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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7757-7758 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.7854
Is Restoring Platinum Sensitivity the Best Goal for Cetuximab in Recurrent/Metastatic Nasopharyngeal Cancer?Head and Neck Cancer Medical Oncology Unit, Medical Department–Istituto Nazionale Tumori, Milan, Italy To the Editor: Recurrent and/or metastatic nasopharyngeal cancer (NPC) is a chemosensitive neoplasm, with response rates exceeding 50% in chemotherapy-naive patients.1 Further chemotherapy lines, including cisplatin-based regimens, in patients with either recurring or progressing disease following previous platinum-based chemotherapy given as part of the primary treatment and/or for treatment of recurrence, provide response rates ranging from 14% to 77%.2-12 Median time to progression of responsive cases ranges from 4 to 25.3 months2,3,5,6,9,11,12 as compared with 2.5 to 6 months in patients with stable disease (SD).2,3,11 In this latter group of patients, a recent study by Chan et al13 reported that adding cetuximab to cisplatin obtained an overall response rate of 11.7%, along with 48.3% of patients with SD. The authors claim that these results, together with a favorable toxicity profile, justify the use of the combination. Moreover, they would support the finding that "cetuximab seems to be able to overcome resistance to previously administered chemotherapy." In our opinion, these results are unsatisfactory. Their overall response rate compares unfavorably with rates in other published studies on platinum-based pretreated cases. We understand that disease stabilization might well be an end point. However, the proportion of patients with SD is not tantamount to disease stabilization, since SD, recorded as the best response according to conventional response criteria, simply means that the patient did not have an early progression (only early progressions are codified as progressive disease, all the other cases being either partial response/complete response or SD, so that a patient might qualify for SD even if this response lasts for only a few weeks). Of course, time to treatment progression (TTP) is a much more appropriate method of rendering the real entity of disease stabilization. In this study, median TTP was 81 days. Interestingly, TTP was 173 days for partial responders, and 106 days for patients with SD. In a way, these results further confirm the clinical relevance of achieving a response, even under the perspective of disease stabilization. In other words, a significant freedom from disease progression was obtained in this series only for those patients achieving a partial response. The authors combined cetuximab with carboplatin in an effort to restore sensitivity to platinum, assuming that platinum is the most effective drug in the regimen. This strategy was employed with more success in recurrent/metastatic squamous cell head and neck cancer (SCCHN) and in metastatic colorectal cancer (CRC), by adding cetuximab to cisplatin and irinotecan, respectively.14,15 One may speculate on possible reasons for this different outcome. First, in contrast with studies on SCCHN and CRC, 30% of patients of the Chan et al series were heavily pretreated (receiving treatment as their third to seventh line of chemotherapy). Patients were enrolled onto the trial with progressive recurrent and/or metastatic disease while receiving or within 12 months after the completion of treatment with platinum-based chemotherapy. This type of selection was proposed to define a patients' population "progressive after platinum-based chemotherapy." However, it still probably includes cisplatinum-sensitive patients, because the authors themselves found that prolonged overall survival was dependent on the interval (> 90 days v < 90 days) between recent platinum-based chemotherapy and platinum-based second line chemotherapy, thus indicating that a platinum-free interval might be critical. Indeed, an homogeneous selection of patients based on recognized prognostic factors may be exceedingly important in studies of metastatic NPC.16,17 Second, NPC has long been recognized as a separate entity in the study of head and neck cancer, namely for its biologic, therapeutic, and prognostic features. Most importantly, in this regard, responsiveness of NPC to second line nonplatinum-containing regimens is far superior to SCCHN. In NPC, therefore, the combination of cetuximab with antineoplastic agents other than cisplatin could be well tried, unlike SCCHN, in which restoring sensitivity to cisplatin might be considered as its most reasonable use. This could aim at an increased response rate, not simply disease stabilization. In NPC, to date, response should be considered the first goal of medical treatment, since all available evidence suggests that it may translate into long-term survival,5,12 and possibly cure.18 Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
REFERENCES 1. Ma BB, Chan AT: Recent perspectives in the role of chemotherapy in the management of advanced nasopharyngeal carcinoma. Cancer 103:22-31, 2005[CrossRef][Medline] 2. Fandi A, Taamma A, Azli N, et al: Palliative treatment with low-dose continuous infusion 5-fluorouracil in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma type. Head Neck 19:41-47, 1997[CrossRef][Medline] 3. Lin JC, Jan JS, Hsu CY: Outpatient weekly chemotherapy in patients with nasopharyngeal carcinoma and distant metastasis. Cancer 83:635-640, 1998[CrossRef][Medline]
4. Hasbini A, Mahjoubi R, Fandi A, et al: Phase II trial combining mitomycin with 5-fluorouracil, epirubicin, and cisplatin in recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type. Ann Oncol 10:421-425, 1999 5. Chua DTT, Kwong DLW, Sham JST, et al: A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. Eur J Cancer 36:736-741, 2000 6. Ma B, Tannock I, Pond G, et al: Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer 95:2516-2523, 2002[CrossRef][Medline]
7. Foo KF, Tan EH, Leong SS, et al: Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 13:150-156, 2002 8. Airoldi M, Pedani F, Marchionatti S, et al: Carboplatin plus taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma. Tumori 88:273-276, 2002[Medline]
9. Ngan RKC, Yiu HHY, Lau WH, et al: Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: Report of a phase II study. Ann Oncol 13:1252-1258, 2002 10. Chua DTT, Sham JS, Au GK: A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 39:361-366, 2003[CrossRef][Medline] 11. Altundag K, Aksoy S, Gullu I, et al: Salvage ifosfamide-doxorubicin chemotherapy in patients with recurrent nasopharyngeal carcinoma pretreated with Cisplatin-based chemotherapy. Med Oncol 21:211-215, 2004[CrossRef][Medline] 12. Poon D, Chowbay B, Cheung YB, et al: Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma. Cancer 103:576-581, 2005[CrossRef][Medline]
13. Chan ATC, Hsu MM, Goh BC, et al: Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 23:3568-3576, 2005 14. Baselga J, Trigo J, Bourhis J, et al: Cetuximab plus cisplatin/carboplatin is active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck progressing to the same dose and schedule platinum based regimen. Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 900)
15. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 16. Ong YK, Heng DM, Chung B, et al: Design of a prognostic index score for metastatic nasopharyngeal carcinoma. Eur J Cancer 39:1535-1541, 2003 17. Toh CK, Heng D, Ong YK, et al: Validation of a new prognostic index score for disseminated nasopharyngeal carcinoma. Br J Cancer 92:1382-1387, 2005[CrossRef][Medline]
18. Fandi A, Bachouchi M, Azli N, et al: Long-term disease-free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type. J Clin Oncol 18:1324-1330, 2000
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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