|MINI SYMPOSIUM: HEAD AND NECK
|Year : 2012 | Volume
| Issue : 1 | Page : 1-5
Palliative weekly chemotherapy along with cetuximab in recurrent and metastatic head and neck cancers: A retrospective analysis
RR Rangaraju1, JB Sharma1, AK Dewan2, AK Anand3, Rawat Sheh4, A Jena5, AK Chaturvedi6
1 Senior Consultant Medical Oncology, BLKCC, Senior Consultant Medical Oncology, Action Balaji Cancer Hospital, New Delhi, India
2 Director HN Surgical Oncology, Rajiv Gandhi Cancer Institute, New Delhi, India
3 Director Radiation Oncology, Max Cancer centre, Saket, New Delhi, India
4 Senior Consultant, Radiation Oncology, RGCI, New Delhi, India
5 Senior consultant MRI, RGCI, New Delhi, India
6 Senior Consultant Imaging, RGCI, New Delhi, India
|Date of Web Publication||25-Jul-2012|
R R Rangaraju
Senior Consultant Medical Oncology, BLKCC, Senior Consultant Medical Oncology, Action Balaji Cancer Hospital, New Delhi
Background: This study was undertaken to report the results of weekly combination chemotherapy with cetuximab in recurrent/metastatic head and neck squamous cell carcinoma (R/M SCCHN). Materials and Methods: Retrospective analysis of 35 R/M SCCHN patients who received cetuximab with weekly paclitaxel and platin (cisplatin/carboplatin) from SCCHN August 2006 to October 2008 at our Institute was performed. Results: Thirty-five patients (33 [94.3%] males and 2 [5.7%] females) received the planned weekly chemotherapy protocol. Median age of these patients was 52 years. Of the SCCHN 32 evaluable patients, 25 patients showed symptomatic improvement and 7 showed no improvement. Radiological responses using RECIST criteria reported CR in 1 patient (3.1%), PR in 17 patients (53.1%), and SD in 6 patients (18.8%). The remaining six patients demonstrated disease progression while two could not be assessed. Median overall survival (OS) was 8.016 months (95% CI; 6.572--9.461) and median PFS was 5.782 months (95% CI; 4.521--7.044). The major chemotherapy-related grades 2 and 3 toxicity recorded was cetuximab-induced rash reported in 24 patients. No treatment-related death within 30 days was observed. Conclusion: Cetuximab with weekly combination chemotherapy (Paclitaxel + Platinum compound) has shown promise, demonstrating comparable response and outcomes with acceptable toxicity in R/M SCCHN patients.
Keywords: R/M squamous cell carcinoma of the head and neck, cetuximab, weekly chemotherapy, weekly paclitaxel
|How to cite this article:|
Rangaraju R R, Sharma J B, Dewan A K, Anand A K, Sheh R, Jena A, Chaturvedi A K. Palliative weekly chemotherapy along with cetuximab in recurrent and metastatic head and neck cancers: A retrospective analysis. Indian J Cancer 2012;49:1-5
|How to cite this URL:|
Rangaraju R R, Sharma J B, Dewan A K, Anand A K, Sheh R, Jena A, Chaturvedi A K. Palliative weekly chemotherapy along with cetuximab in recurrent and metastatic head and neck cancers: A retrospective analysis. Indian J Cancer [serial online] 2012 [cited 2013 May 22];49:1-5. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/1/98906
| » Introduction|| |
Recurrent and metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is a common problem in developing countries like India.  R/M SCCHN carries a poor prognosis with a median overall survival of 6-9 months and a median progression-free survival of 2-4 months. , Most patients with R/M SCCHN qualify either for palliative chemotherapy or best supportive care, as surgery and radiotherapy are generally not an option.  The standard approach to first-line treatment of this disease in patients with good performance status has been to use a platinum-based doublet regimen with either 5-fluorouracil (5-FU) or a taxane. , With advent of targeted therapy, combination of antiepidermal growth factor receptor (EGFR) agents with chemotherapy has changed the paradigms of management.
EGFR overexpression has been detected in 90% of SCCHN specimens and is associated with poor survival, radioresistance, and locoregional failure.  Cetuximab, that targets extracellular kinase domain of EGFR receptor, is the best-studied EGFR inhibitor.  Encouraging results in preclinical studies led to phase I and II trials, where it has shown remarkable consistency in efficacy in pretreated R/MSCCHN patients. Cetuximab has yielded response rates up to 5--15% when used as a single agent. , A phase II study established the safety and efficacy of cetuximab with cisplatin.  In comparison with cisplatin monotherapy, the combination improved overall survival from 8 to 9.2 months. Outcomes of a study evaluating polychemotherapy (cetuximab+ cisplatin+ 5 FU) demonstrated a median survival of 9.76 months.  These results set the stage for the landmark phase III EXTREME trial which was instrumental in establishing the role of cetuximab in first-line therapy for R/M SCCHN. 
Weekly administration of platinum in recent trials has been demonstrated to have reduced toxicity with similar efficacy and has remained the preferred choice outside context of clinical trials in the dose range of 30-40 mg/m 2 .  Paclitaxel schedules have also undergone revisions in breast, lung, and ovarian cancers and currently it is a well established that weekly paclitaxel is more effective, less toxic, and well tolerated than three weekly paclitaxel.  Weekly taxanes with carboplatin has been used as induction chemotherapy or palliative chemotherapy.  Therefore addition of cetuximab, a novel antitumor agents, to the regimen of paclitaxel and platinum agents can be considered as a logical option. This retrospective study aimed to assess the results of weekly cetuximab with paclitaxel and platinum combination in patients of R/M SCCHN. We analyzed responses, progression-free survival and overall survival, documented the side effects, in these patients treated with weekly chemotherapy (paclitaxel and a platinum compound) and cetuximab.
| » Materials and Methods|| |
We reviewed the clinical records of patients of R/M SCCHN patients who received cetuximab with weekly paclitaxel and a platinum agent (cisplatin or carboplatin) from August 2006 to October 2008 at our institute.
All patients were ≥18 years of age and had histologically or cytologically confirmed R/M SCCHN. They were previously treated with single or multimodal therapy using surgery, radiotherapy, or concurrent chemo-radiotherapy. They had performance status of 0--2; at least one bio-dimensionally measurable lesion; and adequate hematologic, renal, and hepatic function. Nasopharyngeal primary tumors did not form a part of this analysis.
The patients received weekly cetuximab along with single agent (Cisplatin or carboplatin [n=4]), 2 drugs [paclitaxel + cisplatin or carboplatin [n=23]), as described in [Table 1]. In a small number of patients (n=8), ifosfamide was used as a third chemotherapy agent. All patients had received appropriate premedication and adequate hydration. Baseline evaluation included estimation of complete blood count, liver function tests, and cardiac and pulmonary evaluation, X-ray or CT scan of the chest. Local imaging was done either with computerized tomography scan (CT) or magnetic resonance imaging (MRI). Response evaluation was carried out according to RECIST (Response Evaluation Criteria in Solid Tumours) criteria at the end of two cycles and subsequently after every two cycles.  Patients had received treatment for a maximum duration of 6 months or till intolerance or disease progression.
Overall survival (OS) was calculated from the time of the initiation of chemotherapy to the date of death or last confirmed day of survival. Progression-free survival (PFS) was calculated from the time of initiation of chemotherapy to documentation of progression or death from any cause. Chemotherapy-related toxicities were graded in accordance with the National Cancer Center Institute Common Toxicity Criteria version 2. 
Data were analyzed using SPSS (statistical package for social sciences) 19.0 software. The mean number of days of progression-free survival was compared using the Mann--Whitney test. Kaplan--Meir analysis was used to compare the overall survival and progression-free survival.
| » Results|| |
Thirty-five patients (33 [94.3%] males and 2 [5.7%] females) received the planned treatment. Median age was 55 years (SD + 10.8). [Table 2] summarizes the prior treatment received. Twenty-two patients (62.9%) had the history of smoking/chewing tobacco. Sites of the primary lesion recorded from data were tongue (n=15), larynx (n=2), valeculla (n=2), buccal mucosa (n=5), pharynx (3), alveolus (2), parotid (1), tonsil (1), pyriform fossa (3), and retromolar trigone (1).
Of the 35 patients, one patient was not evaluable and the responses were analyzed in 34 patients. Two patients expired during treatment due to progressive disease.
Of the 34 evaluable patients, 30 patients had symptomatic improvement and 4 had no symptomatic improvement. Radiological assessment with RECIST criteria revealed CR in 1 patient (3.1%), PR in 19 patients (54.3%), and SD in 7 patients (20.0%). The remaining 7 (20.0%) patients had disease progression. Overall response was observed in 27 patients (82.9%).
Median overall survival (OS) was 9.2 months (95% CI; 7.790--10.610). Among responders (CR, PR), the median survival was 10.00 months (95% CI, 7.005-12.995). In patients with SD it was 9.2 months (95% CI; 6.463-11.937) and with PD it was 6.20 months (95% CI; 6.463-11.937) [Figure 1]. The analysis by Log-rank (Mantle-Cox) analysis was significant with a P value of 0.003 (χ2 11.768, df 2).
|Figure 1: Overall survival in responders, non responders and disease stabilization|
Click here to view
Median progression-free survival (PFS) was 5.867 months (95% CI; 3.490--8.244) in all patients, while in responders, stable disease and nonresponders the median PFS was 6.433 months (CR, PR; 95% CI 5.703-7.164); 4.933 months (SD, 95% CI 3.650-6.216); and 2.133 months (95% CI 0.850-3.416), respectively [Figure 2]. The analysis by Log-rank (Mantle-Cox) analysis was significant with a P value of 0.000 ( 2 23.054, df 2).
|Figure 2: Progression free survival in responders, non responders and disease stabilization|
Click here to view
Adverse events observed in this study are listed in [Table 3]. The major treatment-related toxicity was cetuximab-induced skin rash in 24 patients. Severity of rash was mild in 8 patients (26.7%), moderate in 13 patients (43.3%), and severe in 3 patients (10.0%). Hematological toxicity was observed in 5 (16.50%) patients. There was delay in treatment due to toxicity in 10 patients (33.33%). Dose modifications were required in 5 (16.50%) patients. No treatment-related death was observed.
| » Discussion|| |
In this retrospective study, we analyzed 35 patients who received cetuximab in combination with weekly chemotherapy doublet (Paclitaxel +cisplatin/carboplatin) at a single institution in India, as first-line therapy in RM SCCHN. Our results indicate a survival with a median OS of 9.2 months in all patients and 10.0 months among patients with clinical benefit. The overall median PFS was 5.867 months with 6.433 months in patients with clinical benefit. Unlike the EXTREME study, we have used the cetuximab for a limited period and not until progression.
Available data on cetuximab in first-line therapy with platinum agents or combination chemotherapy (taxane and platinum) have demonstrated a remarkable consistency in efficacy in patients with R/M-SCCHN.  In our study from a single institution with a small sample size (n=35), we observed response rates and median survival times, similar to published trials [Table 4]. One study randomized 117 chemotherapy-naive patients to either cisplatin (100 mg/m 2 every 4 weeks) with placebo or cisplatin with cetuximab, and observed a statistically significant improvement in response rate from 10% to 26% with addition of cetuximab.  Another study evaluated cetuximab in combination with platinum and 5-FU (triplet), showed an overall response rate of 36% with a median survival of 9.76 months. 
The EXTREME study randomized 442 patients to receive either chemotherapy alone (5 FU and cisplatin or carboplatin or the same regimen along with weekly cetuximab followed by cetuximab till progression.  The addition of cetuximab to platinum-5-FU demonstrated survival benefit. The median OS was 7.4 months in the chemotherapy-alone group and 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). It 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 or carboplatin, although response rates with carboplatin were slightly less. In this study, administration of cetuximab with weekly chemotherapy for a duration of 4--6 months (considering economic limitations) without further cetuximab had demonstrated comparable response and survival.
Combination of cetuximab and chemotherapy has been able to demonstrate a survival benefit in R/M SCCHN over past three decades and should be considered as a new standard for as first-line or second-line therapy.  Addition of cetuximab to a weekly paclitaxel and platinum agent seems to be a good option for patients with R/M-SCCHN.  Our study demonstrates that cetuximab with weekly paclitaxel and a platinum agent is a well-tolerated regime with almost similar efficacy. With a massive burden of SCCHN in India, trials integrating anti-EGFR agents and other targeted agents with chemotherapy are warranted in the future to establish the treatment guidelines.
| » Acknowledgments|| |
Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India,(study site) Konnpal Anil Sharma, Ruchika Khetrapal, (study co-ordinators) are greatly acknowledged.
| » References|| |
|1.||Chocolatewala NM, Chaturvedi P. Role of human papilloma virus in the oral carcinogenesis: An Indian perspective. J Cancer Res Ther 2009;5:71-7. |
|2.||Specenier PM, Vermorken JB. Recurrent head and neck cancer: Current treatment and future prospects. Expert Rev Anticancer Ther 2008;8:375-91. |
|3.||Tsao A S. Novel therapies in metastatic head and neck squamous cell carcinoma. Commun Oncol 2009;6:310-6. |
|4.||Vermorken JB, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol 2010;21:vii252-61. |
|5.||Marur S, Forastiere A. Update on role of chemotherapy in head and neck squamous cell cancer. Indian J Surg Oncol 2010;1:85-95. |
|6.||Molin Y, Fayette J. Current chemotherapies for recurrent/metastatic head and neck cancer. Anticancer Drugs 2010;22:621-5. |
|7.||Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol 2008;6:742-50. |
|8.||Cohen EE. Standard and Emerging Systemic Therapies for Recurrent and/or Metastatic Squamous Cell Head and Neck Cancer. Illinois: American Society of Clinical Oncology. 348-51 [Last cited on 2012 May 08]. Available from: http://www.asco.org/ASCOv2/Home/Education%20and%20Training/Educational%20Book/PDF%20Files/2007/07head_neck03.pdf. |
|9.||Shin DM, Donato NJ, Perez-Soler R, Shin HJ, Wu JY, Zhang P, et al. Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 2001;7:1204-13. |
|10.||Burtness B, Goldwasser MA, Flood W, Matter 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. |
|11.||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. |
|12.||Vermorken J, Mesia R, Rivera F, Remener E, Kawecki A, Rottery S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-27. |
|13.||Gupta T, Agarwal JP, Ghosh-Laskar S, Parikh PM, D'Cruz AK, Dinshaw KA. Radical radiotherapy with concurrent weekly cisplatin in loco-regionally advanced squamous cell carcinoma of the head and neck: A single-institution experience. Head Neck Oncol 2009;1:17. |
|14.||Kikuchi J, Yamazaki K, Kinoshita I, Asahina H, Imura M, Kikuchi E, et al. Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer. Jpn J Clin Oncol 2004; 34:505-9. |
|15.||Nishino M, Jackman DM, Hatabu H, Yeap BY, Cioffredi LA, Yap JT, et al. New Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for advanced non-small cell lung cancer: Comparison with original RECIST and impact on assessment of tumor response to targeted therapy. AJR Am J Roentgenol 2010;195:W221-8. |
|16.||Common Toxicity Criteria version 2.0 [Internet]. Bethesda, Md: Cancer Therapy Evaluation Program, 1999 [Last Cited on 2012 May 09]. Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf |
|17.||Tejani MA, Cohen RB, Mehra R. The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics 2010;4:173-85. |
|18.||Petrelli NJ, Winer EP, Brahmer J, Dubey S, Smith S, Thomas C, 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;27:6052-69. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]