Meta-analysis Of Chemotherapy Research Articles

Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): From 2009 to 2021, what’s the update? A Mini Review

Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): From 2009 to 2021, what’s the update? A Mini Review

A frequentist one-step model for a simple network meta-analysis of time-to-event data in presence of an effect modifier.

Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequentist one-step model for evaluating TE in the presence of interaction in a three-node NMA for time-to-event data. One-step, frequentist, IPD-based Cox and Poisson generalized linear mixed models were proposed. We simulated a three-node network with or without a closed loop with (1) no interaction, (2) covariate-treatment interaction, and (3) covariate distribution heterogeneity and covariate-treatment interaction. These models were applied to the NMA (Meta-analyses of Chemotherapy in Head and Neck Cancer [MACH-NC] and Radiotherapy in Carcinomas of Head and Neck [MARCH]), which compared the addition of chemotherapy or modified radiotherapy (mRT) to loco-regional treatment with two direct comparisons. AD-based (contrast and meta-regression) models were used as reference. In the simulated study, no IPD models failed to converge. IPD-based models performed well in all scenarios and configurations with small bias. There were few variations across different scenarios. In contrast, AD-based models performed well when there were no interactions, but demonstrated some bias when interaction existed and a larger one when the modifier was not distributed evenly. While meta-regression performed better than contrast-based only, it demonstrated a large variability in estimated TE. In the real data example, Cox and Poisson IPD-based models gave similar estimations of the model parameters. Interaction decomposition permitted by IPD explained the ecological bias observed in the meta-regression. The proposed general one-step frequentist Cox and Poisson models had small bias in the evaluation of a three-node network with interactions. They performed as well or better than AD-based models and should also be undertaken whenever possible.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis

Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Predictive classifier for intensive treatment of head and neck cancer.

This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011). LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Individual patient data network meta-analysis using either restricted mean survival time difference or hazard ratios: is there a difference? A case study on locoregionally advanced nasopharyngeal carcinomas

BackgroundThis study aimed at applying the restricted mean survival time difference (rmstD) as an absolute outcome measure in a network meta-analysis and comparing the results with those obtained using hazard ratios (HR) from the individual patient data (IPD) network meta-analysis (NMA) on the role of chemotherapy for nasopharyngeal carcinoma (NPC) recently published by the MAC-NPC collaborative group (Meta-Analysis of Chemotherapy [CT] in NPC).Patients and methodsTwenty trials (5144 patients) comparing radiotherapy (RT) with or without CT in non-metastatic NPC were included. Treatments were grouped in seven categories: RT alone (RT), induction CT followed by RT (IC-RT), RT followed by adjuvant CT (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival and locoregional control. The rmstD was estimated at t* = 10 years in each trial. Random-effect frequentist NMA models were applied. P score was used to rank treatments. Heterogeneity and inconsistency were evaluated.ResultsThe three treatments that had the highest effect on OS with rmstD were CRT-AC, IC-CRT, and CRT (respective P scores of 92%, 72%, and 64%) compared to CRT-AC, CRT, and IC-CRT when using HR (respective P scores of 96%, 71%, and 63%). Of the 32 HR and rmstD analyzed, 5 had a different interpretation, 3 with a direction change (different direction of treatment effect) and 2 with a change in significance (same direction but a change in statistical significance). Results for secondary endpoints were overall in agreement.ConclusionThe use of either HR or rmstD impacts the results of NMA. Given the sensitivity of HR to non-proportional hazards, this finding could have implications in terms of meta-analysis methodology.

Association of chemotherapy and radiotherapy for T3N0 nasopharyngeal carcinoma in the area of intensity-modulated radiation therapy

Nasopharyngeal carcinoma (NPC) is a highly radiosensitive tumor (especially non-keratinizing carcinoma) and radiotherapy (RT) is the mainstay of treatment for newly diagnosed tumors. For early stage NPC, RT alone is the standard treatment while for locally advanced (LA) NPC concurrent chemoradiotherapy (CRT) with or without sequential chemotherapy [induction chemotherapy (IC) or adjuvant chemotherapy] is the standard treatment modality according to current guidelines, while the benefit of adjuvant or induction chemotherapy alone in addition to RT is limited (1,2). Indeed, the benefit of a combined modality approach has been demonstrated by several randomized trials and individual patient data meta-analysis (3). Moreover, in the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) that included data on 4,806 patients in nineteen trials, with a median follow-up of 7.7 years, the addition of chemotherapy to RT significantly improved overall survival with an absolute benefit at 5 years of 6.3% (95% CI, 3.5–9.1%).

Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline.

The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation (rt) or surgery, or both, for cure or organ preservation, or both, in patients with locally advanced nonmetastatic (stages iii-ivb) squamous cell carcinoma of the head and neck (lascchn). The Meta-analysis of Chemotherapy in Head and Neck Cancer (mach-nc) reports have, de facto, guided practice since 2000, and so we searched the literature for systematic reviews published from January 2000 to February 2015 in reference to five research questions. A search was also conducted up to February 2015 for randomized trials (rcts) not included in the meta-analyses. Recommendations were constructed using the Cancer Care Ontario Program in Evidence-Based Care practice guidelines development cycle. In addition to updated mach-nc reports, five additional meta-analyses and thirty rcts were identified. Five recommendations for lascchn treatment were generated based on those data. Concurrent chemoradiation (ccrt) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment. The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence. For lascchn patients who are candidates for organ preservation strategies and would otherwise require total laryngectomy, either ccrt or induction chemotherapy, followed by rt or surgery based on tumour response is recommended. The addition of cetuximab to intensified rt (concomitant boost or hyperfractionated schedule) is an alternative to ccrt. Routine use of induction chemotherapy to improve overall survival is not recommended. We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn. A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx. One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting. Concurrent chemoradiation provides one strategy for larynx preservation, but the best strategy is unclear. Use of induction chemotherapy does not improve overall survival, and its use should be limited to patients requiring immediate tumour downsizing before local therapy.

What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis.

Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.

950O - Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 100 randomized trials and 19,248 patients, on behalf of MACH-NC group

950O - Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 100 randomized trials and 19,248 patients, on behalf of MACH-NC group

Erratum to: Bias and precision of methods for estimating the difference in restricted mean survival time from an individual patient data meta-analysis

The difference in restricted mean survival time ( $$ rmstD\left({t}^{\ast}\right) $$ ), the area between two survival curves up to time horizon $$ {t}^{\ast } $$ , is often used in cost-effectiveness analyses to estimate the treatment effect in randomized controlled trials. A challenge in individual patient data (IPD) meta-analyses is to account for the trial effect. We aimed at comparing different methods to estimate the $$ rmstD\left({t}^{\ast}\right) $$ from an IPD meta-analysis. We compared four methods: the area between Kaplan-Meier curves (experimental vs. control arm) ignoring the trial effect (Naive Kaplan-Meier); the area between Peto curves computed at quintiles of event times (Peto-quintile); the weighted average of the areas between either trial-specific Kaplan-Meier curves (Pooled Kaplan-Meier) or trial-specific exponential curves (Pooled Exponential). In a simulation study, we varied the between-trial heterogeneity for the baseline hazard and for the treatment effect (possibly correlated), the overall treatment effect, the time horizon $$ {t}^{\ast } $$ , the number of trials and of patients, the use of fixed or DerSimonian-Laird random effects model, and the proportionality of hazards. We compared the methods in terms of bias, empirical and average standard errors. We used IPD from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) and its updated version MAC-NPC2 for illustration that included respectively 1,975 and 5,028 patients in 11 and 23 comparisons. The Naive Kaplan-Meier method was unbiased, whereas the Pooled Exponential and, to a much lesser extent, the Pooled Kaplan-Meier methods showed a bias with non-proportional hazards. The Peto-quintile method underestimated the $$ rmstD\left({t}^{\ast}\right) $$ , except with non-proportional hazards at $$ {t}^{\ast } $$ = 5 years. In the presence of treatment effect heterogeneity, all methods except the Pooled Kaplan-Meier and the Pooled Exponential with DerSimonian-Laird random effects underestimated the standard error of the $$ rmstD\left({t}^{\ast}\right) $$ . Overall, the Pooled Kaplan-Meier method with DerSimonian-Laird random effects formed the best compromise in terms of bias and variance. The $$ rmstD\left({t}^{\ast },=,10,\kern0.5em ,\mathrm{years}\right) $$ estimated with the Pooled Kaplan-Meier method was 0.49 years (95 % CI: [−0.06;1.03], p = 0.08) when comparing radiotherapy plus chemotherapy vs. radiotherapy alone in the MAC-NPC and 0.59 years (95 % CI: [0.34;0.84], p < 0.0001) in the MAC-NPC2. We recommend the Pooled Kaplan-Meier method with DerSimonian-Laird random effects to estimate the difference in restricted mean survival time from an individual-patient data meta-analysis.

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis

A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): An update on 4,798 patients.

6022 Background: In a previous MAC-NPC individual patient data (IPD) meta-analysis, the addition of chemotherapy (CT) to radiotherapy improved overall survival (OS) in nasopharyngeal carcinoma (NPC...

A joint model for the dependence between clustered times to tumour progression and deaths: A meta-analysis of chemotherapy in head and neck cancer

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.

Collaborative Dysphagia Care for Chemoradiation Patients

Collaborative Dysphagia Care for Chemoradiation Patients

Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer.

Since our individual patient data (IPD) meta-analysis of supportive care and chemotherapy for non-small cell lung cancer (NSCLC), published in 1995, many trials have been completed. We have carried out an updated IPD meta-analysis to assess newer regimens and determine conclusively the effect of chemotherapy. To assess the effect on survival of supportive care and chemotherapy versus supportive care alone in advanced NSCLC. All randomised controlled trials (RCTs), published or unpublished. We searched bibliographic databases, trials registers, conference proceedings and reference lists of relevant trials. Searches were completed to November 2009. Trials had to have commenced accrual on or after 1 January 1965 and should have included patients with NSCLC who had received either chemotherapy and supportive care or supportive care alone. Patients should have not received any previous chemotherapy or had any prior malignancy. For trials included in 1995 we sought updated follow up. For new trials we sought survival and baseline characteristics for all patients. We combined results from RCTs to calculate individual and pooled hazard ratios (HRs). We obtained data on 2714 patients from 16 RCTs. There were 1293 deaths among 1399 patients assigned supportive care and chemotherapy and 1240 among 1315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR = 0.77; 95% CI 0.71 to 0.83, P < 0.0001), equivalent to a relative increase in survival of 23%, an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29% or an absolute increase in median survival of 1.5 months (from 4.5 months to six months). There was no clear evidence that this effect was influenced by the drugs used (P = 0.63) or whether they were used as single agents or in combination (P = 0.40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = 0.77). There was no clear evidence of a difference in the relative effect of chemotherapy across patient subgroups. Quality of life could not be formally assessed. All trials were of good methodological quality with no risk of bias. This meta-analysis of chemotherapy in the supportive care setting demonstrates that chemotherapy improves overall survival in all patients with advanced NSCLC. Patients who are fit enough and wish to receive it should be offered chemotherapy.

Meta-Analysis of Chemotherapy With Irinotecan or Oxaliplatin-Involved Regimen for Untreated Metastatic Advanced Colorectal Cancer

A large number of randomized controlled trials involving chemotherapy in the management of advanced colorectal cancer were conducted. 5-FU/LV in combination with irinotecan (IRI) or oxaliplatin (OXA) was used. The aim of the meta-analysis was to compare and evaluate the effectiveness and safety of the two therapeutic approaches for patients with advanced colorectal cancer. A literature search, study selection and assessment, data collection, and analysis were undertaken by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Randomized controlled trials (RCTs) or quasi-RCTs comparing IRI versus OXA, in combination with 5-FU/LV in the treatment of advanced colorectal cancer were performed. Seven studies involving 2,107 patients met the inclusion criteria. The OXA + 5-FU/LV regimen showed a significant increase in survival by lower hazard ratios (HR) [HR 1.28; 95% CI (1.13-1.45)] and was associated with lower toxicities. The OXA + 5-FU/LV regimen was superior or equal to the IRI + 5-FU/LV regimen in prolonging time to progression and median survival. The IRI + 5-FU/LV regimen resulted in higher hazard ratios in nausea vomiting/emesis and diarrhea [HR 1.99, 95% CI (1.19-3.31); HR 1.83, 95% CI (1.38-2.44)] and lower hazard ratios in paresthesia, sensory neuropathy, and thrombocytopenia [HR 0.09, 95% CI (0.03-0.23); HR 0.04 95% CI (0.01-0.13); HR 0.19 95% CI (0.05-0.64)] than the OXA + 5-FU/LV regimen. Compared with IRI, OXA is more appropriate for the treatment of advanced colorectal cancer when combined with 5-FU/LV. OXA + 5-FU/LV should be considered as the first-line standard of care for advanced CRC patients.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients

Background Our previous individual patient data (IPD) meta-analysis showed that chemotherapy improved survival in patients curatively treated for non-metastatic head and neck squamous cell carcinoma (HNSCC), with a higher benefit with concomitant chemotherapy. However the heterogeneity of the results limited the conclusions and prompted us to confirm the results on a more complete database by adding the randomised trials conducted between 1994 and 2000. Methods The updated IPD meta-analysis included trials comparing loco-regional treatment to loco-regional treatment + chemotherapy in HNSCC patients and conducted between 1965 and 2000. The log-rank-test, stratified by trial, was used to compare treatments. The hazard ratios of death were calculated. Results Twenty-four new trials, most of them of concomitant chemotherapy, were included with a total of 87 trials and 16,485 patients. The hazard ratio of death was 0.88 ( p < 0.0001) with an absolute benefit for chemotherapy of 4.5% at 5 years, and a significant interaction ( p < 0.0001) between chemotherapy timing (adjuvant, induction or concomitant) and treatment. Both direct (6 trials) and indirect comparisons showed a more pronounced benefit of the concomitant chemotherapy as compared to induction chemotherapy. For the 50 concomitant trials, the hazard ratio was 0.81 ( p < 0.0001) and the absolute benefit 6.5% at 5 years. There was a decreasing effect of chemotherapy with age ( p = 0.003, test for trend). Conclusion The benefit of concomitant chemotherapy was confirmed and was greater than the benefit of induction chemotherapy.

Controversies surrounding the use of neoadjuvant chemotherapy in locally advanced head and neck cancer

Summary What guidelines can be given on the treatment of locallyadvanced HNSCC today? The choice of treatment has oftenbeen dictated by the primary site, patient preferences (e.g.,organ preservation) and the experience of the treatment team.CT–RT may be considered the gold standard treatment forpatients with resectable locally advanced disease. For unresect-able disease, CT–RT as well as induction TPF followed byCT–RT may be appropriate. Cetuximab/RT is a good optionfor patients who cannot receive chemotherapy. We mustredouble our efforts to find appropriate predictive and prognos-tic features that could be used to improve treatment selectionpathways, minimize toxicity and maximize efficacy. In thatsense multidisciplinary work is the base of future research. References 1 Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int. J. Cancer 94, 153–156 (2001). 2 Pignon JP, Bourhis J, Domenge C, Designe L. Meta-analysis of chemotherapy in head and neck squamous cell carcinoma. On behalf of the MACH-NC collaborative group.

Redefining the Role of Induction Chemotherapy in Head and Neck Cancer

Redefining the Role of Induction Chemotherapy in Head and Neck Cancer

Investigating trial and treatment heterogeneity in an individual patient data meta‐analysis of survival data by means of the penalized maximum likelihood approach

In a meta-analysis combining survival data from different clinical trials, an important issue is the possible heterogeneity between trials. Such intertrial variation can not only be explained by heterogeneity of treatment effects across trials but also by heterogeneity of their baseline risk. In addition, one might examine the relationship between magnitude of the treatment effect and the underlying risk of the patients in the different trials. Such a scenario can be accounted for by using additive random effects in the Cox model, with a random trial effect and a random treatment-by-trial interaction. We propose to use this kind of model with a general correlation structure for the random effects and to estimate parameters and hazard function using a semi-parametric penalized marginal likelihood method (maximum penalized likelihood estimators). This approach gives smoothed estimates of the hazard function, which represents incidence in epidemiology. The idea for the approach in this paper comes from the study of heterogeneity in a large meta-analysis of randomized trials in patients with head and neck cancers (meta-analysis of chemotherapy in head and neck cancers) and the effect of adding chemotherapy to locoregional treatment. The simulation study and the application demonstrate that the proposed approach yields satisfactory results and they illustrate the need to use a flexible variance-covariance structure for the random effects.