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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 4  |  Page : 487-492
 

Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: A prospective observational study


1 Department of Medical Oncology, Jawaharlal Nehru Cancer Hospital and Research Centre, Bhopal, Madhya Pradesh, India
2 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
3 Department of Medical Oncology, Jubilee Mission Medical College and Research Institute, Thrissur, Kerala, India
4 Department of Pathology, Action Cancer Hospital, New Delhi, India

Date of Web Publication21-Apr-2017

Correspondence Address:
DC Doval
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_7_17

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 » Abstract 

BACKGROUND: In squamous cell carcinoma of the head and neck (SCCHN), epidermal growth factor receptor is expressed at very high levels. Hence, we have done this study to assess the response and tolerability of cetuximab and platinum-based chemotherapy in recurrent and metastatic (R/M) head and neck squamous cell cancer (HNSCC) in view of paucity of data from the Indian subcontinent. MATERIALS AND METHODS: In this prospective study, patients of R/M SCCHN were randomly enrolled from September 2012 to April 2015. Chemotherapy (cisplatin/carboplatin/5-fluorouracil) and cetuximab-based treatment were administered up to 6 cycles or unacceptable toxicity. The response rates (RRs), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: In total, fifty patients were enrolled. The median age was 51.0 years. A total of 255 cycles of treatment were administered (median = 6 cycles/patient). Four patients (8.0%) experienced complete response and 21 (42.0%) experienced partial response. Twenty-one patients (42.0%) had stable disease and four patients (8.0%) experienced progressive disease. The disease control rate was 92.0%. Median PFS was 5.3 months (95% confidence interval [CI]: 4.52–6.14 months). Median OS was 9.933 months (95% CI: 8.58–11.28 months). There was statistically significant correlation between overall response and Eastern Cooperative Oncology Group performance status (P = 0.014), site of tumor (P = 0.027), and histological grade of tumor (P = 0.001). The main Grade 3/4 side effects seen were hematological in 44 (88%) and gastrointestinal in 28 (56%) patients. CONCLUSIONS: The RR of cetuximab plus chemotherapy of >45% and the promising PFS rates are strong arguments for clinically testing this combination and this treatment schedule further in R/M HNSCC.


Keywords: Chemotherapy, cetuximab, head and neck cancer


How to cite this article:
Tiwari S, Goel V, John M, Patnaik N, Doval D. Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: A prospective observational study. Indian J Cancer 2016;53:487-92

How to cite this URL:
Tiwari S, Goel V, John M, Patnaik N, Doval D. Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: A prospective observational study. Indian J Cancer [serial online] 2016 [cited 2019 Dec 11];53:487-92. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/487/204784



 » Introduction Top


Head and neck squamous cell cancer (HNSCC) are the sixth most common cancers worldwide.[1] They are heterogeneous group of neoplasm arising from the oral cavity, oropharynx, hypopharynx, larynx, sinuses, and other sites within the upper aerodigestive tract. According to the GLOBOCAN 2012, the overall burden of death and incident cases of HNSCC worldwide are approximately 415,388 and 984,430, respectively.[2] In most countries, incidence and mortality rates have either remained stable or increased during the past four decades. It is because of increased incidence of human papillomavirus infection, increased tobacco habit, and more health facility.

In India, HNSCC accounts for approximately 30%–33% of all cancers. In male, HNSCC is the most common cancer followed by lung, stomach, and colon cancer. In female, it is the 5th most common cancer after breast (metro cities), cervix, colorectal, and ovary. Overall, it is the 3rd most common cancer on both sexes. The estimated number of HNSCC for the year 2010 in male and female are 122,643 and 53,148, which by the year 2020 will rise to 153,636 and 64,765 cases (19% of all cancers). The male to female ratio in India is 4:1. The stage of presentation is Stage III (locally advance) (80%) and Stage IV (6%–7%).[3]

Squamous cell carcinoma of the head and neck (SCCHN) is primarily a disease of older adults, occurring most frequently in patients older than age 45. Most of the patients present in locally advance stages, i.e., Stage III (about 80%), their 5-year survival rates remain as low as 40% despite of multimodality treatment. Moreover, these patients are at high risk for recurrence, and the risk of second primary tumors in view of field cancerization is also high and thus should be closely monitored.

Patients with recurrent and/or metastatic (R/M) SCCHN have a poor prognosis and outcome, particularly those whose disease has progressed on previous platinum-containing therapy. The epidermal growth factor receptor (EGFR) is expressed at very high levels in SCCHN and is associated with a poor prognosis.[4],[5] Several Phase III studies have shown that the EGFR-targeting monoclonal antibody, cetuximab, offers clinical benefit for patients with R/M SCCHN. Cetuximab monotherapy is active in patients whose cancer progresses on platinum-containing therapy or combination.[6] Tumor response and patient survival are in excess of what is achieved with commonly used therapies in this setting. Addition of a platinum chemotherapy regimen to cetuximab in patients with disease that progresses on platinum seems to confer no further benefit over cetuximab alone, either in terms of response rate (RR) or survival. In the first-line setting, cetuximab plus platinum and 5-fluorouracil (5-FU) significantly prolongs overall survival (OS) compared with platinum and 5-FU combination alone.[7] The superior survival observed with cetuximab compared with platinum-based treatment demonstrates that cetuximab is the very active treatment for R/M SCCHN and is of particular clinical significance.

Many studies have demonstrated the survival benefit of using cetuximab with chemotherapy in R/M head and neck cancer patients. Most of these studies are from Western countries, and there is a paucity of data from the Indian subcontinent, so we decided to do study the response and tolerability of cetuximab and platinum-based chemotherapy in R/M HNSCC in Indian patients.

Objective of the study

  • To evaluate the objective RRs, progression-free survival (PFS), and OS after treatment with targeted therapy (cetuximab) in combination with chemotherapy regimen in R/M head and neck cancer
  • To evaluate the toxicity profile of the chemotherapy and targeted therapy (cetuximab) combination.



 » Materials and Methods Top


Study design

This study was conducted in the Department of Medical Oncology, Rajiv Gandhi Cancer Hospital Institute and Research Centre, New Delhi. This institute is 280–300 bedded tertiary care, comprehensive cancer center with advance laboratory and research facility.

Patients who had confirmed histological diagnosis of R/M SCCHN, ineligible for local therapy (surgery and/or radiotherapy) with evidence of at least one lesion that is bidimensionally measurable by computed tomography (CT) or magnetic resonance imaging (MRI)/positron emission tomography (PET), and attending Department of Medical Oncology for definitive chemotherapy were enrolled in this study.

Fifty-eight patients with R/M HNSCC with primary sites of oral cavity, oropharynx, hypopharynx, and larynx were enrolled in study but final evaluation of fifty patients done.

The study protocol was approved by the Institutional Ethic Review Boards, and all patients provided informed written consent before treatment.

Chemotherapy and targeted therapy were administered on an inpatient basis. Each treatment cycle lasted 3 weeks. Standard treatment was defined as 6 cycles unless there was disease progression or unacceptable toxicity. Both chemotherapy (cisplatin/carboplatin/5-FU) and cetuximab were administered intravenously.

Injection cetuximab was administered in a dose of 400 mg/m 2 as loading dose over 2 h infusion on day 1 followed by subsequent weekly dose (day 8 and 15) of 250 mg/m 2 in normal saline over 1 h infusion at least 1 h before start of chemotherapy. Injection cisplatin was administered as a 60-min infusion in a dose of 60–75 mg/m 2 divided over 2 days with adequate pre- and post-chemotherapy hydration. Carboplatin was given as a 90-min infusion in 5% dextrose at a dose of area under the curve 5 in patients who were either intolerant to cisplatin or in whom cisplatin was contraindicated. The patients received an infusion of 5-FU at a dose of 500–750 mg/m 2/day for 3 days under continuous infusion. Antiemetic medications with 5-HT3 antagonists and steroids were administered before chemotherapy.

Patients received a maximum of 6 cycles of chemotherapy. Patients with unacceptable toxic effect of any drug will receive only the tolerated drug until disease progression. After the maximum of 6 cycles, patients who have at least stable disease (SD) will receive cetuximab monotherapy until the disease progress or unacceptable toxic effect.

Evaluations before each cycle of therapy included a complete history, physical examination, complete blood cell count, calculation of creatinine clearance, and measurement of blood chemistry values. The duration of any Grade 3 or 4 toxicity was documented by retesting every other day. To administer chemotherapy, patients were required to maintain a white blood cell >4000/mm 3, absolute neutrophil count >1500/mm 3, platelet count >100,000/mm 3, and serum creatinine <1.4 mg%.

The National Cancer Institute Common Toxicity Criteria (v. 4.0) were used to grade side effect of the total dose and number of cycles of chemotherapy received; days of interruption in chemotherapy were also specified in the pro forma to assess the tolerability and compliance of each patient.

Patients who had received at least one cycle of chemoimmunotherapy and had follow-up measurements performed to assess change in tumor size were assessable for response. RECIST response criteria (version 1.1) were used to define the antitumor effects with tumor size defined as the sum of the longest diameter of all target lesions. Responses were assessed just before the fourth cycle of chemotherapy and 3 weeks after completion of 6 cycles by clinical tumor measurements and documentation of the tumor size of measurable and nonmeasurable disease, using CT/MRI/PET scans, whatever scan used in baseline evaluation and follow-up for individual patient. All sites with measurable lesions were followed for response.

Data analysis

All analyses were performed with the statistical software SPSS version 21 (SPSS, Inc., Chicago, IL, USA). For response and progression data, two-sided 95% confidence intervals (CIs) were calculated based on an exact binomial probability at an alpha level of 0.05. PFS was estimated using Kaplan–Meier method. Data were analyzed using Chi-square test and Fisher's exact test, wherever appropriate. Statistical significance was defined as P< 0.05.


 » Results Top


Fifty-eight histological proven patients of R/M HNSCC of primary sites oral cavity, oropharynx, hypopharynx, and larynx were recruited in the study according to inclusion and exclusion criteria, and patient's consent was taken. Four patients did not receive chemotherapy because of deterioration in general condition because of rapid tumor progression after registration but before treatment, and this patient has not been included in the analysis. Of the rest, three were lost to follow-up without a radiologic response evaluation. One patient unfortunately had cerebrovascular events before treatment started; thus, fifty patients were evaluated for response, PFS, and toxicity.

Baseline patient and disease characteristics

The median age at presentation was 51.0 years (range, 31–69 years). More than two-third of patients were of age <65 years. The study included 46 men and 4 women, with good Eastern Cooperative Oncology Group performance status (ECOG PS) (46, 92% had ECOG PS 0–1). There was no statistically significant correlation seen between the age of the patient with the ECOG PS (P = 0.106). However, most of the patients with PS of two were beyond their fifth decade. The most frequent primary location of tumor was hypopharynx (n = 17). Fifty percent tumors were moderately differentiated squamous cell carcinoma. Twelve percent of tumors were reported as not otherwise specified. The majority of patients at the time of presentation were Stage IV (n = 34, 68% of whom 40% were Stage IVa). Most patients (38, 76%) had received prior therapy for cancer-related disease either alone or as a part of multimodality therapy as follows: Surgery (13, 26%), radiotherapy (36, 72%), and chemotherapy (28, 56%). After initial multimodality therapy, 38% of patients presented as recurrent disease and 36% presented as metastatic (including recurrent). Only 26% of patients in the study were upfront metastatic. Seventy-four percent of patients were addicted to tobacco (smoke/nonsmoke form) [Table 1].
Table 1: Baseline patient and disease characteristics (n=50)

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A total of 255 cycles of treatment were administered with a median number of 6 cycles/patient (range, 2–6 cycles). A total of 816 weeks of cetuximab were administered with median number of 18 weeks/patient (range, 6–26 weeks). A total of 17 patients (34%) had 1 or more adjustment including dose delay (n = 6, 12.0%) and dose reduction (n = 11, 22%). Grade 3 or 4 neutropenia caused dose delays, omissions, or reductions in 16% of treated patients, and Grade 3 or 4 thrombocytopenia was the reason for adjustment in 13% of treated patients. Thirty-seven patients (74.0%) patients received cisplatin-based chemotherapy while 13 patients (26.0%) were given carboplatin-based regimens. During study, no patient was shifted from cisplatin to carboplatin. Carboplatin was administered to those patients who had either poor PS or advance age.

Responses were assessing by RECIST response criteria (version 1.1). Fifty patients were assessable for response. Of the 50 enrolled patients, 4 patients (8.0%) experienced a complete response (CR) and 21 (42.0%) experienced a partial response (PR) for an overall RR (ORR) of 50%. Twenty-one patients (42.0%) had SD and four patients (8.0%) experienced progressive disease (PD). The disease control rate (CR + PR + SD) was 92.0%. Median PFS was 5.3 months (95% CI: 4.52–6.14 months) [Figure 1]. Median OS was 9.933 months (95% CI: 8.58–11.28 months) [Figure 2].
Figure 1: Kaplan–Meier distribution of progression-free survival

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Figure 2: Kaplan–Meier distribution of overall survival

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On multivariate analysis of the present study, it was found that there was statistically significant correlation between overall response and ECOG PS (P = 0.014), site of tumor (P = 0.027), and histological grade of tumor (P = 0.001) [Figure 3],[Figure 4],[Figure 5].
Figure 3: Eastern Cooperative Oncology Group performance status in relation to best response. CR = Complete response; PR = Partial response; PD = Progressive disease; SD = Stable disease; ECOG = Eastern Cooperative Oncology Group; PS = Performance status

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Figure 4: Best response in relation to disease site distribution. CR = Complete response; PR = Partial response; PD = Progressive disease; SD = Stable disease

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Figure 5: Best response in relation to disease histology. CR = Complete response; PR = Partial response; PD = Progressive disease; SD = Stable disease; SCC = Squamous cell carcinoma; MD-Moderately differentiated; WD = Well differentiated

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Hematologic toxicity was evaluated in all patients and in all cycles. Grade 3 or 4 leukopenia was experienced by 25 patients (50%), but febrile neutropenia occurred in only 5 (10%) patients. Grade 3 or 4 anemia occurred in 15 (30%), and Grade 3 or 4 thrombocytopenia was experienced by 9 patients (18%). While 12 patients (24%) required red cell transfusions, only 1 patient required platelet support. No patient experienced significant hemorrhage.

Overall Grade 3–4 adverse events (AEs) were reported in 44 (88%) patients; however, Grade 4 events occurred in only 26 (52%) patients. The most common Grade 3–4 nonhematological AEs were gastrointestinal (GI) toxicity and mucositis which happened in 28 (56%) patients. Grade 3 nausea/vomiting was experienced by ten patients (20%), and Grade 3 or 4 diarrhea was experienced by eight patients (16%). The most common GI AEs was anorexia, seen in 22 (44%) patients. The most common electrolyte abnormalities reported were hypomagnesemia in eight (16%) patients. There were nine cardiac events happened, but only two patients (4%) had Grade 3 events, rest other had Grade 1–2. Two patients (4%) who were on cisplatin-based therapy developed Grade 3 renal dysfunction, for which therapy was discontinued. Cetuximab-related Grade 3–4 infusional reaction developed in eight patients (16%) of which in four patients (8%), cetuximab was permanently discontinued. During treatment, four patients developed severe infection, two patients had pneumonia, and another two had GI infection followed by septic shock. Cetuximab-induced skin rashes developed in 32 patients but Grade 3 rashes developed only in 7 patients (14%). No Grade 4 skin rashes developed in any patient.


 » Discussion Top


HNSCCs, which include cancers of the oral cavity, oropharynx, hypopharynx, and larynx, are the sixth most common cancers worldwide and comprise approximately 6% of all malignancies.[1] In India, it accounts for approximately 30%–33% of all cancers (WHO). According to the GLOBOCAN 2012, in India, in male, it is the most common type seen in North India and Northeast and in female, it is the third most common type malignancy.[2]

Most studies on cetuximab and platinum-based chemotherapy in R/M HNSCC have been reported from Western countries. Indian patients are culturally and ethnically different from their Western counterparts, so the course of disease and response to different chemotherapeutic regimens may be different in an Indian scenario. The present study was prospectively designed to look at the efficacy, PFS, and tolerability of targeted therapy (cetuximab) in combination with platinum and 5-FU-based chemotherapy regimes in fifty patients with R/M HNSCC who presented at a tertiary care cancer hospital of North India.

The median age at presentation in the present study was 51.0 years which is slightly younger than most of the published study on the subject. In EXTREME trial,[7] the median age was 56.0 years, and in a Japanese trial, it was 61.0 years. The majority of the patients were male (92.0%), with PS 0–1 (92.0%) and which is also similar to reported literature.[7],[8],[9]

There was no statistically significant correlation seen between the age of the patient with the ECOG PS (P = 0.106). However, most of the patients with PS of 2 were beyond their fifth decade.

In our study population, 74.0% of patients were tobacco users in any form (smoke/nonsmoke) which is almost similar to global statistics.

The present study demonstrates that the combination of cetuximab with platinum (cisplatin/carboplatin) and 5-FU was effective in R/M HNSCC. Twenty-five of fifty patients included (50.0%) showed ORR which is slightly higher than what observed in cetuximab and chemotherapy arm in the EXTREME trial (36.0). This may be due to small number and younger age of patients in our trial. However, another trial done in Japan [8] on 33 patients had ORR 42%, which is similar to our study. We also observed CR in four patients (8.0%) which is similar to multicenter Japanese trial [8] (3.0%) and single center European trial [9] (6.5%).

The median PFS reported in this study was 5.3 months (95% CI: 4.52–6.14 months) which is similar to other study done in the past.[7],[8],[9] In Japanese study, the median PFS was 4.1 months, which may be because of high median age (61 years) and more number of hypopharynx cancer patients. However, given that the 95% CIs of the median PFS in all three trials including our study are overlapping which suggest that PFS in all these studies is similar.

On subgroup analysis of our study, it was observed a significant interaction of ORR with ECOG PS, tumor site, and tumor histology.

ORR in PS 0 was 58.6% and in PS 1 and 2 was 41%. No patients in ECOG PS 2 achieved response (P = 0.014). It indicates that PS is an important prognostic factor for chemotherapy response and thus survival.

Similarly, tumor histology and disease site are also important prognostic factor for chemotherapy response according to the present study. Well-differentiated tumor and cancer of oral cavity/oropharynx had significantly better response than poorly differentiated tumor and cancer of hypopharynx/larynx.

The response is also comparable or even better to the RR shown by cetuximab with other drug combination in R/M HNSCC. The combination of cetuximab with paclitaxel,[10] cetuximab with bevacizumab [11] and oxaliplatin, infusion - 5-FU, and cetuximab [12] has been studied and showed promising result.

Overall, the combination of cetuximab with platinum and 5-FU was very well tolerated in our study. The overall toxicity observed in the present trial was similar to that observed in the cetuximab arm in the EXTREME trial,[7] and no fatal outcome occurred. However, the incidence of Grade 3/4 AEs was higher compared with the EXTREME trial. Both hematological toxicity such as neutropenia, leukopenia, febrile neutropenia, and thrombocytopenia and nonhematological such as anorexia, vomiting and mucositis, skin rashes, electrolyte imbalance, and infection were higher than EXTREME trial. This toxicity happened despite reduced dose of chemotherapy protocol was used in our study (cisplatin - 75 mg/m 2 and 5-FU - 750 mg/m 2). However, the incidence of AEs of the present study was almost similar to that of multicenter Japanese trial.[8] This is most probably explained by poor tolerability of combination chemotherapy with cetuximab in Asian population.

There are very few published studies regarding outcomes of targeted therapy (cetuximab) with platinum and 5-FU-based chemotherapy in patients with R/M HNSCC in India. To the best of our knowledge, there is no published literature of Indian patients regarding the use of cetuximab and platinum/5-FU-based chemotherapy in R/M HNSCC.

One possible limitation to the study is the lack of complete follow-up to give an assessment of OS and 1- and 2-year survival rates which would allow a comprehensive comparison with other studies and a better assessment of the efficacy of the chemotherapy regimen.

The findings of our study have significant implications for clinical practice. The clinical outcome and toxicity profile of patients receiving cetuximab with chemotherapy for R/M HNSCC have been observed to be similar to that reported from the Western countries and Japan. There is accumulating evidence now that cetuximab and platinum-based chemotherapy is safe and effective in R/M HNSCC, and the findings of the current study affirm that the same findings may also be extrapolated for an Indian population. However, further long-term studies and randomized trials on Indian patients are warranted for confirmation.


 » Conclusions Top


On the basis of our experience, it can be concluded that the combination of cetuximab plus platinum (cisplatin/carboplatin) and 5-FU-based chemotherapy is active and well tolerated in Indian patients with R/M HNSCC. The RR of >45% and the promising PFS rates are strong arguments for clinically testing this combination and this treatment schedule further in R/M HNSCC. To the best of our knowledge, this is the first such study conducted in India. More research is required, especially in the Indian subcontinent, to assess the efficacy and tolerability of this regimen in Indian patients for confirmation and deserves further study.

Recommendation

To confirm the findings of the present study, further randomized controlled trials in Indian population should be done. Further trials with more numbers of patients and with longer follow-up should be done. There should be a comparative study, which should include chemotherapy regimen of the present study and other regimen used in R/M HNSCC. There should be a comparative study between cetuximab with newer targeted therapy.

Acknowledgments

We thank the Rajiv Gandhi Cancer Institute and Research Centre Hospital staff, especially people working in the Department of Medical Oncology. We also thank the Action Cancer Hospital staff, especially people working in the Department of Histopathology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008;371:1695-709.  Back to cited text no. 1
    
2.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://www.globocan.iarc.fr. [Last accessed on 2016 Jan 16].  Back to cited text no. 2
    
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Shenoi R, Devrukhkar V, Chaudhuri S, Sharma BK, Sapre SB, Chikhale A. Demographic and clinical profile of oral squamous cell carcinoma patients: A retrospective study. Indian J Cancer 2012;49:21-6.  Back to cited text no. 3
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Ongkeko WM, Altuna X, Weisman RA, Wang-Rodriguez J. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol 2005;124:71-6.  Back to cited text no. 4
    
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Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007;25:2164-70.  Back to cited text no. 5
    
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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.  Back to cited text no. 6
    
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Rivera F, García-Castaà±o A, Vega N, Vega-Villegas ME, Gutiérrez-Sanz L. Cetuximab in metastatic or recurrent head and neck cancer: The EXTREME trial. Expert Rev Anticancer Ther 2009;9:1421-8.  Back to cited text no. 7
    
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Yoshino T, Hasegawa Y, Takahashi S, Monden N, Homma A, Okami K, et al. Platinum-based chemotherapy plus cetuximab for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of a phase II trial. Jpn J Clin Oncol 2013;43:524-31.  Back to cited text no. 8
    
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de Mello RA, Gerós S, Alves MP, Moreira F, Avezedo I, Dinis J. Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: A retrospective study in a single comprehensive European cancer institution. PLoS One 2014;9:e86697.  Back to cited text no. 9
    
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Hitt R, Irigoyen A, Cortes-Funes H, Grau JJ, García-Sáenz JA, Cruz-Hernandez JJ; Spanish Head and Neck Cancer Cooperative Group (TTCC). Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012;23:1016-22.  Back to cited text no. 10
    
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Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, et al. Cetuximab and bevacizumab: Preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2013;24:220-5.  Back to cited text no. 11
    
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Clark JI, Greene JB, Lau Clark A, Dalal JS, Hofmeister CC. Phase I pilot study of oxaliplatin, infusional 5-FU, and cetuximab in recurrent or metastatic head and neck cancer. Med Oncol 2013;30:358.  Back to cited text no. 12
    


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