Current Recommendations for Systemic Therapy of Recurrent and/or Metastatic Head and Neck Squamous Cell Cancer

For palliation of patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC), the major classes of commonly used cytotoxic chemotherapeutic agents are platinum agents (cisplatin, carboplatin), taxanes (paclitaxel, docetaxel), and antimetabolic agents (methotrexate, 5-fluorouracil). Cetuximab, a monoclonal antibody directed against the extracellular domain of the epidermal growth factor receptor, also shows modest activity against R/M HNSCC. Because the overall management of patients with R/M HNSCC often involves multidisciplinary input, this review focuses on data that help guide decision-making in scenarios in which palliative chemotherapy is planned. Avenues for ongoing research are also presented.

Abstract

For palliation of patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC), the major classes of commonly used cytotoxic chemotherapeutic agents are platinum agents (cisplatin, carboplatin), taxanes (paclitaxel, docetaxel), and antimetabolic agents (methotrexate, 5-fluorouracil). Cetuximab, a monoclonal antibody directed against the extracellular domain of the epidermal growth factor receptor, also shows modest activity against R/M HNSCC. Because the overall management of patients with R/M HNSCC often involves multidisciplinary input, this review focuses on data that help guide decision-making in scenarios in which palliative chemotherapy is planned. Avenues for ongoing research are also presented.

Medscape: Continuing Medical Education Online

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscape.org/journal/jnccn; (4) view/print certificate.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Distinguish prognostic factors for survival in cases of R/M HNSCC

  • Evaluate different therapeutic approaches to patients with R/M HNSCC

  • Analyze the use of cytotoxic agents in the management of R/M HNSCC

  • Analyze the use of cetuximab in the management of R/M HNSCC

General Considerations and Prognostic Factors

For patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC) who are considered incurable with surgery or radiation, platinum agents, taxanes, methotrexate, 5-fluorouracil (5-FU), and cetuximab are the drugs that medical oncologists most commonly consider for palliative cancer-directed treatment. Available data supporting the observed activity of these agents are derived from clinical trials focusing on the spectrum of primary sites within the upper aerodigestive tract, but nasopharynx cancers are generally considered as a separate group. Even with combination regimens, objective radiographic responses are achieved in fewer than 40% of patients in most large studies.1,2 Performance status and extent of prior therapy have long been associated with outcomes in patients with R/M HNSCC.3 Among all patients with HNSCC, advanced stage, history of tobacco or alcohol abuse, low reported quality of life, and lack of private medical insurance (in the United States) have been associated with inferior overall survival.46 In regions where betel quid chewing is common, this exposure has been linked to poor prognosis among individuals with squamous cell carcinoma of the buccal mucosa.7

In a combined analysis of 2 randomized studies of cisplatin-based chemotherapy for patients with R/M HNSCC (n = 399; ECOG 1393 and ECOG 1395), 5 factors were found to be independent predictors of overall survival. Shorter overall survival was independently associated with weight loss greater than 5%, ECOG performance status 1 (vs. 0), prior radiation therapy, hypopharyngeal or oral cavity primary site (vs. others), and well to moderate tumor cell differentiation.8 The objective response rate was 32% and median overall survival was 7.8 months for the entire population. For patients with R/M HNSCC, malignant hypercalcemia is a negative prognostic marker that is usually associated with end-stage diease.9

More recently, human papilloma virus (HPV) status has been shown to strongly predict outcomes in patients with locally or regionally advanced oropharynx squamous cell carcinoma,10 but the prognostic impact of HPV in R/M HNSCC is less well understood. A consistent observation across studies of patients with R/M HNSCC is that the durability of response to chemotherapy alone is generally measured in months, not years. However, a small percentage of patients with R/M HNSCC experience long-term survival.8 Table 1 summarizes negative prognostic factors for patients with HNSCC.

Table 1

Factors Associated With Inferior Overall Survival for Patients With HNSCC

Table 1

Key Lessons From Clinical Studies of Cytotoxic Agents

Cisplatin, 5-FU, and Methotrexate

The efficacy of cisplatin against HNSCC was first described in 1977.11 A randomized phase III trial with a 2 × 2 factorial design (n = 116 subjects) compared cisplatin with bleomycin versus cisplatin plus bleomycin versus “no treatment.”12 Among all patients treated with chemotherapy, the response rate was 25%. Median survival times in the cisplatin plus bleomycin and the bleomycin monotherapy groups did not differ significantly from those of the control group. The salient finding was that treatment with cisplatin versus no treatment was associated with a 10-week improvement in median overall survival. Notably, a trend was seen toward worse survival in the bleomycin group.12 This is the only randomized study showing an improvement in overall survival with chemotherapy versus no treatment in patients with recurrent or advanced head and neck cancer. The singularity of this result probably reflects that subsequent clinical studies for this patient population generally have not included a placebo group, because of both logistical and ethical concerns about these designs after this initial proof-of-principle.

In a randomized comparison of cisplatin versus methotrexate in patients (n = 44) with HNSCC who experienced recurrence after surgery or radiation, response rates (cisplatin, 23.5%; methotrexate, 28.6%) and median survival (∼ 6 months) were similar in both arms.13 Cisplatin and methotrexate also showed comparable antitumor activity in the palliative setting in a randomized comparison among 100 patients with inoperable, locally advanced, or metastatic head and neck cancer. Cisplatin was associated with a response rate of 8% and median survival time of 18 weeks, versus 16% and 20 weeks, respectively, for methotrexate.14 An important general concept regarding clinical studies in R/M HNSCC is that no single chemotherapeutic agent has conclusively shown superiority in terms of overall survival over another drug in a randomized clinical trial.

The combination of cisplatin plus infusional 5-FU (CF) showed a remarkable response rate of 70% among 30 subjects with R/M HNSCC treated at a single institution,15 and the CF regimen was studied extensively in the 1980s and 1990s. A randomized comparison of the doublet versus monotherapy (CF vs. cisplatin vs. 5-FU; n = 249) showed that response rates and hematologic toxicities were highest in the CF group (32% vs. 17% for cisplatin and 13% for 5-FU), but median survival was approximately 5.7 months for all groups.16

The largest randomized study (n = 382 subjects) of that era for patients with R/M HNSCC compared CF, CABO (cisplatin, methotrexate, bleomycin, and vincristine), and cisplatin monotherapy.17 Again, response rates were higher with the combination chemotherapy regimens (34% for CABO vs. 31% for CF vs. 15% for cisplatin), but no significant difference in overall survival was seen among the arms. This study underscores that cytotoxic chemotherapy combination regimens, as opposed to monotherapy, historically have yielded higher objective response rates, and generally improve overall survival for patients R/M HNSCC, and that the combination regimens generally are associated with increased treatment-related toxicities. Table 2 illustrates the data from the CABO study and other major randomized phase III trials involving platinum-based regimens for patients with R/M HNSCC.

Table 2

Selected Randomized Phase III Trials of Cisplatin-Containing Regimens for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Table 2

Carboplatin may be better tolerated in this setting because it is generally less emetogenic, nephrotoxic, and neurotoxic than cisplatin. In a small phase II study for patients with R/M HNSCC, carboplatin monotherapy was associated with a response rate of 26% among 31 subjects.18 These findings were confirmed in a subsequent report in which carboplatin produced a response rate of 24% among 29 subjects with recurrent HNSCC.19

CF was compared with carboplatin plus 5-FU (CbF) and methotrexate in a 3-arm randomized clinical trial (n = 261 subjects).20 One concern is that the protocol called for a starting carboplatin dose (300 mg/m2) that differs from the area of the curve (AUC) dosing now more typically used for this agent, with guidelines for carboplatin dose escalation to achieve grade 2 myelosuppression that can be difficult to reproducibly follow. Renal, hematologic, and cardiac toxicities were most prominent in the CF group. Response rate was highest for the CF group (32% for CF; 21% for CbF, and 10% for methotrexate), but no significant difference was seen in median overall survival among the groups. Notably, this trial was not statistically powered to provide a definitive comparision of CF verus CbF, and concerns about the dosing of carboplatin (300 mg/m2) also compromise efficacy comparisons between CF and CbF. The comparison is further limited by the fact that the CF schedule was every 3 weeks and the CbF schedule was every 4.20

The Taxanes

In the 1990s, taxanes showed impressive objective response rates (paclitaxel, 40%; docetaxel, 42%) in small nonrandomized studies for patients who had not undergone prior chemotherapy for R/M HNSCC.21,22 In a randomized study (n = 218) comparing combination cisplatin plus paclitaxel (CP) with CF, no significant difference was seen in response rate (CF, 27%; CP, 26%) or overall survival (CF, 8.7 months; CF, 8.1 months). Observed toxicities were also similar, although gastrointestinal and hematologic toxicities were less common with CP.23 CP and CF both became accepted as palliative regimens for patients with R/M HNSCC, but tolerability of cisplatin can be problematic in this patient population, particulary among individuals who may have residual toxicities from prior cisplatin-based therapy.

Carboplatin plus paclitaxel, both in every-3-week24,25 and weekly26 dosing schedules, has been evaluated in phase II studies with a wide range of reported response rates (26%–52%) and median survival times (4.9–12.8 months). Whether carboplatin plus paclitaxel has comparable efficacy or a favorable safety profile compared with CP has not been rigorously evaluated in a prospective randomized study in patients with R/M HNSCC.

Taxanes have also been evaluated in phase II studies of triplet chemotherapy for subjects with advanced HNSCC. TIP (paclitaxel, ifosfamide, cisplatin),27 TIC (paclitaxel, ifosfamide, carboplatin),28 and modified TPF (docetaxel, cisplatin, 5-FU)29 were associated with encouraging response rates (44%–59%) in phase II studies, but median survival times (8.8–11 months) were comparable to those achieved with doublet chemotherapy in recurrent or metastatic disease.23

No combination cytotoxic chemotherapy has shown superiority over another in a randomized prospective trial for patients with R/M HNSCC. CP and CF doublets have comparable efficacy as palliative regimens for advanced HNSCC based on randomized clinical trial data. Triplet cytotoxic regimens have been less extensively studied and should not be used outside of a clinical trial in the treatment of R/M HNSCC. These studies illustrate the inherent limitations regarding the efficacy and tolerability of cytotoxic chemotherapy, and strategies to incorporate molecularly targeted agents in the management of patients with advanced HNSCC became the focus of subsequent clinical research.

Other Cytotoxic Agents With Activity Against R/M HNSCC

Other agents with reported single-agent activity in phase II studies include pemetrexed, vinorelbine, and ifosfamide. Pemetrexed yielded an objective response rate of 26.5% among 25 subjects with R/M HNSCC.30 In a phase II study of pemetrexed plus gemcitabine for treatment of patients with R/M HNSCC, response rate and overall survival were similar to what would be expected for pemetrexed alone.31 Gemcitabine has robust palliative activity against advanced nasopharyngeal carcinoma,32 but 2 phase II studies for patients with R/M HNSCC yielded response rates of 13% and 0%, respectively.33,34 Therefore, gemcitabine is recommended for advanced nasopharyngeal carcinoma but not for R/M HNSCC. Pemetrexed is an attractive candidate for further study in R/M HNSCC.

Weekly vinorelbine is generally well tolerated in the palliative setting, and has been associated with response rates of 7.5% and 16% in 2 phase II studies.35,36 Ifosfamide monotherapy also has yielded modest response rates (4%–26%) in patients with R/M HNSCC who received prior chemotherapy.37 Irinotecan resulted in objective responses in approximately 20% of subjects as first-line therapy for R/M HNSCC, but was not active as second-line therapy.38 Neither vinorelbine, ifosfamide, irinotecan, nor pemetrexed has been evaluated in a randomized phase III study for R/M HNSCC. Earlier studies described activity for bleomycin, vinblastine, cyclophosphamide, and adriamycin,39 although these agents are not commonly applied in contemporary practice.

Cetuximab: Targeting the Epidermal Growth Factor Receptor

Cetuximab represents the first biologic agent to enter routine clinical practice as a palliative agent for patients with advanced head and neck cancer. Cetuximab, a chimeric monoclonal antibody, binds to the extracellular domain of the epidermal growth factor receptor (EGFR). Virtually all HNSCCs express EGFR, and high levels of EGFR expression are associated with worse prognosis in this disease.40,41

Cetuximab has modest palliative activity in platinum-refractory advanced HNSCC. Among 96 patients with documented disease progression on platinum-based chemotherapy, the addition of cetuximab to the same platinum regimen yielded an objective response rate of 10%.42 Similarly, among 25 patients who experienced disease progression during treatment with CP or CF, the addition of cetuximab to cisplatin produced 5 objective responses.43 Because of the design of these studies, whether these responses were from inherent antitumor activity of cetuximab or reversal of cisplatin-resistance cannot be discerned. To distinguish these possibilities, Vermorken et al.44 designed a phase II study in which 103 subjects who experienced treatment failure on platinum-based chemotherarpy were assigned to cetuximab monotherapy. The objective response rate was 13% and median time to progression was 70 days. Among patients who then received cetuximab plus platinum-based therapy, none experienced a major response.44

Cetuximab has been evaluated in 2 randomized phase III trials for patients with R/M HNSCC. One study randomized patients who had not received any prior chemotherapy for R/M HNSCC to either cetuximab plus cisplatin or placebo plus cisplatin. Objective response rate favored the cetuximab arm (26% vs. 10%; P = .03). However, progression-free and overall survivals did not differ significantly between the groups.45

The EXTREME trial randomized 442 subjects with R/M HNSCC to receive PF (or CbF, per investigator's choice) with or without cetuximab. No prior therapy for recurent or metastatic disease was allowed. After 6 cycles of the triplet regimen in the experimental group, subjects continued cetuximab monotherapy until disease progression or unacceptable side effects. No crossover occurred between groups. The addition of cetuximab to the platinum doublet was associated with significant improvements in all outcomes: response rate (36% vs. 20%), progression-free survival (5.6 vs. 3.3 months), and overall survival (10.1 vs. 7.4 months).46 The efficacy results of the EXTREME trial are shown in Table 2, in the context of other randomized phase III trials of platinum-containing regimens for patients with R/M HNSCC.

Because no crossover occurred for patients in the control group of the EXTREME study, whether the 10.1-month overall survival in the triplet group could also have been achieved with sequential therapy is unclear (e.g., platinum doublet until progression, followed by cetuximab monotherapy). The EXTREME study shows that the triplet regimen should be considered in symptomatic patients with a good performance status in whom an objective response is needed.

Currently, no published randomized prospective data are available to evaluate the addition of cetuximab to taxane chemotherapy in R/M HNSCC. The addition of cetuximab to weekly paclitaxel and carboplatin showed encouraging activity as induction chemotherapy for patients with newly diagnosed stage IVA and IVB HNSCC.47 However, weekly docetaxel plus cetuximab yielded a response rate of only 12% in a phase II study for 51 subjects with platinum-refractory HNSCC.48 Therefore, the most appropriate setting for the use of taxanes plus cetuximab for patients with R/M HNSCC is a clinical trial.

No clinical or molecular predictors exist to guide patient selection for EGFR-targeted therapy in advanced HNSCC. EGFR gene copy number as determined with FISH (fluorescence in situ hybridization) was found to have no association with efficacy of cetuximab in the EXTREME study.49 K-RAS exon 12/13 mutations50,51 and EGFR tyrosine kinase domain mutations52,53 are too uncommon in HNSCC to merit consideration as biomarkers. EGFR variant III (EGFRvIII) lacks the extracellular binding domain for cetuximab and has been detected in a significant proportion in HNSCC,54 but further study is needed to determine if EGFRvIII could potentially serve as a biomarker in this patient population. The EGFR-R521K genotype may be associated with skin toxicity and clinical activity of cetuximab, and merits further evaluation as a potential biomarker for cetuximab responsiveness in this disease.48

Refinements regarding the dose and schedule also remain an area of clinical study in R/M HNSCC. In a phase I dose escalation study for patients with metastatic colorectal cancer, the pharmacokinetic parameters for cetuximab 500 mg/m2 every 2 weeks were similar to those achieved with the standard cetuximab dose and schedule (400 mg/m2 loading dose, followed by 250 mg/m2 weekly).55 For patients with R/M HNSCC, a randomized phase II study of 2 doses of cetuximab administered every 2 weeks has recently completed accrual,56 and results are anticipated in 2011.

Selected Clinical Research Topics in R/M HNSCC

Targeting the tyrosine kinase domain of EGFR remains an investigational strategy of great interest in HNSCC. Gefitinib, 500 mg/d, showed modest activity (response rate, 10.6%; median survival, 8.1 months) in a phase II study,57 but was no better than methotrexate in a large randomized phase III study (n = 486) for patients with recurrent HNSCC. This dosage of gefitinib had a numerically higher response rate (7.6%) than 250 mg/d (2.7%), but neither dose showed a statistically significant improvement in response rate compared with methotrexate (3.9%), and treatment with gefitinib was associated with more tumor-hemorrhage events.58 Erlotinib monotherapy (150 mg/d) was associated with a response rate of 4.3% in a phase II study for patients with advanced HNSCC.59

Several studies have explored VEGF (vascular endothelial growth factor) receptor–targeting agents in R/M HNSCC. The biologic rationale for this approach is supported by the observation that high levels of tumor VEGF expression are associated with inferior overall survival in HNSCC.60 However, phase II studies of agents such as sunitinib and sorafenib did not provide compelling evidence of superior improvement in progression-free survival over other available agents, and further monotherapy studies of these agents in advanced HNSCC is not anticipated.61,62 Combined targeting of EGFR and VEGF with erlotinib and bevacizumab was associated with a 15% response rate in a phase II study, and this report suggests a biomarker-driven strategy for continued study of this combination.63 A randomized trial of chemotherapy with or without bevacizumab in patients with R/M HNSCC is in progress (ECOG 1305).

EGFR and other transmembrane receptors converge to control a variety of intracellular signaling pathways, such as the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. A collaborative international tissue microarray project showed that activation of this pathway seems to be a characteristic of HNSCC.64 The first agents impacting this pathway to enter clinical study were rapamycin and related compounds (e.g., everolimus, temsirolimus) that inhibit the serine/threonine kinase activity of mTOR in the mTORC1 compex,65 Temsirolimus reduces growth of HNSCC cell lines in xenograft models,66 and everolimus inhibits tumor growth in a murine oral squamous cell model system that is driven by an oncogenic K-ras mutant and p53 loss.67 In a pilot pharmacodynamic clinical study, temsirolimus significantly decreased pS6 and p4E-BP1 in HNSCC tumors.68 In view of the well-described ability of mTOR inhibitors to sensitize cancer cells to platinum and taxane chemotherapy,6971 clinical studies are underway to determine if mTOR inhibition may enhance the efficacy of chemotherapy in R/M HNSCC.

Clinical Considerations for Selection of Chemotherapeutic Regimen for R/M HNSCC

When considering palliative systemic therapy for patients with R/M HNSCC, management recommendations are based on several factors, including the performance status and medical comorbidities of the patient, presence or absence of symptoms, and a clinical impression of whether the disease is growing in an indolent or aggressive fashion. Currently, no biomarkers are clinically available to inform the choice of one agent over another for patients with head and neck cancer.

For frail patients with indolent asymptomatic disease, a period of expectant observation before consideration of systemic therapy may be prudent. In patients with progressive disease who require treatment in the context of borderline performance status in which cisplatin may not be well tolerated, commonly used options to consider include weekly monotherapy with methotrexate, paclitaxel, or cetuximab. No randomized data currently show a clear efficacy difference among these drugs in this setting. For fit patients with aggressive symptomatic disease in whom the need for an objective response is paramount, the application of cisplatin plus 5-FU plus cetuximab is supported by randomized phase III data.46 Because of the cumulative nature of cisplatin-related toxcities, substitution with carboplatin is necessary for many patients.

Time to failure since prior combined modality therapy may also figure into the clinical decision-making process. If the patient had primary refractory disease or early recurrence (< 6 months) after treatent with definitive radiation plus concurrent cisplatin, this is platinum-refractory disease on clinical grounds. Palliation with nonplatinum monotherapy (e.g., a taxane) may be a reasonable option in this setting. Currently, no prospective randomized data are available in R/M HNSCC to guide the selection of paclitaxel versus docetaxel, or weekly versus every-3-week dosing of taxanes.

Because of the modest efficacy of systemic therapy against R/M HNSCC, it is prudent to obtain radiographic response assessment early, typically after 2 cycles of treatment. A patient experiencing disease progression despite treatment with a platinum–5-FU doublet regimen might subsequently receive monotherapy with non–cross-resistant agents, such as cetuximab, methotrexate, or a taxane. If available, participation in a clinical trial should always be considered for patients with adequate performance status.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network

Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Matthew G. Fury, MD, PhD, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Disclosure: Matthew G. Fury, MD, PhD, has disclosed the following relevant financial relationships:

Participated in funded or unfunded research on a technology, process, or product development for: Novartis Pharmaceuticals Corporation; Genentech Inc.; Bristol-Myers Squibb Company Served as an advisory board member, speakers bureau member, expert witness, or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.

David G. Pfister, MD, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Disclosure: David G. Pfister, MD, has disclosed the following relevant financial relationships:

Participated in funded or unfunded research on a technology, process, or product development for: Novartis Pharmaceuticals Corporation; Imclone

CME AUTHOR

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

References

  • 1

    ColevasAD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol2006;24:26442652.

    • Search Google Scholar
    • Export Citation
  • 2

    VermorkenJBSpecenierP. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol2010;21(Suppl 7): vii252vii261.

  • 3

    Al-SarrafM. Chemotherapy strategies in squamous cell carcinoma of the head and neck. Crit Review Oncol Hematol1984;1:323355.

  • 4

    DeleyiannisFWThomasDBVaughanTLDavisS. Alcoholism: independent predictor of survival in patients with head and neck cancer. J Natl Cancer Inst1996;88:542549.

    • Search Google Scholar
    • Export Citation
  • 5

    Karnoven-GutierrezCARonisDLFowlerKE. Quality of life scores predict survival among patients with head and neck cancer. J Clin Oncol2008;26:27542760.

    • Search Google Scholar
    • Export Citation
  • 6

    KwokJLangeveinSMArgirisA. The impact of health insurance status on the survival of patients with head and neck cancer. Cancer2010;116:476485.

    • Search Google Scholar
    • Export Citation
  • 7

    LeeJJJengJHWangHM. Univariate and multivariate analysis of prognostic significance of betel quid chewing in squamous cell carcinoma of the buccal mucosa in Taiwan. J Surg Oncol2005;91:4147.

    • Search Google Scholar
    • Export Citation
  • 8

    ArgirisALiYForastiereA. Prognostic factors and long-term survivorship in patients with recurrent or metastatic carcinoma of the head and neck: an analysis of two Eastern Cooperative Oncology Group randomized trials. Cancer2004;101:22222229.

    • Search Google Scholar
    • Export Citation
  • 9

    PenelNBerthonCEverardF. Prognosis of hypercalcemia in aerodigestive tract cancers: a study of 136 recent cases. Oral Oncol2005;41:884889.

    • Search Google Scholar
    • Export Citation
  • 10

    AngKKHarrisJWheelerR. Human papillomavirus and survival of patients with oropharyngeal cancer. New Engl J Med2010;363:2435.

  • 11

    WittesRECvitkovicEShahJ. CIS-Dichlorodiammineplatinum (II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep1977;61:359366.

    • Search Google Scholar
    • Export Citation
  • 12

    MortonRPRugmanFDormanEB. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial. Cancer Chemother Pharmacol1985;15:283289.

    • Search Google Scholar
    • Export Citation
  • 13

    HongWKSchaeferSIssellB. A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck. Cancer1983;52:206210.

    • Search Google Scholar
    • Export Citation
  • 14

    GroseWELehaneDEDixonDO. Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck: a Southwest Oncology Group Study. Cancer Treat Rep1985;69:577581.

    • Search Google Scholar
    • Export Citation
  • 15

    KishJAWeaverAJacobsJ. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid carcinoma of the head and neck. Cancer1984;53:18191824.

    • Search Google Scholar
    • Export Citation
  • 16

    JacobsCLymanGVelez-GarciaE. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol1992;10:257263.

    • Search Google Scholar
    • Export Citation
  • 17

    ClavelMVermorkenJBCognettiF. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cersus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol1994;5:521526.

    • Search Google Scholar
    • Export Citation
  • 18

    EisenbergerMHornedoJSilvaH. Carboplatin (NSC-241-240): an active platinum analog for the treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol1986;4:15061509.

    • Search Google Scholar
    • Export Citation
  • 19

    Al-SarrafMMetchBKishJ. Platinum analogs in recurrent and advanced head and neck cancer: a Southwest Oncology Group and Wayne State University Study. Cancer Treat Rep1987;71:723726.

    • Search Google Scholar
    • Export Citation
  • 20

    ForastiereAAMetchBSchullerDE. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol1992;10:12451251.

    • Search Google Scholar
    • Export Citation
  • 21

    ForastiereAShankDNeubergD. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial (PA390). Cancer1998;82:22702274.

    • Search Google Scholar
    • Export Citation
  • 22

    DreyfussAIClarkJRNorrisCM. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. J Clin Oncol1996;14:16721678.

  • 23

    GibsonMKLiYMurphyB. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and cancer (E1395): an Intergroup Trial of the Eastern Cooperative Oncology Group. J Clin Oncol2005;23:35623567.

    • Search Google Scholar
    • Export Citation
  • 24

    ClarkJIHofmeisterCChoudhuryA. Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma. Cancer2001;92:23342340.

    • Search Google Scholar
    • Export Citation
  • 25

    FerrariDFioreJCodecaC. A phase II study of carboplatin and paclitaxel for recurrent and metastatic head and neck cancer. Anticancer Drugs2009;20:185190.

    • Search Google Scholar
    • Export Citation
  • 26

    MoosmannPEgliFStahelRAJostL. Weekly paclitaxel and carboplatin combination chemotherapy in patients with advanced squamous cell carcinoma of the head and neck. Onkologie2003;26:568572.

    • Search Google Scholar
    • Export Citation
  • 27

    ShinDMGlissonBSKhuriFR. Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol1998;16:13251330.

    • Search Google Scholar
    • Export Citation
  • 28

    ShinDMKhuriFRGlissonBS. Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer2001;91:13161323.

    • Search Google Scholar
    • Export Citation
  • 29

    JaninisJPapadakouMXidakisE. Combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil in previously treated patients with advanced/recurrent head and neck cancer: a phase II feasibility study. Am J Clin Oncol2000;23:126131.

    • Search Google Scholar
    • Export Citation
  • 30

    PivotXRaymondELaguerreB. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer2001;85:649655.

    • Search Google Scholar
    • Export Citation
  • 31

    FuryMGHaqueSStambukH. A phase 2 study of pemetrexed plus gemcitabine every 2 weeks for patients with recurrent or metastatic head and neck squamous cell cancer. Cancer2011;117:795801.

    • Search Google Scholar
    • Export Citation
  • 32

    ZhangLZhangYHuangPY. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol2008;61:3338.

    • Search Google Scholar
    • Export Citation
  • 33

    CatimelGVermorkenJBClavelM. A phase II study of gemcitabine (LY 188011) in patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Ann Oncol1994;5:543547.

    • Search Google Scholar
    • Export Citation
  • 34

    SamlowskiWEGundackerHKueblerJP. Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. Invest New Drugs2001;19:311315.

    • Search Google Scholar
    • Export Citation
  • 35

    DegardinMOliveiraJGeoffroisL. An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol1998;9:11031107.

    • Search Google Scholar
    • Export Citation
  • 36

    SaxmanSMannBCanfieldV. A phase II trial of vinorelbine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Am J Clin Oncol1998;21:398400.

    • Search Google Scholar
    • Export Citation
  • 37

    AiroldiMCortesinaGGiordanoC. Ifosfamide in the treatment of head and neck cancer. Oncology2003;65(Suppl 2):3743.

  • 38

    MurphyBA. Topoisomerases in the treatment of metastatic or recurrent squamous cell carcinoma of the head and neck. Expert Opin Pharmacother2005;6:8592.

    • Search Google Scholar
    • Export Citation
  • 39

    WittesRE. Chemotherapy of head and neck cancer. Otolaryngol Clin North Am1980;13:515520.

  • 40

    AngKKBerkeyBATuX. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res2002;62:73507356.

    • Search Google Scholar
    • Export Citation
  • 41

    Rubin GrandisJMelhemMFGoodingWE. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst1998;90:824832.

    • Search Google Scholar
    • Export Citation
  • 42

    BaselgaJTrigoJMBourhisJ. 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. J Clin Oncol2005;23:55685577.

    • Search Google Scholar
    • Export Citation
  • 43

    HerbstRSArquetteMShinDM. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol2005;23:55785587.

    • Search Google Scholar
    • Export Citation
  • 44

    VermorkenJBTrigoJHittR. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based chemotherapy. J Clin Oncol2007;25:21712177.

    • Search Google Scholar
    • Export Citation
  • 45

    BurtnessBGoldwasserMAFloodW. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer. J Clin Oncol2005;23:86468654.

    • Search Google Scholar
    • Export Citation
  • 46

    VermorkenJBMesiaRRiveraF. Platinum-based chemotherapy plus cetuximab in head and neck cancer. New Engl J Med2008;359:11161127.

  • 47

    KiesMSHolsingerFCLeeJJ. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol2010;28:814.

    • Search Google Scholar
    • Export Citation
  • 48

    KlinghammerKKnodlerMSchmittelA. Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res2010;16:304310.

    • Search Google Scholar
    • Export Citation
  • 49

    LicitraLMesiaRRiveraF. 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. Ann Oncolin press.

    • Search Google Scholar
    • Export Citation
  • 50

    YarbroughWGShoresCWitsellDL. ras mutations and expression in head and neck squamous cell carcinomas. Laryngoscope1994;104:13371347.

  • 51

    AndersonJAIrishJCNganBY. Prevalence of RAS oncogene mutation in head and neck carcinomas. J Otolaryngol1992;21:321326.

  • 52

    Loeffler-RaggJWitsch-BaumgartnerMTzankovA. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur J Cancer2006;42:109111.

    • Search Google Scholar
    • Export Citation
  • 53

    LeeJWSoungYHKimSW. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res2005;11:28792882.

  • 54

    SokJCCoppelliFMThomasSM. Mutant epidermal growth factor recepor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res2006;12:50645073.

    • Search Google Scholar
    • Export Citation
  • 55

    TaberneroJCiardielloFRiveraF. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose escalation cetuximab. Ann Oncol2010;21:15371545.

    • Search Google Scholar
    • Export Citation
  • 56

    ClinicalTrials.gov. Cetuximab at either 500 or 750 mg/m2 every other week for recurrent or metastatic head and neck squamous cell cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT00661427. Accessed April 6 2011.

    • Search Google Scholar
    • Export Citation
  • 57

    CohenEERosenFStadlerWM. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol2003;21:19801987.

    • Search Google Scholar
    • Export Citation
  • 58

    StewartJWSCohenEEWLicitraL. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol2009;27:18641871.

    • Search Google Scholar
    • Export Citation
  • 59

    SoulieresDSenzerNNVokesEE. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol2004;22:7785.

    • Search Google Scholar
    • Export Citation
  • 60

    KyzasPACunhaIWIonnidisJP. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res2005;11:14341440.

    • Search Google Scholar
    • Export Citation
  • 61

    Machiels J-PHHenrySZanettaS. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol2010;28:2128.

    • Search Google Scholar
    • Export Citation
  • 62

    WilliamsonSKMoonJHuangCH. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group study S0420. J Clin Oncol2010;28:33303335.

    • Search Google Scholar
    • Export Citation
  • 63

    CohenEEWDavisDWKarrisonTG. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol2009;10:247257.

    • Search Google Scholar
    • Export Citation
  • 64

    MolinoloAAHewittSMAmornphimolthamP. Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the Head and Neck Cancer Tissue Array Initiative. Clin Cancer Res2007;13:49644973.

    • Search Google Scholar
    • Export Citation
  • 65

    FiglinRABrownEArmstrongAJ. NCCN Task Force Report: mTOR inhibition in solid tumors. J Natl Compr Canc Netw2008;6(Suppl 5):S122.

  • 66

    EkshyyanORongYRongX. Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther2009;8:22552265.

    • Search Google Scholar
    • Export Citation
  • 67

    RaimondiARMolinoloAGutkindJS. Rapamycin prevents early onset of carcinogenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. Cancer Res2009;69:41594166.

    • Search Google Scholar
    • Export Citation
  • 68

    EkshyyanOMillsGMLianT. Pharmacodynamic evaluation of temsirolimus in patients with newly diagnosed advanced stage head and neck squamous cell carcinoma. Head Neck2010;32:16191628.

    • Search Google Scholar
    • Export Citation
  • 69

    ShiYFrankelARadvanyiLG. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res1995;55:19821988.

  • 70

    BeuvinkIBoulayAFumagalliS. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damage induced apoptosis though inhibition of p21 translation. Cell2005;120:747759.

    • Search Google Scholar
    • Export Citation
  • 71

    AissatNLe TourneauCGhoulA. Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines. Cancer Chemother Pharmacol2008;62:305313.

    • Search Google Scholar
    • Export Citation

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Correspondence: Matthew G. Fury, MD, PhD, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 532, New York, NY 10021. E-mail:furym@mskcc.org

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