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Standard treatment for unresectable papillary thyroid carcinoma (PTC) is a multi-kinase inhibitor, including lenvatinib and sorafenib. Rearranged during transfection (RET) fusions are found in approximately 10% of PTC. Here, we present a case of metastatic RET fusion-positive PTC with long-term disease control by selective RET inhibition. A 72-year-old woman with PTC and multiple lymph nodes and lung metastases progressed after initial lenvatinib and subsequent sorafenib treatment. Reintroduction of lenvatinib led to marked tumour shrinkage. During the rechallenge with lenvatinib, molecular screening of the tumour specimen revealed a CCDC6-RET gene fusion. The patient was enrolled in a phase 1/2 trial of the potent and specific RET inhibitor selpercatinib. All target and non-target lesions responded to selpercatinib in parallel with a remarkable decrease in serum thyroglobulin levels. Although a new lesion appeared in the right adrenal gland 14 months after the initiation of selpercatinib, ongoing stable disease was observed in all lesions over 28 months, including the new adrenal lesion. Adverse events included grade 3 fatigue, grade 2 anorexia, and grade 4 thrombocytopaenia but were easily manageable by suspension and dose reduction of selpercatinib. Selective kinase inhibition with selpercatinib provides RET fusion-positive PTC with clinical benefits, even in patients heavily pre-treated with multi-kinase inhibitors. This case supports the importance of routine molecular profiling in patients with PTC to identify uncommon but actionable gene alterations, such as RET gene fusions.

Recent progress in molecular biology and translational research has initiated an era of personalized medicine in head and neck clinical oncology. The genetic information defined by biomarker analysis in tumors and individuals is indispensable for the administration of molecular targeting agents. The epidermal growth factor receptor (EGFR) signaling pathway is an important therapeutic target in head and neck squamous cell carcinoma (HNSCC). The use of an anti-EGFR monoclonal antibody (mAb), cetuximab (Cmab), has been approved for the treatment of patients with head and neck cancer. Although KRAS mutation has been established as a potential biomarker for predicting the efficacy of anti-EGFR mAb in colorectal cancer, little is known about predictive markers for Cmab in head and neck cancer. Optimal predictive and prognostic markers as well as safety markers are required to promote the appropriate clinical use of Cmab and to determine malignant phenotypes in head and neck cancer. This article first reviews the role of EGFR signaling in HNSCC. The article then focuses on Ras/Raf/Mek/Erk and PTEN/PI3K/Akt signaling pathways as predictive markers for Cmab. Subsequently, the molecular basis and clinical outcome of human papillomavirus (HPV)-positive cancer is highlighted, and the potential role of anti-EGFR target therapy for HPV-positive HNSCC is discussed. Finally, the possible mechanism for resistance to anti-EGFR target therapy is reviewed, and I discuss approaches to overcome the resistance with reference to an ongoing clinical trial.

BackgroundTo fill the data gap between clinical trials and real-world settings, this study assessed the overall effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) during Japanese real-world clinical practice.MethodsThis was a multicenter, retrospective study in Japanese patients with recurrent or metastatic HNC who received nivolumab for the first time between July and December 2017. Data on the clinical use, effectiveness, and safety of nivolumab were extracted from patient medical records.ResultsOverall, 256 patients were enrolled in this study. The median duration of nivolumab treatment was 72.5 days, with patients receiving a median of 6.0 (range 1–27) doses. Median overall survival (OS) was 9.5 (95% confidence interval [CI] 8.2–12.0) months and the estimated 12-month OS rate was 43.2%. The objective response rate (ORR) was 15.7% overall and 21.1%, 7.1%, and 13.6% in patients with primary nasopharynx, maxillary sinus, and salivary gland tumors, respectively, who had been excluded from CheckMate 141. Grade ≥ 3 immune-related adverse events occurred in 5.9% of patients. No new safety signals were identified compared with adverse events noted in CheckMate 141.ConclusionsThe effectiveness and safety of nivolumab in real-world clinical practice are consistent with data from the CheckMate 141 clinical trial. Therapeutic response was also observed in the groups of patients excluded from CheckMate 141.Trial registration numberUMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436)

BackgroundA multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS.MethodsEsophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse.ResultsThe median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2–63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%).ConclusionsLong-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.

BackgroundDistant 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. MethodsWe 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.ResultsThe 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.ConclusionThe 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.

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.

BackgroundMucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported.PurposeThis phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma.Patients and methodsEligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity.ResultsTwenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2–2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9–70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment.ConclusionAlthough this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.

BackgroundDefinitive 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 factorsMethodsSixty-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).ResultsThe 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.ConclusionCRT may provide better locoregional control than RT alone in high-risk stage II laryngeal cancer.

Background Aspiration pneumonia is one of the most important side effects of chemoradiotherapy (CRT) and bio-radiotherapy (BRT) in patients with head and neck cancer (HNC). Aspiration pneumonia can lead to cancer-related mortality in HNC patients. However, the relationship between aspiration pneumonia occurring during CRT or BRT for HNC and treatment outcomes in HNC patients is not well characterized. In this study, we assessed the influence of aspiration pneumonia on treatment outcomes and sought to identify the clinical risk factors for aspiration pneumonia during definitive CRT and BRT in HNC patients. Methods We retrospectively assessed the data pertaining to patients with locally advanced HNC who received definitive CRT or BRT at the Shizuoka Cancer Center between August 2006 and December 2016. Results Among the 374 HNC patients who received CRT or BRT, 95 (25.4%) developed aspiration pneumonia during treatment. Aspiration pneumonia was significantly associated with therapeutic response to CRT or BRT (multivariate adjusted odds ratio for complete response, 0.52, p  = 0.020) and poor overall survival (multivariate adjusted hazard ratio for overall survival, 1.58, p  = 0.024). The multivariate analyses identified four independent factors for aspiration pneumonia: poor oral hygiene, high N-classification, hypoalbuminemia before treatment, and inpatient treatment. Conclusions Aspiration pneumonia occurring during CRT or BRT has a detrimental effect on the therapeutic response and survival of HNC patients. Careful attention should be paid to these risk factors for aspiration pneumonia in HNC patients undergoing CRT or BRT.