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p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r =–0·744, p=0·0035). The proportion of patients with p16+/HPV– oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5–82·7) for p16+/HPV+, 40·4% (38·6–42·4) for p16–/HPV–, 53·2% (46·6–60·8) for p16–/HPV+, and 54·7% (49·2–60·9) for p16+/HPV–. 5-year disease-free survival was 84·3% (95% CI 82·9–85·7) for p16+/HPV+, 60·8% (58·8–62·9) for p16–/HPV–; 71·1% (64·7–78·2) for p16–/HPV+, and 67·9% (62·5–73·7) for p16+/HPV–. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. Patients with discordant oropharyngeal cancer (p16–/HPV+ or p16+/HPV–) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16–/HPV– oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society. [ABSTRACT FROM AUTHOR]

Computed tomography images acquired during routine cancer care provide an opportunity to determine body composition with accuracy and precision. Quantification of skeletal muscle is of interest owing to its association with clinical outcomes. However, the standards of precision testing considered mandatory in other areas of radiology are lacking from the literature in this area. We aim to describe the change in skeletal muscle over time at different anatomical levels using the precision error. Thirty-eight male patients with squamous cell carcinoma of the head and neck were evaluated at two time points encompassing their treatment plan. Precision testing consisted of analyzing the cross-sectional area (CSA) of the skeletal muscle and total adipose tissue of 76 CT studies (38 images at baseline repeated twice and 38 follow-up images repeated twice) measured by a skilled observer. The % coefficient of variation (%CV), the root-mean-square standard deviation (RMS SD) and the corresponding 95% least significant change (LSC) were calculated for four anatomical levels: upper arm, thigh, chest and abdomen. The median time between scans was 223.6 (SD 31.2) days. Precision error (% CV) for total skeletal muscle cross sectional area was 0.86% for upper arm, 0.26% for thigh, 0.39% for chest and 0.63% for abdomen. The corresponding LSC values in upper arm, thigh, chest and abdomen were 2.4%, 0.7%, 1.1% and 1.8%, respectively. Based on the LSC for RMS SD, patients were classified in two categories according to muscle cross-sectional area: stable (i.e within LSC value) or gained and loss. To compare the four anatomical levels, the proportion of patients with muscle loss exceeding the LSC value was 74.3% for arm, 86.2% for thigh, 82.9% for chest and 76.3% for abdomen. For these same anatomic regions, the mean muscle loss for those patients classified below the LSC was 14.6% (SD 9.3), 13.4% (SD 7.8), 11.9% (SD 6.5) and 11.6% (SD 5.5), respectively. Only the loss of muscle area was significantly higher in thigh (p = 0.023), using L3 as the reference level. We recommend the uniform use of a standard precision test when reporting muscle change over time. LSC values vary from 0.7 to 2.4% depending on anatomic site; with the lowest precision error to detect change in the thigh. Based on this analysis, muscle wasting appears to be systemic and while present in limbs and trunk is significantly higher in the thigh than in the chest, abdomen or upper arm. [ABSTRACT FROM AUTHOR]

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16INK4a/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC.Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16INK4a, HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16INK4a, respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16INK4a showed strongest diagnostic accuracy and prognostic value.Conclusions: Double positivity for HPV-DNA/p16INK4a, a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly. [ABSTRACT FROM AUTHOR]

Summary Background Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. Methods 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients’ treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. Results 21.9% Patients experienced grade 3–4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125–0.680, p = 0.004); OR for severe toxicity: 0.299 (CI: 0.0909–0.999, p = 0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. Conclusion Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity. [ABSTRACT FROM AUTHOR]

Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov , NCT03040999 , and is active but not recruiting. Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68–1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA. [ABSTRACT FROM AUTHOR]

Objectives: It has been reported that patients with HPV-positive oropharyngeal cancer (OPC) have a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor.Materials and Methods: We included 412 OPC patients treated at our center from 1991 to 2014 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6∗I mRNA detection and/or p16INK4a immunohistochemistry. We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor.Results: Fifty-one (12.4%) out of 412 OPCs included in the study were HPV-related. Five-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 57.0% and 89.0% (P<0.001), respectively. Corresponding estimates for 10-year SPN-free survival were 35.2% versus 78.5% (P<0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates where 62.0% versus 97.6% (P<0.001) and 42.2% versus 97.6%, (P<0.001), for 5-year and 10-year survival rates, respectively. HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs.Conclusion: HPV-related OPC patients have a significant lower risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption. [ABSTRACT FROM AUTHOR]

The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis. • The study includes 7654 oropharyngeal cancer patients. • HPV impacts overall and disease-free survival, regardless of p16 status. • HPV exerts substantial influence on survival, regardless of stage. • Incorporating HPV in cancer staging, with p16, is crucial for precise prognosis.. [ABSTRACT FROM AUTHOR]

Background: Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14·0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting.Methods: This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m2 was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m2 on day 1-4, cisplatin 100 mg/m2 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m2 cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695.Findings: Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34·4 months (IQR 26·6-44·8) in the TPEx group and 30·2 months (25·5-45·3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14·5 months [95% CI 12·5-15·7] in the TPEx group and 13·4 months [12·2-15·4] in the EXTREME group; hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p<0·0001). In the TPEx group, 118 (45%) of 263 patients had at least one serious adverse event versus 143 (54%) of 265 patients in the EXTREME group. 16 patients in the TPEx group and 21 in the EXTREME group died in association with adverse events, including seven patients in each group who had fatal infections (including febrile neutropenia). Eight deaths in the TPEx group and 11 deaths in the EXTREME group were assessed as treatment related, most frequently sepsis or septic shock (four in each treatment group).Interpretation: Although the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment.Funding: Merck Santé and Chugai Pharma. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors.Methods and Materials: This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT. Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy.Results: A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy-three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT.Conclusions: According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN.Methods and Materials: A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil [5-FU], 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF.Results: Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%).Conclusions: C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose. [ABSTRACT FROM AUTHOR]

Objectives: Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT.Materials and Methods: This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of < 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL).Results: Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153).Conclusion: Noninferiority of cet+RT over cis+RT was not demonstrated. [ABSTRACT FROM AUTHOR]