In this study, irradiation of the internal mammary and medial supraclavicular nodes plus whole breast or thoracic-wall radiation therapy in women with localized breast cancer was linked to increased ...disease-free survival but only a marginal gain in overall survival.
The first filter stations for the lymphatic drainage of the breast are the axillary and internal mammary lymph nodes.
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Surgical studies have shown that the incidence of metastatic involvement of the internal mammary nodes varies between 4% and 9% in patients with axillary node–negative breast cancer and between 16% and 65% in patients with axillary node–positive breast cancer.
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As a consequence, surgical dissection of the internal mammary nodes was attempted but abandoned in the 1970s, since no improvement in survival was observed.
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Elective irradiation of the regional nodes remained widely used until the late 1980s, when it became . . .
This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after ...surgery or radiosurgery of brain metastases.
Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2.
Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm.
After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.
The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the ...progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients.
In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson’s grade. Patients with atypical meningioma (WHO grade II) and Simpson’s grade 1–3 Arm 1 entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4–5 Arm 2 and Grade III Simpson grade 1–3 or 4–5 Arm 3&4 in which few patients were expected.
Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson’s grade 1–3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%.
These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I–III) is superior to 70% when treated with high-dose (60 Gy) RT.
Summary Background Since 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. Methods Patients 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. Findings Between 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). Interpretation A 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. Funding Fonds Cancer, Belgium.
Summary Background The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data ...to compare adjuvant chemotherapy with observation for patients with rectal cancer. Methods We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival. Findings We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio HR 0·97, 95% CI 0·81–1·17; p=0·775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0·91, 95% CI 0·77–1·07; p=0·230) or distant recurrences (0·94, 0·78–1·14; p=0·523) compared with observation. However, in subgroup analyses, patients with a tumour 10–15 cm from the anal verge had improved disease-free survival (0·59, 0·40–0·85; p=0·005, pinteraction =0·107) and fewer distant recurrences (0·61, 0·40–0·94; p=0·025, pinteraction =0·126) when treated with adjuvant chemotherapy compared with patients undergoing observation. Interpretation Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10–15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted. Funding None.
Summary Background EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 ...years, chemotherapy—irrespective of timing—significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. Methods We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m2 per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m2 per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00002523. Findings 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8–13·1), 10-year overall survival was 49·4% (95% CI 44·6–54·1) for the preoperative radiotherapy group and 50·7% (45·9–55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83–1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0–56·4) for the adjuvant chemotherapy group and 48·4% (43·6–53·0) for the surveillance group (HR 0·91, 95% CI 0·77–1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5–48·8) for the preoperative radiotherapy group and 46·4% (41·7–50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79–1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2–51·6) for the adjuvant chemotherapy group and 43·7% (39·1–48·2) for the surveillance group (HR 0·91, 95% CI 0·77–1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1–27·6) with radiotherapy alone, 11·8% (7·8–15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1–18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7–15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). Interpretation Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. Funding EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.
This phase III trial compared adjuvant whole-brain radiotherapy (WBRT) with observation after either surgery or radiosurgery of a limited number of brain metastases in patients with stable solid ...tumors. Here, we report the health-related quality-of-life (HRQOL) results.
HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue. Statistical significance required P ≤ .05, and clinical relevance required a ≥ 10-point difference.
Compliance was 88.3% at baseline and dropped to 45.0% at 1 year; thus, only the first year was analyzed. Overall, patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow-up period (for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months, and fatigue at 8 weeks). Exploratory analysis of all other HRQOL scales suggested worse scores for the WBRT group, but none was clinically relevant.
This study shows that adjuvant WBRT after surgery or radiosurgery of a limited number of brain metastases from solid tumors may negatively impact some aspects of HRQOL, even if these effects are transitory. Consequently, observation with close monitoring with magnetic resonance imaging (as done in the EORTC trial) is not detrimental for HRQOL.
Summary Background We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to ...confirm whether previously reported progression-free survival was sustained. Methods This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0–3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen >0·2 μg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at α=0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov , number NCT00002511. Findings 1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10·6 years (range 2 months to 16·6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 39·4% of 502 patients in postoperative irradiation group vs 311 61·8% of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0·49 95% CI 0·41–0·59; p<0·0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70·8% 66·6–75·0 vs 59·7% 55·3–64·1; p=0.001). Interpretation Results at median follow-up of 10·6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. Funding Ligue Nationale contre le Cancer (Comité de l'Isère, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust.
Summary Background We 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. Methods For 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. Findings Between 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. Interpretation In 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. Funding AstraZeneca; Ligue Nationale Contre le Cancer (France), through the EORTC Charitable Trust.
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