Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial.

BACKGROUND: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN). PATIENTS AND METHODS: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20. RESULTS: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash. CONCLUSION: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN.

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers.

The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress. During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, with which they must cope to survive. Moreover, chemotherapy represents an additional extrinsic challenge that cancer cells are facing and to which they adapt in the case of resistance. As of today, resistance to chemotherapy and targeted therapies is one of the important issues that oncologists have to deal with for treating cancer patients. In this review, we first describe the key molecular mechanisms controlling the UPR and their implication in solid cancers. Then, we review the literature that connects cancer chemotherapy resistance mechanisms and activation of the UPR. Finally, we discuss the possible applications of targeting the UPR to bypass drug resistance.

Prognostic and therapeutic factors of gliosarcoma from a multi-institutional series.

The aims of this multicentre retrospective study were to identify prognostic or therapeutic factors impacting on overall survival in patients with gliosarcoma. The analysis included all patients treated for gliosarcoma between 1998 and 2014 in seven French academic centres. Seventy-five patients with a median age of 60 years (range from 23 to 79 years) were treated with a combination of surgery (n = 66), radiotherapy (adjuvant for 64 patients and exclusive for 8 patients) and temozolomide based chemotherapy (n = 58). Median follow-up was 12 months (range from 2 to 71 months). Two-year overall survival (OS) and disease free survival rates were 12 % (95 % CI 4-20 %) and 2 % (95 % CI 0-6 %), respectively. The median OS was 13 months. Treatment at recurrence consisted of chemotherapy (n = 38) (bevazicumab for 18 patients, repeat temozolomide for 10 patients), salvage surgery (n = 8) and radiochemotherapy (n = 1). In univariate analysis, younger age, higher total dose of radiotherapy, longer time to recurrence and treatment at recurrence significantly increased OS. In multivariate analysis, high total dose of radiotherapy (HR = 0.97, p = 0.007) and treatment at recurrence (HR = 0.28, p < 0.001) were favourable prognostic factors of OS. Radiotherapy at a minimum dose of 54 Gy and salvage treatment increased OS of gliosarcoma. Unlike glioblastoma, in our analysis, TMZ based chemotherapy was not associated with an improvement in OS compared to patients who received radiation therapy only.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Chemoradiotherapy for cancer of the esophagus: contribution of the leucovorin, 5-fluorouracil bolus, and infusion-cisplatin-radiotherapy schedule starting with two neoadjuvant chemotherapy cycles: results from a pilot study.

To assess feasibility and tolerance of a modification in the usual radiochemotherapy regimen for esophageal cancer by using a leucovorin, 5-fluorouracil bolus, and infusion-cisplatin regimen (six cycles), beginning with two cycles of chemotherapy before conventional radiotherapy (50 Gy), 33 patients, 30 were men, 62.8 +/- 9.5 years, were treated for an esophageal carcinoma (29 squamous cell), 27 of these were in stage III (based on computed tomography scan). Neoadjuvant chemotherapy was well tolerated; concomitant radiochemotherapy was associated with severe adverse events mostly hematological in 23 patients. Complete response was achieved in 70%; median overall survival was 14 months, and 2-year survival was 40 +/- 11%. More than one-third of cycles could be performed as outpatients. This regimen seems safe and efficient, and could be conducted in an outpatient basis.