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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.4–6 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.
Factors Associated With Inferior Overall Survival for Patients With HNSCC
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.
Selected Randomized Phase III Trials of Cisplatin-Containing Regimens for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
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,69–71 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
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