The integration of chemotherapy into the management of locoregional disease will be reviewed elsewhere in this issue. The present review will focus on recurrent and/or metastatic disease.
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) carries a dismal prognosis with a median survival of about 6 months. The overall response rate with single agent cytotoxics ranges between 15 and 30%. Higher response rates are reported with combination regimens. However, these higher response rates have never translated into a better survival [1,2]. This finally changed with the publication of the Erbitux in first-line Treatment for Recurrent or Metastatic Head and Neck Cancer (EXTREME) study [3••].
Chemotherapy combined with epidermal growth factor receptor directed mAb
In the EXTREME trial (Table 1), 442 patients with previously untreated R/M SCCHN were randomized between cisplatin, at a dose of 100 mg/m2 or carboplatin, at an area under the curve of 5 mg/ml.min, on day 1, followed by 5-fluorouracil, at a dose of 1000 mg/m2/day for 4 days, every 3 weeks for a maximum of six cycles, or the same regimen and the epidermal growth factor receptor (EGFR)-targeted immunoglobulin-G1 mAb cetuximab, at an initial loading dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Patients with stable disease who received chemotherapy and cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. No crossover was permitted. The primary endpoint was overall survival (OS). The addition of cetuximab to platinum–fluorouracil significantly prolonged the median OS from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy and cetuximab [hazard ratio for death, 0.80; 95% confidence interval (CI), 0.64–0.99; P = 0.04]. The addition of cetuximab prolonged the median progression-free survival (PFS) time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P < 0.001) and increased the response rate from 20 to 36% (P < 0.001). Protocol-defined subgroup analyses showed that the beneficial effects of adding cetuximab to platinum–fluorouracil chemotherapy on OS and PFS were evident in nearly all subgroups analyzed. The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19 and 13%, respectively), neutropenia (23 and 22%) and thrombocytopenia (11% in both groups). Sepsis occurred in nine patients in the cetuximab group and in one patient in the chemotherapy-alone group (P = 0.02). Among the 100 patients who received cetuximab as maintenance treatment, the median PFS was 12 weeks from the start of maintenance treatment. There were two tumor responses during cetuximab maintenance treatment.
Preplanned multivariate analysis identified the Karnofsky score as having the greatest prognostic relevance for OS time. There were 11 cases of grade 3 or 4 hypomagnesemia in the cetuximab group, as compared with three cases in the chemotherapy-alone group (P = 0.05). Of the 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. EGFR gene copy number, as determined by fluorescent in situ hybridization (FISH), is not a predictive biomarker for cetuximab efficacy in R/M SCCHN . In the Study of Panitumumab EffiCacy in paTients with RecUrrent and/or Metastatic head and neck cancer (SPECTRUM) trial, similar patients as in the EXTREME trial were randomized to receive cisplatin/5-fluorouracil with or without panitumumab, which is a fully human EGFR-directed immunoglobulin-G2 mAb. Enrollment has been completed. The combination was well tolerated and efficacy data are awaited in 2010 .
Cytotoxics: single agents
The taxanes are among the most active drugs in SCCHN. Encouraging results were reported with weekly schedules of docetaxel and paclitaxel, even in patients with progressive disease after platinum-based treatment [6–8]. Cho et al.  treated 23 patients with docetaxel 35 mg/m2 for 3 weeks, every 4 weeks for a maximum of six cycles. The overall response rate was 13.0% and the disease control rate was 34.7%. Median PFS and OS were 9 weeks (95% CI 7.6–10.4 weeks) and 29 weeks (95% CI 10.8–47.1 weeks), respectively. The most common hematologic toxicity (HTOX) was grade 1–2 anemia (26.1%). Nonhematologic toxicities (NHTOX) were mild and manageable. Grau et al.  treated 60 patients with platinum-resistant disease with paclitaxel 80 mg/m2 weekly. They reported an overall response rate of 43.3% and a disease control rate of 58.3%. Median time to tumor progression for patients who responded to therapy was 6.2 months and the median OS in that group of patients was 8.5 months. The main toxic effects were leukopenia (26.6%), anemia (43.3%), fatigue (37.4%), alopecia (18.7%), rash/desquamation (13.3%) and thrombophlebitis (6.8%). Knoedler et al.  treated 84 platinum-pretreated patients with weekly cetuximab and docetaxel 35 mg/m2 on day 1, 8 and 15 of a 4-week cycle. The partial response rate and disease control rate were 12 and 39%, respectively. Response to protocol treatment was unrelated to previous platinum sensitivity. Median PFS and OS were 4 and 7 months, respectively. Grade 3 or 4 toxicities included gastric perforation in one patient, pneumonia in seven and skin toxicities. Ixabepilone is a tubulin-polymerizing agent with potential activity in SCCHN. Eastern Cooperative Oncology Group (ECOG)  conducted a randomized phase II trial comparing ixabepilone 6 mg/m2/day × 5 days every 21 days (arm A) or 20 mg/m2 on days 1, 8 and 15 (arm B) of a 28-day cycle. Eligible were patients with SCCHN who had received less than two prior regimens for metastatic/recurrent disease. Eighty-five eligible patients were entered. There was one response in a taxane-exposed patient among 32 patients treated on arm A. Arm B had a better activity with a response rate of 14% in taxane-naive patients. No taxane-exposed patients on arm B responded. Common grades 3 and 4 toxic effects were fatigue, neutropenia and sensory/motor neuropathy. Median survival in taxane-naive and taxane-exposed patients for arm B was 7.8 and 6.5 months, respectively. The authors concluded that these data did not stimulate further use of this drug in previously treated head and neck cancer patients. The Spanish Head and Neck Cancer Group  treated 40 patients who relapsed after platinum-based chemotherapy, with capecitabine 1250 mg/m2 twice daily (b.i.d.) for 14 days every 21 days. Grade 3 or 4 HTOX was reported in six patients and grade 4 NHTOX in two patients [one dysphagia and one palmar–plantar erythrodysesthesia (PPE)]. However, grade 3 NHTOX included mainly asthenia, but in addition also dysphagia (three cases), mucositis  and four cases of PPE. Seven patients were not evaluable for response due to early treatment cessation (three died, two due to toxicity, two as result of a decrease in performance status). The response rate in evaluable patients was 22.5% and the median OS was 6.2 months. Despite the above mentioned observations, the investigators considered the treatment well tolerated.
OSI-7904L is a novel liposomal formulation of a noncompetitive thymidylate synthase inhibitor that failed to demonstrate any efficacy in patients with recurrent or metastatic disease . S-1 is an oral fluoropyrimidine, which has demonstrated promising single agent activity in SCCHN patients with a relapse after cisplatin-based chemotherapy. Thirty-three patients received S-1 40 mg/m2 b.i.d. for 4 weeks followed by a 2-week rest in 6-week cycles (median two cycles; range 1–6). The regimen was well tolerated (only mild stomatitis and fatigue, and only two cases of grade ≥2 PPE) and of benefit to the patients with an overall response rate of 27%, and another 27% showing stabilization with symptomatic improvement. .
Cytotoxics: novel combinations
Cisplatin/infusional 5-fluorouracil has been the most commonly used combination regimen for many years. However, the clinical benefit of cisplatin in a palliative setting is hampered by its toxicity profile. In a randomized, multicenter phase III trial, Jehn et al.  replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin). Forty-six patients were evaluable for outcome and toxicity. Overall, grade 3 and 4 HTOX were more frequent in the cisplatin arm (31.7 versus 12%), with grade 4 leukopenia occurring in 22.2%. However, 16% of the patients in the experimental arm experienced grade 3 anemia compared with only 9.5% treated with the cisplatin regimen. Four percent of the patients in the lipoplatin arm developed grade 4 neuropathy, whereas in the cisplatin arm, 19% developed grade 3 neuropathy and none developed grade 4. In the cisplatin arm, 23.8% of patients suffered from grade 3 renal toxicity. In contrast, no grade 3 or 4 renal toxicity occurred in patients treated with lipoplatin. In the cisplatin arm 38.8% of the patients obtained an objective partial response and 50% a disease stabilization, whereas 19 and 64%, respectively did in the lipoplatin arm, therefore leading to a similar disease control rate, but with less renal and neurotoxicity.
Recently, other new combinations of cytotoxic agents have been tested in phase II trials.
The vast majority of these studied combinations included either a platinum or a taxane.
Gilbert et al.  treated 40 patients with a combination of irinotecan and cisplatin 30 mg/m2 weekly for 4 weeks followed by a 2-week rest. Seventy-one percent of the patients treated at the initial dose of 65 mg/m2 of irinotecan experienced grade 3 or 4 toxicity. This led to a reduction of the dose of irinotecan to 50 mg/m2. Grade 3 or 4 toxicity still occurred in 17% of the patients at this lower dose. The overall response rate was 35% at the 65 mg/m2 dose level and 22% at the 50 mg/m2 dose level. ECOG  treated 52 patients with docetaxel 35 mg/m2 and irinotecan 60 mg/m2 on days 1 and 8, every 21 days. The response rate was 15% in the 20 chemonaive patients and 3% in the 32 patients who had received one prior chemotherapy regimen. Median PFS in the two groups was 3.3 and 1.9 months and median OS was 8.2 and 5.0 months, respectively. Common serious toxicities were diarrhea, fatigue and anorexia. These results did not suggest that this combination was an advantage over docetaxel alone or platinum-based regimens. Ferrari et al.  treated 27 patients with paclitaxel 175 mg/m2 and carboplatin at an area under the concentration time curve 5 mg/ml.min for a maximum of four cycles. One patient (3.7%) had a complete response, whereas six patients (22.2%) obtained a partial response. Stable disease was observed in seven patients (25.9%). The overall response rate was 25.9% (95% CI 11.1–46.3), whereas the disease control rate was 51.8% (95% CI 32.0–71.3). The median OS was 8.0 months (range 2–27 months), with a 1-year survival of 30.5%. The median PFS was 1.0 month (range 0–14). Grades 3–4 neutropenia was observed in two patients (7.4%), grade 3–4 anemia and thrombocytopenia in four patients (14.8%) and one patient (3.7%), respectively. Nine patients (33.3%) experienced grade 1–2 and one patient (3.7%) grade 3 peripheral neuropathy. Chang et al.  treated 28 patients with cisplatin 40 mg/m2 administered as a continuous infusion for 24 h on day 1, high-dose 5-fluorouracil 2000 mg/m2/day and leucovorin 100 mg/m2/day, both administered as a continuous infusion for 48 h on days 1 and 2, and methotrexate 40 mg/m2 given by bolus infusion, 4 h before 5-fluorouracil and leucovorin on day 1. The treatment was repeated every 2 weeks. The overall response rate was 25%, and 14% of the patients achieved a stable disease status. Only three (10.7%) patients developed grade 3–4 neutropenia, and none developed grade 3–4 NHTOX. Hanai et al.  conducted a phase I/II study with a combination of docetaxel and cisplatin (interval not defined in the english abstract of this Japanese study, but presumably 3 weeks). In the phase I part of the study the recommended doses of docetaxel and cisplatin were assessed at 60 and 80 mg/m2, respectively. They now treated 22 R/M SCCHN patients at this recommended dose level (nine still being part of the phase I and 13 in the phase II part). The overall response rate was 22.7%. Grade 3 or 4 neutropenia occurred in 55% of patients, but without major infectious complications and NHTOX was generally mild.
A phase II study  of paclitaxel 60 mg/m2 and epirubicin 20 mg/m2, both given on days 1, 8 and 15, and repeated every 28 days, and another phase II trial  with gemcitabine 1000 mg/m2 and pemetrexed 500 mg/m2 every 2 weeks, were both closed at the first interim analysis because of lack of efficacy.
A large global placebo-controlled randomized phase III trial comparing cisplatin 75 mg/m2 every 3 weeks with or without pemetrexed 500 mg/m2 has recently completed accrual. A separate pharmacokinetic study showed that the pharmacokinetics of free platinum derived from cisplatin is not altered by co-administration with pemetrexed and therefore, as expected no unexpected cisplatin-induced toxicities were observed when these drugs are combined . Another interesting and unexpected pharmokinetic interaction was observed by Airoldi et al.  when combining paclitaxel and pegylated liposomal doxorubicin (PLD). They used a weekly dose of 80 mg/m2 of paclitaxel in combination with 12.5 mg/m2 PLD biweekly, but when given together administered at successively wider intervals of 0, 1, 3, 12 or 24 h. Grade 3 or 4 neutropenia occurred in 30% of the patients. Only 3% of the patients experienced severe hand–foot syndrome. The overall response rate was 30%, with 3% complete responses. The disease control rate was 73%. Median response duration and median survival were 5.5 and 10 months, respectively. The pharmacokinetics of paclitaxel was strongly affected by the administration interval with a reduction of the area under the curve by 75% when the two drugs were administered without interval. Therefore, a schedule with paclitaxel on day 1 and PLD on day 2 seems advisable for further studies.
The combination of docetaxel 30 mg/m2 on day 1, 8 and 15, and capecitabine 1000 mg b.i.d. on days 5–18 of the 28-day cycle, was tested by Zhang et al.  and considered to be well tolerated by the patients. Response rate and disease control rate were 13 and 33%, respectively.
Tyrosine kinase inhibitors
In general, the results with oral tyrosine kinase inhibitors have been disappointing. Sunitinib is a multitargeted tyrosine kinase inhibitor of rearranged during transfection proto-oncogene (RET), vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR) and c-KIT. A high incidence of fatal and nonfatal hemorrhagic complications in R/M SCCHN was repeatedly reported [24–26]. The objective response rate was consistently less than 5%. Gefitinib is an EGFR tyrosine kinase inhibitor. In the IMEX trial [27••], 482 patients were randomized between gefitinib 250 or 500 mg/day or methotrexate 40 mg/m2 intravenous (i.v.) weekly. Neither gefitinib 250 nor 500 mg/day improved survival compared with methotrexate. Median OS was 5.6, 6 and 6.7 months, respectively. Overall response rates were 2.7, 7.6 and 3.9%, respectively. Cohen et al.  reviewed individual patient data from five clinical trials of erlotinib, lapatinib, or gefitinib to determine whether there are clinical characteristics that are associated with clinical benefit. Performance status (P = 0.04), older age (P = 0.02) and development of rash (P < 0.01), diarrhea (P = 0.03) or oral side effects (P = 0.02) were independently associated with clinical benefit. Older age, better performance status and development of rash were associated with longer PFS and OS. EGFR mechanistic toxicities that developed during therapy were also highly associated with benefit and suggest a relationship between drug exposure and outcome . ECOG [29••] conducted a randomized, placebo-controlled trial of docetaxel 35 mg/m2 on days 1, 8 and 15 every 28 days, with or without gefitinib 250 mg/day. The combination was well tolerated and improved the time to progression from 2.0 to 3.5 months (P = 0.03). However, this did not translate into an improved OS.
Other targeted agents
3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP Triapine; Vion Pharmaceuticals, New Haven, Connecticut, USA) is an inhibitor of ribonucleotide reductase. In a multicenter phase II study , 32 patients with R/M SCCHN received 3-AP Triapine 96 mg/m2, daily (q.d.) for 4 days every 14 days. Thirteen patients had previously been treated with chemotherapy. Grade 4 neutropenia was documented in 22% of the patients. The overall response rate was 5.9% (95% CI 0.2–28.7%). Median time to disease progression was 3.9 months.
Lonafarnib is a potent, specific inhibitor of farnesyl transferase. A phase II study of lonafarnib  was conducted to determine its efficacy and safety in patients with platinum-refractory SCCHN. Most treatment-related toxicities were grade 1–2. No objective response was observed after enrollment of 15 patients and the study was closed to further accrual. Median time to progression and survival time were 2.04 and 9.17 months, respectively. Dasatinib is a potent inhibitor of src-family kinases, ephA2, PDGFR, Abl and c-kit. Dasatinib, 2 × 100 mg/day, led to high hospitalization and treatment discontinuation rates. No objective responses were observed . Twenty-one patients with up to one prior line of chemotherapy were treated with ispinesib (SB-715992; 18 mg/m2 i.v. over 1 h every 21 days), which is an inhibitor of the mitotic kinesin spindle protein (KSP), in a phase II study at Princess Margaret Hospital. No objective responses were documented . Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacetylase inhibitor. At a dose of 400 mg q.d., vorinostat is well tolerated but no objective responses were observed in chemotherapy-pretreated patients . Nuclear factor-κB (NF-κB) dysregulation contributes to chemoresistance. Bortezomib is an inhibitor of NF-κB. ECOG  conducted a randomized phase II trial comparing the combination of bortezomib 1.3 mg/m2 on day 1, 4, 8 and 11 and irinotecan 125 mg/m2 day 1 and 8, every 21 days to single agent bortezomib with the addition of irinotecan upon tumor progression. Single agent bortezomib was well tolerated. However, the response rate was only 3%. The combination was too toxic.
Combined targeting of epidermal growth factor receptor and vascular endothelial growth factor receptor
Cohen et al.  combined erlotinib 150 mg/day and bevacizumab in patients with R/M SCCHN. In the phase I portion of the study, no dose-limiting toxic effects were observed at the highest dose level of bevacizumab (15 mg/kg every 3 weeks). Forty-eight patients were treated at that dose level. The most common toxic effects were rash and diarrhea. Three patients had serious bleeding events of grade 3 or higher. The overall response rate was 14.6% with 8.3% complete responses. Median time of OS and PFS were 7.1 months (95% CI 5.7–9.0) and 4.1 months (2.8–4.4), respectively.
Higher ratios of tumor-cell phosphorylated VEGFR-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with a higher response rate. A response rate of 20% and a disease control rate of 76% were reported with a combination of weekly cetuximab and bevacizumab 15 mg/kg every 3 weeks. Median OS was 8.1 months. Toxicity was manageable .
Recchia et al.  treated patients who showed disease control after chemotherapy with a combination of docetaxel, ifosfamide and cisplatin chemotherapy, with low-dose subcutaneous interleukin-2 and oral 13-cis-retinoic acid as maintenance immunotherapy. Median PFS and OS were 11.1 and 21.8 months, respectively. Statistically significant, progressive increases in lymphocytes and natural killer cells and a decrease in VEGF were observed in patients treated with maintenance immunotherapy. CD44v6 is a tumor-associated antigen abundantly expressed in SCCHNs and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a mAb against CD44v6. In a clinical phase I trial , the maximum tolerated dose was determined at 300 mg/m2. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Objective responses were observed at 200, 275 and 325 mg/m2. However, skin toxicity with a fatal outcome in a parallel trial led to the termination of the development program of BIWI 1.
The addition of cetuximab to platin-based chemotherapy led to a significant prolongation of OS in patients with R/M SCCHN. In contrast, the results with oral tyrosine kinase inhibitors have been disappointing. The testing of novel targeted agents, either as single agents or in combination with other targeted agents or cytotoxics is an exciting area of clinical research.
J.B.V. participated in Advisory Boards on Head and Neck Cancer of Merck-Serono, Amgen, Sanofi-Aventis, Ely-Lilly, Boehringer-Ingelheim and Genmab and received honoraria from Merck-Serono, Amgen, Sanofi-Aventis, Ely-Lilly, Boehringer-Ingelheim for scientific presentations.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (290).
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