Abstract 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 5.6 years. 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 < 0.0001) and laryngeal tumours ( 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.
Abstract 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.
•MACH-NC second update with 107 randomized trials (19805 patients) investigating chemotherapy (CT) in non-metastatic HNSCC.•Overall Survival (OS) improved by CT, benefit superior for concomitant CT ...(HR 0.83 0.79; 0.86) over induction or adjuvant CT.•Direct comparison confirmed the superiority of concomitant over induction CT on OS.
The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.
Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.
For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI 0.79; 0.86; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 0.90; 1.01) or adjuvant CT (1.02 0.92; 1.13). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 0.74; 0.95, p = 0.005).
The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
Background
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.
Methods
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).
Results
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).
Conclusions
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.
The ω score measures the proportion of patients' overall event risk attributable to cancer. Based on 2 large meta‐analyses of head and neck cancer, an ω score has been created and externally validated to predict the benefit of intensive treatment.
Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain ...largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.
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•mTORC2 deficiency promotes MPEC generation and reduces SLECs during Listeria infection•Primed mTORC2-deficient T cells have effector functions and produce higher IL-2 levels•mTORC2-deficient memory CD8 T cells mount more potent recall responses•mTORC2 deficiency promotes CD8 memory generation via nuclear accumulation of Foxo1
Zhang et al. demonstrate that mTORC2 deficiency favors CD8 T cell memory differentiation during the primary antigen-specific T cell response to Listeria infection. The effects result from higher Foxo1 transcriptional activity without dampening effector functions. They also show enhanced recall responses by mTORC2-deficient memory CD8 T cells.
We have designed and validated a novel generic platform for production of tetravalent IgG1-like chimeric bispecific Abs. The VH-CH1-hinge domains of mAb2 are fused through a peptidic linker to the N ...terminus of mAb1 H chain, and paired mutations at the CH1-CL interface mAb1 are introduced that force the correct pairing of the two different free L chains. Two different sets of these CH1-CL interface mutations, called CR3 and MUT4, were designed and tested, and prototypic bispecific Abs directed against CD5 and HLA-DR were produced (CD5xDR). Two different hinge sequences between mAb1 and mAb2 were also tested in the CD5xDR-CR3 or -MUT4 background, leading to bispecific Ab (BsAbs) with a more rigid or flexible structure. All four Abs produced bound with good specificity and affinity to CD5 and HLA-DR present either on the same target or on different cells. Indeed, the BsAbs were able to efficiently redirect killing of HLA-DR(+) leukemic cells by human CD5(+) cytokine-induced killer T cells. Finally, all BsAbs had a functional Fc, as shown by their capacity to activate human complement and NK cells and to mediate phagocytosis. CD5xDR-CR3 was chosen as the best format because it had overall the highest functional activity and was very stable in vitro in both neutral buffer and in serum. In vivo, CD5xDR-CR3 was shown to have significant therapeutic activity in a xenograft model of human leukemia.
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.
•The season of radiotherapy delivery (fall/winter versus spring/summer) was queried.•Season of treatment does not influence either PFS or LRF in head and neck cancer.•No impact was seen even in ...Northern countries where differences are expected to be greater.
A single institution retrospective study suggested that head and neck squamous cell cancer (HNSCC) patients receiving radiotherapy (RT) during “dark” season (fall/winter) may have better outcomes than those treated during ”light” season (spring/summer), possibly secondary to seasonal variations in cell cycle progression. We investigated the impact of season of RT in two large, multi-institutional, prospective datasets of randomized trials.
Individual patient data from the MACH-NC and MARCH meta-analyses were analyzed. Dark season was defined as mid-radiotherapy date during fall or winter and light the reverse, using equinoxes to separate the two periods. Primary endpoint was progression-free survival (PFS) and secondary endpoint was locoregional failure (LRF). The effect of season was estimated with a Cox model stratified by trial and adjusted on sex, tumor site, stage, and treatment. Planned sensitivity analyses were performed on patients treated around solstices, who received “complete radiotherapy”, patients treated with concomitant radio-chemotherapy and on trials performed in Northern countries.
11320 patients from 33 trials of MARCH and 6276 patients from 29 trials of MACH-NC were included. RT during dark season had no benefit on PFS in the MARCH (hazard ratioHR: 1.01 95%CI 0.97;1.05,p=0.72) or MACH-NC dataset (HR:1.00 95%CI 0.94;1.06,p=1.0. No difference in LRF was observed in the MARCH (HR:1.00 95%CI 0.94;1.06,p=0.95) or MACH-NC dataset (HR:0.99 95%CI 0.91; 1.07,p=0.77). Sensitivity analyses showed similar results.
Season of RT had no impact on PFS or LRF in two large databases of HNSCC.
•Addition of chemotherapy to surgery improved overall survival in head & neck cancer.•Improvement of overall survival was greater with concomitant chemotherapy.•Induction chemotherapy did not ...significantly improved overall survival.•Women benefited from chemotherapy more than men.•Effect of sex on survival should be investigated more in head and neck cancer.
To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965–2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I2 statistic.
Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 95%CI: 0.85–0.99 p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69–0.92). The benefit of chemotherapy was greater in women (HRwomen = 0.63, 95%CI: 0.50–0.80) compared to men (HRmen = 0.96, 95%CI: 0.89–1.04; p for interaction = 0.001).
This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.
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