|Year : 2016 | Volume
| Issue : 4 | Page : 471-477
Current status of systemic therapy for recurrent and/or metastatic squamous cell carcinoma of the head and neck
LA Jacob, T Chaudhuri, KC Lakshmaiah, KG Babu, L Dasappa, MCS Babu, AH Rudresha, KN Lokesh, LK Rajeev
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Web Publication||21-Apr-2017|
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Head and neck squamous cell carcinoma (HNSCC) is now the seventh most common cancer worldwide. The median overall survival for patients with recurrent and/or metastatic (R/M) HNSCC remains <1 year despite modern systemic chemotherapy and targeted agents. Palliative systemic therapy for patients with R/M HNSCC typically includes a platinum-based doublet, with an understanding that the increase in efficacy compared with single agents is primarily related to improved response rate, and not survival. Till date, the only systemic therapy regimen to demonstrate survival superiority over platinum-5-fluorouracil (5-FU) doublet is platinum, FU, and cetuximab. Epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have achieved only a modest success in R/M HNSCC. Immunotherapy represents an attractive treatment option for R/M HNSCC, with encouraging preliminary data from studies involving immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab) and toll-like receptor agonists (e.g., motolimod). Given the poor prognosis of R/M HNSCC, enrollment of patients into clinical trials to investigate novel systemic agents, is necessary for further improvement of oncologic outcomes in this patient population.
Keywords: Immunotherapy, recurrent and/or metastatic head-neck cancer, systemic chemotherapy, targeted therapy
|How to cite this article:|
Jacob L, Chaudhuri T, Lakshmaiah K, Babu K, Dasappa L, Babu M, Rudresha A, Lokesh K, Rajeev L. Current status of systemic therapy for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Indian J Cancer 2016;53:471-7
|How to cite this URL:|
Jacob L, Chaudhuri T, Lakshmaiah K, Babu K, Dasappa L, Babu M, Rudresha A, Lokesh K, Rajeev L. Current status of systemic therapy for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Indian J Cancer [serial online] 2016 [cited 2017 Apr 28];53:471-7. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/471/204786
| » Introduction|| |
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide and there has been a significant increase in the global incidence of HNSCC over the past decade. More than half of the patients with HNSCC present with potentially curable, locally advanced (LA) disease. Historically, single-modality treatment with surgery or radiotherapy was the main-stay of treatment for HNSCC; however, the advent of functional organ preservation in the past few decades has shifted the treatment paradigm to include concurrent chemo-radiation. While early-stage disease is routinely treated with surgery or radiation alone, LA disease typically requires site-specific multimodal therapy. Despite of such multimodality approach, 30%–60% of patients still develop local recurrences, and approximately 20%–30% develop distant metastases. A few patients with a loco-regional recurrence can still be salvaged by surgery or re-irradiation, with a curative intent. However, most of the patients with recurrent or metastatic (R/M) disease only qualify for palliation. Treatment options in these patients include supportive care only, or in addition to single-agent chemotherapy, combination chemotherapy, or targeted therapies either alone or in combination with cytotoxic agents. The choice of treatment depends on many factors such as performance status of the patient, co-morbidity, prior treatment, recurrence-free interval, symptoms, patient preference, and logistics. This review focuses on the current status and evidence-based data of systemic therapy in R/M HNSCC.
| » Systemic Chemotherapy|| |
A large number of single chemotherapeutic agents (e.g., cisplatin, carboplatin, 5-fluorouracil [5-FU], methotrexate, edetrexate, bleomycin, ifosfamide, and hydroxyurea) have been investigated in the past three decades, in patients R/M HNSCC.,,,,,,, These drugs produced an overall response rate (ORR) of about 15%–40%, which persisted for a short duration, 3–5 months. Several new active chemotherapeutic drugs (e.g., capecitabine, S-1, pemetrexed, vinorelbine, irinotecan, paclitaxel, and docetaxel) have been introduced in the recent past,,,,,, and taxanes are the highest scoring agents among them, producing an ORR varying between 20% and 43%. Unfortunately, there are very few direct comparative studies between conventional single chemotherapeutic agents, that is, there have been direct comparisons between methotrexate with edetrexate, cisplatin,, paclitaxel, and docetaxel. Apart from the Phase III trial of edetrexate versus methotrexate, none of the other studies was large enough for any survival comparison. In several Phase II studies, the reported ORR with taxanes,, were significantly higher than methotrexate, although there was no indication of any superiority of one agent over another in terms of survival. Clearly, these findings need to be explored in Phase III studies.
It is currently unclear whether any of the conventional cytotoxic agents provides survival benefit when compared with best supportive care (BSC) alone, as till date, there is no sufficiently powered randomized controlled trial, addressing this issue.
Combination chemotherapy in patients with R/M HNSCC was tried with a goal of achieving higher and more durable response rates. Several studies performed in 1980s, comparing single agent with combination chemotherapy have shown superior ORRs with the latter.,, Single agent cisplatin was compared with cisplatin, methotrexate and leucovorin in a Phase III trial by Jacobs et al. and the reported ORRs were 18% and 33%, respectively. Other trials comparing single agent methotrexate with a combination of cisplatin, bleomycin, vinblastine, or vincristine showed higher responses with combination chemotherapy., The Wayne State University cisplatin plus infusional 5-FU (PF) regimen gradually emerged as the most commonly used combination chemotherapy in this setting. Several nonrandomized trials indicated a better outcome with this regimen than what was observed with single-agent therapy, at least in terms of ORRs. Three large multicenter randomized Phase III trials performed in the 1990s reported a statistically significant improvement in ORRs for the PF combination regimen compared to single agent chemotherapy.,, However, there was no clinically meaningful survival advantage, and this gain in response rates was obtained at the cost of increased toxicity. Browman and Cronin performed a meta-analysis of 15 trials where single agent was compared to combination chemotherapy. They concluded that the combination of agents produced a statistically significant improvement in responses. The PF combination seemed to be the most widely used. The addition of other agents to this combination resulted in higher toxicities without any improvement in response rates or survival.
In the Phase III trial performed by Forastiere et al. 277 patients were randomized to receive PF, carboplatin-5-FU or standard dose methotrexate. The PF regimen produced a significantly higher ORR than methotrexate (P < 0.001), but the comparison of carboplatin-5-FU with methotrexate was of only borderline significance (P = 0.05). Median duration of response and median survival were similar for all three arms. Moreover, in a randomized comparison of carboplatin plus methotrexate versus single-agent methotrexate reported by Eisenberger et al. there was no difference in ORR. Taken together, these data indicate that carboplatin is probably less effective than cisplatin in this setting, at least in terms of response rates.
Platinum-taxane doublet combinations
Among the newer chemotherapy agents, taxanes are the most extensively investigated drugs in combination chemotherapy regimens.,,,, With the encouraging single agent activity of taxanes in earlier studies,,,, an intergroup trial E1395 was initiated by Eastern Cooperative Oncology Group (ECOG) group that directly compared paclitaxel (175 mg/m 2 on day 1) and cisplatin (75 mg/m 2 on day 1) combination with the classical PF regimen. No difference in ORRs (27% vs. 26%), median survival (8.1 vs. 8.7 months), or quality of life was observed. The overall Grade 3/4 toxicity rate was similar between the two groups. However, Grade 3/4 mucositis (31%) was only seen in the PF arm. Keeping in mind the more favorable toxicity profile, paclitaxel, and cisplatin combination may be a valuable alternative to the classical PF regimen.
Till date, there is no published randomized comparison between, cisplatin, and carboplatin, in the form of platinum-taxane doublet combination regimen, in R/M HNSCC. According to cross-trial comparisons, carboplatin plus paclitaxel did not seem to be much different from cisplatin plus paclitaxel combination. However, that statement might not be true in case of docetaxel-platinum doublets. In two different Phase II studies of docetaxel plus cisplatin doublet in R/M disease setting, reported by Schöffski et al. and Glisson et al. the reported ORRs were 53.7% and 40%, with 15% and 6% complete response (CR) rate, respectively., In both of these studies, these high response rates were associated with unacceptably high rate of hematologic toxicity (≥Grade 3 neutropenia 79% and 71%). On the other hand, a Phase II trial, conducted by the Southwest Oncology Group indicated only moderate activity of carboplatin plus docetaxel in this setting. In that study, the reported response probability was only 25%, which also came at the cost of increased hematologic toxicity (≥Grade 3 neutropenia = 61%). Taken together, these data clearly indicate that carboplatin is less effective than cisplatin, when used in a doublet combination with docetaxel in this setting, at least in terms of response rates.
Platinum-taxane triplet combinations
After the publication of TAX 323 and TAX 324 studies, TPF regimen (docetaxel, cisplatin, and infusional 5-FU) has become the new standard of care for induction chemotherapy in locoregionally advanced HNSCC., With the encouraging results of this platinum-taxane triplet combination in the induction setting, there is a growing interest of using TPF and other triplet regimens in R/M disease setting also. Till date, there are several published reports of using different triplet regimens in this setting. The initial reports came in the form of two Phase II studies, of using TIP (paclitaxel, ifosfamide, and cisplatin) and TIC (paclitaxel, ifosfamide, and carboplatin) regimens in R/M setting, conducted by Shin et al., The reported ORRs were 58% and 59%, with a CR rate of 17% and median overall survival (OS) of 15.7 and 9.7 months, with TIP and TIC regimen, respectively. However, both of these regimens were associated with a significantly high rate of febrile neutropenia (FN), 27% and 30%, respectively. In another Phase II feasibility study, Janinis et al. observed an ORR of 44%, a median time to progression of 7.5 months and a median OS of 11 months, with TPF regimen. The reported FN rate was 15% in this study, despite of using prophylactic granulocyte-colony stimulating factor in most of the patients, and there was no toxic deaths.
Hence, from the above data, it can be safely concluded that platinum-taxane triplet combinations provide higher response rates in R/M disease setting also, but at the cost of significantly increased hematologic toxicity and infection risk. As of today, there is no published randomized Phase III comparison between these triplet regimens with platinum doublets. So, we really do not know whether these favorable response rates of triplet regimens, are associated with any survival benefit or not. Clearly with the above limitations of the published data, triplet regimens should be used very judiciously, outside a clinical trial setting. They can be a preferable option in certain clinical situations where their favorable response rate matters, for example, in younger patients with symptomatic disease and good performance status, who require rapid response for prompt symptom control.
| » Targeted Therapy|| |
Last two decades have seen a better understanding of the molecular mechanisms underlying HNSCC and advances in molecular biology have paved the path for the development of newer targeted agents. Several biological therapies have been investigated in HNSCC, including drugs that target growth factors and their receptors, signal transduction, cell cycle control, prostaglandin synthesis, protein degradation, hypoxia, and angiogenesis. Among all of them, the best documented improvements in clinical outcome have been provided by the drugs targeting epidermal growth factor receptor (EGFR). EGFR inhibitors are of particular interest in HNSCC, because EGFR is over-expressed in >90% of HNSCC. EGFR over-expression and increased EGFR copy number have been related to poor prognosis in HNSCC., Monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs), are the two EGFR targeting strategies, which are currently in clinical practice. While mAbs target the extracellular domain of the receptor due to their large size, TKI's act intracellularly.
It is the best investigated mAb till date, which is a human–murine chimeric immunoglobulin G1 (IgG1) mAb. This drug has been tested in R/M HNSCC patients, both in second-line after failure of platinum-based chemotherapy and in first-line in combination with platinum-based chemotherapy. Three Phase II studies have examined the role of cetuximab in second-line setting after failure of platinum-based chemotherapy.,, All patients received intravenous (IV) cetuximab at an initial loading dose of 400 mg/m 2 followed by weekly dose of 250 mg/m 2, either alone  or combined with platinum agent., The outcome of these three studies were remarkably similar. The reported ORR was 10%–13%, with disease control in 46%–55% of patients and median OS of 5.2–6.1 months.
In patients with R/M HNSCC, cetuximab has been tested in first-line therapy with platinum-based chemotherapy,,, taxane-based chemotherapy, platinum-taxane-based chemotherapy, or platinum-pemetrexed-based chemotherapy. In the EXTREME study reported by Vermorken et al. 442 patients were randomized (1:1) to receive either chemotherapy alone (cisplatin or carboplatin on day 1 followed by infusional 5-FU for 4 days) or combined with weekly cetuximab. Chemotherapy cycles were administered every 3 weekly for a maximum of six cycles. Thereafter, in the combination arm, single agent cetuximab was continued until disease progression or unacceptable toxicity. The addition of cetuximab to platinum–5-FU, significantly prolonged the median OS from 7.4 to 10.1 months (P = 0.04), the median progression-free survival (PFS) from 3.3 to 5.6 months (P < 0.001), and increased the response rate from 20% to 36% (P < 0.001). The beneficial effect was evident in both the patients treated with cisplatin–5-FU and the patients treated with carboplatin–5-FU; although, the response rates with carboplatin–5-FU were below those obtained with cisplatin–5-FU. The most common Grade 3 or 4 adverse events (AEs) in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%), 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). Of the 219 patients received cetuximab, 9% had Grade 3 skin reactions and 3% had Grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths.
After almost three decades without any real progress, this is the first time that a clinically meaningful survival advantage with a new regimen over standard platinum-based doublet has been demonstrated in a randomized trial. Cetuximab and platinum-based chemotherapy is now considered the new standard for the treatment of R/M HNSCC patients who can tolerate platinum-based chemotherapy.
Panitumumab is a fully human IgG2 mAb, which binds very strongly to the EGFR receptor. It is also evaluated both in first and second-line therapy, in R/M disease setting. In a Phase II multicenter study (PRISM), Rischin et al. evaluated the safety and efficacy of panitumumab as second-line monotherapy (at a dose of 9 mg/kg Q3 weekly). The reported ORR and disease control rate (DCR) were 4% and 39%, respectively. Median PFS was 1.4 months, and median OS was 5.1 months. The most common AEs were acneiform rash/dermatitis (69%), fatigue (33%), dry skin (21%), and hypomagnesemia (21%). Wirth et al. evaluated the efficacy of docetaxel plus cisplatin chemotherapy with or without panitumumab as first-line treatment, in a randomized Phase II trial (PARTNER). PFS and ORR were higher in the panitumumab arm, but at the cost of increased Grade 3 and 4 AEs. The crossover design with 57% of arm two patients received panitumumab as second-line monotherapy, confounded the interpretation of OS.
In the Phase III randomized SPECTRUM trial, reported by Vermorken et al. similar patients to those in the EXTREME trial were randomized (1:1) to receive cisplatin–5-FU with or without panitumumab. The primary endpoint was OS and was analyzed by intention to treat. The addition of panitumumab to platinum–5-FU, resulted in a nonsignificant improvement of median OS from 9.0 to 11.1 months (P = 0.1403), and a significant improvement of the median PFS from 4.6 to 5.8 months (P = 0·0036). Several Grade 3 or 4 AEs were more frequent in the panitumumab group than in the control group: skin or eye toxicity (19% vs. 2%), diarrhea (5% vs. 1%), hypomagnesaemia (12% vs. 4%), hypokalemia (10% vs. 7%), and dehydration (5% vs. 2%). Treatment-related deaths occurred in 4% in the panitumumab group and 2% in the control group. Sixty-seven percent of the study population was assessed for p16 status, and of them 22% were p16 positive. Median OS in patients with p16-negative tumors was significantly longer in the panitumumab group than in the control group, 11·7 months versus 8·6 months (P = 0·0115). However, this difference was not shown for p16-positive patients. Ultimately the authors concluded that, p16 status could be a prognostic and predictive biomarker in patients treated with panitumumab and chemotherapy.
It is also a fully human IgG1 anti-EGFR mAb. In a Phase III randomized trial in patients who failed standard platinum-based chemotherapy, zalutumumab has been tested versus BSC. However, in this ZALUTE trial, conducted by Machiels et al. 78% of patients in the BSC arm received weekly methotrexate. There was a strong trend in favor of the zalutumumab for median OS (6.7 vs. 5.2 months, P = 0.0649), which was the primary end point of the study. Moreover, there was a significant improvement of median PFS in favor of the experimental arm (9.9 vs. 8.4 weeks; P = 0.0010).
Till date, there is no published data of nimotuzumab and matuzumab in R/M HNSCC.
Tyrosine kinase inhibitors
Single-agent tyrosine kinase inhibitors
Single-agent lapatinib (1500 mg/day) was associated with disappointing results (0% ORR) in a Phase II study of 42 patients in R/M disease setting. Single arm studies with gefitinib and erlotinib were also not encouraging. The reported ORR with these two drugs, varied between 1.8% and 10.6%, with a median PFS of 3–4 months.,,, The toxicity with these two oral TKIs, was generally mild, consisting of skin rash and diarrhea, which were dose-dependent. Some of these single-arm studies also suggested that the outcome with these agents might be predicted by the severity of skin reaction. In a large Phase III randomized study, Stewart et al. evaluated the role of dose-escalation of gefitinib in this disease setting. In this three arm study, 482 patients with R/M HNSCC, unresponsive to platinum or unfit for platinum, were randomized to receive either gefitinib 250 mg/day or gefitinib 500 mg/day or methotrexate 40 mg/m 2 IV weekly. But, none of the gefitinib arms showed any survival benefit in comparison to single-agent methotrexate.
Final results of a randomized, open-label, Phase II study that compared afatinib (BIBW 2992) to cetuximab in 124 patients with platinum-refractory R/M HNSCC were recently published. In Stage I, patients were randomized to daily afatinib or weekly cetuximab until disease progression or unacceptable toxicity, at which time crossover was permitted (Stage II). Stage I results demonstrated comparable antitumor activity (tumor shrinkage, ORR) and median PFS (13.0 weeks with afatinib vs. 15.0 weeks with cetuximab; P = 0.71). Approximately half (56%) the patients crossed over to the other treatment arm (Stage II); disease progression was the primary reason. DCR by independent central review was 33% for afatinib (vs. 19% with cetuximab), and median PFS was 9.3 weeks (vs. 5.7 weeks) during Stage II. Grade ≥ 3 toxicities were more frequent in patients treated with afatinib (47% vs. 16%). The authors concluded that patients may benefit from sequential therapy, especially treatment with afatinib after cetuximab failure. Afatinib was the first TKI to demonstrate antitumor activity in R/M HNSCC, which appeared to be at least comparable to cetuximab. In the LUX-Head and Neck 1 trial of afatinib versus methotrexate in R/M HNSCC after failure of platinum-based therapy, afatinib was associated with a significant improvement in the primary endpoint of PFS compared with methotrexate (2.6 vs. 1.7 months; P = 0.030); but median OS was not improved (P = 0.70). The objective RR was 10% with afatinib (vs. 6% with methotrexate), and DCR was 49% (vs. 39%). The most common Grade 3/4 treatment-related AEs were rash/acne (10%) and diarrhea (9%). A more recently presented biomarker analysis found a propensity for greater PFS benefit with afatinib versus methotrexate in the settings of p16-negative (2.7 vs. 1.6 months; P = 0.029), phosphatase and tensin homolog-high (2.9 vs. 1.4 month; P = 0.014), human epidermal growth factor receptor 3 (HER3)-low (2.9 vs. 2.0 months; P = 0.014), and EGFR-amplified (2.8 vs. 2.2 months; P = 0.162) disease.
Dacomitinib is an irreversible TKI that targets EGFR, ErbB2/HER2, and ErbB4/HER4. A Phase II study of dacomitinib monotherapy in 69 patients with R/M HNSCC demonstrated an ORR of 12.7%; median PFS and OS were 12.1 and 34.6 weeks, respectively. Diarrhea, acneiform dermatitis, and fatigue were the most frequent Grade ≥3 AEs.
Vandetanib is a multitargeted TKI, including EGFR and vascular endothelial growth factor receptor. The preliminary results of a Phase II study of vandetanib plus docetaxel versus docetaxel alone for R/M HNSCC demonstrated a partial RR of 13% with vandetanib plus docetaxel versus 7% with docetaxel alone, and a median PFS of 9 versus 3.2 weeks; serious AEs were comparable between arms.
Tyrosine kinase inhibitor combinations with chemotherapy
In a Phase I/II study of erlotinib and cisplatin in a population of platinum-sensitive patients with R/M disease, Siu et al. reported a response rate of 21% and a median OS of 7.9 months. In two Phase II studies with small group of patients, combinations of the TKIs with cisplatin plus docetaxel have shown interesting results and did not cause more hematologic toxicity than normally observed with this chemotherapy doublet., Docetaxel (35 mg/m 2 on days 1, 8 and 15, every 4 weekly), with or without gefitinib (250 mg/day) was tested in R/M disease setting, in a randomized Phase III trial, conducted by ECOG. In this study, the combination of docetaxel plus gefitinib improved the median time to progression significantly from 2.0 to 3.5 months (P = 0.03), but this did not translate into an improved median OS (6.0 vs. 7.3 months, P = 0.60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 vs. 5.2 months; P = 0.04). The combination arm was well tolerated, except for Grade 3/4 diarrhea.
| » Immunotherapy|| |
In two encouraging early reports, pembrolizumab, a humanized anti-programmed death receptor 1 (PD-1) antibody, yielded ORR of approximately 18%–20% as single agents, in patients with R/M HNSCC., More remarkably, the responses seemed to be durable in these patients with refractory disease. Moreover, this drug seemed to be relatively well tolerated, with serious AEs occurring in approximately 10%–17% of patients. Large randomized studies are now under way with this agent to test its efficacy against current standards of care.
Nivolumab, an anti-PD-1 checkpoint inhibitor, improved survival in patients with R/M HNSCC who progressed within 6 months of platinum-based therapy, according to the recently reported results of the Phase III CheckMate-141 trial., This international Phase III trial, enrolled 361 patients with R/M HNSCC of the oral cavity, pharynx, or larynx that progressed within 6 months of platinum-based therapy. They were randomized 2:1 to receive nivolumab at 3 mg/kg every 2 weeks or weekly treatment with investigator's choice (methotrexate, docetaxel, or cetuximab). Human papillomavirus (HPV) status was documented by p16 expression. Nivolumab reduced the risk of death by 30% compared with standard therapy using investigator's choice (P =0.0101). One-year survival was 36% in the nivolumab arm versus 16.6% in the control arm, representing an absolute improvement of 20%. Median OS was 7.5 months for nivolumab versus 5.1 months for those assigned to investigator's choice. The survival benefit was observed in the overall study population, regardless of tumor PD-L1 expression or HPV p16 status, but the magnitude of benefit was greater in those who stained positive for PD-L1 ≥1% and in HPV-positive cancers. The safety profile and quality of life of the patients treated with nivolumab was favorable compared to investigator's choice therapy. Nivolumab is the first systemic therapy agent to demonstrate a significant survival benefit in platinum-refractory R/M HNSCC patients in a randomized Phase III trial setting. Clearly, it represents a new standard of care option for the patients with platinum-refractory R/M HNSCC.
It is a small-molecule toll-like receptor (TLR-8) agonist that activates myeloid dendritic cells, monocytes, and natural killer cells. A Phase Ib study in patients with R/M HNSCC administered escalating doses of this agent in combination with cetuximab and demonstrated an ORR of 17% and a DCR of 50%. These data and preclinical results demonstrating that motolimod has synergistic antitumor activity with platinum and FU, paved the path of a currently ongoing randomized Phase II study (NCT01836029) comparing the EXTREME regimen with or without motolimod.
| » Summary|| |
Unfortunately, the outcome of the patients with R/M HNSCC is still dismal. In the absence of distant metastatic disease, salvage surgery, and re-irradiation are reasonable options. The use of systemic therapies is very much dependent on the performance status of the patient, co-morbidity, symptoms and logistics. Still the cornerstone of palliation for patients with R/M HNSCC is a platinum-based backbone. Platinum doublets induce higher response rates than single agent chemotherapy but do not demonstrate a survival advantage and are associated with increased toxicity. After decades without real progress, a recent European randomized trial showed that adding cetuximab, to a standard first-line chemotherapy regimen (platinum plus 5-FU) leads to an important survival benefit and this has changed the treatment practice. EGFR inhibitors have achieved only a modest success in R/M HNSCC, illustrating the importance of identifying predictive biomarkers and finding ways to overcome resistance against the currently available systemic therapy. Immunotherapy represents an attractive treatment option in this patient population, with encouraging recent data from studies involving immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab) and TLR agonists (e.g., motolimod). Clearly, enrollment of patients into clinical trials to investigate novel systemic agents and identify predictive biomarkers is necessary for further improvement of oncologic outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 2005;92:1341-8.
Vermorken JB. Medical treatment in head and neck cancer. Ann Oncol 2005;16 Suppl 2:ii258-64.
Campbell JB, Dorman EB, McCormick M, Miles J, Morton RP, Rugman F, et al.
A randomized phase III trial of cisplatinum, methotrexate, cisplatinum + methotrexate, and cisplatinum + 5-fluoro-uracil in end-stage head and neck cancer. Acta Otolaryngol 1987;103:519-28.
Morton RP, Rugman F, Dorman EB, Stoney PJ, Wilson JA, McCormick M, et al
. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of head and neck: A randomized factorial phase III controlled trial. Cancer Chemother Pharmacol 1992;15:283-9.
Eisenberger M, Hornedo J, Silva H, Donehower R, Spaulding M, Van Echo D. Carboplatin (NSC-241-240): An active platinum analog for the treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 1986;4:1506-9.
Eisenberger M, Krasnow S, Ellenberg S, Silva H, Abrams J, Sinibaldi V, et al.
A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer. J Clin Oncol 1989;7:1341-5.
Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, et al.
Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol 1995;13:1649-55.
Tapazoglou E, Kish J, Ensley J, Al-Sarraf M. The activity of a single-agent 5-fluorouracil infusion in advanced and recurrent head and neck cancer. Cancer 1986;57:1105-9.
Cervellino JC, Araujo CE, Pirisi C, Francia A, Cerruti R. Ifosfamide and mesna for the treatment of advanced squamous cell head and neck cancer. A GETLAC study. Oncology 1991;48:89-92.
Buesa JM, Fernández R, Esteban E, Estrada E, Barón FJ, Palacio I, et al.
Phase II trial of ifosfamide in recurrent and metastatic head and neck cancer. Ann Oncol 1991;2:151-2.
Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2644-52.
Martinez-Trufero J, Isla D, Adansa JC, Irigoyen A, Hitt R, Gil-Arnaiz I, et al
. Phase II study of capecitabine as palliative treatment for patients with squamous head and neck cancer with locoregional and/or metastatic relapse after previous platinum-based treatment: Final results of Spanish Head and Neck Cancer Group. J Clin Oncol 2009;27 15 Suppl: 312s. [Abstr 6047].
Park S, Lee S, Park J, Cho E, Shin D, Lee J. Phase II study of oral S-1 in pretreated patients with recurrent or metastatic head and neck cancer. J Clin Oncol 2008; 26 15 Suppl: 692s. [Abstr 17007].
Murphy BA. Topoisomerases in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. Expert Opin Pharmacother 2005;6:85-92.
Grau JJ, Caballero M, Verger E, Monzó M, Blanch JL. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol 2009;129:1294-9.
Hitt R, Amador ML, Quintela-Fandino M, Jimeno A, del Val O, Hernando S, et al.
Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Cancer 2006;106:106-11.
Hong WK, Schaefer S, Issell B, Cummings C, Luedke D, Bromer R, et al
. A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck. Cancer 1983;52:206-10.
Grose WE, Lehane DE, Dixon DO, Fletcher WS, Stuckey WJ. Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: A Southwest Oncology Group Study. Cancer Treat Rep 1985;69:577-81.
Vermorken JB, Catimel G, de Mulder P, Hoekman K, Hupperts P, Ruggeri E, et al
. Randomized phase II trial of weekly methotrexate versus two schedules of three-weekly paclitaxel in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 1999;18:395a. [Abstr 1527].
Guardiola E, Peyrade F, Chaigneau L, Cupissol D, Tchiknavorian X, Bompas E, et al.
Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer 2004;40:2071-6.
Jacobs C, Meyers F, Hendrickson C, Kohler M, Carter S. A randomized phase III study of cisplatin with or without methotrexate for recurrent and squamous cell carcinoma of head and neck: A North California Oncology group study. Cancer 1983;52:1563-9.
Drelichman A, Cummings G, Al-Sarraf M. A randomized trial of the combination of cis-platinum, oncovin and bleomycin (COB) versus methotrexate in patients with advanced squamous cell carcinoma of the head and neck. Cancer 1983;52:399-403.
Williams SD, Velez-Garcia E, Essessee I, Ratkin G, Birch R, Einhorn LH. Chemotherapy for head and neck cancer. Comparison of cisplatin + vinblastine + bleomycin versus methotrexate. Cancer 1986;57:18-23.
Urba SG, Forastiere AA. Systemic therapy of head and neck cancer: Most effective agents, areas of promise. Oncology (Williston Park) 1989;3:79-88.
Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, et al.
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 Oncol 1992;10:257-63.
Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al.
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 Oncol 1992;10:1245-51.
Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, et al.
Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus 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 Oncol 1994;5:521-6.
Browman GP, Cronin L. Standard chemotherapy in squamous cell head and neck cancer: What we have learned from randomized trials. Semin Oncol 1994;21:311-9.
Shin DM, Glisson BS, Khuri FR, Ginsberg L, Papadimitrakopoulou V, Lee JJ, et al.
Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. J Clin Oncol 1998;16:1325-30.
Schöffski P, Catimel G, Planting AS, Droz JP, Verweij J, Schrijvers D, et al.
Docetaxel and cisplatin: An active regimen in patients with locally advanced, recurrent or metastatic squamous cell carcinoma of the head and neck. Results of a phase II study of the EORTC Early Clinical Studies Group. Ann Oncol 1999;10:119-22.
Shin DM, Khuri FR, Glisson BS, Ginsberg L, Papadimitrakopoulou VM, Clayman G, et al.
Phase II study of paclitaxel, ifosfamide, and carboplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma. Cancer 2001;91:1316-23.
Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, et al.
Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23:3562-7.
Samlowski WE, Moon J, Kuebler JP, Nichols CR, Gandara DR, Ozer H, et al.
Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): A Southwest Oncology Group Phase II study. Cancer Invest 2007;25:182-8.
Glisson BS, Murphy BA, Frenette G, Khuri FR, Forastiere AA. Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol 2002;20:1593-9.
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al.
Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.
Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al.
Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
Janinis J, Papadakou M, Xidakis E, Boukis H, Poulis A, Panagos G, et al.
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 Oncol 2000;23:128-31.
Cohen EE. Novel therapeutic targets in squamous cell carcinoma of the head and neck. Semin Oncol 2004;31:755-68.
Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, et al.
Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62:7350-6.
Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al.
Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006;24:4170-6.
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortés-Funes H, Hitt R, et al.
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 Oncol 2005;23:5568-77.
Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, et al
. 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 Oncol 2005;23:5578-87.
Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al.
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 therapy. J Clin Oncol 2007;25:2171-7.
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. 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. J Clin Oncol 2005;23:8646-54.
Bourhis J, Rivera F, Mesia R, Awada A, Geoffrois L, Borel C, et al
. Phase I/II study of cetuximab in combination with cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:2866-72.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al
. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27.
Hitt R, Irigoyen A, Cortes-Funes H, Grau JJ, Garcia-Saenz JA, Cruz-Hernandez JJ, et al
. Phase II study of combination cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (SCCHN): Spanish Head and Neck cancer cooperative group (TTCC) study. Ann Oncol 2012;23:1016-22.
Buentzel J, de Vries A, Micke O. Experience with cetuximab plus paclitaxel/carboplatinum in primary platinum-resistant recurrent head and neck cancer. J Clin Oncol 2007;25 18 Suppl: 318s. [Abstr 6077].
Vermorken JB, Licitra L, Stohlmacher-Williams J, Dietz A, Lopez-Picazo JM, Hamid O, et al
. Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 2013;49:2877-83.
Rischin D, Spigel DR, Adkins D, Wein R, Arnold S, Singhal N, et al
. PRISM: Phase 2 trial with panitumumab monotherapy as second-line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck 2016;38 Suppl 1:E175661.
Wirth LJ, Dakhil SR, Kornek G, Axelrod R, Adkins D, Pant S, et al
. PARTNER: A randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). J Clin Oncol 2013;31. [Suppl; abstr 6029].
Vermorken JB, Stöhlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, et al
. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial. Lancet Oncol 2013;14:697-710.
Machiels JH, Subramanian S, Ruzsa A, Repassy G, Lifrenko I, Flygare A, et al
. An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE). J Clin Oncol 2010;28. [Suppl 18s; abstr LBA5506].
de Souza JA, Davis DW, Zhang Y, Khattri A, Seiwert TY, Aktolga S, et al
. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2012;18:2336-43.
Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, et al
. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980-7.
Cohen EE, Kane MA, List MA, Brockstein BE, Mehrotra B, Huo D, et al
. Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2005;11:8418-24.
Kirby AM, A'Hern RP, D'Ambrosio C, Tanay M, Syrigos KN, Rogers SJ, et al
. Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer. Br J Cancer 2006;13:631-6.
Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyropsine kinase inhibitor, in patients with recurrent or metastatiuc squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77-85.
Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, et al.
Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol 2009;27:1864-71.
Seiwert TY, Fayette J, Cupissol D, Del Campo JM, Clement PM, Hitt R, et al.
A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol 2014;25:1813-20.
Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, et al.
Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): An open-label, randomised phase 3 trial. Lancet Oncol 2015;16:583-94.
Cohen EE, Licitra LF, Fayette J, Gauler TC, Clement PM, Grau JJ, et al
. Biomarker analysis in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients (pts) treated with second-line afatinib versus methotrexate (MTX): LUX-Head & Neck 1 (LUX-H & N1). J Clin Oncol 2015;33. [Suppl: Abstract 6023].
Abdul Razak AR, Soulières D, Laurie SA, Hotte SJ, Singh S, Winquist E, et al.
A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol 2013;24:761-9.
Limaye S, Riley S, Zhao S, O'Neill A, Posner M, Adkins D, et al
. A randomized phase II study of docetaxel with or without vandetanib in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). Oral Oncol 2013;49:835-41.
Siu LL, Soulieres D, Chen EX, Pond GR, Chin SF, Francis P, et al
. Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 2007;25:2178-83.
Belon J, Irigoyen A, Rodriguez I, et al
. Preliminary results of a phase II study to evaluate gefitinib combined with docetaxel and cisplatin in patients with recurrent and/or metastatic squamous-cell carcinoma of the head and neck. J Clin Oncol 2005;23 16 Suppl:515s. [Abstr 5563].
Kim ES, Kies MS, Glisson BS, et al
. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/metastatic head and neck cancer. J Clin Oncol 2007;25 18 Suppl:302s. [Abstr 5521].
Argiris A, Ghebremichael M, Gilbert J, Lee JW, Sachidanandam K, Kolesar JM, et al.
Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: An Eastern Cooperative Oncology Group trial. J Clin Oncol 2013;31:1405-14.
Chow LQ, Burtness B, Weiss J, Berger R, Eder JP, Gonzalez EJ, et al
. A phase Ib study of pembrolizumab (Pembo; MK-3475) in patients (pts) with human papilloma virus (HPV) – Positive and negative head and neck cancer (HNC). Ann Oncol 2014;25 Suppl 4:S1-41.
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956-65.
Gillison ML, Blumenschein G Jr., Fayette J, et al
. Nivolumab vs investigator's choice for recurrent or metastatic head and neck squamous cell carcinoma: CheckMate-141. 2016 AACR Annual Meeting. Abstract CT099. Presented; 19 April, 2016.
Ferris RL, Blumenschein GR, Fayette J, Guigay J, Colevas AD, Licitra LF, et al
. Further evaluations of nivolumab (nivo) versus investigator's choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol 2016;34. [Suppl; abstr 6009].
Chow LQ, Eaton KD, Baik C, et al
. Phase Ib trial of TLR8 agonist VTX-2337 in combination with cetuximab in patients with recurrent or metastatic squamous cell carcinomas of the head and neck (SCCHN). Presented at the Multidisciplinary Head and Neck Cancer Symposium, Scottsdale, AZ, 20-22 February, 2014