Comparison of the accuracy of clinical prediction of survival and palliative prognostic index for patients with head and neck squamous cell carcinoma in the end-of-life setting.

OBJECTIVE: In the end-of-life stage of head and neck squamous cell carcinoma (HNSCC), predicting survival is essential to determine treatment procedure and place of care. Several reports have compared actual survival (AS) and clinical prediction of survival (CPS), a subjective prognostic prediction by attending physicians. However, specific studies focusing on patients with HNSCC are limited. Likewise, a comparison of the accuracy of CPS and palliative prognostic index (PPI), a prognostic tool using subjective assessment, has not been sufficiently investigated. This study aimed to clarify the correlation between AS and CPS/PPI and compare the accuracy of CPS and PPI in end-stage HNSCC. METHODS: This retrospective study included patients with HNSCC in the end-of-life setting. Patients were recruited from the National Hospital Organization Shikoku Cancer Center between April 2011 and March 2019. Data on basic demography and clinical parameters when patients decided to start end-of-life care at the head and neck oncology division were collected. We examined the correlation between AS and CPS using Spearman's correlation coefficients. The area under the receiver operating characteristic curve of CPS and PPI for 30-day survival prediction were compared for predictive accuracy. RESULTS: Among 98 eligible patients, 59 patients were enrolled in this study and analyzed. Of the 59 patients, CPS and PPI were calculated for 30 patients, whereas, only the PPI was calculated for 29 patients. The median AS and CPS were 35 (IQR: 9-73) days and 30 (IQR: 7-83) days, respectively. CPS and PPI (30 cases) were moderately correlated (r = 0.72, p<0.01). AS and CPS/PPI (30 cases) were significantly correlated (p<0.01) and showed a strong correlation (r = 0.86 and 0.80, respectively). In the 30-day survival prediction, the AUROCs of CPS and PPI (30 cases) were 0.967 (95%CI: 0.919-1) and 0.884 (95%CI: 0.767-1), respectively. Both CPS and PPI (30 cases) showed high accuracy in predicting the 30-day prognosis, with no significant difference (p = 0.077). The AUROC of PPI (59 cases) was 0.840 (95%CI: 0.711-0.969). CONCLUSIONS: AS and CPS/PPI showed significant correlations. The high accuracy of CPS may have been influenced by the fact that multiple head and neck cancer specialists at a comprehensive cancer center estimated CPS. Both CPS and PPI showed high prognostic accuracy in predicting 30-day survival. This suggests that PPI is useful in centers among physicians and healthcare workers unfamiliar with head and neck cancer.

Prospective Phase II Open-Label Randomized Controlled Trial to Compare Mandibular Preservation in Upfront Surgery With Neoadjuvant Chemotherapy Followed by Surgery in Operable Oral Cavity Cancer.

PURPOSE: The objective of this study was to explore the potential role and safety of neoadjuvant chemotherapy (NACT) in tumor shrinkage and resultant mandibular preservation in oral cancers compared with conventional surgical treatment. METHODS: This study was a single-center, randomized, phase II trial of treatment-naive histologically confirmed squamous cell carcinoma of the oral cavity with cT2-T4 and N0/N+, M0 (American Joint Committee on Cancer, seventh edition) stage, necessitating resection of the mandible for paramandibular disease in the absence of clinicoradiologic evidence of bone erosion. The patients were randomly assigned (1:1) to either upfront surgery (segmental resection) followed by adjuvant treatment (standard arm [SA]) or two cycles of NACT (docetaxel, cisplatin, and fluorouracil) at 3-week intervals (intervention arm [IA]), followed by surgery dictated by postchemotherapy disease extent. All patients in the IA received adjuvant chemoradiotherapy, and patients in the SA were treated as per final histopathology report. The primary end point was mandible preservation rate. The secondary end points were disease-free survival and treatment-related toxicity. RESULTS: Sixty-eight patients were enrolled over 3 years and randomly assigned to either SA (34 patients) or IA (34 patients). The median follow-up was 3.6 years (interquartile range, 0.95-7.05 years). Mandibular preservation was achieved in 16 of 34 patients (47% [95% CI, 31.49 to 63.24]) in the IA. The disease-free survival (P = .715, hazard ratio 0.911 [95% CI, 0.516 to 1.607]) and overall survival (P = .747, hazard ratio 0.899 [95% CI, 0.510 to 1.587]) were similar in both the arms. Complications were similar in both arms, but chemotherapy-induced toxicity was observed in the majority of patients (grade III: 14, 41.2%; grade IV: 11, 32.4%) in the IA. CONCLUSION: NACT plays a potential role in mandibular preservation in oral cancers with acceptable toxicities and no compromise in survival. However, this needs to be validated in a larger phase III randomized trial.

Role of Nutritional Status in the Treatment Outcome for Esophageal Squamous Cell Carcinoma.

Undernourishment is reported to impair treatment response, further leading to poor prognosis for cancer patients. We aimed to investigate the role of nutritional status on the prognosis of squamous cell carcinoma (SCC) of the esophagus, and its correlation with anticancer immune responsiveness. We retrospectively reviewed 340 esophageal-SCC patients who completed curative treatment and received a nutrition evaluation by the Patient-Generated Subjective Global Assessment (PGSGA) score at the beginning and completion of neoadjuvant treatment at our hospital. The correlation between the nutritional status and various clinicopathological parameters and prognosis were examined. In addition, the role of nutritional status in the regulation of the anticancer immune response was also assessed in cancer patients and in a 4-nitroquinoline 1-oxide (4NQO)-induced esophageal tumor model. Our data revealed that malnutrition (patients with a high PGSGA score) was associated with advanced stage and reduced survival rate. Patients in the group with a high PGSGA score were correlated with the higher neutrophil-to-lymphocyte ratio, higher proportion of myeloid-derived-suppressor cells (MDSC) and increased IL-6 level. Furthermore, surgical resection brought the survival benefit to patients in the low PGSGA group, but not for the malnourished patients after neoadjuvant treatment. Using a 4NQO-induced tumor model, we found that nutrition supplementation decreased the rate of invasive tumor formation and attenuated the immune-suppressive microenvironment. In conclusion, malnutrition was associated with poor prognosis in esophageal-SCC patients. Nutritional status evaluated by PGSGA may be useful to guide treatment decisions in clinical practice. Nutritional supplementation is suggested to improve prognosis, and it might be related to augmented anticancer immune response.

Impact on patients with oral squamous cell carcinoma in different anatomical subsites: a single-center study in Taiwan.

The incidence of oral cavity squamous cell carcinoma (OSCC) is particularly high in South Asia. According to the National Comprehensive Cancer Network, OSCC can arise in several subsites. We investigated survival rates and the clinical and pathological characteristics of OSCC in different anatomical subsites in the Taiwanese population. We retrospectively analyzed data for 3010 patients with OSCC treated at the Changhua Christian Hospital. Subsequently, we compared clinical and pathological features of OSCC in different subsites. Pathological T4 stage OSCCs occurred in the alveolar ridge and retromolar trigone in 56.4% and 43.7% of cases, respectively. More than 25% of patients with tongue OSCC and 23.4% of those with retromolar OSCC had lymph node metastasis. The prognosis was worst for hard palate OSCC (hazard ratio 1.848; p < 0.001) and alveolar ridge OSCC (hazard ratio 1.220; p = 0.017). Retromolar OSCC recurred most often and tongue OSCC second most often. The risk for cancer-related mortality was highest for hard palate OSCC, followed by alveolar ridge and retromolar OSCC. We found distinct differences in survival among the different subsites of OSCC. Our findings may also help prompt future investigations of OSCC in different subsites in Taiwanese patients.

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma.

BACKGROUNDPatients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability.METHODSWe present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI.RESULTSThe MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately.CONCLUSIONMuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.FUNDINGNational Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.

Comparison of the efficacy and safety of the EXTREME regimen for treating recurrent or metastatic head and neck squamous cell carcinoma in older and younger adult patients.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. AIMS: The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. METHODS AND RESULTS: Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged <70 years) adult patients. Of the 86 patients examined in this study, 21 (24.4%) were older adults. There was no difference in overall response rate (46.9% vs 38.5%, P = .76), median progression-free survival [5.7 months vs 5.8 months, hazard ratio (HR) 0.88, 95% confidence interval (CI) = 0.52-1.51, P = .66] and overall survival (OS) (14.6 months vs 15.2 months, HR 0.79, 95% CI 0.43-1.43, P = .44) in younger vs older patients. There was also no difference in the incidence of grade 3/4 adverse events between groups. The exploratory analysis for geriatric nutritional risk index (GNRI) showed the association with lower GNRI (≤98) and poor OS in older adult patients (37.7 months vs 7.0 months, HR 0.53, 95% CI 0.31-0.89, P = .002). CONCLUSIONS: The EXTREME regimen with optimal dose modification is safe and effective for both older and younger adult patients with HNSCC. The GNRI can be an indicator to select the older adult patients who can get benefit from the EXTREME regimen.

ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system.

Objectives: Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that integrin beta 2 (ITGB2) is important for host defense, its expression profile and role in tumors, especially in cancer associated fibroblasts (CAFs) are still unknown. Methods: Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the ITGB2 expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare ITGB2 expression in normal fibroblasts (NFs) and cancer associated fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of ITGB2 expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of ITGB2 expressing CAFs in multiple in vitro and in vivo assays. Results: We found that CAFs exhibited significantly higher ITGB2 expression than the matched NFs. In addition, higher ITGB2 expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that ITGB2-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically, ITGB2 regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from ITGB2-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the ITGB2-expressing CAFs medium. Conclusions: Our study uncovered the ITGB2high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.

Phase III study of nivolumab alone or combined with ipilimumab as immunotherapy versus standard of care in resectable head and neck squamous cell carcinoma.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) often requires postoperative chemoradiation with high risk of toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining nivolumab (N), a PD-1-inhibitor and ipilimumab (I), a CTLA4- inhibitor, may improve DFS due to antitumor effects of immunotherapy. The IMSTAR-HN study compares neoadjuvant N and N ± I 6 months after adjuvant therapy versus standard therapy as first-line treatment for LA-HNSCC. Eligible patients have treatment-naive LA-HNSCC, Eastern cooperative oncology group performance score (PS) ≤1 and no distant metastasis. 276 patients will be randomized into two arms. Primary endpoint is DFS and secondary endpoint includes locoregional control (LRC) and overall survival (OS). This study is one of the first in HNSCCs implementing immunotherapy in first-line treatment in a curative setting. Clinical Trial Registration: NCT03700905 (ClinicalTrials.gov).

Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13-01).

BACKGROUND: By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. METHODS: This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. RESULTS: A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). CONCLUSIONS: In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Comparison of Survival Estimates Following Recurrence, Persistence, or Second Primary Malignancy in Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: This study investigated survival among patients with oropharyngeal squamous cell carcinoma (OPSCC) after recurrence, persistence, and second primary malignancies (SPMs). STUDY DESIGN: Retrospective cohort study. SETTING: Patients were treated at a tertiary cancer center. SUBJECTS AND METHODS: Patients with OPSCC who had completed treatment between 2001 and 2017 were included. Survival estimates of 4 groups of patients were calculated: (1) patients who were disease free after initial treatment, (2) patients who had persistent disease, (3) those with recurrent disease, and (4) patients with SPMs. Cox proportional hazard models and parametric survival analyses (using Weibull distributions) were used to obtain hazard ratios (HRs) and time ratios (TRs). RESULTS: The cohort included 364 patients. The crude overall SPM prevalence was 8.2%. Mean overall survival (OS) time in years for patients who remained disease free after treatment was 4.02 years. Among patients who experienced recurrence, the recurrence-free survival (RFS) was 2.58 years while their mean (SD) OS was 3.67 (2.7) years. Participants who experienced persistence had a mean (SD) OS of 1.67 (1.68) years. Patients with observed SPMs had a mean (SD) OS of 6.39 (4.06) years since their primary cancer but shortened survivals of 1.75 (2.34) years since the secondary diagnosis. Differences were present even after accounting for human papillomavirus (HPV) and smoking status. CONCLUSIONS: Our findings stress the importance of active surveillance as per current National Comprehensive Cancer Network guidelines, irrespective of the HPV status or smoking status. Prospective studies with a larger number of SPM cases and longer follow-up are needed to validate survival trends even beyond 5 years.

Adherence of head and neck squamous cell carcinoma patients to tumor board recommendations.

BACKGROUND: Multidisciplinary team (MDT) meetings or tumor boards (TBs) are fundamental components of cancer treatment. Although their primary function is improved outcomes, this aspect is often underreported. The main objective of this study was to analyze the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) discussed at TBs, and to compare the effect of adherence and nonadherence to recommended treatment plans on outcomes. METHODS: Retrospective data analysis was conducted of HNSCC patients those who were adherent and nonadherent to TB therapy recommendations during 2008-2009 at a comprehensive cancer center. Fisher's exact test and t test were used for group-wise comparison, and Kaplan-Meier and logistic regression models, for survival analysis and determination of the contributing factors to nonadherence. RESULTS: Comprehensive Treatment plans were recommended by TBs in 293 HNSCC patients with curative intent. Seventy-two patients were excluded based on the selection criteria. Among the remaining 221 patients, 172 (77.9%) were adherent to TB recommendations, while 49 (22.1%) failed to comply. Patient (n = 36; 73.5%), clinician (n = 2; 4.1%), and disease-related (n = 11; 22.4%) factors were significant contributors to nonadherence. Mean (±standard deviation (SD)) survival time was 55.6 ± 2.32 and 29.1 ± 4 months in the adherent and nonadherent groups, (P < .0001, respectively). Multivariate analyses showed that gender, ethnicity, higher T-stage, and multimodal treatment were associated with nonadherence. CONCLUSION: Adherence to TB recommendations improved overall survival, reflecting the importance of interdisciplinary expertise in contemporary cancer treatment. Early identification and intervention is crucial in "at risk" patients to prevent subsequent drop-out from optimal cancer care.

Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma.

In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.

Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma.

Locally recurrent head and neck squamous cell carcinoma (HNSCC) is often unresectable, and a repeat course of radiotherapy is associated with incremental toxicities. Boron neutron capture therapy (BNCT) is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues. However, the relationships among the dose resulting from BNCT, tumor response to BNCT, and survival are not completely understood. Recently, a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival. In this article, the findings, strengths and limitations of this study are discussed in depth, and the significance of the study and motivations for future research are highlighted.

Effect of preoperative immunonutrition on complications after salvage surgery in head and neck cancer.

BACKGROUND: Patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma are at high risk of postoperative complications due to the adverse effects of radiotherapy on wound healing. Malnutrition is an additional risk factor and we tested the hypothesis that preoperative administration of immunonutrition would decrease complications in this high risk population. METHODS: This single armed study with historical control included consecutive patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma. We compared outcomes before and after implementation of preoperative immunonutrition and adjusted the regression analysis for gender, age, body mass index, Nutritional Risk Screening (NRS 2002), tobacco and alcohol consumption, tumor localization, tumor stage, and type of surgery. The primary endpoint was overall complications from surgery within a follow-up of 30 days. RESULTS: Ninety-six patients were included (intervention group: 51, control group: 45). Use of preoperative immunonutrition was associated with a significant reduction in overall complications (35% vs. 58%, fully-adjusted odds ratio 0.30 (95%CI 0.10-0.91, p = 0.034). Length of hospital stay was also significantly reduced (17 days vs. 6 days, p = < 0.001). No differences in mortality and hospital readmission were found. These results remained robust in multivariate analysis. CONCLUSIONS: In patients undergoing salvage surgery for recurrent head and neck squamous cell carcinoma, preoperative immunonutrition exhibited favorable effects on the complication rate and consequently reduced the length of hospital stay. By improving both tissue regeneration and immune response, immunonutrition may help to improve surgical outcomes in this high-risk population.

Economic burden of chemotherapy-treated recurrent and/or metastatic squamous cell carcinoma of the head and neck in France: real-world data from the permanent sample of national health insurance beneficiaries.

Aims: Overall survival (OS) of patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is extremely poor. New therapeutic options emerge but need to establish their economic value. The objective was to describe the direct and related costs of R/M SCCHN in France. Materials and methods: We selected all adult patients treated with chemotherapy for R/M SCCHN between 1 January 2009 and 31 December 2014 from the permanent sample of the French national health insurance database (EGB). Data were analyzed from the index date (first chemotherapy) until patients' death or 31 December 2015. "Treatment period" and "end-of-life" (EoL) (from last chemotherapy until death) were distinguished. Costs included all hospitalizations for SCCHN and ambulatory care. Costs of hospitalized and non-hospitalized adverse events (AEs) were estimated. Results: Among 267 patients identified, 85% were men, 44% had metastases at the index date and the mean age was 62.0 years (±9.9). The most common tumor location was oropharynx (29%) but 39% of patients had multiple locations. Median OS was 9.3 (95% CI: 7.9-11.8) months for the overall population. The average total direct cost per patient was €49,954, broken down into €32,908 (95% CI: 29,525-36,290) for hospitalizations and €17,047 (14,941-19,152) for ambulatory care. Main cost drivers were drug acquisition and administration (€14,538) during the treatment period (209 days on average) and palliative care (€3,750) during the EoL period (125 days). Regarding related costs, around 12% of patients received disability pensions (€1,397 per patient [624-2,171]) and sick leave payments (€1,592 [888-2,297]). "Metabolism and nutrition disorders" and "Infections and infestations" were the most expensive hospitalized AEs (€1,513 and €1,180 per patient, respectively). Febrile neutropenia was the most expensive non-hospitalized AE (€766 per patient). Conclusions: This analysis of real-world data confirms the poor prognosis of patients with R/M SCCHN and provides cost data for future economic evaluations.

Induction TPF chemotherapy followed by CRT with fractionated administration of cisplatin in patients with unresectable locally advanced head and neck cancer.

BACKGROUND: In treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), the use of docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by high-dose cisplatin chemoradiotherapy (CRT) carries concerns over toxicity. We evaluated the feasibility of TPF as induction chemotherapy (IC) to Japanese patients and the tolerability of CRT with fractionated administration of cisplatin after IC. METHODS: Patients with unresectable stage III, IV SCCHN received IC followed by CRT. IC consisted of three 3-week cycles of docetaxel 70-75 mg/m2 on day 1, cisplatin 70-75 mg/m2 on day 1, and 5-fluorouracil 750 mg/m2 on days 1-5. Patients subsequently received IMRT concomitant with fractionated administration of cisplatin (20 mg/m2) on days 1-4, repeated every 3 weeks. The primary endpoint was completion of the three cycles of IC. RESULTS: Forty-eight patients were enrolled. The IC treatment completion rate was 85%. Grade 3-4 toxicities of TPF were neutropenia (79%) and febrile neutropenia (15%). Thirty-eight patients (79%) achieved a response after IC. Forty patients subsequently underwent CRT. Thirty-three patients (83%) completed the planned cycles of fractionated administration of cisplatin, but seven (18%) did not. Grade 3-4 toxicities during CRT were neutropenia (23%), mucositis (53%), and dysphagia (33%). With a median follow-up of 36.1 months, 3-year overall survival was 65%. CONCLUSION: TPF IC is feasible and CRT with fractionated administration of cisplatin after IC is tolerable. IC followed by CRT appears to be a useful and safe sequential treatment. (Trial registration no. UMIN000024686).

From VA Larynx to the future of chemoselection: Defining the role of induction chemotherapy in larynx cancer.

Organ preservation protocols utilizing induction chemotherapy as a selection agent have played a critical role in the treatment of advanced laryngeal squamous cell carcinoma (LSCC). The selection of patients who will have a good response to chemoradiation allows for organ preservation in a significant group of patients and minimizes the rate of surgical salvage. While there remains debate regarding its utility when compared to surgery or other organ preservation regimens, the data does suggest an important role for induction chemotherapy in LSCC. In addition, there are continued opportunities to identify pretreatment biomarkers for induction chemotherapy, whether genetic, epigenetic or cellular, that could predict response to treatment and select patients to therapy (whether organ preservation or surgery). As our understanding of the biology of larynx cancer advances, induction paradigms have utility for the development and adoption of novel agents and therapeutics. The background of induction chemotherapy as a selection agent and future directions of this approach are discussed.

Survival benefit of post-operative chemotherapy for intermediate-risk advanced stage head and neck cancer differs with patient age.

OBJECTIVES: The National Comprehensive Cancer Network (NCCN) guidelines state that surgical patients with advanced-stage head and neck cancer (HNC) and risk factors other than extranodal extension (ENE) or positive margins should consider post-operative chemoradiation (POCRT). The goal of our study was to determine if POCRT is associated with overall survival (OS) compared with post-operative radiation therapy (PORT) and whether this varies with patient age. MATERIAL AND METHODS: We conducted a retrospective study of 5319 adult patients with stage III-IV HNC who received primary surgical treatment with POCRT or PORT in the National Cancer Database (2010-2013). Patients with distant metastases, ENE, and positive margins were excluded. Intermediate risk features included pT3-T4, pN2-N3 disease, and lymphovascular invasion. Our main outcome was overall survival (OS). Statistical analysis included chi-squared tests and Cox proportional hazards regressions. RESULTS: On multivariable analysis for non-oropharyngeal cancer patients <70 years, POCRT was associated with improved OS for T1-4N2-3 disease (hazard ratio [HR], 0.73, 95% confidence interval [CI]; 0.58-0.93) but was not associated with OS for T3-4N0-1 disease (HR, 0.92; 95% CI, 0.71-1.19). For patients ≥70 years, POCRT was not associated with improved OS for patients with T1-4N2-3 disease (HR, 1.21; 95% CI, 0.79-1.86) or T3-4N0-1 disease (HR, 1.08; 95% CI, 0.71-1.65). For oropharyngeal cancer patients with HPV-positive disease, POCRT was associated with decreased OS (HR, 9.52; 95% CI, 2.38-38.08). CONCLUSION: Chemoradiation may offer a survival benefit for non-oropharyngeal intermediate-risk advanced-stage HNC patients <70 years of age with T1-4N2-3 disease, but may not benefit those ≥70 years of age or those with T3-4N0-1 disease.