Nicole Duez

Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC).

A randomized clinical trial was conducted by the European Organization for Research and Treatment for Cancer (EORTC) Gastrointestinal Cancer Cooperative Group to study the effectiveness of irradiation therapy administered in a dosage of 34.5 Gy, divided into 15 daily doses of 2.3 Gy each before radical surgery for rectal cancer (T2, T3, T4, NX, MO). Four hundred sixty-six patients were entered in the clinical trial between June 1976 and September 1981. Tolerance and side effects of pre- operative irradiation were acceptable. The overall 5-year survival rates were similar in both groups. When considering only the 341 patients treated by surgery with a curative aim, the 5-year survival rates were 59.1% and 69.1% in the control group and in the combined modality group, respectively (p = 0.08). The local recurrence rates at 5 years were 30% and 15% in the control group and the adjuvant radiotherapy group, respectively (p = 0.003). Although this study did not show preoperative radiotherapy to have a statistically significant benefit on overall survival, it does have a clear effect on local control of rectal cancer. Therefore, before performing radical surgery, this adjuvant therapy should be administered to patients who have locally extended rectal cancer.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

BACKGROUND If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING EORTC Charitable Trust.

Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma In Situ: 15-Year Recurrence Rates and Outcome After a Recurrence, From the EORTC 10853 Randomized Phase III Trial

PURPOSE Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing LR and its impact on survival after local treatment for DCIS. PATIENTS AND METHODS Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years. RESULTS Radiotherapy reduced the risk of any LR by 48% (hazard ratio [HR], 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer-specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively). CONCLUSION At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.

Interim analysis of a phase III study on preoperative radiation therapy in resectable rectal carcinoma. Trial of the gastrointestinal tract cancer cooperative group of the European organization for research on treatment of cancer (EORTC)

To improve surgical results of potentially operable rectal cancer (T2, T3, T4, Mo), the European Organization for Research on Treatment of Cancer (EORTC) conducted a two‐arm randomized clinical trial to evaluate the effect of administering radiotherapy before radical surgery. Four hundred ten patients were allocated to be treated either by surgery alone or by 34.5 Gy of radiotherapy (in 19 days overall) followed by surgery. The tolerance of the adjuvant radiation therapy was fairly good. The 5‐year survival rate was 65% overall and showed no difference between both therapeutic regimens. Similarly, the metastases‐free rate was the same in both groups. In contrast, the preoperative radiation therapy showed a marked effect on local control of the disease, the comparison of the time to local recurrence being highly significant between the two treatment groups (P = 0.001). The proportion of patients free of local recurrence at 5 years was 85% in the combined treatment versus 65% in the group of patients treated by surgery alone.

Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.

PURPOSE In a randomized clinical trial (European Organization for the Research and Treatment of Cancer [EORTC] no. 40813) on adjuvant chemotherapy in gastric cancer, results obtained after administration of the FAM2 regimen (fluorouracil [5-FU], doxorubicin, and mitomycin) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival, time to progression, and disease-free interval. PATIENTS AND METHODS Three hundred fourteen patients who had undergone curative resection for stage II or stage III (International Union Against Cancer [UICC] 1978) gastric adenocarcinoma were randomized to receive chemotherapy (treatment arm) or no further treatment (control arm). The chemotherapy schedule was repeated every 43 days for seven cycles. The log-rank test and the Cox model were used for statistical analysis. RESULTS Of 314 patients, 159 comprised the control group and 155 the FAM2 group. Nineteen FAM2 patients never received chemotherapy. The median number of cycles was five. Of the patients started on adjuvant treatment, severe hematologic and nonhematologic toxicity (grades 3 or 4, World Health Organization [WHO] scale) occurred, respectively, in 6% to 9% and in 1% to 29% of cases. The overall 5-year survival rate was 70% for stage II and 32% for stage III patients. No statistically significant difference was found between overall survival of the two treatment arms (P = .295). However, time to progression was significantly delayed in the FAM2 arm (P = .020) and disease-free survival showed borderline significance (P = .068). CONCLUSION FAM2, in view of its high toxicity, cannot be advocated as standard adjuvant treatment for gastric cancer. Large-scale clinical trials using more active, less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023).

LBA1001 Background: Sentinel node biopsy (SNB) is standard in assessing axillary lymph node status for cN0 breast cancer patients. In case of a positive SNB, if treatment is advised, axillary lymph node dissection (ALND) is the current standard. Although ALND provides excellent regional control, it may give harmful side effects. Axillary radiotherapy (ART) instead of ALND was hypothesized to provide comparable regional control and less side effects. METHODS From 2001 to 2010, patients with cT1E2N0 primary breast cancer were enrolled in the EORTC phase III non-inferiority AMAROS trial. Patients were randomized between ALND and ART in case of a positive SNB. Primary endpoint was 5-year axillary recurrence rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), quality of life (QOL), shoulder movement and lymphedema at 1 and 5 years. RESULTS Of the 4,806 patients entered in the trial, 744 in the ALND-arm and 681 in the ART-arm had a positive SNB, 60% with a macrometastasis. The two treatment-arms were comparable regarding age, tumor size, grade, tumor type, and adjuvant systemic treatment. With a median follow up of 6.1 years, the 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND versus 1.03% (7/681) after ART. The planned non-inferiority test was underpowered because of the unexpectedly low number of events. The axillary recurrence rate after a negative SNB was 0.8% (25/3131). There were no significant differences between treatment arms regarding OS (5 yr estimates: 93.27% ALND, 92.52% ART, p=0.3386) and DFS (5 yr estimates: 86.90% ALND, 82.65% ART, p=0.1788). Lymphedema was found significantly more often after ALND (1yr: 40% ALND, 22% ART, p<0.0001 and 5yr: 28% ALND, 14% ART, p<0.0001). There was a nonsignificant trend toward more early shoulder movement impairment after ART. These findings were compatible with a trend in two QOL items in the arm symptom scale: swelling (ART better) and movement (ALND better). There were no other differences in QOL. CONCLUSION ALND and ART after a positive SNB provide excellent and comparable regional control. ART reduces the risk of short-term and long-term lymphedema compared to ALND. CLINICAL TRIAL INFORMATION NCT00014612.

Activity of cisplatin in adenocarcinoma of the pancreas

The activity of cisplatin in metastatic adenocarcinoma of the pancreas was assessed in 33 patients. Cisplatin was administered in a dose of 100 mg/m2, every 4 weeks. There were 2 complete responses and 5 partial responses (a response rate of 21%). The median duration of response was 5 months (range, 2+ to 15 months). Cisplatin is a modestly active drug in advanced pancreatic cancer.

Osteosarcoma of the limbs: report of the EORTC-SIOP 03 trial 20781 investigating the value of adjuvant treatment with chemotherapy and/or prophylactic lung irradiation

The European Organization for Research on Treatment of Cancer (EORTC) trial 20781, concerning osteosarcoma of the limbs is reported. After definitive treatment of the primary tumor with amputation or irradiation, adjuvant treatment was given, randomized into either 9 months of chemotherapy according to a modified Rosen schedule, or elective bilateral lung irradiation of 20 Gy, or 3 months of chemotherapy followed by lung irradiation. The 4‐year disease‐free survival and total survival were 24% and 43%, respectively, with no difference between the treatment arms. In the radiotherapy arms the lung metastases were more frequently suitable for surgical treatment. The survival of patients with either tibia localizations or higher age was somewhat better. Local recurrences occurred in 16% of patients, 50% of them with distant metastases. The trial was executed from 1978 to 1983; 205 patients were evaluable and eligible, and three toxic deaths occurred in the chemotherapy arms. Elective lung irradiation provided the same survival as the adjuvant chemotherapy given in that time.

Cis-platinum as second-line chemotherapy in advanced gastric adenocarcinoma. A phase II study of the EORTC gastrointestinal tract cancer cooperative group☆

Thirty-four patients with measurable metastatic gastric adenocarcinoma refractory to prior chemotherapy were treated with cis-platinum 100 mg/m2 in a 6-hr infusion at 3-week intervals. Thirty-one patients were evaluable for response. There were three complete and three partial responses. Median duration of response was 4 months. Toxicity consisted mainly of nausea and vomiting and was severe in 12 patients. One patient had a severe but reversible renal failure. These results confirm other data reported in the literature. Cis-platinum has activity in gastric adenocarcinoma and should now be further investigated in first-line chemotherapy.

Palliative therapy of inoperable oesophageal carcinoma with radiotherapy and methotrexate: Final results of a controlled clinical trial☆

Between May 1976 and January 1982, 170 patients were entered in a randomized study comparing a combined treatment consisting of methotrexate followed by irradiation versus radiotherapy alone in patients with non metastatic inoperable oesophageal cancer. Methotrexate was administered subcutaneously in 4 days to a total dose of 24 mg/m2. Radiotherapy was performed, in both groups, at a dose of 56.25 Gy in 25 fractions (5 weeks). The administration of methotrexate did not lead to an increased intolerance to radiotherapy but severe hematological toxicities were observed in 7.8% of the cases. No difference in the duration of survival was detected. Initial performance status of the patients and their weight loss prior to entry on trial were the factors that were most predictive of the patients prognosis.