Toxicities of systemic agents in squamous cell carcinoma of the head and neck (SCCHN); A new perspective in the era of immunotherapy
TL;DR: An overview of the toxicity profile of the different systemic agents is provided and a perspective into the future of SCCHN treatment is provided.
Abstract: Squamous cell carcinoma of the head and neck (SCCHN) is a difficult to treat malignancy and represents the seventh most common cancer worldwide. Systemic therapy has a critical role in the treatment of locally advanced and recurrent/metastatic disease. Cytotoxic chemotherapy has been primarily used along with radiation and surgery, with cisplatin being the standard of care choice of therapy. When contraindications to cisplatin exist, other agents such as carboplatin, taxanes, 5-fluorouracil, and cetuximab are used. Similarly, in the advanced or metastatic setting, platinum agents, taxanes and cetuximab have been predominantly utilized. With the recent approval of novel agents such as pembrolizumab and nivolumab, and their distinct toxicity profiles, an understanding of the potential sequelae of the different systemic agents is essential to the careful selection of agents in the advanced disease setting. Going forward, choosing novel agents will be weighed against traditional chemotherapy, and understanding the toxicities at stake is critical in this process. In addition to providing an overview of the toxicity profile of the different systemic agents, we also provide a perspective into the future of SCCHN treatment.
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TL;DR: Topical administration of immunoliposomes containing 5‐FU using iontophoresis is a promising strategy for SCC treatment and shows promise in reducing tumor aggressiveness and resulting in cells with less aggressive characteristics.
63 citations
TL;DR: This study established and validated chimeric antigen receptor (CAR)-T cells targets in head and neck squamous cell carcinoma and demonstrated to recognize and kill CD70-positive HNSCC cells efficiently, but notCD70-negative cancer cells.
51 citations
TL;DR: Using next-generation sequencing, the precise profiling of tumor-infiltrating lymphocytes has great promise to identify hypoimmunogenic cancer that would benefit from a rationally designed combinatorial approach.
Abstract: Precision medicine is an approach to disease prevention and treatment that takes into account genetic variability and environmental and lifestyle influences that are unique to each patient. It facilitates stratification of patient populations that vary in their susceptibility to disease and response to therapy. Shared databases and the implementation of new technology systems designed to advance the integration of this information will enable health care providers to more accurately predict and customize prevention and treatment strategies for patients. Although precision medicine has had a limited impact in most areas of medicine, it has been shown to be an increasingly successful approach to cancer therapy. Despite early promising results targeting aberrant signaling pathways or inhibitors designed to block tumor-driven processes such as angiogenesis, limited success emphasizes the need to discover new biomarkers and treatment targets that are more reliable in predicting response to therapy and result in better health outcomes. Recent successes in the use of immunity-inducing antibodies have stimulated increased interest in the use of precision immunotherapy of head and neck squamous cell carcinoma. Using next-generation sequencing, the precise profiling of tumor-infiltrating lymphocytes has great promise to identify hypoimmunogenic cancer that would benefit from a rationally designed combinatorial approach. Continued interrogation of tumors will reveal new actionable targets with increasing therapeutic efficacy and fulfill the promise of precision therapy of head and neck cancer.
41 citations
Cites background from "Toxicities of systemic agents in sq..."
...Targeted therapy approved for use in HNSCC is the EGFR inhibitor, cetuximab (Saba et al. 2017)....
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...inhibiting downstream signaling cascades (Saba et al. 2017)....
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...Cetuximab competitively antagonizes binding of epidermal growth factor (EGF) and transforming growth factor α (TGFα) to EGFR, thereby inhibiting downstream signaling cascades (Saba et al. 2017)....
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TL;DR: The aim of this cohort study was to assess the relationship of fat‐free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, and the effect of the current TF regime on body composition and muscle strength in patients treated with chemoradiation vs. bioradiation.
Abstract: BACKGROUND Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat-free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength. METHODS Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition. RESULTS In this cohort (68% male, mean age 59 ± 8 years), the incidence of baseline muscle wasting, defined as FFMI < P10 , was 29%. Muscle wasting was present in 23 of 100 (23%) chemoradiation patients and 17 of 37 (46%) bioradiation patients (P = 0.009). Muscle-wasted patients required more unplanned hospitalizations during CRT (P = 0.035). In the chemoradiation subset, dose-limiting toxicity was significantly higher in wasted vs. non-wasted patients (57% vs. 25%, P = 0.004). Median follow-up was 32 months. Multivariate Cox regression analysis identified muscle wasting as independent unfavourable prognostic factor for overall survival [hazard ratio 2.1 (95% CI 1.1-4.1), P = 0.022] and cisplatin as favourable prognostic factor [hazard ratio 0.3 (95% CI 0.2-0.6), P = 0.001]. Weight and HGS significantly decreased during CRT/BRT, -3.7 ± 3.5 kg (P < 0.001) and -3.1 ± 6.0 kg (P < 0.001), respectively. Sixty-four per cent of the patients required TF 21 days (range 0-59) after CRT/BRT initiation. Total weight loss during CRT/BRT was significantly (P = 0.007) higher in the total oral diet group (5.5 ± 3.7 kg) compared with the TF group (3.0 ± 3.2 kg). Loss of FFM and HGS was similar in both groups. CONCLUSIONS In LAHNSCC patients undergoing CRT/BRT, FFMI < P10 is an unfavourable prognostic factor for overall survival, treatment toxicity, and tolerance. Patients experience significant weight and FFM loss during treatment. Current TF regime attenuates weight loss but does not overcome loss of muscle mass and function during therapy. Future interventions should consider nutritional intake and additional strategies specifically targeting metabolism, loss of muscle mass, and function.
39 citations
Cites background from "Toxicities of systemic agents in sq..."
...Hematologic toxicity, ototoxicity, and renal failure were only determined in the population who received cisplatin as radiosensitizer, because cetuximab is not myelosuppressive and less nephrotoxic and neurotoxic than cisplatin.(22) Overall dose-limiting toxicity (including neutropaenia, renal failure,...
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TL;DR: The most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives are summarized.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives.
27 citations
References
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The Royal Marsden NHS Foundation Trust1, European Institute of Oncology2, University of Colorado Denver3, Aix-Marseille University4, Baylor University5, University of Michigan6, University of Zurich7, Cross Cancer Institute8, Peter MacCallum Cancer Centre9, Netherlands Cancer Institute10, Hospital General Universitario Gregorio Marañón11, Memorial Sloan Kettering Cancer Center12, Huntsman Cancer Institute13, Yale University14, University of Melbourne15, University of Sydney16, Cornell University17, Ludwig Institute for Cancer Research18, University of Utah19, Yale Cancer Center20, Odense University Hospital21, Bristol-Myers Squibb22, Harvard University23
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
6,318 citations
"Toxicities of systemic agents in sq..." refers background in this paper
...…resulting in FDA approval of both agents (Ferris et al., 2016; Seiwert et al., 2016) Similarly, clinical trials are ongoing to evaluate a potential role for ipilimumab, a CTLA-4 antagonist, in head and neck cancer, as it already has been approved for the treatment of melanoma (Larkin et al., 2015)....
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University of Alabama at Birmingham1, University of Wisconsin-Madison2, Autonomous University of Barcelona3, Eli Lilly and Company4, University of Texas MD Anderson Cancer Center5, University of Virginia6, University of the Witwatersrand7, University of Colorado Boulder8, Gdańsk Medical University9, University of Alabama10, Merck KGaA11, ImClone Systems12
TL;DR: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoreGional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head andneck.
Abstract: BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)
4,705 citations
TL;DR: This work has shown that novel genes identified in DNA microarray profiling have the potential to identify novel genes that are involved in mediating resistance to 5-FU, and these genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to5-FU-based chemotherapy.
Abstract: 5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.
4,177 citations
University of Pittsburgh1, University of Texas MD Anderson Cancer Center2, Stanford University3, University of Duisburg-Essen4, University of Chicago5, Institut Gustave Roussy6, University of Michigan7, Emory University8, Complutense University of Madrid9, Harvard University10, University of Zurich11, Kobe University12, Bristol-Myers Squibb13, Ohio State University14
TL;DR: 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.
Abstract: BackgroundPatients 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. MethodsIn 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. ResultsThe 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...
3,246 citations
"Toxicities of systemic agents in sq..." refers background or result in this paper
...Both these agents have recently been studied in clinical trials with encouraging results, resulting in FDA approval of both agents (Ferris et al., 2016; Seiwert et al., 2016) Similarly, clinical trials are ongoing to evaluate a potential role for ipilimumab, a CTLA-4 antagonist, in head and neck…...
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...…other patient reported quality of life meaures, including dyspnea, insomnia, pain, etc. was actually noted o be nearly stable or slightly improved, compared to the standard herapy group, which reported clinically meaningful worsening of hysical, role, and social functioning (Ferris et al., 2016)....
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...Early data already published suggests that immune checkpoint inhibitors might be superior to investigator’s choice medication in the second-line recurrent/metastatic disease setting (Ferris et al., 2016)....
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TL;DR: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracils) significantly prolonged the median overall survival and improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.
Abstract: Background Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. Methods We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. Results
2,940 citations