoglutethimide and hydrocortisone or placebo for 2 years in a double blind randomized trial between April 1980 and March 1985. Two hundred and eighty-six patients were eligible for the study of whom 145 received active drug and 141 received placebo. At the present time significantly fewer patients have relapsed or died without previous relapse in the treatment arm (P = 0.002); 43 of 145 (30%) patients receiving aminoglutethimide have relapsed or died compared with 63 of 141 (40%) of those receiving placebo. Local recurrence is also significantly reduced (P = 0.002) since only 6 patients receiving active treatment developed local recurrence compared to 21 receiving placebo. Side effects were severe enough to necessitate complete withdrawal or reduction of therapy in 27 of 145 (19%) in the treatment arm of the study compared with 21 of 141 (15%) in the placebo arm. A single treatment-related death occurred, due to agranulocytosis. Aminoglutethimide and hydrocortisone therefore delay relapse after surgery for primary breast cancer in postmenopausal women. It is too early to assess any effect on overall survival.

Thirty-nine of 225 patients with small cell lung cancer developed brain metastases after the initiation of chemotherapy. Treatment with high-dose dexamethasone in all 39 patients and cranial irradiation in 32 patients resulted in a complete neurological recovery in only eight of 39 patients (20%). Twenty-one of 39 patients (53%) failed to derive lasting benefit from their palliative treatment. Thirteen of 24 patients with limited disease with cranial relapse had no clinical evidence of other distant metastases prior to death and in these patients the CNS disease was an important cause of morbidity. On the basis of this study, it appears that palliative treatment of overt cranial metastases is relatively unsuccessful and that patients with limited disease represent a group with much to gain from effective prophylactic cranial irradiation.

The requirement for palliative chest radiotherapy in patients with non-small cell lung cancer (NSCLC) was assessed in a study of 134 inoperable patients not suitable for radical radiotherapy. Immediate chest radiotherapy was judged necessary in 86 (64%) because of significant symptoms from intrathoracic tumour or involvement of proximal airways. Forty-eight patients were monitored regularly without initial radiotherapy and of these, 26 (54%) required later chest irradiation because of progressive and significant symptoms due to intrathoracic disease. Median symptom-free survival in this group was 10 months. The requirement for immediate or delayed chest irradiation could not be predicted from either patient or tumour characteristics. The proportion of patients with NSCLC requiring palliative chest irradiation may have been overestimated from this study population; even so 22 of 134 patients (16%) did not at any stage in their illness require radiotherapy for chest symptoms.

CNS relapse after PCI may reflect either suboptimal radiation dose schedules or reseeding from other sites of active disease. A retrospective study has been undertaken to investigate these alternative mechanisms of treatment failure. Between August 1981 and December 1983, 30 patients with SCLC treated by induction chemotherapy, followed by high-dose cyclophosphamide (7 Gm/m2), were selected for PCI on the basis of clinical, radiological, and bronchoscopic CR. Pretreatment CT brain scans were normal in all patients, and 20 Gy mid-plane dose in 5 daily fractions were delivered by lateral fields to whole brain using megavoltage X rays and localizing check films. Progressive focal neurological signs of cranial metastases developed in 7/30 (23%) patients 3-11 months after PCI, confirmed on CT scanning in 4 patients. Relapse at other sites, predominantly the thorax, occurred in all seven patients at intervals of 1-6 months prior to CNS relapse. Published clinical data of tumor volume doubling times in SCLC predict longer CNS relapse-free intervals after PCI than those observed in our patients if reseeding was responsible for relapse. This suggests that incomplete eradication of intracranial disease is the main cause of CNS relapse after PCI. Higher equivalent radiation doses may improve the results of PCI.

Tumour growth delay has been investigated as an endpoint of radiation effect in selected patients with superficial metastases measured by calipers and ultrasound. Of 42 patients referred for study with two or more nodules, 17 were suitable for entry into protocols evaluating single or multifraction treatment. The reproducibility of tumour growth delay to the same dose schedule was evaluable in four patients and the sensitivity to 10-20% differences in total dose was evaluable in three patients. No significant size dependency was detected in the response of nodules to radiotherapy and the findings suggest that the growth delay endpoint is sensitive to 20% differences in radiation dose. Evaluable patients with multiple measurable nodules are uncommon but constitute a valuable resource for the testing of biological response modifiers, including radiosensitizers.

A prospective randomised trial comparing a single fraction of 8 Gy with 30 Gy in 10 daily fractions for the relief of metastatic bone pain was performed. In 28 months, 288 patients were randomised. Pain was assessed using a questionnaire completed by the patient at home on a daily basis. No difference was found in the speed of onset or duration of pain relief between the two treatment regimes, and pain relief was independent of the histology of the primary tumour.

Within an original consecutive series of 94 patients, 36 eligible patients with small cell lung carcinoma were treated with high-dose cyclophosphamide 7 g/m2 after conventional chemotherapy with VP16, adriamycin, and vincristine. The first 17 also underwent autologous bone marrow rescue. Treatment was well tolerated apart from one treatment-related death. Measurable tumour was still present in 15 patients before high-dose cyclophosphamide, and although 12 (80%) of these achieved further tumour response, these responses were all short-lived, with a median duration of 9 weeks. In 14 limited-disease patients already in complete remission before high-dose therapy the initial result was better, but 11 (79%) have now relapsed following overall median response duration of 10 months. High-dose cyclophosphamide after conventional chemotherapy is feasible and achieves a high response rate, but it does not appear to be associated with significant survival benefit either overall or in patient subgroup.

Carboplatin, a cisplatin analog without significant clinical nephrotoxicity, has been evaluated in the treatment of 56 patients with small cell lung carcinoma at a dose of 300-400 mg/m2 iv monthly in a phase II study. Twenty-three patients (41%) achieved a response, including five (9%) complete remissions. Of 30 previously untreated patients, 18 (60%) achieved a response, including three (10%) complete remissions. Median response duration was 4.5 months (range, 2-9). No nephrotoxicity was seen and hydration was not required. Nausea or vomiting occurred in only 24 patients (43%) and was rarely severe. Myelosuppression was dose-limiting: 20 patients (36%) developed leukopenia and eight (14%) developed thrombocytopenia, but leukopenic infections occurred in only three patients. Carboplatin is a very active new agent in the treatment of small cell lung cancer, with less toxicity and better tolerance than cisplatin. It merits further investigation in combination chemotherapy and against non-small cell lung cancer.

High-dose lymphatic irradiation is a contributory factor to the morbidity of treatment after local excision and high-dose radiotherapy for early stage breast cancer and may detract significantly from the cosmetic result. The apparent inability of lymphatic irradiation to influence the survival of patients with early stage breast cancer supports an argument for the selective avoidance of regional radiotherapy in a proportion of patients. Based on a review of the effects of lymphatic radiotherapy on lymphatic control, complications, cosmesis, survival and the effects of withholding lymphatic irradiation, recommendations are made for the selective treatment of patients at high risk of regional recurrence. In patients submitted to full axillary dissection, node negative patients require no lymphatic irradiation. After full axillary dissection radiotherapy is confined to the supraclavicular fossa in patients with heavy axillary involvement. A policy for patients having limited axillary dissection is discussed which identifies approximately 50% of patients as eligible for careful watch policy following local excision and high-dose radiotherapy to the primary disease.

Acute and delayed normal tissue damage has been investigated in 63 advanced stage testicular non-seminoma patients receiving elective involved-field irradiation after chemotherapy and in 53 patients who had chemotherapy given for relapse after prior irradiation. The risk of death from complications due to chemotherapy was 0% and 9.4% (p less than 0.025) in the two groups respectively. Gastro-intestinal damage and/or subcutaneous fibrosis was present in 12.6% and 24.5% of patients respectively, although only three patients have serious persisting disability. In patients receiving 35-45 Gy to the retroperitoneum the incidence of normal tissue damage was 0% and 25% (p less than 0.001), respectively. In addition to the sequence in which chemotherapy and radiotherapy was delivered, the time interval between completion of radiotherapy and start of chemotherapy was important with 6/6 patients receiving drugs within 2 months of irradiation developing fibrosis. Abdominal surgery appeared not to influence the risk of damage. Of nine patients receiving drugs after infradiaphragmatic and supra-diaphragmatic irradiation two died of neutropenic sepsis.

A study of the factors affecting relapse following combination chemotherapy has been undertaken in 64 previously untreated patients with Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. Bulk disease was significantly more common in the treatment failure group, being present in 23 out of 37 patients who failed compared to eight out of 27 patients who remain relapse-free (P less than 0.025). Reduced drug dosage was associated with treatment failure in 19 out of 37 patients receiving suboptimal chemotherapy compared to only four of 27 patients in the relapse-free group (P less than 0.01). Patients over the age of 50 years were more likely to receive suboptimal drug dosages (P less than 0.05).

A study of the relationship between bulk disease and sites of relapse has been undertaken in 95 patients treated by radiotherapy for early stage Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. In a group of 80 pathologically staged patients the pattern of relapse in 39 patients confirms an association between recurrence and sites of bulk involvement in the mediastinum, neck and axilla. Bulk disease predisposes to recurrence by virtue of local failure inside the treatment volume as well as marginal recurrence. A small number of patients relapsed initially in sites that were irradiated prophylactically.

The outcome of serious radiation injuries to the pelvic viscera in 400 patients treated by radiotherapy for carcinoma of the uterus between January 1974 and December 1978 has been reviewed. Twenty-eight instances of serious radiation damage have been found, 13 of predominantly small bowel damage, 11 of predominantly large bowel damage and 4 of bladder damage. Many patients had involvement at multiple sites. Fourteen patients have died, and 9 survivors have artificial abdominal stomas. Leaking anastomoses and progressive sepsis were major problems in the postoperative period and could be related either to inadequate resection of irradiated bowel or to damage to other organs at operation. The possibilities of earlier diagnosis and better surgical procedures are discussed.

One hundred and six patients dying of malignant melanoma have been studied to test alternative explanations of long disease-free intervals following primary excision. The time intervals from excision to relapse with local, lymphatic-borne or blood-borne recurrences do not correlate with the subsequent survival of the patient. If the experimental technique is valid, it supports the hypothesis that a long latent interval following primary excision represents a variable period of growth restraint followed by reactivation of disease rather than a period of continuous tumour growth throughout the disease-free interval.