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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 928-930 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.950
Gefitinib and Cisplatin-Based Chemotherapy in Non-Small-Cell Lung Cancer: Simply a Bad Combination?Cell Biology and Preclinical Models Unit, INT-Fondazione Pascale, Naples, Italy To the Editor: The results of two randomized phase III studies, published in the March 1, 2004, issue of the Journal of Clinical Oncology, have clearly demonstrated that the addition of gefitinib to chemotherapy in untreated patients with non-small-cell lung cancer (NSCLC) has no effect on overall survival, time to progression, or response rate.1,2 The continuous schedule of administration of gefitinib might be in part responsible for these negative findings, since the antiproliferative effects of gefitinib might render tumor cells less sensitive to cytotoxic agents, as acutely discussed by Dr Baselga in his interesting Editorial.3 In this respect, I would like to add few points that I believe might be helpful to interpret the negative results of the aforementioned trials. In both INTACT (Iressa NSCLC Trial Assessing Combination Treatment) trials, patients were treated with a platinum-based regimen—either gemcitabine/cisplatin or paclitaxel/carboplatin.1,2 However, several preclinical studies have suggested a direct correlation between epidermal growth factor receptor (EGFR) activation and sensitivity to cisplatin, even in the absence of effects on cell proliferation. In particular, in1990, Christen et al demonstrated that treatment of ovarian carcinoma cells with EGF increased sensitivity to cisplatin, in the absence of any mitogenic effect.4 Interestingly, blockade of protein synthesis did not prevent the ability of EGF to affect cisplatin sensitivity. In agreement with these observations, Nishikawa et al isolated in vitro a cervical carcinoma cell line with increased sensitivity to cisplatin (ME180R) as compared with the parental cell line.5 The ME180R cisplatin-sensitive cell line showed levels of EGFR expression significantly higher as compared with the parental cells, and treatment of the parental cells with EGF increased their sensitivity to cisplatin. The sensitive cell line showed a reduced ability to repair cisplatin-induced DNA damage as compared with parental cells. In addition, Dr Arteaga et al demonstrated, in a very nice article, that reduction of the expression of the EGFR in MDA-MB-468 breast cancer cells resulted in a reduced sensitivity to cisplatin, without affecting their growth rate.6 This phenomenon was specific for cisplatin and its analog carboplatin, and it was associated with lower levels of DNA adducts following cisplatin treatment in the low-expressing EGFR cisplatin-resistant breast cancer cells as compared with cells expressing high levels of EGFR. However, such difference in DNA adducts did not account for the huge difference in IC50 for cisplatin observed between clones with high and low levels of EGFR expression, suggesting a direct effect of the EGFR on the apoptotic response to cisplatin independent of direct DNA damage. In agreement with this hypothesis, it has been more recently demonstrated that cervical carcinoma cells selected for low sensitivity to cisplatin express low levels of EGFR and high levels of p21WAF1, which might ultimately regulate sensitivity to cisplatin-induced apoptosis.7 Therefore, the above-mentioned results had clearly demonstrated that, at least in some experimental models, a negative interaction between blockade of the EGFR and sensitivity to cisplatin might occur. A brief suspension of gefitinib treatment before administration of cytotoxic drugs could have avoided any kind of interference between these agents. In this respect, two preclinical studies predicted synergism between gefitinib and chemotherapy.8,9 In the article by Ciardiello et al, tumor cells were treated with gefitinib the day after treatment with cytotoxic agents in the in vitro assays.8 By using this approach, synergism was observed for the combinations of gefitinib with different drugs, including oxaliplatin. However, several data suggest that the spectrum of activity of oxaliplatin and the mechanisms through which this drug induces DNA damage and apoptosis are significantly different as compared with cisplatin.10 Results of in vivo studies are shown in the same article. In these experiments, gefitinib was administered for 5 days per week, and therefore, treatment with gefitinib was suspended for 2 days before administration of each cycle of chemotherapy. The schedule of administration of gefitinib in the article by Sirotnak et al, which used combinations of gefitinib with both cisplatinum and carboplatinum, is less accurately described.9 However, a 2-day suspension of gefitinib treatment every week was scheduled in each experiment. Therefore, additive or synergistic effects of gefitinib in combination with different cytotoxic drugs were observed in preclinical studies in which an intermittent schedule of administration of gefitinib was employed. Interestingly, a high activity of gefitinib in combination with the FOLFOX-4 regimen (oxaliplatin, leucovorinm and fluorouracil) has been recently reported to occur in patients with colon carcinoma.11 In this trial, treatment with gefitinib started with the second cycle of chemotherapy. Therefore, the patients were not pretreated with gefitinib before administration of chemotherapy for at least two cycles of treatment. In conclusion, important lessons should be taken from the results of the INTACT studies. It is quite evident that preclinical data need to be carefully interpreted before scheduling clinical trials. In the case of gefitinib, contrasting results have been reported in the literature on the effects of EGFR blockade on the activity of cytotoxic drugs, with particular regards to cisplatin. More accurate preclinical studies should have explored the importance of the schedule of administration in these combinations. However, small phase II trials, aimed to identify the best schedule of administration of gefitinib and cytotoxic agents, could have provided important information. Therefore, these small, focused studies are strongly recommended to explore the activity of combinations of target based agents and cytotoxic drugs, rather than large phase III clinical trials. Author's Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have 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. Other Remuneration: Nicola Normanno, AstraZeneca. For a detailed description of these 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 of the Information for Contributors found in the front of every issue. Acknowledgment N. Normanno is supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC). REFERENCES
1. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004
2. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 2. J Clin Oncol 22:785-794, 2004
3. Baselga J: Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer: How do we go from INTACT to imapct? J Clin Oncol 22:759-761, 2004 4. Christen RD, Hom DK, MacLeod CL, et al: Epidermal growth factor regultes the in vitro sensitivity of human ovarian carcinoma cells to cisplatin. J Clin Invest 86:1632-1640, 1990
5. Nishikawa K, Rosenblum MG, Newman RA, et al: Resistance of human cervical carcinoma cells to tumor necrosis factor correlates with their increased sensitivity to cisplatin: Evidence of a role for DNA repair and epidermal growth factor receptor. Cancer Res 52:4758-4765, 1992
6. Dixit M, Yang J-L, Poirier MC, et al: Abrogation of cisplatin-induced programmed cell death in human breast cancer cells by epidermal growth factor antisense RNA. J Natl Cancer Inst 89:365-373, 1997
7. Donato NJ, Perez M, Kang H, et al: EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervical carcinoma cells progress from high to low cisplatin sensitivity. Clin Cancer Res 6:193-202, 2000
8. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000
9. Sirotnak FM, Zakowsky MF, Miller VA, et al: Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa) an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6:4885-4892, 2000
10. Raymond E, Faivre S, Chaney S, et al: Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther 1:227-235, 2002 11. Fisher GA, Cho CD, Halsey J, et al: A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. Presented at the 2004 Gastrointestinal Cancer Symposium, San Francisco, CA, January 22-24, 2004 Related Articles
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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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