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Gefitinib should not be ignored by oncologists and researchers
Novel agents for cancer therapy and cancer multidrug resistance promote an evolutionary arms race
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Xiaolong Yan, MD, PhD Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Jian Wang, Yongan Zhou, Yunfeng Ni, Xiaofei Li, Jing Han
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yanxiaolong{at}fmmu.edu.cn Xiaolong Yan, et al.
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Dear Editor, The article written by Drs. Ma and Adjei [1] has provided an excellent overview on "Novel Agents on the Horizon for Cancer Therapy." We benefited a great deal from the extensive content. This review also elucidated the success of target-based cancer agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. However, the authors avoided mentioning gefitinib, which had a winding pathway to success. This may lie in the fact that AstraZeneca informed the FDA that a large randomized study failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). At the same time, AstraZeneca also withdrew its application to market gefitinib in Europe shortly after this announcement in 2004. The study results in Asia were quite different. Treatment with gefitinib is most effective in women, patients who have never smoked, patients with pulmonary adenocarcinomas, and patients of Asian origin. In these populations, such treatment is associated with favorable rates of objective responses, progression-free survival, and overall survival [2-3]. These populations also have a relatively high incidence of somatic mutations in the region of the EGFR gene that encodes the tyrosine kinase domain [4]. NSCLC patients who had a base-pair deletion at exon 19 (del746_A750) or a point mutation at exon 21 (L858R), were highly responsive to gefitinib [5]. Lately, in the study by Mok et al [6], patients of East Asian origin with adenocarcinoma who had little or no exposure to tobacco smoke were treated with either gefitinib or standard double chemotherapy. The results showed 25 percent of patients on gefitinib had no cancer growth within 12 months, compared with 7 percent on chemotherapy. The median overall survival is slightly better with gefitinib than with chemotherapy. The presence of an EGFR mutation was a robust predictor of improved progression-free survival with gefitinib, as compared with carboplatin Cpaclitaxel, and of the benefit of gefitinib with respect to the objective response rate, indicating that patients in whom an EGFR mutation has been identified will benefit most from first-line therapy with gefitinib. The non-randomized European study by Rosell et al [7] shows the feasibility of large-scale screening for EGFR mutations in patients with advanced non-small cell lung cancer for selection for erlotinib therapy. Overall, the rate of survival of patients carrying an EGFR mutation who were treated with the tyrosine kinase inhibitor was relatively high, as compared with that of historical control subjects who were treated with chemotherapy. Accumulating studies show promising treatment effects with gefitinib on NSCLC patients with EGFR mutation recently. Those studies show us molecular analysis of EGFR and other pathways in the patient's tumor cells (including key mutations, copy-number changes of genes, and expression and activation of genes) may play a dominate role in individualized therapy of cancer. Based on those studies, the European Commission granted marketing authorization for oral gefitinib for locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor-tyrosine kinase (EGFR-TK) across all lines of therapy on July 1, 2009. Later, the American Society of Cinical Oncology updated the clinical practice guideline on chemotherapy for stage IV NSCLC. In the guideline, the first-line use of gefitinib may be recommended for patients with a known EGFR mutation. Either docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy [8]. The winding pathway of gefitinib sets us a very good example that detailed information, such as gender, ethnicity, confirmed habits, and molecular analysis, should be considered in targeted therapy, especially in this era when novel agents are on the horizon for cancer therapy. Yours Sincerely, Xiaolong Yan, MD, PhD (1) Jian Wang, MD, PhD (1) Yunfeng Ni, MD (1) Yongan Zhou, MD, PhD (1) Xiaofei Li, MD, PhD (1) Jing Han, MD, PhD (2) 1. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province, 710038, China 2. Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province, 710038, China Correspondence to: Prof. Xiaofei Li (lxfchest@fmmu.edu.cn, Department of Thoracic Surgery,) or Jing Han(hanjing@fmmu.edu.cn, Department of Ophthalmology); Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China [1] Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA Cancer J Clin 2009;59:111-137. [2] Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809-1818. [3] Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-1537. [4] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-967. [5] Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139. [6] Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin- paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957. [7] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-967. [8] Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small cell lung cancer. Clin Oncol. 2009 Dec 20;27:6251-66. |
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Xiaofang Xu, dentist Department of Oral Biology, School of Stomatology, The Fourth Military Medical University, 145 Chang, Bin Liu
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xiaofangxu-fmmu{at}hotmail.com Xiaofang Xu, et al.
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Dear Editor, We have recently read the excellent article written by Drs. Ma and Adjei [1] with great interest. The authors reviewed the various types of cancer targets and novel target-based anticancer drugs which are still in early phase clinical evaluation. They have provided a broad introduction to the classes of chemotherapeutic agents which are likely to enter the field of clinical practice in the near future. However, it is disappointing that the authors failed to call readers' attention to the multidrug resistance (MDR) polymorphism in cancer chemotherapy. The novel target-based, "tumor cell-specific" drugs had been intensified; however, cancer cells always showed resistance to those drugs immediately. For example, the imatinib mesylate mentioned by authors had a high rate of cytogenetic and haematologic responses in patients with chronic-phase CML in whom previous therapy had failed. Unfortunately, not long after initial use of imatinib, resistance to the drug was demonstrated in CML patients [2-4]. Cancer universally produces MDR which involves cellular and non-cellular mechanisms employed by cancer cells to survive cytotoxic actions of various structurally and functionally unrelated drugs; hence cancer MDR is still a major cause of failure in the clinical therapy of cancer patients. Development of novel agents for cancer therapy and the cancer MDR promote an evolutionary arms race. In this battlefield, we have to emphasize the knowledge of mechanisms of MDR in research of novel anticancer drugs, as Sun Tzu stated in The Art of War, "Know your enemy and know yourself; you will never be defeated in any battles." With best regards, Xiaofang Xu, DDS Correspondence: Bin Liu, DDS, PhD, Department of Oral Biology, School of Stomatology, The Fourth Military Medical University, 145 Chang Le Xi Road, XiĄŻan, Shaanxi Province 710032, P. R. China; E-mail: kqyljd@fmmu.edu.cn or Xiaofang Xu, DDS, Department of Oral Biology, School of Stomatology, The Fourth Military Medical University, 145 Chang Le Xi Road, XiĄŻan, Shaanxi Province 710032, P. R. China; E-mail: xiaofangxu- fmmu@hotmail.com References: [1] Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA
Cancer J Clin 2009; 59:111-137. |
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