Optimal treatment for recurrent/metastatic head and neck cancer

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Annals of Oncology 21 (Supplement 7): vii252–vii261, 2010 doi:10.1093/annonc/mdq453

Optimal treatment for recurrent/metastatic head and neck cancer J. B. Vermorken* & P. Specenier

symposium article

Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium

While a large proportion of patients presenting with stage I and II squamous cell carcinoma of the head and neck (SCCHN) will remain disease free after single modality treatment, the majority of patients presenting in a more advanced disease stage and very often treated with a form of combined modality treatment, will eventually relapse, either locoregionally only, at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Prognostic factors analysis in such patients treated with (platinum-based) chemotherapy has identified five adverse prognostic factors, which seems worthwhile to take into consideration when performing trials; one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG performance status, weight loss, location of the primary tumor and prior radiotherapy). Moreover, it has been shown that response to systemic therapy has a major impact on survival. None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice.

introduction Squamous cell carcinoma of the head and neck (SCCHN) is considered to be the final stage of a multi-step process evolving from normal histology to hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia, carcinoma in situ, to invasive carcinoma. Particular chromosomal alterations appear to be associated with distinct stages of tumor progression [1]. Underlying genetic instabilities including the loss of heterozygocity (LOH) of certain chromosomes (3p14, 9p21, 17p13, 8p, 11q, 13q, 14q, 6p, 4q27 and 10q23) and amplification, deletion, up-regulation or down-regulation of certain oncogenes or tumor-suppressor genes, including epidermal growth factor receptor (EGFR), p53, Rb, p65, cyclooxygenase 2 (COX-2), p16, cyclin D1 and phosphatase and tensin homolog (PTEN) have been identified as genetic alterations in each of the pathological stages of this disease [1]. Head and neck cancer is the sixth most common cancer worldwide [2] and there has been a significant increase in the global incidence of SCCHN over the past decade [3]. At present, >650 000 new cases of head and neck cancer are diagnosed each year worldwide [4, 5]. In Europe alone, it is *Correspondence to: Prof. J. B. Vermorken, Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium. E-mail: [email protected]

estimated that there are 143 000 new cases and >68 000 deaths due to the disease each year [5]. The management of SCCHN is complex and requires a multidisciplinary approach involving medical oncologists, radiation oncologists, head and neck surgeons, radiologists, speech therapists, social workers, psychologists, plastic and/or reconstructive surgeons, dentists with particular interest and expertise in head and neck cancer [6, 7]. Single-modality treatment with surgery or radiotherapy is generally recommended for the 40% of patients who present with stage I or II disease. Each of the two modalities results in similar survival with cure rates ranging between 60% and 90% depending on tumor site and extension of the disease. The choice between the treatment modalities depends on tumor site, extension of the disease, patient preference, comorbidities, expertise of the multidisciplinary team, available equipment, etc. Salvage with the alternative treatment modality is frequently possible in cases of local relapse after the primary treatment. Over the years, significant advances in surgical and radiation techniques have reduced the toxic effects without compromising the outcome. For the 60% of the patients who present with locally advanced disease at diagnosis, combined modality therapy is generally recommended. For patients with unresectable disease the current standard treatment is concurrent cisplatin-based

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Annals of Oncology

chemoradiation. This is also the standard for patients with resectable disease when organ preservation is desired and, as adjuvant treatment, for patients with high-risk pathological findings at surgical resection. Despite such an approach, the majority of patients develop local and/or regional recurrences and distant metastases occur in 20%–30% of patients [4, 6–10]. A few patients with a locoregional recurrence can be salvaged by surgery or re-irradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single-agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Treatment choice should be based on factors such as performance status (PS), co-morbidity, prior treatment, symptoms, patient preference and logistics [9]. Goals of treatments in these circumstances are mainly symptom control and prevention of new cancer-related symptoms, improvement in quality of life (QoL) and if assessable, objective tumor response (OR), disease stabilization (SD) or both combined (disease control; DC) and in addition prolongation of overall survival (OS) and progression-free survival (PFS). Unfortunately, correlation between objective tumor reduction (or DC) and subjective benefit (symptom control and QoL) has not been adequately studied, underscoring the importance of clinical trials in this patient group [10] Patients with R/M-SCCHN can have specific problems related to their social habits such as ongoing heavy tobacco and alcohol use or the use of other carcinogens, which may lead to poor cognitive function, co-morbid medical conditions (cardiovascular and/or pulmonary diseases) and malnutrition. Moreover, typically disease-related problems may be present, such as infections (local, aspiration pneumonia, systemic), hypercalcemia, local pain or bleeding (arterial, venous, capillary), which can all influence QoL and OS and may necessitate active supportive care [11].

prognostic factors patients undergoing re-irradiation Prognosis is poor when a recurrence or new primary head and neck cancer develops in an area previously treated with radiation [12]. In the absence of disease at distant sites, salvage surgery may provide a durable DC in 15% of such patients [13]. However, in those with positive surgical margins, or adverse pathologic features the outcome is still expected to be poor after salvage surgery. For the many patients with unresectable disease at the time of recurrence, the disease was uniformly fatal, and only palliative treatment options, as described above, were left and for some this meant the use of platinum-based chemotherapy, providing a typical median survival of 6 months [9]. However, in recent years the practice of full-dose reirradiation has come forward as an option and literature data indicate that with the use of re-irradiation durable DC in 10% of patients with unresected tumors and in 20% of those with resected tumors can be obtained [14, 15]. Because considerable toxicity might go along with this approach,

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symposium article Tanvetyanon et al. [12], in a retrospective study, tried to define which patients might benefit from re-irradiation and who most likely will not. They reviewed the medical records of 103 patients who had undergone radiation between January 1998 and 2008 and in whom there had been significant overlap of reirradiation field and the previously irradiated area. They studied potential prognostic factors, including co-morbidity and pre-existing organ dysfunction, for survival after reirradiation. In this study, co-morbidity was assessed by Charlson index and Adult Comobidity Evaluation-27 (ACE-27) grading and organ dysfunction was defined as feeding tube dependency, functioning tracheostomy or soft tissue defect including uncovered open wound of skin or mucosa, fistula or osteonecrosis. Approximately 70% of patients had also received chemotherapy concurrent with radiation. In the multivariate analysis, co-morbidity (by either Charlson index or ACE-27), radiation dose, organ dysfunction, recurrent tumor stage, tumor bulk at re-irradiation and time interval between previous radiation and re-irradiation were all independent prognostic factors. Median OS was 5.5 months among those with both organ dysfunction and co-morbidity per Charlson index, and 4.9 months per ACE-27, compared with 59.6 and 44.2 months, respectively, among the patients with neither organ dysfunction nor co-morbidity (P < 0.001 and P < 0.001).

patients receiving chemotherapy Prognostic factors and characteristics of long-term survivors in R/M-SCCHN patients treated with platinum-based combination chemotherapy regimens were identified from an analysis of two Eastern Cooperative Oncology Group (ECOG) randomized trials (E1395 and E1393) [16]. The median followup of the patients in these two trials was 4.7 years; survival rates at 1, 2, 3 and 5 years were 32%, 12%, 7% and 3.6%, respectively and median OS was 7.8 months. The OR rate was 32%. On multivariate analysis, the investigators were able to identify one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG PS, weight loss, location of the primary tumor and prior radiotherapy) as independent predictors of OS. They constructed a prognostic model for OS based on the presence of these five independent prognostic factors and were able to categorize the patients into two groups with significantly different outcome, i.e. one in which patients had only two or fewer adverse prognostic factors and another in which patients had three or more poor prognostic factors. The first group had a median survival that was nearly twice that of the second group (0.98 years compared with 0.52 years). They also identified that the same variables and the presence of residual tumor at the primary site were independent predictors of response to chemotherapy. In fact, response to chemotherapy was found to be of prognostic significance. When the investigators added response to chemotherapy to the model, the location of the primary tumor lost its prognostic significance but all other parameters, including tumor cell differentiation, retained their significance as independent predictors of survival. Predictors of 2-year survivorship were response to chemotherapy (complete or partial response versus no response), white race (versus others), ECOG PS of 0 (versus 1), poor cell differentiation (versus well/moderate) and no prior radiotherapy. Interestingly, all long-term survivors had

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symposium article locally recurrent disease at study entry. The take-home messages from this analysis are that (i) response to systemic therapy has a major impact on survival, (ii) patients with locally recurrent disease, but not the patients with distant metastases, who are primarily treated with chemotherapy, will rarely be cured of their disease, and (iii) future trials in patients with R/M-SCCHN should take the five adverse prognostic factors into consideration. It is therefore clear that for any definitive conclusion on the superiority of one treatment over another, cross-trial comparisons are rather misleading and may lead to incorrect conclusions as result of variations in tumor and patient characteristics. Illustrative of this are the favorable data in some of the non-randomized trials with new cytotoxic agents and the negative randomized trials when these same agents are compared in a randomized trial versus standard methotrexate (see below). This is also true both for the first-line and secondline settings. For making a fair judgement on its value, a new drug should be tested in a direct comparison against a standard treatment or a placebo or tested as an adjunct to standard therapy versus standard therapy alone.

systemic treatment single-agent chemotherapy A large number of conventional single agents have been investigated in the past in patients with R/M-SCCHN [11, 14]. The four most active and most extensively used agents are methotrexate, cisplatin, 5-fluorouracil (5-FU) and bleomyin. These drugs produced a response of short duration, 3–5 months, in 15%–30% of cases and only rarely complete response (CR). Several new active agents (defined as inducing responses in ‡15% of cases) have been introduced more recently, such as pemetrexed, vinorelbine, irinotecan, capecitabine, orzel, S-1 and the taxanes paclitaxel and docetaxel [10, 17–22]. The taxanes are among the highest scoring agents, with response rates varying between 20% and 43%, illustrating the earlier mentioned variability in patient and tumor characteristics. For most of the conventional agents, but also of the newer agents, no direct comparison has been made with the standard palliative agent methotrexate. There are a few exceptions to this unfortunate situation, i.e. there have been direct comparisons with methotrexate for the methotrexate analog edetrexate [23], the platinum compound cisplatin [24, 25] and the taxanes [26, 27]. Apart from the phase III trial on edetrexate versus methotrexate, none of the other studies was large enough to allow for a survival comparison, but there was no indication of any superiority. Nevertheless, in the randomized phase II study of docetaxel versus methotrexate [27], the response rate was reported as significantly higher in the docetaxel arm with 27% [95% confidence interval (CI) 21.7% to 32.3%] OR compared with 15% (95% CI 11.2% to 18.8%) in the methotrexate arm. Whether this increased activity of docetaxel in the R/M disease setting has significance for treatment outcome will need to be explored in a phase III trial. It is currently unclear whether any of the cytotoxic agents prolongs survival when compared with supportive care alone as

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an adequately powered randomized controlled trial has never been performed. Only one small study in the past was designed to demonstrate clinical benefit over best supportive care (BSC) only, using randomized controlled trial methodology. In that trial, 31 patients treated with single-agent cisplatin demonstrated prolonged survival compared with 26 patients treated with supportive measures only [28]. An interesting aspect of this trial was the demonstration that patients who respond do so quickly. Of the 16 responders, 75% responded after the first cycle and the remaining 25% after the second cycle [10].

combination chemotherapy standard platinum-based combinations. Combination chemotherapy is very often considered in younger patients with a good performance, in particular when favorable prognostic factors for response to chemotherapy are available [11]. The Wayne State University cisplatin/infusional 5-FU (PF) regimen gradually emerged as the most commonly used combination chemotherapy regimen in patients with SCCHN. With that regimen, non-randomized trials indicated a better outcome than what was observed with single-agent treatment, at least with respect to OR rates and CR rates [29]. However, response rates were notably lower for the subsets of patients who had prior surgery and radiation and those who had metastatic disease [10]. In a number of randomized phase III trials performed in the 1990s, this PF regimen was shown to be superior to single-agent regimens, in terms of response rates but not in terms of meaningful survival advantage, and this gain in response rates was obtained at the cost of more toxicity [30–32]. The phase III trial reported by Forastiere et al. [30] highlights additional important information, which is of use for daily practice. In this study 277 patients were randomized to receive PF, carboplatin–5-FU (CF) or standard dose methotrexate. With respect to response rate, PF scored significantly higher than methotrexate (P < 0.001), but the comparison of CF with methotrexate was of only borderline significance (P = 0.05). Median response duration and median survival time were similar for all three treatment groups. In support of this difference between PF and CF, it is to be mentioned that the CF combination also induced fewer responses than the PF regimen in a randomized phase III trial in the neoadjuvant setting [33]. Moreover, there was no difference in response rate in a randomized comparison of carboplatin plus methotrexate versus single-agent methotrexate [34]. Taken together, these data clearly indicate that carboplatin is less active than cisplatin in the treatment of SCCHN. platinum–taxane combinations. Of the newer agents, the taxanes have been studied most extensively in combination chemotherapy regimens [20, 35–39]. Regimens with carboplatin and paclitaxel did not seem to be much different from regimens with cisplatin and paclitaxel. However, a recently reported phase II trial in R/M-SCCHN (including patients with ECOG 0–2) conducted by the Southwest Oncology Group indicated only moderate activity of carboplatin plus docetaxel. The paclitaxel plus cisplatin (PP) combination was directly compared with the PF regimen in the Intergroup trial E1395

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conducted by ECOG [38]. Patients received either paclitaxel 175 mg/m2 (over 3 h) and cisplatin 75 mg/m2, both on day 1, or the classical PF regimen. The OR rate was 27% with PP and 26% with PF. The overall grade 3/4 toxicity rate was similar between the two groups. However, grade 3/4 mucositis (31%) was only observed in the PF arm, while the occurrence of neurotoxicity was similar in the two groups. Median OS was 8.7 months in the PF group and 8.1 months in the PP group. Considering the more favorable toxicity profile, PP may be a valuable alternative to PF. two-drug and three-drug platinum–taxane combinations. The TPF regimen, which consists of docetaxel, cisplatin and infusional 5-FU, has become the new standard for induction chemotherapy in the locoregionally advanced disease setting since the publication of the TAX323/EORTC24971 (Europe) and TAX324 studies (USA) [40, 41]. There is a temptation to use this regimen or other three-drug regimens also in the R/M disease setting. Janinis et al. [42] observed an overall response rate of 44%, a median time to progression of 7.5 months and a median OS of 11 months. Of note, despite the use of G-CSF in this study, febrile neutropenia occurred rather frequently (in 15% of patients). The TIP and TIC regimens reported by Shin et al. [36, 37], which consist of paclitaxel, ifosfamide and cisplatin (TIP) or carboplatin (TIC), are the most active regimens ever tested in the MD Anderson Cancer Center. Response rates of 58% and 59% were reported with CR rates of 17%, in both regimens of long duration (median 15.7+ months with TIP and median 9.7 months with TIC), but an unacceptably high incidence of febrile neutropenia (27% with TIP and 30% with TIC). Our personal experience with the DIP regimen (docetaxel, ifosfamide, cisplatin) in the locoregionally advanced disease setting [43], showing responses in 95% (after two cycles), 82% grade 4 neutropenia and 36% febrile neutropenia are in line with these observations. Overall, it can be concluded that platinum–taxane-containing triplets induce high response rates, also in patients with R/M-SCCHN. However, they are associated with substantial hematologic toxicity and a high complication rate. As these triplets have never been directly compared with PF in a randomized phase III study in this setting, they should not

be recommended outside clinical trials. Moreover, as none of the combination chemotherapy regimens demonstrated an OS benefit when compared with single-agent methotrexate, cisplatin or 5-FU, combination chemotherapy should preferably be used in younger patients with good PS and with symptomatic disease who require prompt symptom relief.

targeted therapies Several biological therapies have been chosen in head and neck cancer patients because of their different mechanism of action, greater selectivity (target of action is overexpressed as compared with normal tissue), different toxicity profile or because they play a role in carcinogenesis [9, 44]. These include drugs that target growth factors and their receptors, signal transduction, cell cycle control, prostaglandin synthesis, protein degradation, hypoxia and angiogenesis [45]. As randomized trials leading to a further improvement in outcome have only been performed with drugs targeting the growth factors and/or growth factor receptors, in particular those of the HER family, this will be the main focus of this part of the article. epidermal growth factor receptor and ErbB2. The epidermal growth factor receptor (EGFR) inhibitors are of particular interest, because EGFR and its ligand TGF-a are overexpressed in the vast majority of cases of SCCHN. In contrast, ErbB2 expression in SCCHN ranges between 40% and 60% [46]. EGFR overexpression and increased EGFR copy number have been related to poor prognosis in patients with SCCHN [47, 48]. Its prognostic role is more specifically related to the treatment received, such as radiotherapy [47, 49] and chemotherapy [50]. Recently it was found, however, that both EGFR expression and FISH determination were not predictive of response to anti-EGFR therapy with cetuximab [51]. Two of the potential EGFR targeting strategies are currently in clinical use: monoclonal antibodies (mAbs) directed at the extracellular domain of the receptor, and the small molecule and ATP-competitive tyrosine kinase inhibitors (TKIs). Table 1 summarizes some important EGFR inhibitors under clinical investigation in R/M-SCCHN. EGFR-activated signaling pathways and the effect of activation on cell proliferation and survival are well documented [52]. Ligand binding to the EGFR

Table 1. Selection of relevant EGFR-targeting agents under clinical investigation in SCCHN Agent Monoclonal antibodies Cetuximab Matuzumab Nimotuzumab Zalutumumab Panitumumab Tyrosine kinase inhibitors Gefitinib Erlotinib Lapatinib Canertinib

Toxicity IMC225 EMD72000 h-R3 2F8 ABX-EGF

Chimeric human/murine Humanized mouse Humanized mouse Human Human

IgG1 IgG1 IgG1 IgG1 IgG2

Skin Skin Systemic/hemodynamic Skin Skin

ZD1839 OSI-774 PKI-166 GW-572016 CI-0033

Reversible Reversible Reversible Reversible Irreversible

EGFR EGFR EGFR/ErbB2 EGFR/ErbB2 EGFR

Skin/GI Skin/GI Skin/GI/systemic/hepatic Skin/GI/systemic Skin/oral/GI/systemic

From Specenier P and Vermorken JB, Targ Oncol 2007; 2: 73–88 [44]. GI, gastrointestinal.

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is followed by stimulation of a number of different signal transduction cascades, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)–Akt pathway. The mAbs and TKIs act at different points on the pathway to disrupt signaling. However, it is likely that the effects of these agents are not mediated by disruption of EGFR signaling pathways alone. Also, antibody-dependent cellular cytotoxicity (ADCC) is thought to be an important mechanism of action, but for a long time it was thought that this only referred to IgG1 mAbs [53, 54]. However, very recently it was discovered that also human IgG2 mAbs against EGFR effectively trigger ADCC but, in contrast to IgG1, only by cells of the myeloid lineage [55]. The ability of many EGFR inhibitors to enhance the effects of radiation and/or chemotherapy has been demonstrated both in vitro and in vivo [56]. In vitro and in vivo data indicate that the combined use of an EGFR-targeted mAb and a TKI increases the impact of either agent alone on downstream signaling, apoptosis, proliferation and tumor (xenograft) growth [57, 58], and this may be of interest for the clinical situation, in particular for the R/M disease setting.

monoclonal antibodies cetuximab. The best-studied mAb thus far is cetuximab, which is a human–murine chimeric immunoglobulin G1 (IgG1) mAb, which competitively binds to the extracellular domain of the EGFR. Cetuximab has been tested in R/M-SCCHN, either in second-line therapy after failure of platinum-based chemotherapy or in first-line therapy in combination with platinum-based chemotherapy. Moreover, it has been tested as part of the combined modality treatment of locoregionally advanced SCCHN. This latter application is beyond the scope of this article. cetuximab in second-line therapy. Three phase II trials examined the role of cetuximab in platinum-refractory or platinumresistant disease. All patients received cetuximab intravenously (i.v.) at an initial loading dose of 400 mg/m2 followed by weekly 250 mg/m2 [59–61]. In two of these studies cetuximab was added to the platinum compound that was reintroduced [59, 60], in one study cetuximab was given alone [61]. There was a remarkable similarity in outcome in these three studies. Responses were seen in 10%–13% of patients, DC was observed in 46%–55% of patients and median OS was 5.2–6.1 months. This similarity, irrespective of whether cetuximab was administered as a single agent or added to a platinum-based

regimen, indicates that the observed responses were attributable to cetuximab alone rather than to the reversal of platinum resistance by cetuximab. Interestingly, the median survival of 5–6 months achieved with cetuximab in platinum-refractory disease was reaching a level very close to that with first-line therapy in randomized trials and represented an increase in survival of 2.5 months compared with platinum-refractory historical controls [62]. Based on these results and particularly considering the fact that 50% of the patients showed DC, cetuximab monotherapy seems to be a good option for patients with R/M-SCCHN who have progressed on platinum-based chemotherapy. It is also approved for that indication in the USA. cetuximab in first-line therapy. Table 2 summarizes the data on cetuximab in first-line therapy, showing a remarkable consistency in efficacy in patients with R/M-SCCHN, whether treated with platinum-based chemotherapy [63–65], taxanebased chemotherapy [66] or platinum–taxane-based chemotherapy [67]. Burtness et al. [63] assigned 117 patients to cisplatin 100 mg/m2 every 4 weeks either with weekly cetuximab or with weekly placebo. The primary end point of this study was PFS. The study was designed to detect a difference in median PFS of 2 months i.e. 2 months with cisplatin plus placebo and 4 months with the experimental arm. However, the observed median PFS in the control arm was longer than expected (2.7 months). The median PFS in the cetuximab arm was 4.2 months and that difference did not reach statistical significance (P = 0.09). In fact, the actual power to detect a 2-month difference in this situation was only 50%. The OR rate was 26% in the experimental arm versus 10% in the control arm (P = 0.03). Median OS was not significantly different (9.2 months versus 8 months, P = 0.21). Development of cetuximab-related skin toxicity was associated with an improved OS [hazard ratio (HR) 0.42, P = 0.01]. In the EXTREME study [65] 442 patients were randomized to receive either chemotherapy alone (cisplatin 100 mg/m2 or carboplatin AUC 5 mg/ml/min on day 1 followed by 5-FU 1000 mg/m2/day for 4 days) or the same regimen combined with weekly cetuximab (initial loading dose of 400 mg/m2 followed by weekly doses of 250 mg/m2). Cycles were repeated every 3 weeks for a maximum of six cycles. Thereafter, in the combined arm, cetuximab was continued as a single agent until disease progression or unacceptable toxicity, whichever came first. No crossover was permitted in this study. Excluded were patients who had received prior chemotherapy except when this had

Table 2. Cetuximab in first-line therapy of recurrent/metastatic squamous cell carcinoma of the head and neck Author/study

Phase

Regimen

ORR (%)

PFS (months)

OS (months)

Burtness et al. (2005) [63]

III

Bourhis et al. (2006) [64] Vermorken et al. (2008) [65]

I/II III

Hitt et al. (2007) [66] Buentzel et al. (2007) [67]

II II

CDDP + cetuximab CDDP + placebo PF + cetuximab PF + cetuximab PF Paclitaxel + cetuximab Pacli/carbo + cetuximab

26* 10 36 36** 20 60 56

4.2 2.7 5.1 5.6** 3.3 5.0 5.0

9.2 8.0 9.8 10.1*** 7.4 NR 8.0

CDDP, cisplatin; PF, platinum (cis or carbo) + 5-fluorouracil; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; *P = 0.03; **P < 0.001; ***P = 0.04.

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been part of their primary treatment provided this chemotherapy was ended at least 6 months before inclusion in the study. The primary end point was OS. The addition of cetuximab to platinum–5-FU significantly prolonged the median OS from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (HR for death, 0.80; 95% CI 0.64–0.99; P = 0.04). The addition of cetuximab also prolonged the median PFS from 3.3 to 5.6 months (HR for progression, 0.54; 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 also in this study response rates with carboplatin–5-FU were below those obtained with cisplatin–5FU independent of the treatment arm. Moreover, protocoldefined 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). 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. This is the first time in >30 years that superiority (in terms of survival) of a new regimen over standard platinum-based combination chemotherapy has been observed. Cetuximab and platinum-based chemotherapy is now considered as a new standard for the treatment of R/M-SCCHN for those who are able to tolerate platinum-based combination chemotherapy regimens [7, 68]. panitumumab. Panitumumab (ABX-EGF) is a fully human IgG2 antibody which binds very strongly to the receptor [44, 69]. It blocks ligand binding and induces internalization of the receptor but no receptor degradation. Side-effects include pruritus, skin rash, dyspnea, fatigue, abdominal pain, asthenia and diarrhea. Panitumumab at a weekly dose of 2.5 mg/kg has acceptable tolerability and encouraging clinical activity in patients with a variety of tumor types. Its pharmacokinetic profile allows more convenient 3-weekly administration (9 mg/ kg). Three studies with panitumumab in the R/M disease setting are of interest, i.e. the PRISM study, the PARTNER study and the SPECTRUM study. The PRISM study is a phase II study with single-agent panitumumab in second-line therapy, the PARTNER study is a randomized phase II study in first-line therapy studying docetaxel plus cisplatin with or without panitumumab and in the SPECTRUM trial, similar patients to those in the EXTREME trial were randomized to receive cisplatin–5-FU with or without panitumumab. Enrolment in this latter trial has been completed. The combination was safe and efficacy data are awaited in 2010 [70]. zalutumumab. Zalutumumab [44] is also a fully human IgG1 EGFR-directed mAb. The frequency of acneiform rashes with this compound increases with dose. This mAb is currently

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undergoing phase III testing in patients who failed standard platinum-based chemotherapy versus BSC [71]. However, in this so-called ZALUTE trial a great majority of patients in the BSC arm (78%) received weekly methotrexate as allowed by the protocol. There was a strong trend in favor of the zalutumumab arm for OS (median 6.7 versus 5.2 months, P = 0.0649), which was the primary end point of the study. There was a statistically highly significant difference in PFS in favor of the experimental arm (median 9.9 versus 8.4 weeks; P = 0.0010). The results of this trial confirm the activity of EGFR-directed mAbs in patients with platinum-refractory SCCHN [72]. matuzumab. Matuzumab is a humanized IgG1 mAb that in a phase I dose escalation study in stage III/IV laryngeal and hypopharyngeal cancer showed that fever and transient elevations of liver enzymes were the most frequently observed treatment-related adverse events [73]. A weekly dose of 200 mg, based on pharmacokinetic findings, was selected for further studies. No data of randomized trial in R/M-SCCHN are available. nimotuzumab. Nimotuzumab [44] is also a humanized IgG1 mouse antibody. Preliminary data indicate that therapeutic levels of nimotuzumab can be achieved without eliciting skin toxicity, which is the most common side-effect of the other anti-EGFR-directed antibodies. Nimotuzumab has a lower receptor affinity than e.g. panitumumab, cetuximab or matuzumab, and although there is no clinical evidence that higher affinity to the receptor leads to greater efficacy, stronger binding clearly leads to higher toxic effects, i.e. a higher incidence of acneiform rash [74]. A phase IIB clinical study in Indian patients with advanced (stage III and IVa) SCCHN showed only few skin reactions, including urticaria and pruritis, but did show some headache, hypertension and fluctuation in blood pressure [75, 76]. No data on R/M-SCCHN patients are available.

tyrosine kinase inhibitors single-agent use. Table 3 shows the results of studies with tyrosine kinase inhibitors (TKIs) used as single agents. As a reference, also the data with cetuximab in platinum-refractory SCCHN are given [61]. The study population in most of the studies is a mixture with respect to prior platinum treatment of R/M-SCCHN and therefore cannot be considered fully platinum refractory. With a few exceptions (see below) the results with TKIs have been disappointing. Single-arm trials

Table 3. Responses to anti-epidermal growth factor receptor medication Drug

Phase

Reference

Response (%)

Cetuximab Erlotinib Gefitinib

II II II II II IIIa II IIa

Vermorken 2007 [61] Soulieres 2004 [77] Cohen 2003 [78] Cohen 2005 [79] Kirby 2006 [80] Stewart 2009 [81] Abidoye 2006 [82] Seiwert 2010 [83]

13 4.3 10.6 1.8 8.5 7.9 0 21.7

Lapatinib BIBW 2992 a

Randomized studies

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symposium article with gefitinib and erlotinib showed response rates ranging from 0% (in chemotherapy-refractory disease) to 15% (in ‘untreated’ R/M disease patients) and a median PFS of 3.5 months [77– 80]. Drug toxicity was generally mild, consisting of skin rash and diarrhea, more frequent at higher dosages. It has been suggested, based on some of these single-arm studies, that outcome might be related not only to the occurrence and severity of the skin reaction, but also to the dose used. This latter aspect was tested in a large phase III trial (1839 IL/0704; IMEX) in which 482 patients with R/M-SCCHN, unresponsive to platinum or unfit for platinum, were randomized in a threearmed study to receive either gefitinib 250 mg/day or gefitinib 500 mg/day or methotrexate 40 mg/m2 i.v. weekly [81]. Neither gefitinib 250 mg/day nor gefitinib 500 mg/day improved survival compared with single-agent methotrexate. OR rates were 2.7%, 7.6% and 3.9%, respectively and median OS was 5.6, 6 and 6.7 months, respectively. Tumor bleeding was observed more frequently in patients treated with gefitinib than those treated with methotrexate. Single-agent lapatinib (1500 mg/day) was associated with disappointing activity (no ORs) in a phase II study in 42 patients with R/M disease, 15 of whom had previously received treatment with an EGFR inhibitor [82]. Cohen et al. [84] 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. PS (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 PS and development of rash were associated with longer PFS and OS. EGFR mechanistic toxic effects that developed during therapy were also highly associated with benefit and indicate a relationship between drug exposure and outcome [84]. During ASCO 2010, interesting results were reported with BIBW 2992, a highly potent inhibitor of EGFR/erbB1 and erbB2. It retains activity for EGFRvIII mutation and provides a sustained blockage of receptor and inhibition of tumor cell proliferation. Seiwert et al. [83] presented results of a randomized, open-label, phase II study of BIBW 2992 versus cetuximab in R/M-SCCHN patients after failure of platinumcontaining therapy. The primary end point of that study was tumor shrinkage of target lesions before any crossover. Diarrhea, dehydration, epistaxis and asthenia occurred more frequently with BIBW 2992, but also tumor shrinkage occurred more frequently with BIBW 2992 than with cetuximab (OR 21.7% versus 13.3%). The DC was comparable (56.7% versus 61.7%). Median PFS with BIBW 2992 was 16 weeks (95% CI 10–19) and 10 weeks (95% CI 8–17) with cetuximab. BIBW is the first TKI to demonstrate antitumor activity in SCCHN that appears to be at least comparable to cetuximab. The data on response compare favorably versus all the other EGFRIs tested (Table 3). combinations with chemotherapy. A phase I/II trial of erlotinib and cisplatin performed by the Princess Margaret Hospital phase II consortium and the National Cancer Institute of Canada Clinical Trials Group in a population of platinumsensitive R/M-SCCHN patients revealed a response rate of 21% and a median OS of 7.9 months [85]. These data are similar to those reported by Burtness et al. [63] with the combination of

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cisplatin and cetuximab in similar patients, albeit that these latter data were obtained in a randomized trial setting. Combinations of the TKIs with cisplatin plus docetaxel (in Europe with gefitinib; in the USA with erlotinib) have shown interesting results in small groups of patients and did not cause more hematologic toxicity than normally observed with cisplatin plus docetaxel alone [86, 87]. However, ECOG [88] 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 in R/M-SCCHN patients. Although the combination was well tolerated and improved the time to progression from 2.0 to 3.5 months (P = 0.03), this did not translate into an improved OS. The ErbB2-directed antibody trastuzumab was added to paclitaxel and carboplatin in a phase II study that included patients with metastatic or recurrent SCCHN [89]. The response rate (36%) was no higher than what would be expected with this chemotherapy regimen alone.

treatment of R/M-SCCHN: summary Unfortunately, the outcome of patients with R/M-SCCHN is still dismal. In the absence of distant metastatic disease, salvage surgery and re-irradiation should be considered. When considering re-irradiation important prognostic factors, such as interval from previous radiation, recurrent tumor stage and tumor bulk should be taken into account next to the reirradiation dose. It is very doubtful whether patients with both co-morbidity and organ dysfunction might benefit from such an approach. The use (and also choice) of systemic therapies is very much dependent on the general condition of the patient, his/her age and whether he/she has symptomatic disease. Unfavorable prognostic factors for survival are weight loss, an ECOG PS of 1 (versus 0), a primary tumor in the oral cavity or hypopharynx, prior radiotherapy and good/moderate tumor cell differentiation. It seems of importance to take these factors into account when performing trials. None of the trials performed in the past, even those with reasonable sample size, have shown that aggressive platinumbased combination chemotherapy regimens lead to survival benefit when compared with single-agent methotrexate, cisplatin or 5-FU in R/M disease. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed mAb, to a standard chemotherapy regimen (platinum–5-FU) leads to an important survival benefit and this, with support of an additional smaller study in the USA, has changed practice.

disclosures J.B. Vermorken has participated in advisory boards of MerckSerono, Amgen, Genmap, Sanofi-aventis and Oncolytics.

references 1. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008; 359: 1143–1154. 2. Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer 2005; 5: 127–135. 3. http//www.cancer.net (accessed January 2010).

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4. Murar S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc 2008; 83: 489–501. 5. http: //www-dep.iarc.fr/globocan (accessed January 2010). 6. www.nccn.org (accessed on 27 January 2010). 7. Licitra L, Felip E. ESMO Guidelines Working Group. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 (Suppl 4): 121–122. 8. Forastiere AA, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med 2001; 345: 1890–1900. 9. Vermorken JB. Medical treatment in head and neck cancer. Ann Oncol 2005; 16 (Suppl 2): ii258–ii264. 10. Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2006; 24: 2644–2652. 11. Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol 1988; 15: 70–85. 12. Tanvetyanon T, Padhya T, McCaffrey J et al. Prognostic factors for survival after salvage reirradiation of head and neck cancer. J Clin 2009; 27: 1983–1991. 13. Gilbert H, Kagan AR. Recurrence patterns in squamous cell carcinoma of the oral cavity, pharynx, and larynx. J Surg Oncol 1974; 6: 357–380. 14. Hong WK, Bromer R. Chemotherapy in head and neck cancer. N Engl J Med 1983; 308: 75–79. 15. Spencer SA, Harris J, Wheeler RH et al. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J radiat Oncol Biol Phys 2001; 51: 1299–1304. 16. Janot F, de Raucourt D, Benhamou E et al. Randomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. J Clin Oncol 2008; 26: 5518–5523. 17. Murphy BA. Topoisomerases in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. Expert Opin Pharmacother 2005; 6: 85–92. 18. Martinez-Trufero J, Isla D, Adansa JC 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). 19. Park S, Lee S, Park J et al. 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). 20. Schrijvers D, Vermorken JB. Taxanes in the treatment of head and neck cancer. Curr Opin Oncol 2005; 17: 218–224. 21. Grau JJ, Caballero M, Verger E et al. Weekly paclitaxel for platin-resistant stage IV head and neck cancer patients. Acta Otolaryngol 2008; 31: 1–6. 22. Hitt R, Amador ML, Quintela-Fandino M et al. Weekly docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Cancer 2006; 106: 106–111. 23. Schornagel JH, Verweij J, de Mulder PH 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: 1649–1655. 24. Hong WK, Schaefer S, Issell B 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: 206–210. 25. Grose WE, Lehane DE, Dixon DO et al. 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: 577–581. 26. Vermorken JB, Catimel G, de Mulder P 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 Amer Soc Clin Oncol 1999; 18: 395a (Abstr 1527). 27. Guardiola E, Peyrade F, Chaigneau L 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: 2071–2076.

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symposium article 28. Morton RP, Rugman F, Dorman EB et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial. Cancer Chemother Pharmacol 1985; 15: 283–289. 29. Urba SG, Forastiere AA. Systemic therapy of head and neck cancer: most effective agents, areas of promise. Oncology (Williston Park) 1989; 4: 79–88. 30. Forastiere AA, Metch B, Schuller DE 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: 1245–1251. 31. Jacobs C, Lyman G, Velez-Garcı´a E 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: 257–263. 32. Clavel M, Vermorken JB, Cognetti F et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5fluorouracil (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: 521–526. 33. De Andres L, Brunet J, Lopez-Pousa A et al. Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J Clin Oncol 1995; 13: 1493–1500. 34. Eisenberger M, Krasnow S, Ellenberg S 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: 1341–1345. 35. Schantz SP, Harrison LB, Forastiere AA. Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In DeVita VT, Hellman S, Rosenberg SA (eds), Cancer: Principles and Practice of Oncology, 6th edition. Philadelphia: Lippincott-Raven Publishers 2001; 797–860. 36. Shin DM, Glisson BS, Khuri FR 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: 1325–1330. 37. Shin DM, Khuri FR, Glisson BS 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: 1316–1323. 38. Gibson MK, Li Y, Murphy B, Hussain MH 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: 3562–3567. 39. Samlowski WE, Moon J, Kuebler JP 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: 182–188. 40. Vermorken JB, Remenar E, van Herpen C et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–1704. 41. Posner MR, Hershock DM, Blajman CR et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–1715. 42. Janinis J, Papadakou M, Xidakis E 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: 128–131. 43. Specenier P, Van den brande J, Schrijvers D et al. Docetaxel, ifosfamide and cisplatin (DIP) in squamous cell carcinoma of the head and neck. Anticancer Res 2009; 29: 5137–5142. 44. Specenier P, Vermorken JB. Targeted therapies in head and neck cancer. Target Oncol 2007; 2: 73–78. 45. Cohen EEW. Novel therapeutic targets in squamous cell carcinoma of the head and neck. Semin Oncol 2004; 31: 775–768. 46. Xia W, Lau YK, Zhang HZ et al. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res 1999; 5: 4164–4174. 47. Ang KK, Berkey BA, Tu X 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: 7350–7356.

doi:10.1093/annonc/mdq453 | vii259

symposium article 48. Chung CH, Ely K, McGavran L 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: 4170–4176. 49. Eriksen JG, Steiniche T, Askaa J et al. The prognostic value of epidermal growth factor receptor is related to tumor differentiation and the overall treatment time of radiotherapy in squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2004; 58: 561–566. 50. Santini J, Formento JL, Francoual M et al. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 1991; 13: 132–139. 51. Licitra L, Rolland F, Bokemeyer C et al. Biomarker potential of EGFR gene copy number by FISH in the phase III EXRTREME study: platinum-based CT plus cetuximab in first-line R/M SCCHN. J Clin Oncol 2009; 27 (15 Suppl): 302s (Abstr 6005). 52. Scaltriti M, Baselga J. The epidermal growth receptor pathway: a model for targeted therapy. Clin Cancer Res 2006; 12: 5268–5272. 53. Kimura H, Sakai K, Arao T et al. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci 2007; 98: 1275–1280. 54. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004; 173: 4699–4707. 55. Schneider-Merck T, Lammerts van Bueren JJ, Berger S et al. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibodydependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol 2010; 184: 512–520. 56. Rapidis AD, Vermorken JB, Bourhis J. Targeted therapies in head and neck cancer: past, present and future. Rev Recent Clin Trials 2008; 3: 156–166. 57. Huang S, Armstrong EA, Benavente S et al. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 2004; 64: 5355–5362. 58. Matar P, Rojo F, Cassia R et al. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res 2004; 10: 6487–6501. 59. Baselga J, Trigo JM, Bourhis J et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinumrefractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5568–5577. 60. Herbst RS, Arquette M, Shin DM 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: 5578–5587. 61. Vermorken JB, Trigo J, Hitt R 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: 2171–2177. 62. Leon X, Hitt R, Constenla M et al. A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy. Clin Oncol 2005; 17: 418–424. 63. Burtness B, Goldwasser MA, Flood W et al. 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: 8646–8654. 64. Bourhis J, Rivera F, Mesia R 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: 2866–2872. 65. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–1127. 66. Hitt R, Irigoyen A, Nun˜ez J et al. Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma

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Annals of Oncology

67.

68.

69. 70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

of head and neck (SCCHN): Spanish Head and Neck cancer group (TTCC). J Clin Oncol 2007; 25 (18 Suppl): 302s (Abstr 6012). 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). Petrelli NJ, Winer EP, Brahmer J et al. Clinical cancer advances 2009 major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2009; 27: 6052–6069. Carteni G, Fiorentino R, Vecchione L et al. Panitumumab: a novel drug in cancer treatment. Ann Oncol 2007; 18 (Suppl 6): vi16–vi21. Vermorken JB, Sto¨hlmacher J, Davidenko I et al. An analysis of safety in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) receiving chemotherapy (CT) with or without panitumumab (pmab) in a phase III clinical trial (SPECTRUM). J Clin Oncol 2009; 27 (15 Suppl): 313s (Abstr 6050). Machiels JH, Subramanian S, Ruzsa 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: 7s (Suppl): Abstr LBA5506. Vermorken JB, Herbst RS, Leon X et al. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer 2008; 112: 2710–2719. Bier H, Hoffman T, Hauser U et al. Clinical trial with escalating doses of the antiepidermal growth factor receptor humanized monoclonal antibody EMD72000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx. Cancer Chemother Pharmacol 2001; 47: 519–524. Arteaga ME, Ledo´n N, Casaco´ A et al. Systemic and skin toxicity in Cercopithecus aethiops sabaeus monkeys treated during 26 weeks with a high intravenous dose of the anti-epidermal growth factor receptor monoclonal antibody nimotuzumab. Cancer Biol Ther 2007; 6: 1390–1395. Ramakrishnan MS, Eswaraiah A, Crombet T et al. Nimutuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. mAbs 2009; 1: 41–44. Babu KG, Viswanath L, Reddy BK et al. An open-label, randomized, study of h-R3mAb (nimotuzumab) in patients with advanced (stage III or IVa) squamous cell carcinoma of head and neck (SCCVHN): four-year survival results from a phase IIb study. J Clin Oncol 2010; 28 (15 Suppl): 428s (Abstr 5530). Soulieres D, Senzer NN, Vokes EE et al. 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. Cohen EE, Rosen F, Stadler WM et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21: 1980–1987. Cohen EE, Kane MA, List MA 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: 8418–8424. Kirby AM, A’Hern RP, DA´mbrosio C et al. Gefitinib (ZD1839, Iressa) as palliative treatment in recurrent or metastatic head and neck cancer. Br J Cancer 2006; 13; (94): 631–636. Stewart JS, Cohen EE, Licitra L et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2009; 27: 1864–1871. Abidoye OO, Cohen EE, Wong SJ et al. A phase II study of lapatinib (GW572016) in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 2006; 24 (18 Suppl): Abstr 5568. Seiwert TY, Clement PM, Cupissol D et al. BIBW 2992 versus cetuximab in patients with metastatic or recurrent head and neck cancer (SCCHN) after failure of platinum-containing therapy with a cross-over period for progressing patients: preliminary results of a randomized, open-label phase II study. J Clin Oncol 2010; 28 (15 Suppl): Abstr 5501. Cohen EE, Halpern AB, Kasza K et al. Factors associated with clinical benefit from epidermal growth factor receptor inhibitors in recurrent and

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metastatic squamous cell carcinoma of the head and neck. Oral Oncol 2009; 45: 155–160. 85. Siu LL, Soulieres D, en EX 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: 2178–2183. 86. 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).

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symposium article 87. 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). 88. Argiris A, Ghebremichael M, Gilbert J et al. A phase III randomized, placebocontrolled trial of docetaxel with or without gefitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (ECOG). J Clin Oncol 2009; 27 (15 Suppl): 303s (Abstr 6011). 89. Gillison ML, Glisson BS, O’Leary E et al. Phase II trial of trastuzumab (T), paclitaxel (P), and cisplatin (C) in metastatic (M) or recurrent (R) head and neck squamous cell carcinoma (HNSCC): response by tumor EGFR and HER2/neu status. J Clin Oncol 2006; 24 (18 Suppl): 282s (Abstr 5511).

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