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In Reply

Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong Special Administrative Region (HKSAR), Hong Kong, China

We appreciate the comments by Dr Licitra et al on our experience with the antiepidermal growth factor receptor (EGFR) antibody, cetuximab (C225) in patients with nasopharyngeal carcinoma (NPC).¹ They have expressed reservations over the choice of study end points, response rate of this approach, and the definition of "platinum refractoriness" in this study. In response, we would like to emphasize that this study served primarily as a proof-of-concept for EGFR targeting in the treatment of NPC. This study was based on our preclinical work on the biologic relevance of EGFR in NPC and the inhibitory advantage of integrating cetuximab with conventional chemotherapy.^2,3 Reversal of platinum-resistance by cetuximab was not an intended end point of this study, and this concept was raised in the article purely in the context of discussing the postulated mechanisms of cetuximab-carboplatin activity observed in our patients. As discussed in a recent review article, ⁴ the hypothesis that cetuximab may reverse resistance to cisplatin has been demonstrated mainly in the preclinical setting. Although clinical activity has been reported with cetuximab and cisplatin in platinum-refractory patients with head and neck squamous cell carcinoma,⁵ this hypothesis remains to be proven ex vivo.

Our study reported seven partial responders to cetuximab and carboplatin, responses which were confirmed according to the Response Evaluation Criteria in Sold Tumors (RECIST) criteria. Any objective comparisons of the results of this study with other phase II studies should be made in light of their differences in sample size, patient selection, and study design. Our study involved 60 participants from multiple centers, of whom 85% had metastatic NPC and 30% had 2 lines of prior chemotherapy. Other phase II studies often involved a much smaller sample of participants (from 18 to 44 patients) from a single institution, where most patients had only one prior line of platinum-based chemotherapy, and also where patients with locoregional disease were well represented.^6-9 The wide CIs of the response rates reported by these smaller studies would make direct comparisons with our larger study difficult to interpret. Nonetheless, the selection of patients who were more likely to have an inferior treatment outcome is a potential drawback of our study, as this could have reduced the observed magnitude of benefit to cetuximab and carboplatin.

There is no published experience on the re-treatment of patients with platinum within 6 months of completing prior platinum in metastatic NPC. However, if we may draw an analogy with ovarian cancer, in which a platinum-free interval of 6 months predicts inferior response to platinum re-treatment,¹⁰ the platinum-free interval reported in the study should adequately reflect the "platinum-refractoriness" of most patients. As described, the median platinum-free interval, defined as the period from the time platinum was last received to the first dose of cetuximab, was 3.8 months (116 days), and most patients experienced progressive disease within 6.7 months during platinum-chemotherapy (203 days) in this study. Therefore, the chance of recruiting patients who might still be sensitive to platinum should be small.

Licitra et al have raised an interesting point about the need to maintain homogeneity when selecting patients for clinical trials based on recognized prognostic factors of NPC. Works from our institution and from others have identified several key prognostic factors for advanced NPC, including plasma Epstein-Barr virus level¹¹ and isolated intrathoracic metastasis.^12,13 It would be more relevant to incorporate some of these prognostic markers in a phase III setting in order to allow stratified randomization and/or analysis of results according to specific prognostic subgroups. Furthermore, at the time of this study, the influence of molecular heterogeneity in diluting the response to novel therapies in clinical trials had not been recognized.¹⁴ Therefore, the design of future studies on EGFR inhibitors should take into account the known molecular factors that may predict response to these novel agents.⁴

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Chan AT, 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[Abstract/Free Full Text]

2. Ma B, Poon T, To KF, et al: Expression and prognostic significance of epidermal growth factor receptor and HER2 protein in nasopharyngeal carcinoma. Head Neck 25:864-872, 2003[CrossRef][Medline]

3. Sung FL, Poon TC, Hui EP, et al: Antitumor effect and enhancement of cytotoxic drug activity by cetuximab in nasopharyngeal carcinoma cells. In Vivo 19:237-245, 2005[Abstract/Free Full Text]

4. Baselga J, Arteaga CL: Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23:2445-2459, 2005[Abstract/Free Full Text]

5. Baselga J, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21:226a, 2002 (abstr 900)

6. Foo KF, Tan EH, Leong SS, et al: Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 13:150-156, 2002[Abstract/Free Full Text]

7. Chua DT, 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]

8. 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]

9. Chua DT, Kwong DL, Sham JS, 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

10. Alberts DS: Treatment of refractory and recurrent ovarian cancer. Semin Oncol 26:8-14, 1999

11. Chan AT, Lo YM, Zee B, et al: Plasma Epstein-Barr Virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 94:1614-1619, 2002[Abstract/Free Full Text]

12. Teo PM, Kwan WH, Lee WY, et al: Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. Cancer 77:2423-2431, 1996[CrossRef][Medline]

13. Hui EP, Leung SF, Au JS, et al: Lung metastasis alone in nasopharyngeal carcinoma: A relatively favorable prognostic group—A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 101:300-306, 2004[Medline]

14. Betensky RA, Louis DN, Cairncross JG: Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol 20:2495-2499, 2002[Abstract/Free Full Text]

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Related Correspondence

• Is Restoring Platinum Sensitivity the Best Goal for Cetuximab in Recurrent/Metastatic Nasopharyngeal Cancer?
  Lisa Licitra, Paolo Bossi, Laura D. Locati, and Cristiana Bergamini
  JCO 2005 23: 7757-7758 [Full Text]

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