Impact of relative cisplatin dose to skeletal muscle mass on adverse events in patients with head and neck cancer undergoing chemoradiotherapy.

BACKGROUND: Chemoradiotherapy (CRT) with high-dose cisplatin (CDDP) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). Although dosing is based on body surface area (BSA), some patients experience CDDP-related adverse events (AEs). We aimed to evaluate the impact of relative CDDP dose to skeletal muscle mass (SMM) on chemotherapy-associated AEs in patients with HNSCC undergoing CRT with high-dose CDDP. MATERIALS AND METHODS: We retrospectively analyzed data of patients who underwent CRT with high-dose CDDP (80-100 mg/m2, triweekly) between 2010 and 2023. SMM was measured as the cross-sectional muscle area at the third cervical vertebra (C3-SMM) using computed tomography; the skeletal muscle index (SMI) was defined as SMM normalized by squared height. The CDDP index was defined as the prescribed CDDP dose divided by SMI. CDDP-related AEs were assessed during the first cycle using Common Terminology Criteria for Adverse Events v5.0. RESULTS: Overall, 306 patients were identified. The CDDP index cutoff value best associated with grade ≥ 3 AEs was 10.312. Grade ≥ 3 hematological toxicities exhibited stronger association with high CDDP index value than with low CDDP index value (26.9% vs 16.3%, P = .033). Multivariate analysis revealed that high CDDP index value and creatinine clearance < 70 mL/minute were predictive factors for grade ≥ 3 AEs (odds ratio [OR] 2.55, P = .008; OR 3.68, P = .002, respectively). CONCLUSION: The CDDP index based on C3-SMM was an independent predictive factor for grade ≥ 3 CDDP-related AEs. C3-SMM is potentially more useful than BSA for determining the optimal CDDP dose in patients with HNSCC.

Risk prediction model for cisplatin-induced acute kidney injury in patients with head and neck cancer receiving chemoradiotherapy: A re-analysis of a phase II/III JCOG1008 trial.

OBJECTIVES: Acute kidney injury (AKI) represents a major toxicity associated with cisplatin. We developed a risk prediction model for cisplatin-induced AKI in patients with postoperative high-risk head and neck cancer who received chemoradiotherapy during a randomized phase II/III trial, JCOG1008. MATERIALS AND METHODS: Two hundred and fifty-one patients received radiotherapy with weekly cisplatin at 40 mg/m2 (weekly arm) or 3-weekly cisplatin at 100 mg/m2 (3-weekly arm). AKI was defined using the AKI Network classification/staging system as increased serum creatinine of ≥0.3 mg/dL or a ≥1.5-fold increase from baseline 30 days after completing chemoradiotherapy. The Akaike information criterion was used to explore the optimal model by combining explanatory variables at registration. RESULTS: Among the 251 patients (210 men and 41 women (median age; 62 years)), 94 (37.5 %) developed cisplatin-induced AKI. The optimal cisplatin-induced AKI risk prediction model comprised four factors, including a primary site of hypopharynx/larynx (vs. oral cavity/oropharynx), 3-weekly arm (vs. weekly arm), serum albumin of ≤3.5 g/dL (vs. >3.5 g/dL) and creatinine clearance (CCr) of <90 mL/min (vs. ≥90 mL/min). The incidence of cisplatin-induced AKI rose with cumulative count of the four factors. When the cumulative count was ≥2, the positive predictive value for cisplatin-induced AKI was 50.3 %. CONCLUSIONS: We developed a risk prediction model for cisplatin-induced AKI in patients with head and neck cancer who received postoperative chemoradiotherapy using primary site, cisplatin administration method, serum albumin, and CCr. Patients with risk factors unrelated to the cisplatin administration method should adopt a weekly cisplatin regimen.

Radiation-induced xerostomia and cariogenic dietary habits.

PURPOSE: Despite the availability of various prevention methods, dental caries continue to be diagnosed in patients receiving head and neck radiotherapy (RT). Since conventional approaches do not evaluate posttreatment alterations in dietary behaviors, we aimed to assess the influence of radiation-induced xerostomia on post-RT cariogenic dietary habits in patients. METHODS: Fifty-seven patients completed the Xerostomia Questionnaire (XQ) and answered questions regarding daily cariogenic food and beverage (CFB) intake, daily tooth brushing, fluoride application, and subjective total taste acuity (STTA). They also underwent evaluations to determine the Simplified Oral Hygiene Index (OHI-S) score, Saxon test score, number of decayed-missing-filled teeth (DMFT), and proportion of DMFT to the test teeth (DMFT rate). Clinical records were searched for information regarding RT modalities, including the median of the mean dose to the parotid glands, days after the completion of RT, submandibular gland resection, whole-neck irradiation, and the DMFT value and rate before RT. The patients were divided into low and high XQ score groups based on the median XQ score of 47.5 for the two sample tests. Univariable and multivariable regression analyses were used to identify independent factors for frequent CFB intake. RESULTS: Higher XQ scores were associated with a significantly greater frequency of CFB intake (p = 0.028*). Regression analysis also identified a higher XQ score (p = 0.017*) as an independent risk factor for frequent CFB intake. CONCLUSION: Radiation-induced xerostomia increased the frequency of CFB intake.

Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study.

BACKGROUND: In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure. METHODS: We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined. RESULTS: Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively. CONCLUSION: Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

Biomarker analysis for patients with pancreatic cancer treated with nanoliposomal irinotecan plus 5-fluorouracil/leucovorin.

BACKGROUND: Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen. METHODS: We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center. RESULTS: We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014). CONCLUSIONS: Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen.

Prognostic impact of the number of metastatic lymph nodes after surgery in locally advanced hypopharyngeal cancer.

BACKGROUND: Postoperative chemoradiotherapy (CRT) is a standard therapy for patients with high-risk factors for head and neck squamous cell carcinoma, including positive margin and extra-nodal extension (ENE). However, the prognostic impact of the number of pathological metastatic lymph nodes (pLNs) in hypopharyngeal carcinoma (HPC) is unclear. Thus, this study aimed to investigate postoperative prognostic factors for locally advanced hypopharyngeal squamous cell carcinoma (LA-HPSCC) with a focus on the number of pLNs. METHODS: We retrospectively analyzed medical records of 99 consecutive patients with LA-HPSCC who underwent total pharyngo-laryngo-esophagectomy (TPLE) and bilateral neck dissection (ND) between December 2002 and May 2019. RESULTS: The median follow-up time for all censored patients was 63.2 months. The median overall survival (OS) was 101.0 months (95% confidence interval [CI] 48.1-134.9). patients had pLNs ≥ 3. Forty-six (45.5%) patients were diagnosed with ENE. Twenty (20.2%) patients received postoperative CRT. The multivariate analysis revealed that pLNs ≥ 3 (median OS: 163.2 vs. 31.8 months, hazard ratio [HR] 2.39, 95% CI 1.16-4.94, p < 0.01) and ENE (median OS: 161.0 vs. 26.3 months, HR 4.60, 95% CI 2.26-9.36, p < 0.01) were significantly associated with poor prognosis and that postoperative CRT (HR 0.34, 95% CI 0.16-0.72, p < 0.01) was significantly associated with better prognosis. The cumulative incidence of distant metastasis was higher in patients with pLNs ≥ 3 than in those with pLNs < 3 (p < 0.01). CONCLUSION: pLNs ≥ 3 and ENE were significant poor prognostic factors for patients with LA-HPSCC who underwent TPLE and bilateral ND.

Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence.

BACKGROUND/AIM: The recurrence rate of head and neck squamous cell carcinoma (HNSCC) remains high; thus the control of recurrence is a clinical problem to be challenged. To clarify the precise mechanism, specific immunological biomarkers responsible for recurrence were investigated. PATIENTS AND METHODS: The expression levels of immune response-associated and Shizuoka Cancer Center 820 cancer-associated genes, and genetic mutations from whole-exome sequencing were compared between HNSCC patients who developed recurrence (n=8) and HNSCC patients who did not develop recurrence (n=19) using a volcano plot analysis. Cytokine and epithelial-mesenchymal transition marker genes were analyzed using quantitative PCR. Tumor-infiltrating lymphocytes, immune checkpoint molecules, and human papilloma virus status were investigated using immunohistochemistry (IHC). RESULTS: Twenty-seven evaluable patients with HNSCCs received radiation therapy after surgery. Recurrence was identified in 8 patients. TP53 mutations tended to be higher in patients who developed recurrence than in those who did not develop recurrence (75% vs. 31.6%). Gene expression profiling showed the down-regulation of T cell activation genes (ICOS, CD69 and CD83) and the upregulation of the ERBB4, EGFR, VEGF, HIF1A, TGFB1, TWIST1, IL-8, and PAX7 genes, which suggested the activation of the TP53 mutation-TGF-ß1-PAX7 pathway and epithelial-mesenchymal transition. Additionally, IHC indicated a tendency toward a reduction in T cell accumulation and an increase in M2-type macrophage infiltration in tumors that recurred. CONCLUSION: A TP53 mutation-mediated immune-suppressive state in the tumor microenvironment and TGF-ß1-PAX7-mediated EMT might contribute to the promotion of recurrence in patients with HNSCC after postoperative radiotherapy.

Effectiveness and safety of gemcitabine plus nab-paclitaxel in elderly patients with advanced pancreatic cancer: a single-center retrospective cohort study.

PURPOSE: This study aimed to evaluate the effectiveness and safety of gemcitabine (GEM) plus nab-paclitaxel (GnP) in patients aged ≥ 75 years with advanced pancreatic cancer and compare it with monotherapy (GEM or S-1). METHODS: We retrospectively reviewed the data of consecutive patients with advanced pancreatic cancer aged ≥ 75 years who received either GnP or monotherapy (GEM or S-1) between January 2014 and May 2020. The primary efficacy outcome was overall survival (OS). RESULTS: A total of 96 patients were included in this study; 51 were treated with GnP and 45 with monotherapy (31 with GEM and 14 with S-1). The median OS and progression-free survival were 10.8 and 6.7 months in the GnP group and 10.7 and 4.3 months in the monotherapy group, respectively. The treatment effect on OS was consistently favorable in the GnP group across most subgroups, particularly in patients with locally advanced cancer, modified Glasgow prognostic score of 0 or 1, and neutrophil/lymphocyte ratio < 3.1. The disease control rates were 76% and 48% in the GnP and monotherapy groups, respectively, and grade 3 or 4 neutropenia occurred in 23 (45%) and 11 (24%) patients of the GnP and monotherapy groups, respectively. CONCLUSIONS: This study demonstrated that GnP was not superior to monotherapy with regard to OS. However, multivariate analysis showed that GnP treatment positively affected the OS and could be considered as a treatment option, even for elderly patients.

Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial.

PURPOSE: The standard treatment for postoperative high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (100 mg/m2). However, whether chemoradiotherapy with weekly cisplatin (40 mg/m2) yields comparable efficacy with 3-weekly cisplatin in postoperative high-risk LA-SCCHN is unknown. PATIENTS AND METHODS: In this multi-institutional open-label phase II/III trial, patients with postoperative high-risk LA-SCCHN were randomly assigned to receive either chemoradiotherapy with 3-weekly cisplatin (100 mg/m2) or with weekly cisplatin (40 mg/m2) to confirm the noninferiority of weekly cisplatin. The primary end point of phase II was the proportion of treatment completion, and that of phase III was overall survival. A noninferiority margin of hazard ratio was set at 1.32. RESULTS: Between October 2012 and December 2018, a total of 261 patients were enrolled (3-weekly cisplatin, 132 patients; weekly cisplatin, 129 patients). At the planned third interim analysis in the phase III part, after a median follow-up of 2.2 (interquartile range 1.19-3.56) years, chemoradiotherapy with weekly cisplatin was noninferior to 3-weekly cisplatin in terms of overall survival, with a hazard ratio of 0.69 (99.1% CI, 0.374 to 1.273 [< 1.32], one-sided P for noninferiority = .0027 < .0043). Grade 3 or more neutropenia and infection were less frequent in the weekly arm (3-weekly v weekly, 49% v 35% and 12% v 7%, respectively), as were renal impairment and hearing impairment. No treatment-related death was reported in the 3-weekly arm, and two (1.6%) in the weekly arm. CONCLUSION: Chemoradiotherapy with weekly cisplatin is noninferior to 3-weekly cisplatin for patients with postoperative high-risk LA-SCCHN. These findings suggest that chemoradiotherapy with weekly cisplatin can be a possible treatment option for these patients.

Incurable locoregional disease is a strong poor prognostic factor in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Distant metastasis is a poor prognostic factor in recurrent/metastatic squamous cell carcinoma of the head and neck. However, limited information on the prognostic impact of locoregional disease is available, despite its life-threatening features. We investigated the prognostic impact of incurable locoregional disease and distant metastasis in recurrent/metastatic squamous cell carcinoma of the head and neck. METHODS: We retrospectively analyzed 156 patients with recurrent/metastatic squamous cell carcinoma of the head and neck who received palliative chemotherapy between August 2006 and December 2019. RESULTS: The median follow-up time for all censored patients was 12.1 (range 1.9-63.5) months. The median overall survival was 12.4 (95% confidence interval 10.1-15.1) months. Incurable locoregional disease (hazard ratio: 2.31, P = 0.007), liver metastasis (hazard ratio: 2.84, P = 0.006), disease-free interval > 13 months (hazard ratio: 0.51, P = 0.041), cetuximab use (hazard ratio: 0.59, P = 0.007), and immune checkpoint inhibitor use (hazard ratio: 0.56, P = 0.006) were associated with prognosis. The number of distant metastatic sites was not associated with overall survival (1-2: hazard ratio: 0.60, P = 0.16; 3-4: hazard ratio: 1.34, P = 0.50). Patients with incurable locoregional disease had more life-threatening events than those with curable locoregional disease. CONCLUSION: The presence of incurable locoregional disease had a significant prognostic impact, whereas the number of distant metastatic sites had no prognostic impact. Liver metastasis was a poor prognostic factor for recurrent/metastatic squamous cell carcinoma of the head and neck.

Efficacy and safety of S-1 following gemcitabine with cisplatin for advanced biliary tract cancer.

Background Combination therapy of gemcitabine with cisplatin (GC) is a standard first-line therapy for unresectable or recurrent biliary tract cancer (BTC). S-1 is often used as a second-line therapy in clinical practice, based on the results of some clinical studies investigating its efficacy and safety following gemcitabine monotherapy. However, few studies have reported on the clinical outcomes of S-1 following GC. The purpose of this study was to elucidate the efficacy and safety of S-1 following GC for unresectable and recurrent BTC. Methods We retrospectively collected the data of 116 patients (pts) who were treated with S-1 as a second-line therapy following GC for unresectable or recurrent BTC at Shizuoka Cancer Center (November 2009 to July 2019). Results Of these 116 pts., 84 were assessable. Patient characteristics were as follows: intrahepatic bile duct/extrahepatic bile duct/gallbladder cancer, 30/23/31 pts.; metastatic/recurrent/locally advanced, 57/17/10 pts. The median time to treatment failure and overall survival were 2.5 and 6.0 months, respectively. Among 65 pts. with measurable lesions, the overall response rate was 3.1% (2/65 pts) and the disease control rate was 24.6% (19/65 pts). The common grade 3/4 toxicities included anemia (12%), neutropenia (4%), infections (16%), fatigue (6%), and diarrhea (4%). Dose reduction or treatment schedule modification of S-1 was required in 29 pts. (34.5%), and 17 pts. (20%) terminated S-1 due to adverse events. Conclusions The efficacy and safety of S-1 following GC were almost the same as those of S-1 following GEM monotherapy for unresectable or recurrent BTC.

Triplet induction chemotherapy followed by less invasive surgery without reconstruction for human papillomavirus-associated oropharyngeal cancers: Why is it successful or unsuccessful?

BACKGROUND: De-escalating treatments have been focused on for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). We assessed the efficacy of a triplet induction chemotherapy (ICT) followed by surgery with or without neck dissection (ND) for locally advanced OPSCC, aiming at less invasive surgery without free-flap reconstruction and avoiding postoperative irradiation. METHODS: This was a retrospective study of 41 patients with advanced resectable HPV-positive OPSCC who underwent ICT followed by surgery of primary resection with or without ND. Patients underwent triplet ICT, including docetaxel, cisplatin, and 5-fluorouracil, or carboplatin, paclitaxel, and cetuximab. RESULTS: Twenty-nine patients had tonsillar cancer, 15 patients were current smokers, and 18 and 12 patients had T2N1M0 and T1N1M0 status (UICC 8th), respectively. After ICT, a surgical procedure without free-flap reconstruction and tracheostomy was possible in 90.2%. Pathological complete response at both the primary site and lymph nodes was achieved in 73.2%. Of the patients who underwent surgery, no adjuvant radiotherapy was required in 85.0%. Two patients (4.9%) experienced recurrence at regional lymph nodes, but were cured by salvage ND followed by adjuvant radiotherapy. CONCLUSIONS: Upfront ICT using highly responsive triplet chemotherapeutic regimens may enable us to perform less invasive surgery without free-flap reconstruction and to avoid postoperative irradiation to the locoregional field through excellent postoperative pathological features.

Supplemental enteral tube feeding nutrition after hospital discharge of esophageal cancer patients who have undergone esophagectomy.

BACKGROUND: After undergoing esophagectomy to treat esophageal cancer, there are changes in the normal intake patterns in most patients, with more than half found to have an inadequate oral intake at the time of their hospital discharge. However, the use of home supplemental enteral tube feeding nutrition after hospital discharge in esophagectomy patients has yet to be established. The aim of this study was to evaluate the feasibility of 90-day home supplemental enteral tube feeding nutrition in esophagectomy patients. METHODS: This single-center, prospective, and single-arm study evaluated the feasibility of using supplemental tube feeding nutrition intervention for 90 days in esophageal cancer patients who have undergone esophagectomy. RESULTS: This study enrolled 24 post-esophagectomy patients between February 2015 and September 2016. Twenty patients were administered 70% or more of the planned nutrient, with 83% of the patients completing the nutritional intervention procedure. There were no grade 3/4 adverse events observed, with a mean body weight change of - 7.6 ± 6.0%. CONCLUSIONS: Our results showed that routine use of 90-day home supplemental enteral tube feeding nutrition after hospital discharge for esophagectomy patients was both feasible and acceptable. TRIAL REGISTRATION: UMIN000016286.

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

IMPORTANCE: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. OBJECTIVE: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. INTERVENTIONS: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. MAIN OUTCOMES AND MEASURES: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. RESULTS: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. CONCLUSIONS AND RELEVANCE: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. TRIAL REGISTRATION: UMIN Identifier: UMIN000016794.

How Should We Approach Locally Advanced Squamous Cell Carcinoma of Head and Neck Cancer Patients Ineligible for Standard Non-surgical Treatment?

PURPOSE OF REVIEW: Cisplatin has been established as one of the most important agents in multidisciplinary treatment for head and neck cancer (HNC). However, since HNC patients are often elderly and typically have several comorbidities, a limited number of patients can tolerate high-dose cisplatin in real-world HNC populations. We will provide a review of therapeutic alternatives to high-dose cisplatin-based treatment in the setting of definitive and postoperative chemoradiotherapy (CRT) or induction chemotherapy. RECENT FINDINGS: Clinical criteria for CDDP ineligibility have been discussed in HNC. When considering cisplatin-based chemotherapy as part of a non-surgical approach, precise evaluation of the patient's physical condition, nutritional status, and comorbidities is needed. Upfront surgery is an important option with high curability, if a de-intensified non-surgical approach is estimated to be unavoidable. Although no prospective data are available regarding alternatives to definitive cisplatin-based combination therapy for patients undergoing a non-surgical approach, cetuximab, carboplatin, or split-dose cisplatin-based regimens may be employed for cisplatin-ineligible patients in clinical practice. The combination of immune checkpoint inhibitors with radiotherapy may be a promising novel approach, and some trials are currently targeting the specific cohort of patients ineligible for high-dose cisplatin. There are no standard treatments for patients ineligible for high-dose cisplatin. A personalized treatment strategy should be proposed based on the individual benefit-to-risk ratio of each treatment option in patients ineligible for the standard of care. Prospective clinical trials for cisplatin-ineligible patients with locally advanced HNC still need to be performed.

Feasibility and efficacy of chemoradiotherapy with concurrent split-dose cisplatin after induction chemotherapy with docetaxel/cisplatin/5-fluorouracil for locally advanced head and neck cancer.

Chemoradiotherapy (CRT) with concurrent high-dose cisplatin (CDDP) is a standard treatment for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Docetaxel plus CDDP and 5-fluorouracil (TPF) induction chemotherapy (ICT) prior to CRT is considered for patients at high risk of distant metastases. The purpose of the current study was to evaluate the feasibility and efficacy of CRT with split-dose CDDP after TPF-ICT for LA-SCCHN. A total of 21 LA-SCCHN patients treated with TPF-ICT followed by concurrent CRT with split-dose CDDP between January 2011 and December 2017 were retrospectively analysed. The patients' characteristics were i) median age 66 years (48-75 years); ii) male/female, 21/0; iii) performance status 0-1/2, 20/1; iv) larynx/hypopharynx/oropharynx/oral cavity, 4/8/8/1 and v) clinical stage III/IV, 3/18. The numbers of TPF-ICT cycles 1/2/3 were 2/3/16. Median cumulative doses of CDDP in TPF-ICT and CRT were 180.0 and 206.7 mg/m2, respectively. All patients completed 70 Gy RT. The complete response rate was 76.2%. At a median follow-up of 51.5 months, median PFS and OS were not reached and 65.5 months, respectively. The most common grade 3 or worse toxicities during CRT-ICT were stomatitis (48%), dysphagia (21%), anorexia (17%) and leukopenia (14%). However, no grade 2 or worse nephrotoxicity, neurotoxicity or ototoxicity was observed. The results demonstrated that concurrent CRT with split-dose CDDP after TPF-ICT is feasible and effective for LA-SCCHN.

Efficacy and feasibility of induction chemotherapy with paclitaxel, carboplatin and cetuximab for locally advanced unresectable head and neck cancer patients ineligible for combination treatment with docetaxel, cisplatin, and 5-fluorouracil.

BACKGROUND: Docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy (ICT) is a treatment option for locally advanced unresectable head and neck squamous cell carcinoma (LA-HNSCC). However, patients with advanced age, or renal, cardiac or neurogenic dysfunction are ineligible for ICT-TPF. METHODS: We retrospectively assessed 24 unresectable LA-HNSCC patients who received paclitaxel, carboplatin and cetuximab (PCE) as ICT at the Shizuoka Cancer Center between April 2013 and October 2018. RESULTS: Patient characteristics were as follows: median age, 72 years (range 60-81); 0, 1, and 2 performance status (PS), 1, 15, and 8 patients, respectively, and creatinine clearance ≥ 60 mL/min or < 60 mL/min, 8 and 16 patients, respectively. The main reasons for PCE selection were renal impairment, older age, cardiac dysfunction, poor PS, and cerebral infarction. Twenty-two patients (92%) completed two or three cycles of ICT-PCE. After ICT-PCE, one patient (4%) and 20 patients (83%) achieved a complete response and partial response, respectively. Twenty-one patients (87%) advanced to definitive locoregional treatment. Median observation period was 25.2 months. The 12-month progression-free and overall survival rates were 75 and 92%, respectively. Median progression-free survival and overall survival were 29.4 and 34.8 months, respectively. Grade 3 or 4 toxicities included neutropenia (58%), oral mucositis (8%), and febrile neutropenia (4%). CONCLUSIONS: ICT-PCE may be a tolerable and potential option for unresectable LA-HNSCC patients ineligible for TPF.

Chemoradiotherapy for high-risk stage II laryngeal cancer.

BACKGROUND: Definitive radiotherapy (RT) for stage II laryngeal cancer is known to be less effective for locoregional control and survival (LRCS) in patients with high-risk factors (e.g., subglottic extension, impaired cord mobility, or bulky tumor size) than in low-risk patients. The purpose of this study was to evaluate the safety and efficacy of chemoradiotherapy (CRT) for stage II laryngeal cancer patients with high-risk factors METHODS: Sixty-five consecutive patients with stage II laryngeal cancer who received radiotherapy (RT) alone or CRT were retrospectively analyzed. The patients were classified into three groups: RT, low risk (RT-low, n = 26); RT, high risk (RT-high, n = 25); and CRT, high risk (CRT-high, n = 14). RESULTS: The glottis was the most common primary tumor site in all groups. Most patients in the CRT-high group received platinum-based CRT. The 5-year locoregional control and survival (LRCS) rates were 88.3, 44.2, and 85.7% in the RT-low, RT-high, and CRT-high groups, respectively. In multivariate analysis, high-risk disease and CRT were significantly associated with 5-year LRCS rates. CONCLUSION: CRT may provide better locoregional control than RT alone in high-risk stage II laryngeal cancer.