The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial.

PURPOSE: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer. PATIENTS AND METHODS: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented. RESULTS: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively. CONCLUSION: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group.

The European Organisation for Research and Treatment of Cancer (EORTC) 22921 four-arm randomised trial questioned the value of preoperative chemoradiation (XRT-CT) versus preoperative radiation (XRT) and the value of additional postoperative chemotherapy (CT) versus none in T3-T4 M0 resectable rectal cancer patients. We report on the preoperative toxicity, treatment compliance and early deaths (all deaths up to 30 days after surgery) of the two treatment modalities in patients who were entered into trial before January 2001. In the XRT Group (group A), patients received 45 Gy, 25 fractions over 5 weeks. In the XRT-CT Group (group B), two 5-day courses of CT were added to the first and fifth weeks of XRT. For each CT course: 5-fluorouracil (5-FU) 350 mg/m2/day and Leucovorin (LV) 20 mg/m2/day were given. 398 and 400 patients started treatment in groups A and B, respectively. Grade 2+acute diarrhoea occurred in 17.3 and 34.3% of patients in groups A and B, respectively (P<0.005). The other side-effects remained unchanged or were only marginally increased. The compliance with RT was 98.5 and 95.5% in groups A and B, respectively. In group B, 78.7 and 71.1% of the patients received 95-105% of the planned CT doses at the first and second courses, respectively. 6 patients died preoperatively, 2 from toxicity in group B. 8 patients (1%) died within the 30 days after surgery in both groups. At the doses recommended in the protocol, the addition of 5-FU-LV to preoperative XRT slightly increased the amount of acute toxicity. However, the compliance with the radiation protocol or the feasibility of surgery did not decrease.

The Quality Assurance programme of the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC): a critical appraisal of 20 years of continuous efforts.

In 1982, the European Organization for Research and Treatment of Cancer (EORTC) Radiotherapy Group established the Quality Assurance (QA) programme. During the past 20 years, QA procedures have become a major part of the activities of the group. The methodology and steps of the QA programme over the past 20 years are briefly described. Problems and conclusions arising from the results of the long-lasting QA programme in the EORTC radiotherapy group are discussed and emphasised. The EORTC radiotherapy group continues to lead QA in the European radiotherapy community. Future challenges and perspectives are proposed.

Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients?

The aim of this study was to identify patient-, tumour- or treatment-related factors associated with young age that might explain the higher risk of ipsilateral breast recurrence that occurs after breast-conserving therapy (BCT) in young breast cancer patients. In the 'boost versus no boost trial', 5569 early-stage breast cancer patients were entered. All patients underwent tumorectomy followed by whole breast irradiation of 50 Gy. Patients having a microscopically complete excision were randomised between receiving no boost or a 16-Gy boost, while patients with a microscopically incomplete excision were randomised between receiving a boost dose of 10 or 26 Gy. The 5-year local control rate was 82% for patients 60 years of age (P<0.0001). In young patients, the tumour was significantly larger and more often oestrogen and progesterone receptor-negative. Invasive carcinoma and the intraductal component were more often of a high grade. The intraductal component was more frequently incompletely resected in young patients. Re-excisions were performed more often (most probably due to a more frequent incomplete excision at the first attempt). The total volume of breast tissue removed at the tumorectomy was smaller in the younger patient group, even after including the volume removed during re-excision. When relating all these parameters (including age itself) to local control, the multivariate analysis stratified by treatment showed that age was the only independent prognostic factor for local control (P=0.0001). Including the boost treatment as a separate covariate, the analysis retained age and boost treatment as significant factors related to local control (P<0.0001). It was shown that the boost dose significantly reduced the 5-year local recurrence rate from 7 to 4% for patients with a complete excision (P<0.001). For patients 40 years of age or younger, the boost dose reduced the local recurrence rate from 20 to 10% (P=0.002). This large European Orgnaization for Research and Treatment of Cancer (EORTC) trial demonstrated an increased local recurrence rate in young patients. Although several associations between patient, tumour and treatment factors and age were found, that might explain the high local recurrence rate in the younger patients, it appears that age itself and the boost dose were the only factors that were independently related to local control.

Acute toxicity of conventional radiation therapy for high-risk prostate cancer in EORTC trial 22863.

OBJECTIVES: We 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. METHODS: Four 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. RESULTS: Overall, 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%). CONCLUSIONS: The 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.

Postoperative pelvic radiotherapy with or without elective irradiation of para-aortic nodes and liver in rectal cancer patients. A controlled clinical trial of the EORTC Radiotherapy Group.

OBJECTIVE: The purpose of this randomized multicenter study was to assess the impact on disease free and overall survival of low dose irradiation to para-aortic nodes and liver in patients with a locally advanced resected rectal cancer receiving a 50 Gy postoperative pelvic radiotherapy. PATIENTS AND METHODS: Main inclusion criteria were: a curative resection for a histologically proved carcinoma of the rectum, Gunderson-Sosin stages B2-B3, C1-C3, age <70 years. The patients were randomized between pelvic irradiation (Lim-XRT): 50 Gy in 25 fractions over 5 weeks and extended irradiation (Ext-XRT): same scheme/doses in the pelvis and extended fields on para-aortic nodes and liver, delivering 25 Gy in 19 fractions over 25 days. From 1983 to 1992, 484 patients were enrolled by 18 EORTC institutions and 29 patients were ineligible. The end-points were local and distant relapses, toxicity and survival. RESULTS: Compliance to treatment: 87.2% in Lim-XRT arm and 71.8% in Ext-XRT arm. Moderate acute hematological and hepatic toxicities were significantly increased in Ext-XRT arm. Among 325 patients at risk, 44 suffered a severe intestinal complication requiring surgery in 29. The 5- and 10-year estimates of disease free survival were respectively 42 and 31% in Lim-XRT arm and 47 and 31% in Ext-XRT arm (ns). The corresponding figures for overall survival were respectively 45 and 40% in Lim-XRT arm and 48 and 37% in Ext-arm (ns). The 10 years estimate of intra-pelvic failures was approximately 30% in both arms. Patients in Ext-arm appeared to have a slight shorter interval free of liver metastases (P=0.047). CONCLUSION: Low dose irradiation to the para-aortic nodes and liver did not improve survival for patients with resected adenocarcinoma of the rectum.

Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation.

BACKGROUND: Radiotherapy prevents local recurrence of breast cancer after breast-conserving surgery. We evaluated the effect of a supplementary dose of radiation to the tumor bed on the rates of local recurrence among patients who received radiotherapy after breast-conserving surgery for early breast cancer. METHODS: After lumpectomy and axillary dissection, patients with stage I or II breast cancer received 50 Gy of radiation to the whole breast in 2-Gy fractions over a five-week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (2657 patients) or an additional localized dose of 16 Gy, usually given in eight fractions by means of an external electron beam (2661 patients). RESULTS: During a median follow-up period of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard-treatment group and 109 of the 2661 patients in the additional-radiation group. The five-year actuarial rates of local recurrence were 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), yielding a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose. Patients 40 years old or younger benefited most; at five years, their rate of local recurrence was 19.5 percent with standard treatment and 10.2 percent with additional radiation (hazard ratio, 0.46 [99 percent confidence interval, 0.23 to 0.89]; P=0.002). At five years in the age group 41 to 50 years old, no differences were found in rates of metastasis or overall survival (which were 87 and 91 percent, respectively). CONCLUSIONS: In patients with early breast cancer who undergo breast-conserving surgery and receive 50 Gy of radiation to the whole breast, an additional dose of 16 Gy of radiation to the tumor bed reduces the risk of local recurrence, especially in patients younger than 50 years of age.

The influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving therapy in the EORTC 'boost vs. no boost' trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups.

PURPOSE: To analyze the influence of different patient, tumor, and treatment parameters on the cosmetic outcome after breast-conserving therapy at 3-year follow-up. A subjective and an objective cosmetic scoring method was used and the results of both methods were compared. PATIENTS AND METHODS: In EORTC trial 22881/10882, 5569 early-stage breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential fields irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. A total of 5318 patients, having a microscopically complete tumorectomy, were randomized between no further treatment and a boost of 16 Gy to the primary tumor bed. The cosmetic result at 3-year follow-up was assessed by a panel for 731 patients, and by digitizer measurements, measuring the displacement of the nipple, for 1141 patients. Univariate and multivariate analyses were used to evaluate the correlation between various patient, tumor, and treatment factors and cosmesis. RESULTS: The factors associated with a worsened cosmesis according to the panel evaluation were: an inferior tumor location, a large excision volume, the presence of postoperative breast complications, and the radiotherapy boost. According to the digitizer measurements, a central/superior tumor location, a large excision volume, an increased pathological tumor size, an increased radiation dose inhomogeneity, and an increased bra cup size resulted in an increased asymmetry in nipple position. It appeared that the evaluation of the nipple position (whether by panel or by digitizer) is only moderately representative of the overall cosmetic outcome. CONCLUSION: To achieve a good cosmesis, it is necessary to excise the tumor with a limited margin, to avoid postoperative complications, to assess the need for a boost in the individual patient, and to give the radiation dose as homogeneously as possible. As far as the method of evaluation is concerned, the panel evaluation is the most appropriate method for giving an overall impression of the cosmetic result after breast-conserving therapy (BCT). The use of the digitizer is recommended for comparing the cosmetic outcome of two different approaches to BCT or for analyzing cosmetic changes over time.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative group of radiotherapy of the european organization for research and treatment of cancer (EORTC).

BACKGROUND: Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance. AIM: This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck. METHODS: A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions. RESULTS: No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively. CONCLUSION: Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.

Radiation dose homogeneity in an EORTC multicenter trial on breast irradiation.

The influence of the radiation dose on local control and cosmetic outcome in breast-conserving treatment for breast cancer is investigated in EORTC trial 2288110882. In this study 50 Gy is administered to the whole breast, and the effect of an additional dose to the tumor-bearing area (boost dose) is evaluated. The purpose of this analysis is to document the dose homogeneity of the radiation dose as reported in the first 1915 treatment forms, received at the EORTC Data Center. The dose to the prescription Point (A) was within 95 and 110% of 50 Gy in all but 13 (99.3%) patients (median dose 50 Gy) and the minimum and maximum doses in the central plane of the breast were within 95% and 110% of the dose to point A in 82% of patients. The dose to the tumor excision area (point B) was within the homogeneity criteria in 97% of patients, and the boost doses were consistent with randomization in 93% of cases. These data, based on one-third of the randomized patients in trial 22881/10882, demonstrate a high level of homogeneity in radiation doses, despite a number of ambiguities in the protocol, which were efficiently clarified a few months after the beginning of the trial. This high level of consistency is a remarkable achievement given the number of centers, the number of patients, and the number of countries involved in this trial.

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC.

BACKGROUND: Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours. AIM: This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours. METHODS: The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy. RESULTS: The incidence of grade 3 + acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively. CONCLUSION: The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.

Accelerated radiotherapy, carbogen, and nicotinamide in glioblastoma multiforme: report of European Organization for Research and Treatment of Cancer trial 22933.

PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate both qualitative and quantitative scoring methods for the cosmetic result after breast-conserving therapy (BCT), and to compare the usefulness and reliability of these methods. METHODS AND MATERIALS: In EORTC trial 22881/10882, stage I and II breast cancer patients were treated with tumorectomy and axillary dissection. A total of 5318 patients were randomized between no boost and a boost of 16 Gy following whole-breast irradiation of 50 Gy. The cosmetic result was assessed for 731 patients in two ways. A panel scored the qualitative appearance of the breast using photographs taken after surgery and 3 years later. Digitizer measurements of the displacement of the nipple were also made using these photographs in order to calculate the breast retraction assessment (BRA). The cosmetic results after 3-year follow-up were used to analyze the correlation between the panel evaluation and digitizer measurements. RESULTS: For the panel evaluation the intraobserver agreement for the global cosmetic score as measured by the simple Kappa statistic was 0.42, considered moderate agreement. The multiple Kappa statistic for interobserver agreement for the global cosmetic score was 0.28, considered fair agreement. The specific cosmetic items scored by the panel were all significantly related to the global cosmetic score; breast size and shape influenced the global score most. For the digitizer measurements, the standard deviation from the average value of 30.0 mm was 2.3 mm (7.7%) for the intraobserver variability and 2.6 mm (8.7%) for the interobserver variability. The two methods were significantly, though moderately, correlated; some items scored by the panel were only correlated to the digitizer measurements if the tumor was not located in the inferior quadrant of the breast. CONCLUSIONS: The intra- and interobserver variability of the digitizer evaluation of cosmesis was smaller than that of the panel evaluation. However, there are some treatment sequelae, such as disturbing scars and skin changes, that can not be evaluated by BRA measurements. Therefore, the methods of cosmetic evaluation used in a study must be chosen in a way that balances reliability and comprehensiveness.

The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate the influence of a radiotherapy boost on the cosmetic outcome after 3 years of follow-up in patients treated with breast-conserving therapy (BCT). METHODS AND MATERIALS: In EORTC trial 22881/10882, 5569 Stage I and II breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. Patients having a microscopically complete tumor excision were randomized between no boost and a boost of 16 Gy. The cosmetic outcome was evaluated by a panel, scoring photographs of 731 patients taken soon after surgery and 3 years later, and by digitizer measurements, measuring the displacement of the nipple of 3000 patients postoperatively and of 1141 patients 3 years later. RESULTS: There was no difference in the cosmetic outcome between the two treatment arms after surgery, before the start of radiotherapy. At 3-year follow-up, both the panel evaluation and the digitizer measurements showed that the boost had a significant adverse effect on the cosmetic result. The panel evaluation at 3 years showed that 86% of patients in the no-boost group had an excellent or good global result, compared to 71% of patients in the boost group (p = 0.0001). The digitizer measurements at 3 years showed a relative breast retraction assessment (pBRA) of 7.6 pBRA in the no-boost group, compared to 8.3 pBRA in the boost group, indicating a worse cosmetic result in the boost group at follow-up (p = 0.04). CONCLUSIONS: These results showed that a boost dose of 16 Gy had a negative, but limited, impact on the cosmetic outcome after 3 years.

Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC Radiotherapy Co-operative Group.

In 1985, the EORTC Radiotherapy Co-operative Group launched a randomised phase III study comparing high-dose (59.4 Gy in 6.5 weeks) versus low-dose (45 Gy in 5 weeks) radiotherapy with conventional techniques in patients diagnosed with low-grade cerebral glioma. The primary endpoint of the study was survival. No difference in survival was observed between the two treatment strategies. A quality of life (QoL) questionnaire consisting of 47 items assessing a range of physical, psychological, social, and symptom domains was included in the trial to measure the impact of treatment over time. Patients who received high-dose radiotherapy tended to report lower levels of functioning and more symptom burden following completion of radiotherapy. These group differences were statistically significant for fatigue/malaise and insomnia immediately after radiotherapy and in leisure time and emotional functioning at 7-15 months after randomisation. These findings suggest that for conventional radiotherapy for low-grade cerebral glioma, a schedule of 45 Gy in 5 weeks not only saves valuable resources, but also spares patients a prolonged treatment at no loss of clinical efficacy.

Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial.

BACKGROUND AND PURPOSE: A 5 week-hyperfractionated and accelerated radiotherapy regimen without reduction of the total dose was developed to fight tumour repopulation during treatment and tumour hypoxia. The purpose of the study was to try to improve loco-regional control in high risk head and neck carcinoma treated with curative radiotherapy. METHODS AND MATERIALS: From 1985 to 1995, a randomised controlled trial of the EORTC Cooperative Group of Radiotherapy (EORTC 22851) compared the experimental regimen (72 Gy/45 fractions/5 weeks) to standard fractionation and overall treatment time (70 Gy/35 fractions/7 weeks) in T2, T3 and T4 head and neck cancers (hypopharynx excluded). The end-point criteria were local and loco-regional control, overall and disease-free survival, and acute and late toxicities. Five hundred twelve patients were accrued. RESULTS: Patients in the AF (accelerated fractionation) arm did significantly better with regard to loco-regional control (P = 0.02) resulting at 5 years in a 13% gain (95% CI 3-23% gain) in loco-regional control over the CF (conventional fractionation) arm. This improvement is of larger magnitude in patients with poorer prognosis (N2-3 any T, T4 any N) than in patients with more favourable stage. Multivariate analysis confirmed AF as an independent prognostic factor of good prognosis for loco-regional control (P = 0.03). Specific survival shows a trend (P = 0.06) in favour of the AF arm. ACUTE AND LATE TOXICITIES: Acute and late toxicity were increased in the AF arm. Late severe functional irradiation damage occurred in 14% of patients of the AF arm versus 4% in the CF arm. Two cases of radiation-induced myelitis occurred after doses of 42 and 48 Gy to the spinal cord. CONCLUSIONS: This trial shows that accelerated radiotherapy improves loco-regional control in head and neck squamous cell carcinomas. A less toxic scheme should, however, be investigated and documented before using accelerated radiotherapy as a standard regimen of curative radiotherapy for head and neck cancers.

Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.

BACKGROUND: We 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. METHODS: From 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. RESULTS: Data 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). CONCLUSIONS: Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups.

PURPOSE: To investigate the potential gain of the concomitant use of radiotherapy and chemotherapy in improving local control and reducing the need for colostomy, a randomized phase III trial was performed in patients with locally advanced anal cancer. MATERIALS AND METHODS: From 1987 to 1994, 110 patients were randomized between radiotherapy alone and a combination of radiotherapy and chemotherapy. The patients had T3-4NO-3 or T1-2N1-3 anal cancer. Radiotherapy consisted of 45 Gy given in 5 weeks, with a daily dose of 1.8 Gy. After a rest period of 6 weeks, a boost of 20 or 15 Gy was given in case of partial or complete response, respectively. Surgical resection as part of the primary treatment was performed if possible in patients who had not responded 6 weeks after 45 Gy or with residual palpable disease after the completion of treatment. Chemotherapy was given during radiotherapy: 750 mg/m2 daily fluorouracil as a continuous infusion on days 1 to 5 and 29 to 33, and a single dose of mitomycin 15 mg/m2 administered on day 1. RESULTS: The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for radiotherapy alone to 80% for radiotherapy and chemotherapy, and from 85% to 96%, respectively, if results are considered after surgical resections. This led to a significant improvement of locoregional control and colostomy-free interval (P = .02 and P = .002, respectively), both in favor of the combined modality treatment. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The survival rate remained similar in both treatment arms. Skin ulceration, nodal involvement, and sex were the most important prognostic factors for both local control and survival. These remained significant after multivariate analysis. The improvement seen in local control by adding chemotherapy to radiotherapy also remained significant after adjusting for prognostic factors in the multivariate analysis. Event-free survival, defined as free of locoregional progression, no colostomy, and no severe side effects or death, showed significant improvement (P = .03) in favor of the combined-treatment modality. The 5-year survival rate was 56% for the whole patient group. CONCLUSION: The concomitant use of radiotherapy and chemotherapy resulted in a significantly improved locoregional control rate and a reduction of the need for colostomy in patients with locally advanced anal cancer without a significant increase in late side effects.

A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844.

PURPOSE: Cerebral low-grade gliomas (LGG) in adults are mostly composed of astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. There is at present no consensus in the policy of treatment of these tumors. We sought to determine the efficacy of radiotherapy and the presence of a dose-response relationship for these tumors in two multicentric randomized trials conducted by the European Organization for Research and Treatment of Cancer (EORTC). The dose-response study is the subject of this article. METHODS AND MATERIALS: For the dose-response trial, 379 adult patients with cerebral LGGs were randomized centrally at the EORTC Data Center to receive irradiation postoperatively (or postbiopsy) with either 45 Gy in 5 weeks or 59.4 Gy in 6.6 weeks with quality-controlled radiation therapy. All known parameters with possible influences on prognosis were prospectively recorded. Conventional treatment techniques were recommended. RESULTS: With 343 (91%) eligible and evaluable patients followed up for at least 50 months with a median of 74 months, there is no significant difference in terms of survival (58% for the low-dose arm and 59% for the high-dose arm) or the progression free survival (47% and 50%) between the two arms of the trial. However, this prospective trial has revealed some important facets about the prognostic parameters: The T of the TNM classifications as proposed in the protocol appears to be one of the most important prognostic factors (p < 0.0001) on multivariate analysis. Other prognostic factors, most of which are known, have now been quantified and confirmed in this prospective study. CONCLUSION: The EORTC trial 22844 has not revealed the presence of radiotherapeutic dose-response for patients with LGG for the two dose levels investigated with this conventional setup, but objective prognostic parameters are recognized. The tumor size or T parameter as used in this study appears to be a very important factor.