R. Arriagada

A meta-analysis of thoracic radiotherapy for small-cell lung cancer.

BACKGROUND In spite of 16 randomized trials conducted during the past 15 years, the effect of thoracic radiotherapy on the survival of patients with limited small-cell lung cancer remains controversial. The majority of these trials did not have enough statistical power to detect a difference in survival of 5 to 10 percent at five years. This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer. METHODS We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. Trials that included only patients with extensive disease were excluded. RESULTS The meta-analysis included 13 trials and 2140 patients with limited disease. A total of 433 patients with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients: the relative risk of death in the combined-therapy as compared with the chemotherapy group ranged from 0.72 for patients less than 55 years old (95 percent confidence interval, 0.56 to 0.93) to 1.07 (0.70 to 1.64) for patients over 70. CONCLUSIONS Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). Interpretation For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. Funding Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomised controlled trials

Background The role of postoperative radiotherapy in treatment of patients with completely resected non-small-cell lung cancer (NSCLC) remains unclear. We undertook a systematic review and meta-analysis of the available evidence from randomised trials. Methods Updated data were obtained on individual patients from all available randomised trials of postoperative radiotherapy versus surgery alone. Data on 2128 patients from nine randomised trials (published and unpublished) were analysed by intention to treat. There were 707 deaths among 1056 patients assigned postoperative radiotherapy and 661 among 1072 assigned surgery alone. Median follow-up was 3.9 years (2.3-9.8 for individual trials) for surviving patients. Findings The results show a significant adverse effect of postoperative radiotherapy on survival (hazard ratio 1.21 [95% CI 1.08-1.34]). This 21% relative increase in the risk of death is equivalent to an absolute detriment of 7% (3-11) at 2 years, reducing overall survival from 55% to 48%. Subgroup analyses suggest that this adverse effect was greatest for patients with stage I/II, N0-N1 disease, whereas for those with stage III, N2 disease there was no clear evidence of an adverse effect. Interpretation Postoperative radiotherapy is detrimental to patients with early-stage completely resected NSCLC and should not be used routinely for such patients. The role of postoperative radiotherapy in the treatment of N2 tumours is not clear and may warrant further research.BACKGROUND The role of postoperative radiotherapy in treatment of patients with completely resected non-small-cell lung cancer (NSCLC) remains unclear. We undertook a systematic review and meta-analysis of the available evidence from randomised trials. METHODS Updated data were obtained on individual patients from all available randomised trials of postoperative radiotherapy versus surgery alone. Data on 2128 patients from nine randomised trials (published and unpublished) were analysed by intention to treat. There were 707 deaths among 1056 patients assigned postoperative radiotherapy and 661 among 1072 assigned surgery alone. Median follow-up was 3.9 years (2.3-9.8 for individual trials) for surviving patients. FINDINGS The results show a significant adverse effect of postoperative radiotherapy on survival (hazard ratio 1.21 [95% CI 1.08-1.34]). This 21% relative increase in the risk of death is equivalent to an absolute detriment of 7% (3-11) at 2 years, reducing overall survival from 55% to 48%. Subgroup analyses suggest that this adverse effect was greatest for patients with stage I/II, N0-N1 disease, whereas for those with stage III, N2 disease there was no clear evidence of an adverse effect. INTERPRETATION Postoperative radiotherapy is detrimental to patients with early-stage completely resected NSCLC and should not be used routinely for such patients. The role of postoperative radiotherapy in the treatment of N2 tumours is not clear and may warrant further research.

Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer

A randomized trial was conducted at the Institut Gustave-Roussy (IGR) between 1972 and 1980 comparing tumorectomy and breast irradiation with modified radical mastectomy. One hundred and seventy-nine patients with an infiltrating breast carcinoma up to 20 mm in diameter at macroscopic examination were included: 88 had conservative management, and 91 a mastectomy. All patients had a low-axillary dissection with immediate histological examination. For the patients with positive axillary nodes, a complete axillary dissection was undertaken. Overall survival, distant metastasis, contralateral breast cancer and locoregional recurrence rates were not significantly different between the two treatment groups.

Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group.

PURPOSES A randomized trial was conducted to compare tumorectomy and breast irradiation with modified radical mastectomy. We have analyzed the patterns of failure in each arm of the trial and the prognostic factors that have an independent effect on treatment failures and overall survival. PATIENTS AND METHODS The trial included 179 patients with breast cancer of up to 20 mm in diameter at macroscopic examination. Eighty-eight patients had conservative management and 91 a mastectomy. All patients had axillary dissection with frozen-section examination. For patients with positive axillary nodes (N+), a second randomization was performed: lymph node irradiation versus no further regional treatment. Patterns of failure were determined by a competing-risk approach and multivariate analysis. A prognostic-score was determined by multivariate analysis. RESULTS Overall survival, distant metastasis, contralateral breast cancer, new primary malignancy, and locoregional recurrence rates were not significantly different between the two surgical groups, or between lymph node irradiation groups. Most recurrences appeared during the first 10 years. Three distinct prognostic groups were determined taking into account age, tumor size, histologic grading, and number of positive axillary nodes. CONCLUSION Long-term results support conservative treatment with limited surgery and systematic breast irradiation as a safe procedure for the management of small breast cancers. Four easily obtainable clinical and histologic factors may be combined in a prognostic score that is highly predictive of overall and event-free survival.

Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: experience of the Institut Gustave-Roussy

Abstract Between 1970 and 1981, 436 patients with T1 and small T2 breast carcinoma were treated by tumor excision followed by radiotherapy at the Institut Gustave-Roussy. The mean follow-up was 5 years, with 50% of patients followed 5 years. Twenty-four patients have experienced a local-regional (LR) relapse for an actuarial LR control rate of 93% at 5 years and 90% at 10 years. Potential prognostic factors for all 24 local-regional recurrences and for the subgroup with relapses in the breast were analyzed. A high Bloom grade and a low Nominal Standard Dose (NSD) were significant prognostic factors for predicting LR relapse in both groups. Disease-free survival (from initial presentation) was not adversely affected by a solitary breast recurrence, when patients with successful salvage treatment were considered disease free. However, the group of patients with nodal or dermal recurrences had a much worse prognosis. This paper describes the natural history of breast cancer following a local-regional relapse in irradiated patients without mastectomy. Most importantly, we observed that breast relapses following radiotherapy become clinically apparent more slowly than chest wall failures after mastectomy, and if detected early, that these patients may be successfully retreated.

Astro plenary: Effect of chemotherapy on locally advanced non-small cell lung carcinoma: A randomized study of 353 patients

Abstract Most patients with locally advanced non small cell lung carcinoma are treated with external thoracic radiotherapy. Because of the high incidence of distant metastasis the addition of chemotherapy has been proposed. The present randomized study was conducted from June 1983 to February 1989 and included 353 patients. The trial compared arm A, thoracic megavoltage radiotherapy alone at a total dose of 65 Gy in 26 fractions and 45 days, to arm B that comprised the same radiotherapy preceded and followed by 3 monthly cycles of VCPC (vindesine 1.5 mg/m 2 d 1–2, cyclophosphamide 200 mg/m 2 d 2–4, cisplatinum 100 mg/m 2 d 2 and lomustine 75 mg/m 2 d 3). Disease was deemed unresectable but non-metastasic after bronchoscopic, radiologic, CAT, and nuclear scans and physical examinations. Only patients in clinical, radiological, endoscopic, and histological complete remission were considered as locally controlled; these patients were monitored by fiberoptic bronchoscopy and systematic biopsies to the primary site. One hundred seventy-seven patients received thoracic radiotherapy alone and 176 received the combined modality. Twenty-seven percent of arm B patients had an objective response after 2 VCPC cycles. At the time of final assessment, performed 3 months after the end of thoracic radiotherapy in both arms, there were 20% of complete responders in arm A versus 16% in arm B. The two-year survival rate was 14% in arm A versus 21% in arm B ( p = 0.08 logrank test). The distant metastasis rate was 67% in arm A versus 45% in arm B ( p

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. METHODS We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). FINDINGS We received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). INTERPRETATION Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. FUNDING Cancer Research UK, Medical Research Council.

Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial

BACKGROUND The optimum dose of prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC) is unknown. A meta-analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses. This randomised clinical trial compared the effect of standard versus higher PCI doses on the incidence of brain metastases. METHODS Between September, 1999, and December, 2005, 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2.5 Gy) or higher PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h) radiotherapy. All of the treatment schedules excluded weekends. Randomisation was stratified according to medical centre, age (</=60 and >60 years), and interval between the start of induction treatment and the date of randomisation (</=90, 91-180, and >180 days). Eligible patients were randomised blindly by the data centre of the Institut Gustave Roussy (PCI99-01 and IFCT) using minimisation, and by the data centres of EORTC (EORTC ROG and LG) and RTOG (for CALGB, ECOG, RTOG, and SWOG), both using block stratification. The primary endpoint was the incidence of brain metastases at 2 years. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov number NCT00005062. FINDINGS Five patients in the standard-dose group and four in the higher-dose group did not receive PCI; nonetheless, all randomised patients were included in the effectiveness anlysis. After a median follow-up of 39 months (range 0-89 months), 145 patients had brain metastases; 82 in the standard-dose group and 63 in the higher-dose group. There was no significant difference in the 2-year incidence of brain metastases between the standard PCI dose group and the higher-dose group, at 29% (95% CI 24-35) and 23% (18-29), respectively (hazard ratio [HR] 0.80 [95% CI 0.57-1.11], p=0.18). 226 patients in the standard-dose group and 252 in the higher-dose group died; 2-year overall survival was 42% (95% CI 37-48) in the standard-dose group and 37% (32-42) in the higher-dose group (HR 1.20 [1.00-1.44]; p=0.05). The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality: 189 patients in the standard group versus 218 in the higher-dose group died of progressive disease. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. The most common acute toxic events were fatigue (106 [30%] patients in the standard-dose group vs 121 [34%] in the higher-dose group), headache (85 [24%] vs 99 [28%]), and nausea or vomiting (80 [23%] vs 101 [28%]). INTERPRETATION No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in limited-stage SCLC. FUNDING Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The European Organisation for Research and Treatment of Cancer (EORTC) contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the US National Cancer Institute.

Adequate locoregional treatment for early breast cancer may prevent secondary dissemination.

PURPOSE To analyze different events that determine event-free survival (EFS) in a randomized trial on adjuvant radiotherapy in early breast cancer patients with more than 15 years of follow-up evaluation. PATIENTS AND METHODS The trial included 960 patients with a unilateral, operable breast cancer. Surgery consisted of a modified radical mastectomy. The trial compared three arms, as follows: preoperative radiotherapy, postoperative radiotherapy, and no adjuvant treatment. Events were analyzed by a competing-risk approach. A proportional hazards multiple regression model was used to analyze the effects of radiotherapy on the risk of distant metastasis. Similar analyses were performed separately for node-negative [N(-)] and node-positive [N(+)] patients in the two groups that did not include preoperative radiotherapy. RESULTS Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001). In N(+) patients, postoperative radiotherapy decreased the risk of distant dissemination (relative risk, 0.63). When local recurrence was introduced in the model as a time-dependent covariate, this factor was predictive of distant dissemination (P < .0001) and nullified the effect of postoperative radiotherapy. This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence. A similar effect was found in models that used overall survival as an end point. CONCLUSION This study shows that postmastectomy radiotherapy in N(+) breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination.