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To perform a systematic review and meta-analysis of severe adverse events (SAE) reported in early trials combining molecularly targeted therapies (MTT) with radiotherapy (RT), and to compare them to standard therapy. A summary data meta-analysis was performed and compared to the historical standard. Inclusion criteria were phase I and/or II trials published between 2000 and 2011, with glioblastoma multiforme patients treated with RT and MTT. Pooled incidence rates (IR) of SAE were estimated as well as the pooled median progression-free survival (PFS) and overall survival (OS). Nineteen prospective trials (9 phase I, 1 phase I/II and 9 phase II) out of 29 initially selected were included (n = 755 patients). The exact number of patients who had experienced SAE was mentioned in 37 % of the trials, concerning only 17 % of the patients. Information such as the period during which adverse events were monitored, the planned treatment duration, and late toxicity were not reported in the trials. The pooled IR of overall SAE was 131.2 (95 % CI 88.8–193.7) per 1000 person-months compared to 74.7 (63.6–87.8) for standard therapy (p < 0.01). Significant differences were observed for gastrointestinal events (p = 0.05) and treatment-related deaths (p = 0.02), in favour of standard therapy. No significant difference was observed in PFS and OS. Reporting a summary of toxicity data in early clinical trials should be stringently standardized. The use of MTT with RT compared to standard therapy increased SAE while yielded comparable survival in glioblastoma multiforme patients.

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 chemotherapy B. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy in 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.

Contains fulltext : 154382.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To establish the extent to which systematic reviews and meta-analyses of individual participant data (IPD) are being used to inform the recommendations included in published clinical guidelines. DESIGN: Descriptive study. SETTING: Database maintained by the Cochrane IPD Meta-analysis Methods Group, supplemented by records of published IPD meta-analyses held in a separate database. POPULATION: A test sample of systematic reviews of randomised controlled trials that included a meta-analysis of IPD, and a separate sample of clinical guidelines, matched to the IPD meta-analyses according to medical condition, interventions, populations, and dates of publication. DATA EXTRACTION: Descriptive information on each guideline was extracted along with evidence showing use or critical appraisal, or both, of the IPD meta-analysis within the guideline; recommendations based directly on its findings and the use of other systematic reviews in the guideline. RESULTS: Based on 33 IPD meta-analyses and 177 eligible, matched clinical guidelines there was evidence that IPD meta-analyses were being under-utilised. Only 66 guidelines (37%) cited a matched IPD meta-analysis. Around a third of these (n=22, 34%) had critically appraised the IPD meta-analysis. Recommendations based directly on the matched IPD meta-analyses were identified for only 18 of the 66 guidelines (27%). For the guidelines that did not cite a matched IPD meta-analysis (n=111, 63%), search dates had preceded the publication of the IPD meta-analysis in 23 cases (21%); however, for the remainder, there was no obvious reasons why the IPD meta-analysis had not been cited. CONCLUSIONS: Our results indicate that systematic reviews and meta-analyses based on IPD are being under-utilised. Guideline developers should routinely seek good quality and up to date IPD meta-analyses to inform guidelines. Increased use of IPD meta-analyses could lead to improved guidelines ensuring that routine patient care is based on the most reliable evidence available.

Heterogeneity can be a major component of meta-analyses and by virtue of that fact warrants investigation. Classic analysis methods, such as meta-regression, are used to explore the sources of heterogeneity. However, it may be difficult to apply such a method in complex cases or in the absence of an a priori hypothesis. This paper presents a graphical method to identify trials, groups of trials or groups of patients that are sources of heterogeneity. The contribution of these trials to the overall result can also be evaluated with this method. Each trial is represented by a dot on a 2D graph. The X-axis represents the contribution of the trial to the overall Cochran Q-test for heterogeneity. The Y-axis represents the influence of the trial, defined as the standardized squared difference between the treatment effects estimated with and without the trial. This approach has been applied to data from the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) comprising 10,850 patients in 65 randomized trials. The graphical method allowed us to identify trials that contributed considerably to the overall heterogeneity and had a strong influence on the overall result. It also provided useful information for the interpretation of heterogeneity in this meta-analysis. The proposed graphical method identifies trials that account for most of the heterogeneity without having to explore all possible sources of heterogeneity by subgroup analyses. This method can also be applied to identify types of patients that explain heterogeneity in the treatment effect.

In the last decade, a new method has emerged called 'network meta-analysis' to take into account all randomized trials in a given clinical setting to provide relative effectiveness between different treatments, whether or not they have been compared (pairwise) in randomized controlled trials. Network meta-analyses combine the results of direct comparisons from randomized trials with indirect comparisons between trials (i.e. when two treatments were not compared with each other, but have been studied in relation to a common comparator). The purpose of this note is to explain this method, its relevance and its limitations. A worked example in non-metastatic head and neck cancer is presented as illustration.

To evaluate the impact on survival of primary tumour resection in patients with unresectable synchronous metastases from colorectal cancer (CRC).Primary tumour resection in this setting remains controversial.We retrieved individual data of 1155 patients with metastatic CRC included in four first-line chemotherapy trials: Fédération Francophone de Cancérologie Digestive (FFCD)-9601, FFCD-2000-05, Actions Concertées dans les cancers COloRectaux et Digestifs (ACCORD)-13, and ML-16987. Patients with unresectable synchronous metastases were eligible for this study. We used univariate and multivariate analyses (Cox models stratified on the trial) to assess the impact of primary tumour resection and other potential prognostic variables on overall survival (OS) (the primary endpoint).Amongst the 1155 patients, 810 patients met the inclusion criteria and 59% (n = 478) underwent resection of their primary tumour, prior to trial entry (resection group). Compared to patients in the non-resection group (n =3 32 [41%]), those in the resection group were more likely to have a colonic primary, lower baseline carcinoembryonic antigen (CEA) and alkaline phosphatase levels, and normal white-blood-cell count (p0.001 each). Primary tumour resection was independently associated to better OS in multivariate analysis (hazard ratio (HR), 0.63 [0.53-0.75]; p0.001, with a more favourable impact of resection on OS in case of rectal primary and low CEA level. Primary tumour resection was also independently associated to a better progression-free survival in multivariate analysis (HR, 0.82 [0.70-0.95]; p0.001).Primary tumour resection was independently associated to a better OS in patients with CRC and unresectable synchronous metastases.

Summary Background Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. Methods In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m 2 ) and oxaliplatin (100 mg/m 2 ) with or without cetuximab (500 mg/m 2 ), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149. Findings Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52–74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43–65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1–7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7–6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1–13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6–16·0) in the chemotherapy alone group. The most common grade 3–4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group. Interpretation The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option. Funding Institut National du Cancer, Merck Serono.

The objective of this study is to compare the result's of an individual patient-based and a literature-based meta-analysis in chemotherapy in head and neck cancer and to identify the sources of difference. For all head and neck cancer randomized controlled clinical trials comparing chemotherapy and loco-regional treatment with loco-regional treatment alone, both the literature data and the individual patient data are retrieved and meta-analyses performed and compared. Only survival data are used as outcome, although both time to death and mortality at specific time points are considered in different analyses. There are substantial differences between the individual patient-based and the literature-based meta-analyses. The most important reason for the differing results is that the individual patient-based meta-analysis is based on a time to event analysis, whereas the literature-based meta-analysis is based on mortality at a specific time point. Mortality can change substantially with follow-up time. The absolute survival differences in the case study, for instance, increase from 2.6% at 2 years to 5.6% at 5 years. Control Clin Trials 2001;22:538-547 (C) Elsevier Science Inc. 2001.

A meta-analysis is a quantitative synthesis of randomised clinical trials, used to evaluate moderate treatment effects in oncology. It is complementary to large-scale trials. We describes the principles, methods, and limits of meta-analyses. The gold standard for a meta-analysis is to obtain individual patient data directly from each principal investigator, but this is time-consuming and costly. The main steps of a meta-analysis using individual patient data are described. Multidisciplinary collaboration is needed for clinical insight and critical review of the data and results. Meta-analysis should include an evaluation of the trial quality, a quantification of the overall treatment effect, a study of the variations seen in this effect between trials, and pre-planned exploratory analyses to identify groups of patients who may benefit more from the treatment. Statistical methods are explained using real working examples. Since literature-based meta-analysis can lead to seriously biased assessments, meta-analyses of individual patient data should be undertaken systematically when long-term follow-up is needed, when a detailed analysis is important, or when the literature-based meta-analyses are not in agreement. The main factors which influence the quality of a meta-analysis are discussed.

In literature-based meta-analyses of time-to-event data, the number of events in the treated and control groups together with the total number of patients randomized to the two treatment arms are often used as summary statistics. If interest is in mortality at a specified moment in time, the number of events can, in most cases, only be obtained from the Kaplan-Meier curve. The estimated number of events, however, is typically larger than the true number of events. The effect of this overestimation on the Mantel-Haenszel test and the odds ratio is studied in this paper. From these results, it can be concluded that the number of events should not be estimated from the Kaplan-Meier curves for meta-analytic purposes unless virtually no patients are lost to follow-up or censored and there are still many patients at risk in the two groups at the time at which the number of events is to be determined.

Despite more than 70 randomized clinical trials comparing locoregional treatment plus chemotherapy with the same locoregional treatment alone, the effect of chemotherapy on the survival of patients with head and neck squamous cell cancer is uncertain. Indeed, most of the randomized trials have been inconclusive in this regard, and only a few have reported significant results either in favor of or against chemotherapy. This article focuses on four meta-analyses that included a comparison between chemotherapy (neoadjuvant, adjuvant, or concomitant) plus locoregional treatment versus the same locoregional treatment alone and in which survival was the main end-point.

BACKGROUND The Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC) Group has previously shown that chemotherapy improved survival (4% at 5 years) in nonmetastatic head-and-neck squamous cell carcinoma (other than nasopharynx carcinoma) treated by locoregional treatment, with a higher benefit (8%) with chemotherapy concomitant to radiotherapy (1). However, the relatively important heterogeneity of the results limited the conclusions (2) and prompted the MACH-NC group to update the meta-analysis by adding the data from the randomized trials performed between 1994 and 2000 (3). To confirm the difference of effect between timings of chemotherapy, we completed the previous analyses by exploring further the indirect comparison of neoadjuvant and concomitant chemotherapy trials and by updating the meta-analysis of the randomized trials comparing neoadjuvant with concomitant chemotherapy. We conducted in parallel two other individual patient data meta-analyses: the Meta-Analysis on Chemotherapy in NasoPharynx Carcinoma (MAC-NPC) (4) and the Meta-Analysis of Radiotherapy in Carcinoma of Head and Neck (MARCH) (5) on altered fractionated radiotherapy. A decrease of the treatment effect with age both in MACH-NC and MARCH led us to further explore this effect (6).

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Background and Objectives It is now established that liver resection is beneficial for metastases from colorectal cancer. Nevertheless, a surgical margin estimated at less than 10 mm at preoperative imaging is considered an absolute contraindication to surgery by some, and a relative contraindication by others. The true impact of the width of the margin on the prognosis is unclear. Methods From 1984 to 1996, 196 patients underwent curative hepatectomy for liver metastases and were studied prospectively. Surgery was to be curative (or a complete R0 resection) and mortality was to be avoided. Of these 196 patients, 136 had surgical margins of less than 10 mm. Sixty-eight percent had multiple liver metastases and 15% had extrahepatic metastatic lesions. Clinical and pathological factors were studied specifically and a multivariate analysis was carried out. Results Overall 5-year survival rate of these 136 patients (taking into account postoperative mortality which attained 1.5%) was 27.8% and the disease-free survival was 22.9%. The surgical margin was 0 mm in 30 cases. The sole prognostic factor was the discovery of unsuspected (resectable) extrahepatic lesions at laparotomy (P < 0.001); the width of the free margin had no significant effect. However, in the multivariate analysis of prognostic factors for the entire series (269 hepatectomies), three powerful parameters were identified : (1) the curative nature of resection (P = 0.0007), (2) less than 20% of liver involvement (P = 0.002), and (3) a free margin exceeding 9 mm (P = 0.02). A correlation was found between narrow margins and extensive disease (high number of metastases, bilateral sites, and extended hepatectomy). There was also a greater likelihood of microscopic satellite lesions within 10 mm around the metastases. Conclusions The prognostic impact of the width of the surgical margin should not be overestimated. Hepatectomy for liver metastases can procure long-term survival, even in patients with supposedly poor prognostic factors. Resection is justified as long as it is complete and the risks are minimal. J. Surg. Oncol. 1998;69:88–93. © 1998 Wiley-Liss, Inc.

BACKGROUND Serum neuron specific enolase (NSE) is the most sensitive tumor marker of small cell lung carcinoma (SCLC) at diagnosis. Its prognostic value is still debated. Thus, the authors decided to assess the predictive value, in terms of complete response and survival, of serum NSE measured before and after one cycle of chemotherapy in patients with SCLC. METHODS Sera from 135 patients with histologically proven limited (n = 63) or metastatic (n = 72) SCLC were obtained. Clinical and biologic parameters with a known or suspected prognostic relevance were reviewed. Serum NSE was measured before chemotherapy (D1-NSE) and 28 days after its initiation (D28-NSE). The prognostic value of the parameters under study was evaluated in univariate and multivariate analyses using the Cox proportional hazards model and logistic regression analysis. RESULTS The level of serum NSE was raised in 120 patients (88%) prior to therapy. The probability of a normal D28-NSE value was not affected by the baseline D1-NSE value. Disease extension (P = 0.0005), performance status (P = 0.0001), D28-NSE (P = 0.003), and carcinoembryonic antigen (CEA) levels (P = 0.008) were found to be predictive for survival, whereas age, gender, plasma sodium, serum protides, and D1-NSE were not. Median survival and 2-year overall survival were 15.3 months and 21% (95% confidence interval [CI], 13-31%) when D28-NSE was normal and 8.1 months and 15% (95% CI, 8-27%) when it was not (P < 0.03). Only performance status (P = 0.001), disease extension (P = 0.002), and D28-NSE (P = 0.02) were found to be independent prognostic parameters for survival in the multivariate analysis. A simple prognostic index was developed using these 3 variables. Limited disease, a normal D28-NSE value, and a normal CEA value prior to therapy were the only parameters predictive for complete response in the univariate analysis, and D28-NSE (P = 0.01) and disease extension (P = 0.0001) were found to be independent variables in multivariate analysis. A complete response to therapy occurred in 62% with a normal D28-NSE value and in only 34% in the opposite case. CONCLUSIONS Normal serum D28-NSE is a strong, independent early predictor of both complete response to therapy and survival. This simple tool may be proposed for use in the clinic and in research, in association with an assessment of disease extension and performance status, to predict the outcome of patients with SCLC. Cancer 1998;82:1049-55. © 1998 American Cancer Society.

The meta-analysis included eight trials that compared surgery alone with surgery followed by cisplatin-based chemotherapy, and included 1394 patients. The results showed a 13% reduction in the risk of death, suggesting that adjuvant chemotherapy afforded an absolute benefit of 5% at 5 years (p=0·08). Sex, performance status, age, and histological subtype were not predictive of this effect. These results provided the rationale for a new generation of randomised studies investigating platinum-based combinations, but only two of these studies had enough power to confirm this benefit. The table summarises the results of published trials. The Intergroup (INT)-0115 trial 2 was the only study in which concurrent combination chemotherapy and thoracic radiotherapy were compared with radiotherapy alone. In the postoperative setting of the Big Lung Trial, 3 around 10% of patients with incomplete resection and 3% who received preoperative chemotherapy, were included. Neither of these trials had sufficient power to detect the moderate treatment effect suggested by the overview. The two largest studies—the Adjuvant Lung Project Italy (ALPI) 4 and the International Adjuvant Lung trial (IALT) 5 —each of which included more than 1000 patients, showed moderate compliance (in the ALPI trial, 69% of patients completed the treatment and half of them had treatment modifications; in the IALT study, 74% of patients received a total dose of 240 mg/m 2 cisplatin). Only the IALT study showed a significant difference in terms of overall and disease-free survival; however the results of the ALPI trial are consistent with a beneficial effect of adjuvant chemotherapy, mainly in terms of a reduction of death and events. More recently, two moderate-sized studies showed a significant survival benefit: 15% at 5 years for the National Cancer Institute of Canada (NCIC) BR10 study 6

CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004).To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0-1.5], p = 0.06) but not significantly so for OS (HR=1.1 [0.9-1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0-1.6] in adenocarcinoma vs. 1.6 [1.2-2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49).Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.

Gastric cancer is the fourth most common malignancy in the world, affecting 989000 patients in 2008 (7.8% of all cancers) (1). The most effective treatment for localized disease is surgery, but even after curative resection, recurrence is noted in more than half the cases of advanced-stage disease. This poor outcome has prompted major efforts to explore different adjuvant therapies. However, over the last three decades, despite some successful large-scale trials (2–5), only modest improvement has been achieved in survival. Our group recently reported the results of a meta-analysis of individual data that showed a lower risk of death with postoperative adjuvant chemotherapy than with surgery alone (overall hazard ratio [HR] =0.82; P < .0001) (6). However, the efficacy of adjuvant chemotherapy is still far from satisfactory, and further investigation into more effective treatments for patients with resectable gastric cancer is warranted. Historically, the 5-year overall survival (OS) rate has typically been the most quoted metric for judging the success of a particular treatment. This endpoint has the advantage of being simple to measure, easy to interpret, and clinically meaningful. However, the main disadvantages of this endpoint are that it requires an extended follow-up period and its measurement is potentially diluted by nonmalignant causes of death and therapies for recurrent/advanced disease. A reasonable candidate for a surrogate of OS in the adjuvant setting is disease-free survival (DFS), which is defined here as the time to cancer recurrence, second cancer, or death from any cause. Recent meta-analyses have been used to validate DFS as a surrogate for OS in other tumor types (7,8). If DFS could replace OS in the assessment of the efficacy of new treatments in clinical trials testing adjuvant treatment for patients with curatively resected gastric cancer, the trial duration and costs would be reduced. We performed a comprehensive meta-analysis of data from 3838 individual patients randomized in 17 trials on curatively resected gastric cancer; documented DFS values, which were available for 3371 of the patients from 14 trials, were used to evaluate DFS as a surrogate endpoint for OS.

Purpose Cisplatin plus fluorouracil (PF) induction chemotherapy has been compared with taxane (docetaxel or paclitaxel), cisplatin, and fluorouracil (Tax-PF) in randomized trials in locoregionally advanced head and neck cancers (LAHNCs). The aim of this meta-analysis was to study the efficacy and toxicity of Tax-PF and PF and identify differences in outcomes in subsets of patients. Methods Five randomized trials representing 1,772 patients were identified. Updated individual patient data (IPD) were retrieved for all trials. The log-rank test, stratified by trial, was used for comparison. Interaction or trend tests were used to study the interaction between covariates and treatment. Results Median follow-up was 4.9 years. The hazard ratio (HR) of death was 0.79 (95% CI, 0.70 to 0.89; P < .001; absolute benefit at 5 years: 7.4%) in favor of Tax-PF. Heterogeneity was significant (P = .08, I2 = 51%) and related to one trial. There was no more heterogeneity after exclusion of this trial (P = .99, I2 = 0%), and HR of death was 0.72 (95% CI, 0.63 to 0.83) in favor of Tax-PF. There was no interaction between treatment effect and the following patient covariates: age, sex, performance status, tumor stage, or site. Tax-PF was associated with significant reductions of progression, locoregional failure, and distant failure compared with PF, with HRs of 0.78 (95% CI, 0.69 to 0.87; P < .001), 0.79 (95% CI, 0.66 to 0.94; P = .007), and 0.63 (95% CI, 0.45 to 0.89; P = .009) respectively. Conclusion This IPD meta-analysis shows the superiority of Tax-PF over PF as induction chemotherapy. Its precise role in the management of LAHNC remains to be determined.

Objectives: To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Design: Meta-analysis of individual patient data from randomised trials. Setting: Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC. Participants: 2331 patients with advanced NSCLC. Primary and secondary outcome measures: Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS. Results: The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata. Conclusions: These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation. sanofi-aventis, Paris, France; Ligue Nationale Contre le Cancer, France

Background: STK11 (also called LKB1) is among the 3 most mutated genes in lung adenocarcinoma, but its prognostic and predictive significance in advanced NSCLC patients is still not clear. Recent preclinical and translational evidence suggest its role in conditioning KRAS mutant lung adenocarcinomas aggressiveness and response to targeted treatment. Materials and methods: This retrospective analysis, in a single center, included consecutive NSCLC patients who had undergone a platinum-containing regimen, for which standard or next generation (NGS) sequencing analyses of STK11 gene (exons 1-9) had been successfully performed. STK11 gene was considered mutated if effect on protein was predicted as deleterious. Clinical features along with EGFR (exons 18-21), KRAS (exons 2-4) and TP53 (exons 1-11) mutational status were correlated to STK11 status. Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for stage (advanced yes/no) and histology for progression-free survival (PFS), and smoking status, stage, EGFR/KRAS status and number of lines of chemotherapy for overall survival (OS). Results: Among the 302 patients included between November 2007 and January 2015, 63% were male, 16% non-smoker and median age was 60 year; 75% had an adenocarcinoma, 88% a stage IIIB or IV and 80% no previous treatment for advanced disease; 25 (8%) patients had a STK11 mutation, 30 (10%) an EGFR mutation and 81 (27%) a KRAS mutation. Deletions/insertions, missense and false-sense mutations mainly involved exon 4-6 of STK11. No statistical differences were observed between STK11 status and sex, smoking status, age, stage at diagnosis or histology (adenocarcinoma versus others). Among the 25 patients with STK11 mutation, 13 patients (52%) had a KRAS mutation, compared with 67 (24%) among those without STK11 mutation (p = 0.008). No correlation between STK11 and EGFR or TP53 mutational status was observed. Median follow-up time was 34.8 months (95% confidence interval [CI95]: 30.7-42.3). In univariate analysis, OS was shorter for STK11 mutated patients compared to wild type ones (p = 0.085; HR: 1.53; CI95: 0.94-2.49) with a median OS of 10.4 (CI95: 6.1-15.7) and 17.3 (CI95: 14.0-21.1) months for mutated and wild-type STK11 patients respectively. In multivariate analysis, the HR was 1.21 (CI95: 0.74-1.99; p = 0.45). Similar non-significant results were observed for PFS. Conclusion: We confirm the reported data of a positive correlation between STK11 and KRAS mutations. No correlation between STK11 status and PFS or OS in patients receiving platinum-based treatment was observed when taking into account other prognostic covariates. Citation Format: Francesco Facchinetti, Maria Virginia Bluthgen, Gabrielle Tergemina Clain, Laura Faivre, Jean-Pierre Pignon, David Planchard, Jean-Charles Soria, Benjamin Besse, Ludovic Lacroix. STK11 mutations in non-small cell lung cancer (NSCLC): descriptive analysis and prognostic significance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2250.

11563Background: Radiogenomics is focused on defining the relationship between image and molecular phenotypes. Therefore, we assess the association between metastatic sites at baseline CT and molec...

e15003Background: IAHCT is more and more recognized in the management of LMCRC. Regarding its anti-angiogenic effect bevacizumab (B) could be considered as a good candidate for IAH treatment. This ...

Objective—To determine the prevalence of heart murmurs in chinchillas (Chinchilla lanigera) and determine whether heart murmurs were associated with cardiac disease. Design—Retrospective multi-institutional case series. Animals—260 chinchillas. Procedures—Medical records of all chinchilla patients evaluated at the Tufts University Foster Hospital for Small Animals between 2001 and 2009, the University of California-Davis William R. Pritchard Veterinary Medical Teaching Hospital between 1996 and 2009, and the University of Wisconsin Veterinary Medical Teaching Hospital between 1998 and 2009 were reviewed. Results—Prevalence of heart murmurs was 23% (59/260). Of 15 chinchillas with heart murmurs that underwent echocardiography, 8 had echocardiographic abnormalities, including dynamic right ventricular outflow tract obstruction, mitral regurgitation, hypertrophy of the left ventricle, tricuspid regurgitation, and hypovolemia. Echocardiographic abnormalities were approximately 29 times as likely (OR, 28.7) to be present in chinchillas with a murmur of grade 3 or higher than in chinchillas without a murmur. Conclusions and Clinical Relevance—Results suggested that heart murmurs are common in chinchillas and that chinchillas with heart murmurs often have echocardiographic abnormalities, with valvular disease being the most common. On the basis of these results, we believe that echocardiography should be recommended for chinchillas with heart murmurs, especially older chinchillas with murmurs of grade 3 or higher. Further prospective studies are needed to accurately evaluate the prevalence of cardiac disease in chinchillas with heart murmurs.

BackgroundEpidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France.MethodsBetween March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non–small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings. Cox models were used to investigate the impact of patient characteristics and mutations on progression-free survival (PFS) and overall survival (OS). Added value from mutation status was evaluated using likelihood ratio (LR) tests. Classification and regression tree analysis aimed to identify homogeneous groups in terms of survival.ResultsAmong the 522 patients, 87% were white, 32% were women, and 18% were never-smokers, with 65% presenting with adenocarcinoma. Biological data were available for 307 patients, showing 44 EGFR mutations (14%) and 42 KRAS (14%) mutations. Median PFS was 2.4 months (interquartile range, 1.4–4.6) and median OS 5.6 months (interquartile range, 2.2–14.0). Factors independently associated with PFS were performance status 1 or 2 to 3 (hazards ratio [HR] = 1.5, 95% confidence interval [CI] 1.1–1.9; and HR = 2.3, CI 1.7–3.1, respectively; p < 0.001); former or current smoker status (HR = 1.8, CI 1.4–2.4 and 2.0,CI 1.4–2.8, respectively; p < 0.001); nonadenocarcinoma histology (squamous cell: HR = 0.9 CI 0.7–1.2]; others: HR = 1.6, 1.3–2.1; p < 0.001); at least two metastatic sites (HR = 1.3, CI 1.1–1.6 and 1.6, CI 1.3–2.1, respectively; p < 0.001); prior taxane-based chemotherapy (HR = 1.3, CI 1.0–1.3, p = 0.01); non-white (HR = 0.7, CI 0.5–0.9, p = 0.009). Similar results were found for OS. In addition, EGFR and KRAS mutations were significantly associated with PFS (HR = 0.5, CI 0.3–0.7 and HR = 1.2, CI 0.8–1.8, respectively, versus no mutation; LR p = 0.001). In the OS model, adjusted HR was 0.7 (0.4–1.0) for EGFR mutation and 1.7 (1.1–2.4) for KRAS (LR p = 0.004). Classification and regression tree analysis revealed EGFR mutation to be the primary factor for identifying homogeneous patient subgroups in terms of PFS.ConclusionsEGFR and KRAS status independently impacts outcomes in advanced non–small-cell lung cancer patients treated with EGFR-TKI. However, EGFR status impacts both PFS and OS whereas KRAS only impacts OS. These findings support the nationwide use of EGFR status for patient selection before EGFR-TKI therapy. The role of KRAS mutations remains to be elucidated.

Introduction The staging of node-negative non–small-cell lung cancer is modified in the 7th edition TNM classification. Here, we pool data from the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Cancer and Leukemia Group B-9633 trial to explore the prognostic and predictive effects of the new T-size descriptors and KRAS mutation status. Methods Node-negative patients were reclassified as T2a (>3–⩽5 cm), T2b (>5–⩽7 cm), T3 (>7 cm) or T ⩽ 3 cm (⩽3 cm, but other T2 characteristics). Results Of 538 eligible patients, 288 (53.5%) were T2a, 111 (21%) T2b, 62 (11.5%) T3, whereas 77 (14%) T⩽3 cm were excluded to avoid confounding. KRAS mutations were detected in 104 of 390 patients (27%). T-size was prognostic for disease-free survival ( p = 0.03), but borderline for overall survival (OS; p = 0.10), on multivariable analysis. Significant interaction between the prognostic value of KRAS and tumor size was observed for OS ( p = 0.01), but not disease-free survival ( p = 0.10). There was a nonsignificant trend ( p = 0.24) for increased chemotherapy effect on OS with advancing T-size (hazard ratio [HR] T2a 0.90, [0.63–1.30]; T2b 0.69, [0.38–1.24]; and T3 0.57, [0.28–1.17]). The HR for chemotherapy effect on OS in T2a patients with KRAS wild-type tumors was 0.81 ( p = 0.36), whereas a trend for detrimental effect was observed in those with mutant tumors (HR 2.11; p = 0.09; interaction p = 0.05). Similar trends were observed in T2b to T3 patients with wild-type (HR 0.86; p = 0.62), and KRAS mutant tumors (HR 1.16; p = 0.74; interaction p = 0.58). Conclusion Chemotherapy effect seems to increase with tumor size. However, this small study could not identify subgroups of patients who did or did not derive significant benefit from adjuvant chemotherapy based on T-size or KRAS status.

Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial.To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC.There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006.Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen).Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97).Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

The triangular test has been used to monitor survival data from a randomized trial in patients with small cell lung cancer. The results of consecutive interim analyses and the problems met by the data monitoring committee and the co-ordinators are described. The methods as well as the consequences of the early stopping on the analysis and the results of this trial are discussed. From this experience, we believe that statistical stopping rules--only one of the factors to be taken into account when deciding to stop a trial--should be used with caution. Independent data monitoring committees may be useful in helping to review the ongoing results and advise the participants in the trial.

Combined chemotherapy has demonstrated a degree of efficacy in gastric carcinoma. As 5-fluorouracil (5FU) and cisplatinum are two of the most active drugs, we have tested the efficacy of combined 5FU and cisplatinum in a prospective phase II trial. Cycles were administered every 4 weeks and consisted of 5FU 1000 mg/m 2 /day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m 2 on day 2. Cycles were repeated according to tolerance and efficacy. 87 patients entered the study, 57 with metastatic or recurrent tumour (M) and 30 with locally advanced gastric cancer (LAGC). The response rate for the 83 evaluable patients was 43% [95% confidence interval (CI) 30–56%]. There were four complete responses (5%), 32 partial responses (39%), 34 cases of stable disease and 13 cases of progressive disease. Responses were more frequent in patients with a good performance status ( P = 0.02), with their primary located in the cardia ( P = 0.003), with a non-linitis plastica tumour form ( P = 0.003) or a tumour containing less than 50% of independent cells ( P = 0.016). Median survival was 9 months for the total population. It was better in patients with a good performance status ( P = 0.01), and those who did not have linitis plastica ( P = 0.005). Toxicity was acceptable, although grade 3–4 neutropenia was reported in 22% of the cycles, mucositis in 14% and 3 patients died of septic complications. The combination of 5FU and cisplatinum is effective in terms of tumour response in advanced gastric cancer and warrants testing with the other active regimens.

The observation of time to tumour progression (TTP) or progression-free survival (PFS) may be terminated by a terminal event. In this context, deaths may be due to tumour progression, and the time to the major failure event (death) may be correlated with the TTP. The usual assumption of independence between the TTP process and death, required by many commonly used statistical methods, can be violated. Furthermore, although the relationship between TTP and time to death is most relevant to the anti-cancer drug development or to evaluation of TTP as a surrogate endpoint, statistical models that try to describe the dependence structure between these two characteristics are not frequently used. We propose a joint frailty model for the analysis of two survival endpoints, TTP and time to death, or PFS and time to death, in the context of data clustering (e.g. at the centre or trial level). This approach allows us to simultaneously evaluate the prognostic effects of covariates on the two survival endpoints, while accounting both for the relationship between the outcomes and for data clustering. We show how a maximum penalized likelihood estimation can be applied to a nonparametric estimation of the continuous hazard functions in a general joint frailty model with right censoring and delayed entry. The model was motivated by a large meta-analysis of randomized trials for head and neck cancers (Meta-Analysis of Chemotherapy in Head and Neck Cancers), in which the efficacy of chemotherapy on TTP or PFS and overall survival was investigated, as adjunct to surgery or radiotherapy or both.

Background To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. Methods Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m2/day (protracted IV) and docetaxel (DCT) 20 mg/m2/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/m2, plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. Results Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). Conclusions Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. Trial Registration ClinicalTrials.gov: NCT00112697

Purpose After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. Patients and Methods Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m2) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m2/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. Results Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. Conclusion In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS.

Introduction The recently updated meta-analysis of chemotherapy in head and neck cancer (MACH-NC) demonstrated the benefit of the addition of chemotherapy in terms of overall survival in head and neck squamous cell carcinoma (HNSCC). The magnitude of the benefit according to tumour site is unknown as well as their potential interactions with patient or trial characteristics. Methods Eighty seven randomized trials performed between 1965 and 2000 were included in the present analysis. Patients were divided into four categories according to tumour location: oral cavity, oropharynx, hypopharynx and larynx. Patients with other tumour location were excluded (999, 5.7%). For each tumour location and chemotherapy timing, the logrank-test, stratified by trial, was used to compare treatments. The hazard ratios of death or relapse were calculated. Interactions between patient or trial characteristics and chemotherapy effect were studied. Results Individual patient data of 16,192 patients were analysed, with a median follow-up of 5.6years. The benefit of the addition is consistent in all tumour locations, with hazard ratios between 0.87 and 0.88 ( p -value of interaction=0.99). Chemotherapy benefit was higher for concomitant administration for all tumour locations, but the interaction test between chemotherapy timing and treatment effect was only significant for oropharyngeal ( p p =0.05), and not for oral cavity ( p =0.15) and hypopharyngeal tumours ( p =0.30). The 5-year absolute benefits associated with the concomitant chemotherapy are 8.9%, 8.1%, 5.4% and 4% for oral cavity, oropharynx, larynx and hypopharynx tumours, respectively. Conclusion The benefit of the addition of chemotherapy to locoregional treatment is consistent in all tumour locations of HNSCC. The higher benefit of concomitant schedule was demonstrated only for oropharyngeal and laryngeal tumours but this may be only a consequence of a lack of power.

International audience; BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer.METHODS: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256.FINDINGS: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; pINTERPRETATION: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer.FUNDING: Sanofi-Aventis France.

Context Good Clinical Practice regulates monitoring activities in clinical research. Due to question and design diversity, and limited resources, on-site monitoring is often less intensive in the academic context, and variable. Standardization is needed, and relies on definition and validation of tools accounting for risk. Objective To define, and validate tools, to implement a risk-based monitoring strategy for academic clinical research. Methods Working groups of experienced professionals searched the literature, and built a consensus risk-assessment scale (RAS), and a risk-adapted monitoring plan (RAMP). We allocated 200 protocols to 49 assessors. We assessed the RAS relevance vs. a visual analogue scale (VAS), and its reproducibility through Kraemer's kappa, and intraclass correlation coefficient (ICC) from a random proportional odds model. We identified sources of disagreement through a logistic regression. We described assessors' difficulties during assessment. We applied the RAMP to 10 protocols per risk level, and rated its feasibility (0 = easy to 4 = impossible). Results RAS and RAMP were defined in 4 levels. RAS relevance was good: RAS-risk levels were evenly distributed on VAS-risk (0.6, 2.6, 5.6, and 7.9). Reproducibility was moderate to good: kappa = 0.48, ICC = 0.70. Major disagreements (36%) arose from decision-makers, rather than hands-on managers. Most difficulties occurred in ill-written protocols (17%). RAMP was easily feasible for most protocols (mean score: 0.2 to 0.9). We proposed a standard synopsis for evaluation purpose. Conclusion We defined, and validated risk-based tools. This risk-adapted strategy will be compared to an intensive one in a randomized trial, Optimon, to define a standard of practice for academic clinical research.

The review of randomized trials shows that thoracic radiotherapy combined with chemotherapy decreases the risk of thoracic recurrences and provides a gain in long-term survival of approximately 6% in limited disease when compared to chemotherapy alone. Thoracic radiotherapy and combined radiochemotherapy approaches are composite parameters and the analysis of their effects can be equivocal. The purpose of this paper is to discuss such parameters, namely treatment toxicity, volumes to be treated, total tumor dose, fraction size, timing of radiochemotherapy approaches and the quality of radiotherapy. The analysis of these parameters permits a delineation of questions to be tested in future clinical trials.

Background Several trials have studied the role of altered fractionation radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. Objectives The aim of this individual patient data (IPD) meta-analysis was to assess whether this type of radiotherapy could improve survival. Search methods We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 8 August 2010. Selection criteria We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic head and neck squamous cell carcinomas and grouped trials into three pre-specified treatment categories: hyperfractionated, accelerated and accelerated with total dose reduction. Trials were eligible if they began recruitment after 1969 and ended before 1998. Data collection and analysis We obtained updated individual patient data. Overall survival was the main outcome measure. The secondary outcome measures were local or regional control rates (or both), distant control rates and cause-specific mortality. Main results We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy, corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95% CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007). Authors' conclusions Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.

This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non–small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only. Cancer Res; 70(21); 8288–98. ©2010 AACR.

Purpose The previous individual patient data meta-analyses of chemotherapy in locally advanced non–small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. Methods Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. Results Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. Conclusion Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

CONTEXT Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking. OBJECTIVES To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments. DATA SOURCES Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings. STUDY SELECTION All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified. DATA EXTRACTION As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years. RESULTS There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy. CONCLUSION Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.

Purpose The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Patients and Methods Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. Results The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). Conclusion A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

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.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.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.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.