Jean Bernard Dubois

Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial

BACKGROUNDnWe did a randomised phase III trial comparing external irradiation alone and external irradiation combined with an analogue of luteinising-hormone releasing hormone (LHRH) to investigate the added value of long-term androgen suppression in locally advanced prostate cancer.nnnMETHODSnBetween 1987 and 1995, 415 patients were randomly assigned radiotherapy alone or radiotherapy plus immediate androgen suppression. Eligible patients had T1-2 tumours of WHO grade 3 or T3-4 N0-1 M0 tumours; the median age of participants was 71 years (range 51-80). In both treatment groups, 50 Gy radiation was delivered to the pelvis over 5 weeks, and 20 Gy over 2 weeks as a prostatic boost. Goserelin (3.6 mg subcutaneously every 4 weeks) was started on the first day of irradiation and continued for 3 years; cyproterone acetate (150 mg orally) was given for 1 month starting 1 week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analyses were by intention to treat.nnnFINDINGSn412 patients had evaluable data, with median follow-up of 66 months (range 1-126). 5-year clinical disease-free survival was 40% (95% CI 32-48) in the radiotherapy-alone group and 74% (67-81) in the combined-treatment group (p=0.0001). 5-year overall survival was 62% (52-72) and 78% (72-84), respectively (p=0.0002) and 5-year specific survival 79% (72-86) and 94% (90-98).nnnINTERPRETATIONnImmediate androgen suppression with an LHRH analogue given during and for 3 years after external irradiation improves disease-free and overall survival of patients with locally advanced prostate cancer.

Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin

BACKGROUNDnWe conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer.nnnMETHODSnFrom 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin.nnnRESULTSnData were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001).nnnCONCLUSIONSnAdjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.

External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study

BACKGROUNDnWe did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results.nnnMETHODSnFor this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082.nnnFINDINGSnBetween May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1-12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3-29·7) in the radiotherapy-alone group and 47·7% (39·0-56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33-0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9-47·5) in patients receiving radiotherapy alone and 58·1% (49·2-66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45-0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2-37·5) and 10·3% (5·1-15·4), respectively (HR 0·38, 95% CI 0·24-0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment.nnnINTERPRETATIONnIn patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity.

Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial

BACKGROUNDnSince the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results.nnnMETHODSnPatients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033.nnnFINDINGSnBetween May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001).nnnINTERPRETATIONnA radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years.nnnFUNDINGnFonds Cancer, Belgium.

Acute Toxicity of Conventional Radiation Therapy for High-Risk Prostate Cancer in EORTC Trial 22863

OBJECTIVESnWe analysed the acute toxicity observed in the European Organisation for Research and Treatment of Cancer (EORTC) randomised trial 22863 comparing conventional external irradiation with or without an agonist analogue of gonadotropin-releasing hormone in high-risk prostate cancer patients.nnnMETHODSnFour hundred five patients that received a dose of at least 30 Gy were considered evaluable for acute toxicity assessment. Toxicity was grouped in a few categories: general, genito-urinary, and lower gastro-intestinal. Univariate and multivariate analyses were performed using the World Health Organisation (WHO) toxicity score and grouping together toxicity scores in different bimodal and trimodal groups.nnnRESULTSnOverall, our data show that age, previous surgery and irradiation dose are important predictive factors for acute toxicity, but not the use of combined hormone therapy. Fifteen percent of patients suffered of moderate to severe acute toxicity (WHO G3-G4). Life threatening toxicity was observed in six cases (1.5%).nnnCONCLUSIONSnThe assessment of toxicity combining in different groups the original five scores scale produced conflicting results similar to those commonly reported in literature. Interpretation of the role of pre-treatment factors with uneven distribution in the study requires careful evaluation. These data obtained with conventional curative irradiation of high-risk prostate cancer patients are proposed for comparison with results achieved using modern state-of-the-art irradiation techniques.

Irradiation partielle et accélérée du sein: une réelle perspective thérapeutique pour le cancer du sein de bon pronostic

RésuméAprès une chirurgie conservatrice, la radiothérapie adjuvante de la totalité de la glande mammaire reste le standard thérapeutique. L’irradiation partielle accélérée du sein (IPAS) et focalisée au lit opératoire, délivrée en quelques jours, constitue, dans le contexte de l’individualisation des traitements, une vraie option thérapeutique et un domaine de recherche prometteur qui permettrait une évolution historique de la radiothérapie mammaire. La durée plus courte du traitement (et la possibilité d’instituer rapidement les traitements médicaux), une meilleure observance thérapeutique et l’absence de recours à la mastectomie totale ont été considérées comme des arguments importants pour légitimer l’option de l’IPAS outre-Atlantique. Même si le profil de patientes idéal pour une IPAS n’est pas encore clairement défini, la tentation d’élargir les indications est grande chez les défenseurs du concept. Ce profil sera certainement basé sur un faisceau d’arguments qui seront discutés dans cet article.AbstractAfter conservative surgery, whole-breast radiation therapy remains the standard of care. Accelerated partial breast irradiation (APBI) delivered for one week is a new research avenue in individualized treatment and may lead to historic change in adjuvant breast radiation therapy. In North America, several factors, such as the duration of irradiation allowing early medical treatment, better treatment compliance and the decrease in total mastectomies, allowed the development of APBI. Although the ideal candidate for APBI has not been determined, several teams are advocating increased use of the procedure in a higher proportion of patients. Defining the appropriate selection criteria is crucial for future trials. In this paper, we discuss these selection criteria for better treatment individualization.