Søren M. Bentzen

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial

Summary Background 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. Methods Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy versus 41·6 Gy or 39 Gy in 13 fractions of 3·2 Gy or 3·0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 749 women were assigned to the 50 Gy group, 750 to the 41·6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5·1 years (IQR 4·4–6·0) the rate of local-regional tumour relapse at 5 years was 3·6% (95% CI 2·2–5·1) after 50 Gy, 3·5% (95% CI 2·1–4·3) after 41·6 Gy, and 5·2% (95% CI 3·5–6·9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0·2% (95% CI −1·3% to 2·6%) after 41·6 Gy and 0·9% (95% CI −0·8% to 3·7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0·69 (95% CI 0·52–0·91, p=0·01). From a planned meta-analysis with the pilot trial, the adjusted estimates of α/β value for tumour control was 4·6 Gy (95% CI 1·1–8·1) and for late change in breast appearance (photographic) was 3·4 Gy (95% CI 2·3–4·5). Interpretation The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41·6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

Summary Background 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. Methods Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. Interpretation A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology

Radiation therapy has curative or palliative potential in roughly half of all incident solid tumours, and offers organ and function preservation in most cases. Unfortunately, early and late toxicity limits the deliverable intensity of radiotherapy, and might affect the long-term health-related quality of life of the patient. Recent progress in molecular pathology and normal-tissue radiobiology has improved the mechanistic understanding of late normal-tissue effects and shifted the focus from initial-damage induction to damage recognition and tissue remodelling. This stimulates research into new pharmacological strategies for preventing or reducing the side effects of radiation therapy.

Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma

The value of hyperthermia as an adjuvant to radiotherapy in patients with malignant melanoma was studied in a European multicentre trial. 134 metastatic or recurrent lesions of malignant melanoma in 70 patients were randomly assigned to receive radiotherapy (three fractions of 8 Gy or 9 Gy in 8 days) alone or followed by hyperthermia (43 degrees C for 60 min). Overall, the 2-year actuarial local tumour control was 37 (SE 5)%. Univariate analysis showed a beneficial effect of hyperthermia (radiation alone 28% vs combined treatment 46%, p = 0.008) and radiation dose (24 Gy 25% vs 27 Gy 56%, p = 0.02), but no effect of tumour size (< or = 4 cm 42% vs > 4 cm 29%, p = 0.21). Cox multivariate regression analysis showed the most important prognostic variables to be hyperthermia (odds ratio for 2-year local control 1.73 [95% CI 1.07-2.78], p = 0.023), tumour size (0.91 [0.85-0.99], p = 0.05), and radiation dose (1.17 [1.01-1.36], p = 0.05). Addition of heat did not significantly increase acute or late radiation reactions. Heating was well tolerated, but because of difficulties with equipment only 14% of treatments achieved the protocol objective. The overall 5-year survival rate was 19%, but 38% of the patients for whom all known disease was controlled survived 5 years. Adjuvant hyperthermia significantly improved local tumour control when applied in association with radiation in treatment of malignant melanoma. Successful local treatment of patients with a single or a few metastatic malignant melanoma lesions has significant curative potential.

Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An Introduction to the Scientific Issues

Advances in dose-volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5-10 years are proposed.

Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial

BACKGROUND 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. METHODS In 1986-98, we randomly assigned 1410 women with invasive breast cancer (tumour stage 1-3 with a maximum of one positive node and no metastasis) who had had local tumour excision of early stage breast cancer to receive 50 Gy radiotherapy given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions, all given over 5 weeks. The primary endpoint was late change in breast appearance, which has been reported elsewhere. Here, we report ipsilateral tumour relapse, one of the secondary endpoints. Relapse was defined as any appearance of cancer in the irradiated breast. Analysis was by intention to treat. FINDINGS After a median follow-up of 9.7 years (IQR 7.8-11.8) for the 838 (95%) patients who survived, the risk of ipsilateral tumour relapse after 10 years was 12.1% (95% CI 8.8-15.5) in the 50 Gy group, 14.8% (11.2-18.3) in the 39 Gy group, and 9.6% (6.7-12.6) in the 42.9 Gy group (difference between 39 Gy and 42.9 Gy groups, chi2 test, p=0.027). The sensitivity of breast cancer to dose per fraction was estimated to be 4.0 Gy (95% CI 1.0-7.8), similar to that estimated for the late adverse effects in healthy tissue from breast radiotherapy. INTERPRETATION Breast cancer tissue is probably just as sensitive to fraction size as dose-limiting healthy tissues. If this finding is confirmed, radiotherapy schedules can be greatly simplified by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both.

Time-dose factors in radiotherapy: a review of the human data

The values for alpha/beta (fractionation sensitivity, or recovery capacity) for early and late reactions in human normal tissues are consistent with results from experimental animals. For breast treatments direct analysis indicates that for early reactions alpha/beta is in the range 7 to 11 Gy, while for late effects it is in the range 2 to 4 Gy. Data on recovery kinetics in human tissues is limited but these indicate that recovery may be slower in humans than in rodents. For early skin reactions the halftime of recovery is about 1 h, while for late telangiectasia it is more than 3 h. alpha/beta values for human tumors are more variable than in rodents: some are high (head and neck, lung, skin, cervix) and similar to those for early reacting normal tissues. Others are low, including melanomas, where alpha/beta was estimated at 0.6 (-1.1, 2.5) Gy, and liposarcomas, where direct analysis of cases surveyed from the literature suggested that alpha/beta = 0.4 (-1.4, 5.4) Gy. Repopulation kinetics is faster in the mucosa of the soft palate and faucial pillars (1.8 Gy/day) than in head and neck tumors (up to 1 Gy/day).

Theragnostic imaging for radiation oncology: dose-painting by numbers

Theragnostic imaging for radiation oncology is the use of molecular and functional imaging to prescribe the distribution of radiation in four dimensions-the three dimensions of space plus time-of radiotherapy alone or combined with other treatment modalities in an individual patient. Several new imaging targets for positron-emission tomography, single-photon-emission CT, and magnetic resonance spectroscopy allow variations in microenvironmental or cellular phenotypes that modulate the effect of radiation to be mapped in three dimensions. Dose-painting by numbers is a strategy by which the dose distribution delivered by inverse planned intensity-modulated radiotherapy is prescribed in four dimensions. This approach will revolutionise the way that radiotherapy is prescribed and planned and, at least in theory, will improve the therapeutic outcome in terms of local tumour control and side-effects to unaffected tissue.

International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases

Abstract Purpose : To reach a consensus on a set of optimal endpoint measurements for future external beam radiotherapy trials in bone metastases. Methods : An International Bone Metastases Consensus Working Party invited principal investigators and individuals with a recognized interest in bone metastases to participate in the two surveys and a panel meeting on their preference of choice of optimal endpoints. Results : Consensus has been reached on the following: (a) eligibility criteria for future trials; (b) pain and analgesic assessments; (c) radiation techniques; (d) follow-up and timing of assessments; (e) parameters at follow-up; (f) endpoints; (g) re-irradiation; and (h) statistical analysis. Conclusions : Based on the available literature and the clinical experience of the working party members, an acceptable set of endpoints has been agreed upon for future clinical trials to promote consistency in reporting. It is intended that the consensus will be re-examined every 5 years. Areas of further research were identified.

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial

BACKGROUND To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT). METHODS Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. RESULTS Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks. CONCLUSIONS Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.