Background Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. Methods We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Findings Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14.4 months and median follow-up was 10.7 years (IQR 9.5 to 11.9). The risks of breast cancer recurrence (RR 0.66, 95% CI 0.62 to 0.71; p<0.0001) and death from breast cancer (0.67, 0.61 to 0.73; p<0.0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9.0% (95% CI 7.4 to 10.7; p<0.0001) and 10-year breast cancer mortality was reduced by 6.4% (4.9 to 7.8; p<0.0001), with a 6.5% reduction (5.0 to 8.0; p<0.0001) in all-cause mortality, and no increase in death without recurrence (0.4%, -0.3 to 1.1; p=0.35). The proportional reduction in recurrence was largest in years 0-1 after randomisation (0.53, 99% CI 0.46 to 0.61), with benefits persisting through years 2-4 (0.73, 0.62 to 0.85) and 5-9 (0.80, 0.64 to 1.01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5.7% [95% CI 3.1 to 8.3], 6.8% [4.7 to 9.0], and 10.7% [7.7 to 13.6] in N0, N1-3, and N4+ disease). Interpretation Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy.Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs).Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28.0% vs 31.4%; RR 0.86, 95% CI 0.82-0.89; p<0.0001). 10-year breast cancer mortality was similarly reduced (18.9% vs 21.3%; RR 0.87, 95% CI 0.83-0.92; p<0.0001), as was all-cause mortality (22.1% vs 24.8%; RR 0.87, 95% CI 0.83-0.91; p<0.0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4.1% vs 4.6%; RR 0.88, 95% CI 0.78-0.99; p=0.034). Recurrence reductions were similar in the seven trials (n=10004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24.0% vs 28.3%; RR 0.83, 95% CI 0.76-0.91; p<0.0001), in the six trials (n=11028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28.1% vs 31.3%; RR 0.87, 95% CI 0.80-0.94; p=0.0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30.4% vs 35.0%; RR 0.82, 95% CI 0.74-0.90; p<0.0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0.0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics.Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

Purpose: To assess predictors of outcome in a cohort of Inflammatory Breast Cancer (IBC) patients receiving induction chemotherapy followed by local treatment. Methods: We retrospectively reviewed 95 non-metastatic IBC patient files. Results: Complete clinical response (cCR) was obtained in 15 (16%) patients. Median follow up was 13.4 years (IC95%: 10.4-14.6). Loco-regional control (LC), disease-free survival (DFS), and overall survival (OS) at 5 years were 85%, 41%, and 55%, respectively; cCR was associated with better DFS and OS in multivariate analyses adjusted for age (p = 0.02). Conclusions: Clinical response to upfront chemotherapy predicts the outcome of patients affected by IBC.

This study evaluates the long-term outcomes of a retrospective cohort of breast cancer (BC) patients who had received curatively intended premastectomy radiation therapy (RT). We analysed locoregional control, disease-free survival (DFS) and overall survival (OS), pathological complete remission (pCR), predictors thereof, and immediate safety. The series consisted of 187 patients with a median age of 49 years [43-60] and T2 T4 or N2 tumours. Between 1970 and 1984, they had received slightly hypofractionated RT to the whole breast, ipsilateral supraclavicular fossa and axilla the internal mammary chain (45-55 Gy/18 fractions of 2.5 Gy/34 days) systematically followed by a modified radical mastectomy with an axillary dissection. No other preoperative treatment was given. Among the 166 centrally reviewed tumour biopsy specimens, 22% had a triple-negative (TN) phenotype, 17% were HER2 3 + or amplified and 61% were ER+. The median follow-up was 32 years [23-35]. The 25-year locoregional control rate was 89% [93%-82%] and the 25-year DFS and OS rates were identical, 30% [24%-37%]. A pCR in the tumour and lymph nodes had been achieved in 18 among all patients (10%), but in 26% with TN disease. In the multivariate analysis, the TN status was the only predictive factor of pCR (OR = 5.49, 95% confidence interval [CI] 1.87 16.1,p = 0:002). Also, the pN status (HR = 1.69, [1.28-2.22], p = 0.0002) and TN subtype (HR = 1.80, [1.00-3.26], p = 0.05) exerted a significant prognostic impact on OS. The postoperative complication rate (grade >2) was 19% with 4.3% of localized skin necrosis. Preoperative RT followed by radical surgery is feasible and associated with good long-term locoregional control. (C) 2017 Elsevier Ltd. All rights reserved.

BACKGROUND:The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta-analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013.OBJECTIVES:To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT.SEARCH METHODS:We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations.SELECTION CRITERIA:We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment.DATA COLLECTION AND ANALYSIS:We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow-up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival.MAIN RESULTS:We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate.We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low.AUTHORS' CONCLUSIONS:Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.

BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

BACKGROUND To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Conclusions: Preliminary results showed acute breast edema in 1 out of 4 breast cancer patients undergoing irradiation after any surgical treatment and is more common after neoadjuvant chemotherapy.Updated results with a larger sample size and longer follow-up, as well as data on quality of life, pain and cosmetic results in association with acute and chronic breast edema will be presented at the ESTRO conference.

BACKGROUND:Adjuvant cisplatin-based chemotherapy has become the standard therapy against resected nonsmall-cell lung cancer (NSCLC). Because of variable results on its late effect, we reanalyze the long-term data of the International Adjuvant Lung Cancer Trial (IALT) to describe in details the role of adjuvant chemotherapy.PATIENTS AND METHODS:In the IALT, 1867 patients were randomized between adjuvant cisplatin-based chemotherapy and control, who were followed up for a median of 7.5 years. Of these, 1687 patients were enrolled from 132 centers accepting to report the times to cancer events. We used event history methodology to estimate the effects of adjuvant chemotherapy on the risks of local relapse, distant metastasis, and death.RESULTS:Adjuvant chemotherapy was highly effective against local relapses [HR = 0.73; 95% confidence interval (CI) 0.60-0.90; P = 0.003] and nonbrain metastases (HR = 0.79; 95% CI 0.66-0.94; P = 0.008) but not against brain metastases (HR = 1.1; 95% CI 0.82-1.4; P = 0.61). The effect on noncancer mortality was nonsignificant during the first 5 years (HR = 1.1; 95% CI 0.81-1.5; P = 0.29), whereas the risk of noncancer mortality was subsequently higher with treatment (HR = 3.6; 95% CI 2.2-5.9; P < 0.001). This harmful effect, however, potentially concerned only about 2% of the patients at 8 years.CONCLUSION:Adjuvant cisplatin-based chemotherapy reduced the risk of local relapse and of nonbrain metastasis, thereby improving survival. This treatment exerted no residual effect on mortality during the first 5 years, but a higher risk of noncancer mortality was found thereafter. Detailed long-term follow-up is strongly recommended for all patients in randomized trials evaluating adjuvant treatments in NSCLC.

ative Group (EBCTCG) overview 2 and represents about 3.5% of the worldwide randomized experience. The latter study identified four independent prognostic factors of recurrence: age, histological grade, surgical resection extent, and estrogen receptor status/tamoxifen treatment. Curiously, Wickberg et al provide results in terms of all recurrences adopting a similar definition of that used in the overview. However, in the worldwide studies this definition was related to the fact that several trials only registered the first recurrence and not the

The authors should be congratulated for their manuscript “Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: A meta-analysis” [ [1] Billiet C. Decaluwé H. Peeters S. et al. Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: a meta-analysis. Radiother Oncol. 2014; 110: 3-8 Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar ]. The article is a systematic review of the literature concerning the issue of postoperative radiotherapy (PORT) in non-small cell lung cancer (NSCLC). The authors largely comment on the impact that more sophisticated radiation techniques could have on the patient outcome. Even if well documented, we found some methodology inaccuracies that deserve to be highlighted. The authors have chosen to do a literature-based meta-analysis, investigating the effect on local recurrence (LR) and overall survival (OS) of PORT obtained with cobalt, or linear accelerators (linac). For the treatment effect evaluation, they used relative risks (RR) instead of hazard ratio (HR), which is the method of reference and rely on subgroup analyses instead of comparing them by interaction test. Such data were available in the PORT meta-analysis [ 2 PORT Meta-Analysis Trialists Group Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998; 352: 257-263 Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar , 3 Burdett S. Stewart L. on behalf of the PORT Meta-analysis GroupPostoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer. 2005; 47: 81-83 Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar , 4 Burdett S. Rydzewska L. Tierney J.F. et al. A closer look at the effects of postoperative radiotherapy by stage and nodal status: updated results of an individual participant data meta-analysis in non-small-cell lung cancer. Lung Cancer. 2013; 80: 350-352 Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar ]. They added two trials as compared with the initial PORT individual data-based meta-analysis [ [2] PORT Meta-Analysis Trialists Group Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998; 352: 257-263 Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar ]: an Italian trial (also included in the PORT update published in 2005) and an Austrian trial with no available individual patient data and with some degree of uncertainty on the randomisation procedure [ 2 PORT Meta-Analysis Trialists Group Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998; 352: 257-263 Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar , 3 Burdett S. Stewart L. on behalf of the PORT Meta-analysis GroupPostoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis. Lung Cancer. 2005; 47: 81-83 Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar , 5 Trodella L. Granone P. Valente S. et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol. 2002; 62: 11-19 Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar , 6 Mayer R. Smolle-Juettner F.M. Szolar D. et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest. 1997; 112: 954-959 Crossref PubMed Scopus (112) Google Scholar ]. They analysed overall survival and local failure as a function of the beam quality used (Cobalt only, Linac only, or Cobalt and Linac). As the larger trials included in the PORT meta-analysis are in the “Linac and Cobalt” subgroup, we lack clear and possibly conclusive information on the issue of beam quality. Thus, the rationale of such analysis is interesting, but the underlying material on which this hypothesis-generating modelling study is based seems unfortunately poor. It relies upon four underpowered trials, three of them needing some comments. The Austrian trial, the largest study in the “Linac only” subgroup, included 155 patients, but only 49 patients had mediastinal nodal involvement [ [6] Mayer R. Smolle-Juettner F.M. Szolar D. et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest. 1997; 112: 954-959 Crossref PubMed Scopus (112) Google Scholar ]. The Italian trial included 104 patients with only pathological stage I disease, and even if PORT to the hilar region was delivered with more contemporary techniques, it seems hazardous to extrapolate the results to stage III patients [ [5] Trodella L. Granone P. Valente S. et al. Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol. 2002; 62: 11-19 Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar ]. The Slovenian trial included 74 stage III patients, the radiotherapy technique as well as the delivered dose cannot be considered as optimal for a “curative intent” treatment: 30 Gy in 10 fractions delivered through two parallel opposed fields of 90–120 cm2 [ [7] Debevec M. Bitenc M. Vidmar S. et al. Post-operative radiotherapy for radically resected N2 non-small cell lung cancer: randomised clinical study 1988–92. Lung Cancer. 1996; 14: 99-107 Abstract Full Text PDF PubMed Scopus (87) Google Scholar ]. Thus it seems difficult, based on such evidence, to assert “PORT only significantly improved OS when given with linear accelerators” (RR 0.76 (95% CI 0.61–0.95), p = 0.02). We can only agree with the authors that modern radiotherapy techniques should be evaluated in stage III patients, as already stated in the individual-patient-data meta-analysis published in 1998. This new evaluation is justified for several reasons: (a) the N2 population has changed because of a better selection with pre-treatment PET-CT scan and brain imaging; (b) adjuvant chemotherapy has become a standard of care in these patients; (c) technical advances of radiotherapy may enhance the ability of PORT to improve local relapse-free survival and possibly overall survival. Thus, based on the mentioned studies, one should be cautious in drawing conclusions that are already within the title of the commented article, but the underlying hypotheses remain to be proven, with sufficiently powered new randomised trials.

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.

BACKGROUND:Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. METHODS:We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. FINDINGS:In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. INTERPRETATION:10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. FUNDING:Cancer Research UK; British Heart Foundation; UK Medical Research Council.

PURPOSE:In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation.MATERIAL AND METHODS:We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy.RESULTS:In non-small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non-lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities.CONCLUSION:Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

113 Background: Preoperative radiotherapy (PreopRT) in locally advanced breast cancer patients (LABC) has been rarely reported. The purpose of this study was to determine if pathological response to PreopRT could have prognostic value on locoregional control and survival. Methods: From 1970 to 1984, 203 LABC patients were treated by PreopRT, delivering 45Gy in 25 fractions to the breast, supraclavicular fossa, axilla and ipsilateral internal mammary chain. After a median interval of 38 days (range: 5-121 days), radical mastectomy and axillary dissection was performed independently of radiation response. Chemotherapy or endocrine therapy was prescribed according to physician discretion in 28% and 11% of patients, respectively. Premenopausal patients underwent ovarian ablation. Median follow-up was 26 years. Locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method, the comparison of survival between groups was performed using the log-rank test, multivariate analysis was performed using the Cox model. Results: Thirty-three patients (16.2%) had a pathologic complete response (pCR) in the breast. The 10- and 20-year Kaplan-Meier LC were 90% (95% confidence interval CI: 85-94%) and 84% (95% CI: 77-89%), respectively. The 10 and 20-years DFS were 49% (CI: 42-55%) and 35% (CI: 29-42%), and the 10 and 20-years OS, 56% (CI: 49-63%) and 41% (CI: 35-48%), in that order. Patients with pCR tended to have better DFS (p=0.06) and OS (p=0.07) when compared to patients with partial response or stable/progressive disease. Having a pCR did not significantly influenced LRC (p=0.44). Multivariate analysis showed that a lower number of positive nodes on axillary dissection and younger age were associated with better DFS (p<0.0001 and p=0.02) and OS (p<0.0001 and p=0.007). Conclusions: LCR achieved by PreopRT followed by radical mastectomy in LABC was excellent in this study, despite few patients having adjuvant systemic therapy. Complete pathologic response defined a subgroup of women with a trend toward better DFS and OS. Older patients and those with a higher number of involved axillary nodes had a worse prognosis.

BACKGROUND:Locoregional treatment of inflammatory breast cancer (IBC) is crucial because local relapses may be highly symptomatic and are commonly associated with distant metastasis. With a median follow-up of 20 years, we report here the long-term results of a monocentric clinical trial combining primary chemotherapy (CT) with a schedule of anthracycline-based CT and an alternating split-course of radiotherapy (RT*CT) without mastectomy. METHODS AND MATERIALS:From September 1983 to December 1989, 124 women with nonmetastatic IBC (T4d M0) were treated with three cycles of primary AVCMF chemotherapy (anthracycline, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil) and then an alternating RT*CT schedule followed by three cycles of FAC. Hormonal therapy was systematically administered: ovarian irradiation (12 Gy in four fractions) or tamoxifen 20 mg daily. RESULTS:Local control was achieved in 82% of patients. The 10- and 20-year local relapse rates were 26% and 33%, respectively, but only 10% of locally controlled cases were not associated with concurrent distant metastasis. The 10- and 20-year overall survival rates were 39% and 19%, respectively. Severe fibrosis occurred in 54% of patients, grade 3 brachial plexus neuropathy in 4%, grade 2 pneumonitis in 9%. Grade 1, 2 and 3 cardiac toxicity was observed in 3.8%, 3.8% and 1.2% of cases respectively. CONCLUSIONS:This combined regimen allowed good long-term local control without surgery. Survival rates were similar to those obtained with conventional regimens (primary chemotherapy, total mastectomy, and adjuvant radiotherapy). Since IBC continues to be an entity with a dismal prognosis, this approach, safely combining preoperative or postoperative radiation therapy and systemic treatments, should be reassessed when suitable targeted agents are available.