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Originally published as JCO Early Release 10.1200/JCO.2008.21.5657 on March 16 2009 © 2009 American Society of Clinical Oncology.
In ReplyDepartment of Medical Oncology, Institut Català d'Oncología L'Hospitalet, Barcelona, Spain We appreciate the comments by Gilbert et al1 regarding our study.2 However, they raise some issues that are worth commenting on. The association between radiotherapy and second malignancies in patients with seminoma has been extensively documented.3 This is the main reason we launched our study of first-line chemotherapy in IIA/B seminoma patients. The results of the study showed that chemotherapy constitutes a highly active and well-tolerated therapeutic alternative to radiotherapy for these patients.2 But, as stated by Gilbert et al in their letter, some recent studies have suggested that chemotherapy is also not devoid of long-term adverse effects in patients with germ cell tumors. Specifically, an increased risk of second malignancy as well as cardiovascular disease has been observed. However, it must be pointed out that the largest studies reported that the risk of second malignancy was clearly superior for radiotherapy than for chemotherapy.4,5 In the study quoted by Gilbert et al that was based on a nationwide cohort of 2,707 testicular cancer survivors, the risk of second malignancy was 2.6-fold increased after subdiaphragmatic radiotherapy compared with 2.1-fold after chemotherapy.5 This represents an advantage of chemotherapy over radiotherapy which should be taken into account. The risk of cardiovascular disease, however, was markedly greater after chemotherapy.5 This observation is worrying and needs particular attention because chemotherapy is the treatment most widely used in all situations in advanced germ cell tumors. Research to improve knowledge of the causes and the prevention as well as strategies addressed to closely monitor its occurrence and to avoid associated risk factors are needed. Gilbert et al1 propose a new approach for the treatment of these patients, which is the combination of radiotherapy with one cycle of carboplatin.6 The effect of carboplatin as a potentiator of radiation has long been documented.7 In fact, the activity of this treatment in the Patterson et al6 series seems promising. However, some recent studies have suggested that patients with testicular cancer who had received both chemotherapy and radiotherapy experienced a larger risk of solid tumors compared with radiotherapy or chemotherapy alone.4,8 In the study by Travis et al,4 which was based on a population of 40,576 testicular cancer long-survivors, patients treated with radiotherapy and chemotherapy had an excess relative risk of solid cancer of 2.9, whereas it was 2.0 and 1.8 for patients treated with radiotherapy and chemotherapy alone, respectively. In the study by Travis et al, the number of patients who had received both treatments is small, and probably most of them received aggressive chemotherapy, but this observation should not be ignored. It cannot be ruled out that the radiosensitization produced by carboplatin was associated with an improvement in efficacy but also with an increase in late toxicity. So, in a highly curable disease such as seminoma, reduction of sequelae of the treatment, especially when they could be life threatening, is a priority. Therefore, we recommend caution in the application of more aggressive therapies in these patients, at least until further data about late toxicity of this combination regimen are available. As stated in our article, further studies on long-term survivors with prolonged follow-up are necessary to identify and characterize more accurately long-term specific risks associated with the different available treatment alternatives. In addition, studies focused on identification of new predictive markers of response9 as well as those indicating risk of toxicity would be of great help to select the candidates for each treatment modality. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Gilbert DC, VanAs NJ, Beesley S, et al: Treating IIA/B seminoma with combination carboplatin and radiotherapy. J Clin Oncol 27:2101; 2009. 2. Garcia-del-Muro X, Maroto P, Guma J, et al: Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: A Spanish Germ Cell Cancer Group Study. J Clin Oncol 26:5416–5421, 2008. 3. Zagars GK, Ballo MT, Lee AK, et al: Mortality after cure of testicular seminoma. J Clin Oncol 22:640–647, 2004. 4. Travis LB, Fossa SD, Schonfeld SJ, et al: Second cancers among 40,576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 97:1354–1365, 2005. 5. van den Belt-Dusebout AW, de Wit R, Gietema JA, et al: Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25:4370–4378, 2007. 6. Patterson H, Norman AR, Mitra SS, et al: Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: Comparison with radiotherapy treatment alone. Radiother Oncol 59:5–11, 2001.[CrossRef][Medline] 7. Douple EB, Richmond RC, O'Hara JA, et al: Carboplatin as a potentiator of radiation therapy. Cancer Treat Rev 12:111–124, 1985 (Suppl A.[CrossRef][Medline] 8. Wanderås EH, Fossa SD, Tretli S: Risk of subsequent non-germ cell cancer after treatment of germ cell cancer in 2006 Norwegian male patients. Eur J Cancer 33:253–262, 1997.[CrossRef][Medline] 9. de Haas EC, Zwart N, Meijer C, et al: Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. J Clin Oncol 26:1817–1823, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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