Gefitinib, Methotrexate and Methotrexate plus 5-Fluorouracil as palliative treatment in recurrent head and neck squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Kushwaha VS
PROVIDER: S-EPMC4623054 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. METHODS:In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. RESULTS:The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. CONCLUSIONS:Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).
| S-EPMC5564292 | biostudies-literature
Project description:BACKGROUND:In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ?65 and <65 years. PATIENTS AND METHODS:Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS:Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ?65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS:Advancing age (?65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION:NCT01345682 (ClinicalTrials.gov).
| S-EPMC4959921 | biostudies-literature
Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers
2022-03-01 | PXD001438 | Pride
Project description:BackgroundRecurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC.MethodsWhole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.ResultsApproximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2.ConclusionIn this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches.FundingNational Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.
| S-EPMC4701554 | biostudies-literature
Project description:Head and neck cancer is the 6th most common cancer worldwide with the most common histology being squamous cell carcinoma (HNSCC). While the majority of patients present at a stage where curative intent therapy is possible, when patients recur and/or develop metastatic disease, outcomes are generally poor, especially with systemic therapy alone, and they lag behind other solid tumors. Over the last decade immunotherapy has revolutionized the field of oncology, and anti-PD-1-based therapy has changed the standard of care in recurrent/metastatic (R/M) HNSCC as well. With these gains have come new questions to continue to move the field forward. In this review, we discuss the tumor immune microenvironment and predictive biomarkers and current status and future directions for immunotherapy in recurrent/metastatic head and neck cancer.
| S-EPMC8440813 | biostudies-literature
Project description:Objective:The EXTREME clinical trial revealed that cetuximab plus chemotherapy improved the overall survival time of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) versus chemotherapy alone. The current study examined the cost-effectiveness of cetuximab plus chemotherapy compared with chemotherapy alone in HNSCC patients from the perspective of China. Materials and Methods:A partitioned survival model was implemented for R/M HNSCC patients. Survival information was derived from the CHANGE-2 trial. The model was designed as a ten-year time horizon, a 3-week cycle, and a 3% discount rate for costs and utilities. An incremental cost-effectiveness ratio (ICER) value is less than $30,201/quality-adjusted life-year (QALY) was considered cost-effective in China. We analyzed the uncertainty by performing one-way and probabilistic sensitivity analyses. Results:In the base-case analysis, we found that the ICER of cetuximab plus chemotherapy compared with chemotherapy alone is $172,702/QALY. The results of one-way sensitivity analysis and probabilistic analysis showed that the fluctuations of each variable in its ranges do not cause ICERs to reach acceptable thresholds. Conclusion:The current observations suggested that treatment with cetuximab plus chemotherapy is not a cost-effective strategy for R/M HNSCC patients in China at a $30,201 willingness to pay threshold.
| S-EPMC7661788 | biostudies-literature
Project description:BackgroundAngiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC.MethodsWe did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual.FindingsBetween June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease.InterpretationPazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials.FundingGlaxoSmithKline and Novartis.
| S-EPMC6561471 | biostudies-literature
Project description:BackgroundTreatment options for patients with platinum-refractory, recurrent, metastatic head and neck squamous cell carcinoma (r/m HNSCC) are limited and prognosis is poor. The recent CheckMate 141 clinical trial demonstrated that nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, was efficacious in extending the median overall survival (OS) in this patient population compared with standard therapies. We conducted a cost-effectiveness analysis to determine whether nivolumab is a cost-effective treatment in this patient population and examined various subgroups to determine for which, if any, the treatment is more cost-effective.Materials and methodsWe implemented a state transition model for HNSCC with a patient cohort who had tumor progression 6 months after the last dose of platinum-containing chemotherapy and compared the cost-effectiveness of nivolumab with docetaxel. Treatment effect estimates and adverse event rates were obtained from CheckMate 141. Costs, utilities, and other model inputs were gathered from published sources. We used a Canadian perspective, a 5-year time horizon, and a 1.5% discount rate for the analysis.ResultsNivolumab extended mean OS by 4 months compared with docetaxel and resulted in fewer treatment-related adverse events, producing an incremental effectiveness of 0.13 quality-adjusted life years (QALY). The incremental cost of treatment with nivolumab was $18,823. At a willingness-to-pay threshold of $100,000/QALY, nivolumab was not a cost-effective treatment option for r/m HNSCC, with an incremental cost-effectiveness ratio of $144,744/QALY. Nivolumab would be cost-effective if its price was reduced by 20%. Our subgroup analysis seemed to indicate that nivolumab might be cost-effective for tumors with expression of programmed death-ligand 1 >5%.ConclusionWe conclude that although nivolumab offers clinical benefit for the treatment of r/m HNSCC over current regimens, it is not cost-effective based on its list price. We have also established a value-based price estimate for nivolumab to be cost-effective in this patient population. Further study is required to draw a definitive conclusion on biomarkers for cost-effectiveness.Implications for practiceIn health care settings in which cost considerations are a constraint on choice of therapy, patient selection should be carefully considered to maintain efficiency in the system. Until a biomarker for response to therapy is identified for nivolumab, this medication is unlikely to be cost-effective for most patients with recurrent, metastatic head and neck squamous cell carcinoma.
| S-EPMC5813741 | biostudies-literature
Project description:Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in DPYD, which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Although the association of germline DPYD alterations with toxicity is well-described, the potential contribution of somatic DPYD alterations to 5-FU sensitivity has not been explored. In a patient with metastatic HNSCC, in-depth genomic and transcriptomic integrative analysis on a biopsy from a metastatic neck lesion revealed alterations in genes that are associated with 5-FU uptake and metabolism. These included a novel somatic structural variant resulting in a partial deletion affecting DPYD, a variant of unknown significance affecting SLC29A1, and homozygous deletion of MTAP There was no evidence of deleterious germline polymorphisms that have been associated with 5-FU toxicity, indicating a potential vulnerability of the tumor to 5-FU therapy. The discovery of the novel DPYD variant led to the initiation of 5-FU treatment that resulted in a rapid response lasting 17 wk, with subsequent relapse due to unknown resistance mechanisms. This suggests that somatic alterations present in this tumor may serve as markers for tumor sensitivity to 5-FU, aiding in the selection of personalized treatment strategies.
| S-EPMC6996515 | biostudies-literature
Project description:PurposeTo determine the disease control rate and toxicity of treating patients with aggressive cutaneous squamous cell carcinoma (CSCC) with neoadjuvant gefitinib.Experimental designA prospective phase II clinical trial evaluating neoadjuvant gefitinib given prior to standard treatment with surgery and/or radiotherapy. Patients with stable disease after one cycle received escalated doses. Patients who responded were given gefitinib during radiation therapy, as well as maintenance therapy after definitive treatment. We analyzed the correlation between epidermal growth factor receptor (EGFR) expression, mutation status, and gene copy number on available tissue samples and clinical response.ResultsTwenty-three patients were accrued and 22 patients were evaluable for response prior to definitive local treatment; complete responses were attained by 18.2% of patients and partial responses by 27.3%. Grades 2 to 3 toxicities were observed in 59.1% of patients experiencing class-specific effects during induction therapy. After induction, 11.8% underwent surgery alone, 17.6% had definitive radiation, 11.8% were treated with radiation and concurrent gefitinib, and 47% had surgery with postoperative radiation and concurrent gefitinib. Median follow-up for the censored observations was 32 months. Two-year overall, disease-specific, and progression-free survival rates were 72.1%, 72.1%, and 63.6%, respectively. No EGFR-activating mutations were identified in tumor samples available from 10 patients. No associations between EGFR correlative studies and patient outcomes were identified.ConclusionsGefitinib, in the neoadjuvant setting, was active and well tolerated in patients with aggressive CSCC and did not interfere with definitive treatment. In view of the 18% complete response rate we observed, EGFR tyrosine kinase inhibitors should be further explored in the treatment of aggressive CSCC.
| S-EPMC6167936 | biostudies-literature