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Originally published as JCO Early Release 10.1200/JCO.2008.21.5269 on March 16 2009 © 2009 American Society of Clinical Oncology.
Treating IIA/B Seminoma With Combination Carboplatin and RadiotherapyRoyal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom
Kent Cancer Centre, Maidstone, United Kingdom
Royal Sussex County Hospital, Brighton, United Kingdom
Royal Surrey County Hospital, Guildford, United Kingdom
Royal Marsden Hospital and The Institute of Cancer Research, Sutton, United Kingdom To the Editor: Garcia-del-Muro et al1 recently reported results from treating 72 patients with IIA/B seminoma with combination chemotherapy, giving a 5-year progression-free survival of 90% (95% CI, 82% to 98%) and overall survival of 95% (95% CI, 89% to 100%). Concluding that combination chemotherapy avoided long-term risks associated with radiotherapy (RT) they suggested this as an alternative treatment. While accepting these results, we remain unconvinced that this is a significant step forward in treating this patient group. In addition to the significant acute toxicity, combination chemotherapy for testicular cancer leads to a well-documented two-fold increased risk of cardiovascular disease.2–4 Chemotherapy is also (as for RT) associated with significant increases in second malignancy. Overall the odds ratio favors RT: subdiaphragmatic RT increases the risk of major late complication (second malignancy or cardiovascular disease) by 1.8-fold (95% CI 1.3- to 2.4-fold), whereas chemotherapy increases this risk by 1.9-fold (1.4- to 2.5-fold).5 Further the risk of second malignancy after subdiaphragmatic RT may be reduced by as much as half if treatment is restricted to the para-aortic region.6 Historically, the main stay of treatment has been RT to the para-aortic and ipsilateral pelvic lymph nodes. A review of 313 patients from seven studies with IIA/B seminoma treated with RT alone suggested 22 relapses: a crude relapse rate of 7%,7 though the risks may be higher in stage IIB disease and after relapsing on surveillance; 5-year relapse-free survivals (RFSs) from our previous report of 80 patients treated with RT alone were 84.9% for IIA and 69.4% for IIB.8 We agree that improving outcomes achieved by RT is a worthwhile goal, but believe this can be achieved without resorting to initial combination chemotherapy. We have previously published a series of 33 patients with seminoma stage IIA/B treated with carboplatin (one or two cycles) and RT between 1989 and 1997, achieving a 5-year RFS of 96.9%.8 Subsequently, since 1997, we have treated a further 29 patients (13 IIA and 16 IIB, including three patients who had relapsed while on surveillance for stage I disease). Twenty-eight patients received carboplatin dosed at area under curve (AUC) 7, one patient AUC6. With respect to RT, all patients received 30Gy in 15# MPD administered with 6 MV photons, over 3 weeks, commencing 4 weeks after administration of the carboplatin. RT fields treated the para-aortic (from D10/11 interspace to L5/S1) lymph nodes. The first five patients treated in this series received a boost to the involved node of 5Gy in 3 fractions over 3 days. No relapses have been observed with a median follow-up of 3.4 years (range, 0.6 to 7.5 years), giving a 3-year RFS of 100% (95% CI, 75.3% to 100%). One patient required surgical removal of residual radiological abnormality via retroperitoneal lymph node dissection. Histology from this tissue revealed elements of differentiated teratoma and histological review of the original orchidectomy specimen in the light of this revealed differentiated teratoma in the primary tumor. In stage I disease, the efficacy of carboplatin in safely eliminating clinically undetectable metastatic disease has been demonstrated in a large, randomized controlled trial.9 Our results, now on a cohort of over 60 patients, show that combining a single course of carboplatin with RT in stage IIAB seminoma is well tolerated and achieves excellent rates of long-term cure that compare favorably with the alternative treatments. By using this treatment we can avoid combination chemotherapy and its attendant risks and toxicities in the vast majority of patients. Though we still need to use RT to attain local control, we have been able, using this combination, to reduce both the RT dose (from 35 to 30 Gy) and treatment volume (from dog-leg to para-aortic field) with no obvious loss of control. This reduction in volume and dose should theoretically reduce the hazards of late toxicity associated with RT below those quoted above and, hence, more in favor of this approach.6 The main concern of this approach would be the hazard of using combination therapy. However, single agent carboplatin alone does not appear to result in an increase in cardiovascular or overall mortality, nor the incidence of second nontestes cancers.10 Indeed in reducing relapse, the addition of carboplatin to RT would reduce the need for a salvage regimen of bleomycin, etoposide, and cisplatin in patients relapsing after being treated with RT alone and either RT or second-line chemotherapy after combination chemotherapy. In summary, we believe that a single cycle of carboplatin followed by RT is both safer and more effective than combination chemotherapy in the management of stage IIA/B seminoma and represents perhaps the optimal balance of benefits in terms of minimizing long-term toxicity. This approach is included as the recommended treatment option for relapsing patients in the ongoing Medical Research Council TE24 trial of stage I seminoma surveillance strategies. To confirm these results we suggest a randomized trial of this approach compared with chemotherapy be performed. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT This work was undertaken in The Royal Marsden NHS Trust, which received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust, and the Cancer Research UK Section of Radiotherapy Grant No. C46/A2131. We acknowledge NHS funding to the NIHR Biomedical Research Centre. REFERENCES
1. 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. 2. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513–1523, 2003. 3. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725–1732, 2000. 4. van den Belt-Dusebout AW, Nuver J, de Wit R, et al: Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467–475, 2006. 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. Zwahlen DR, Martin JM, Millar JL, et al: Effect of Radiotherapy Volume and Dose on Secondary Cancer Risk in Stage I Testicular Seminoma. Int J Radiat Oncol Biol Phys 70:853–858, 2008.[Medline] 7. von der Maase H: Do we have a new standard of treatment for patients with seminoma stage IIA and stage IIB? Radiother Oncol 59:1–3, 2001.[CrossRef][Medline] 8. 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] 9. Oliver RT, Mason MD, Mead GM, et al: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: A randomised trial. Lancet 366:293–300, 2005.[CrossRef][Medline] 10. Powles T, Robinson D, Shamash J, et al: The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis. Ann Oncol 19:443–447, 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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