Drug Insight: cetuximab in the treatment of recurrent and metastatic squamous cell carcinoma of the head and neck

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis, particularly those whose disease has progressed on previous platinum-containing therapy. The epidermal growth factor receptor (EGFR) is expressed at very high levels in SCCHN and is associated with a poor prognosis. Several phase II-III studies have shown that the EGFR-targeting monoclonal antibody, cetuximab, offers clinical benefit for patients with SCCHN. Cetuximab monotherapy is active in patients whose cancer progresses on platinum-containing therapy. Tumor response and patient survival are in excess of what is achieved with commonly used therapies in this setting. Addition of a platinum regimen to cetuximab in patients with disease that progresses on platinum seems to confer no further benefit over cetuximab alone, either in terms of response rate or survival. In the first-line setting, cetuximab plus platinum and 5-fluorouracil significantly prolongs overall survival compared with platinum and 5-fluorouracil alone. The superior survival observed with cetuximab compared with platinum-based treatment demonstrates that cetuximab is the most active treatment for recurrent and/or metastatic SCCHN, and is of particular clinical significance.     

Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies

BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitor cetuximab is active in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The activity of cetuximab was compared with that of commonly used treatments in this setting. METHODS: All patients had recurrent and/or metastatic SCCHN and had progressed on cisplatin- or carboplatin-based chemotherapy. Efficacy data from 3 prospective studies (n=278 patients) that administered cetuximab as a single agent (n=103 patients) or combined with either cisplatin/carboplatin (n=96 patients) or cisplatin (n=79 patients) were compared with the results from a retrospective study of patients who received various second-line treatments (all treatments including best supportive care only, n=151 patients; chemotherapy, n=43 patients). Safety data considered were only those from the cetuximab studies. RESULTS: Over the 3 cetuximab trials, overall response rates from 10% to 13% and disease control rates from 46% to 56% were observed. The median time to disease progression ranged between 2.2 months and 2.8 months, and the median overall survival ranged between 5.2 months and 6.1 months. No patients who progressed on cetuximab alone responded to additional platinum. These survival data compared favorably with those from the retrospective study (median survival, 3.4 months [n=151 patients] and 3.6 months [n=43 patients]). Cetuximab-based treatments generally were tolerated well, and cetuximab did not increase the side effects associated with platinum therapy. CONCLUSIONS: Cetuximab has the potential to prolong survival in patients with recurrent and/or metastatic SCCHN who fail on platinum therapy compared with various second-line therapies. Cetuximab did not increase the toxicities associated with chemotherapy. The results obtained by treatment with cetuximab alone after platinum failure did not appear to differ from the results obtained by reintroducing platinum in combination with cetuximab.     

Recent multidisciplinary approach with molecular targeted drugs for advanced head and neck cancer

The multidisciplinary approach is becoming the standard for treatment of advanced head and neck cancer. Combined modality treatment preserves quality of life as well as improving the length of survival time. Molecular targeted drugs have become very important in the multidisciplinary approach for the treatment of advanced head and neck cancer. Cetuximab has been shown to have locoregional control and additional survival benefits in locally advanced squamous cell carcinoma of the head and neck as well as additional survival benefits in distant metastatic/recurrent squamous cell carcinoma of the head and neck. Recently, many clinical studies of the multidisciplinary approach including cetuximab have been carried out in Europe and the US. It has been shown that cetuximab in combination with radiotherapy (RT) is significantly superior to the RT alone in median locoregional control duration and median overall survival (OS). For recurrent or metastatic disease, the results of a phase III randomized control study of CDDP + 5-fluorouracil combination therapy with or without cetuximab reported that OS was significantly longer with than without cetuximab, demonstrating an additional survival benefit of cetuximab. Many trials including induction chemotherapy are being conducted. Clinical trials with cetuximab have also been conducted in Japan. Though combination with cetuximab shows some benefit, further studies are necessary to obtain the standard treatments for a multidisciplinary approach for advanced head and neck cancer.     

Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.

PURPOSE: Therapy of recurrent/metastatic squamous cell carcinoma of the head and neck results in median progression-free survival (PFS) of 2 months. These cancers are rich in epidermal growth factor receptor (EGFR). We wished to determine whether the addition of cetuximab, which inhibits activation of EGFR, would improve PFS. PATIENTS AND METHODS: Patients with recurrent/metastatic squamous cell carcinoma of the head and neck were randomly assigned to receive cisplatin every 4 weeks, with weekly cetuximab (arm A) or placebo (arm B). Tumor tissue was assayed for EGFR expression by immunohistochemistry. The primary end point was PFS. Secondary end points of interest were response rate, toxicity, overall survival, and correlation of EGFR with clinical end points. RESULTS: There were 117 analyzable patients enrolled. Median PFS was 2.7 months for arm B and 4.2 months for arm A. The hazard ratio for progression of arm A to arm B was 0.78 (95% CI, 0.54 to 1.12). Median overall survival was 8.0 months for arm B and 9.2 months for arm A (P = .21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26% [corrected] for arm A and 10% [corrected] for arm B (P = .03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells. CONCLUSION: Addition of cetuximab to cisplatin significantly improves response rate. There was a survival advantage for the development of rash. Progression-free and overall survival were not significantly improved by the addition of cetuximab in this study.     

EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) continues to be a source of significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR), including monoclonal antibodies and small molecule tyrosine kinase inhibitors, have demonstrated activity in this disease. The US Food and Drug Administration has approved the monoclonal antibody cetuximab in conjunction with radiation for locally advanced disease, and as a single agent for recurrent/metastatic disease. In addition, recent data have shown a survival benefit for patients with recurrent/metastatic disease who are treated with platinum, fluorouracil, and cetuximab. These promising results have prompted further study of EGFR inhibitors with radiation and cytotoxic chemotherapy to further increase the benefit of treatment for SCCHN.     

Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. RESULTS: The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. CONCLUSION: The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.     

Cetuximab in the treatment of head and neck cancer

Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G(1) monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.     

Cetuximab in the treatment of head and neck cancer

Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G₁ monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.     

The role of antiangiogenic agents in the treatment of head and neck cancer

Despite progress in the treatment of locally advanced head and neck squamous cell cancer (HNSCC), the prognosis remains dismal and 5-year survival does not exceed 40%. In metastatic and recurrent disease, in spite of the introduction of cetuximab in combination with platinum and fluorouracil, the median overall survival rate remains lower than 11 months. There are many possible reasons for these disappointing results including acquired drug resistance and tumor hypoxia. Angiogenesis plays an important role in HNSCC development and proliferation. Promising preclinical results with antiangiogenic therapies have engendered a number of clinical trials, but so far there have not been any conclusive results on the value of such treatments. This paper aims to review the role of angiogenesis in head and neck cancer and to suggest future perspectives.     

Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck

BackgroundWe evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThe combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed.ResultsCetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3–4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy.ConclusionsCetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.     

Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

BACKGROUND: The objective of this study was to assess the antitumor activity and toxicity profile of weekly docetaxel in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Patients with recurrent, metastatic, incurable squamous cell carcinoma of the head and neck were enrolled. Weekly docetaxel (30 mg/m2) was administered for 4 weeks every 5 weeks for a maximum of 6 cycles. RESULTS: The activity and toxicity of docetaxel were assessed in all 38 patients who were entered on the study. No Grade 3-4 toxicities were recorded. No treatment delays were required because of toxicity or dose reductions. Responses were observed in 42% of patients (95% confidence interval, 26-58%). The median duration of response was 8.39 months, the estimated median overall survival was 11.3 months, and the 1-year survival rate was 39%. CONCLUSIONS: The results of this study suggested that weekly docetaxel was an active agent for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.     

Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck

BackgroundThe efficacy and safety of a novel combination of weekly paclitaxel and the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab for the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck were investigated.Patients and methodsPatients received paclitaxel (80 mg/m²) and cetuximab (400/250 mg/m²), weekly, until disease progression or unacceptable toxicity. The primary end point was response rate.ResultsAmong 46 patients enrolled, the overall response rate was 54% [95% confidence interval (CI) 39% to 69%], with 10 (22%) complete responses and a disease control rate of 80%. Median progression-free and overall survival times were 4.2 (95% CI 2.9–5.5 months) and 8.1 months (95% CI 6.6–9.6 months), respectively. Common grade 3/4 adverse events were acne-like rash (24%), asthenia (17%) and neutropenia (13%). Prior chemotherapy and the development of acne-like rash were associated with tumor response but not survival. No association between tumor EGFR expression or EGFR gene copy number and response or survival was found.ConclusionThe combination of cetuximab and weekly paclitaxel was active and well tolerated by these poor prognosis patients and may be an option for the treatment of medically unfit patients, particularly those for whom platinum is contraindicated.     

Current concepts for the management of head and neck cancer: chemotherapy

Chemotherapy can be administered in patients with locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) either concurrently with irradiation or as induction chemotherapy prior to local treatment or as palliative therapy in patients with recurrent and/or metastatic disease. Cisplatin-based chemoradiation is still the standard for LA-SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is indicated. Areas of active investigation in LA-SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil in recurrent/metastatic disease. Combination chemotherapy in this setting is preferably used in younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. However, a survival benefit was observed when cetuximab was combined with platinum-5-fluorouracil.     

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study

BackgroundThe phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients.Patients and methodsDual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU.ResultsTumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU.ConclusionTumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.     

Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck

Background: A phase III trial demonstrated that cetuximab is the first agent in 30 years to improve survival when added to platinum-based chemotherapy (platinum-fluorouracil) first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). This analysis of the trial assessed the impact of treatment on quality of life (QoL).Patients and methods: The European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30 (QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35) module were used to assess QoL.Results: Of 442 patients randomly assigned, 291 (QLQ-C30) and 289 (QLQ-H&N35) patients completed at least one evaluable questionnaire. For QLQ-C30, cycle 3 and month 6 mean scores for platinum–fluorouracil plus cetuximab were not significantly worse than those for platinum–fluorouracil. Pattern-mixture analysis demonstrated a significant improvement in the global health status/QoL score in the cetuximab arm (P = 0.0415) but no treatment differences in the social functioning scale. For QLQ-H&N35, the mean score for the cetuximab arm was not significantly worse than that for the chemotherapy arm for all symptom scales at all post-baseline visits. At cycle 3, some symptom scores significantly favored the cetuximab arm (pain, swallowing, speech problems, and social eating).Conclusion: Adding cetuximab to platinum–fluorouracil does not adversely affect the QoL of patients with recurrent and/or metastatic SCCHN.     

尼妥珠单抗联合多西他赛和顺铂一线治疗复发或转移性头颈部鳞癌疗效观察

目的 观察尼妥珠单抗联合多西他赛和顺铂一线治疗复发或转移性头颈部鳞癌的疗效及安全性.方法 回顾性分析28例尼妥珠单抗联合多西他赛+顺铂(观察组)及30例多西他赛+顺铂(对照组)一线治疗复发或转移性头颈部鳞癌患者的临床资料,比较两种方案的客观缓解率(ORR)、疾病控制率(DCR)、无进展生存时间(PFS)及总生存时间(O...     

The emerging role of cetuximab in head and neck cancer: a 2007 perspective

The integration of targeted therapies into clinical practice constitutes the paradigm of oncology treatment in the current era. Cetuximab, a recombinant human/mouse chimeric epidermal growth factor (EGFR) monoclonal antibody is a targeted agent that has seen expanding indication in recent years. Originally approved for colorectal cancer, its role in the treatment of squamous cell carcinoma of the head and neck has augmented treatment options for patients who are refractory to or cannot tolerate platinum. This article will review the science underlying cetuximab, data supportings its use in patients with locally advanced and recurrent/metastatic disease, common toxicities of therapy, and the integration of this treatment with radiation therapy.     

Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies

BackgroundThe phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients.MethodsProspectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1–300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers NCT00122460 and NCT00154102, respectively.FindingsTumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit.InterpretationThe addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings.     

Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications

In patients with squamous cell carcinoma of the head and neck (SCCHN), tumor recurrence, secondary tumors, and comorbidities contribute to therapy failure, and treatment approaches often are limited by their toxicity. With the incorporation of targeted therapies, the number of options available for patients with SCCHN is growing. The epidermal growth factor receptor (EGFR) is involved in the development and progression of SCCHN and is associated with a poor prognosis. The anti-EGFR monoclonal antibody (MoAb) cetuximab is the first targeted therapy to be developed for SCCHN. Recent data confirmed a survival advantage and enhanced locoregional control of SCCHN with cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) SCCHN. Single-agent cetuximab conferred clinical benefits for patients with platinum-refractory metastatic disease, and a recent phase 3 trial demonstrated a survival benefit with cetuximab and standard platinum-based therapy in the front-line treatment of recurrent/metastatic disease. Cetuximab has a toxicity profile milder than that of cytoxic agents and does not exacerbate RT toxicity when it is used in combination. Small-molecule EGFR-tyrosine kinase inhibitors also have shown promise in combination with chemoradiotherapy or as single agents, although they are in earlier stages of developmental. Other targeted approaches (eg, antiangiogenics) are also under investigation. Ongoing clinical trials will further define targeted treatment roles in all stages of SCCHN.     

Current Treatment Options for Metastatic Head and Neck Cancer

Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged.