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Originally published as JCO Early Release 10.1200/JCO.2007.15.9103 on October 20 2008 © 2008 American Society of Clinical Oncology. Chemotherapy As an Alternative to Radiotherapy in the Treatment of Stage IIA and IIB Testicular Seminoma: A Spanish Germ Cell Cancer Group Study
From the Institut Català d’Oncología, Institut d’Investigació Biomèdica de Bellvitge; Hospital de Sant Pau, Barcelona; Hospital Universitari Sant Joan, Reus; Hospital Universitario San Carlos; Hospital Gregorio Marañón, Madrid; Hospital Marqués de Valdecilla, Santander; Hospital de Navarra, Pamplona; Hospital Clínico, Valladolid; and Hospital La Fe, Valencia, Spain Corresponding author: Xavier Garcia-del-Muro, MD, Genitourinary Tumors and Sarcoma Unit, Department of Medical Oncology, Institut Català d’Oncologia L’Hospitalet, Avda Gran Via Km 2.7, 08907 L’Hospitalet, Barcelona, Spain; e-mail: garciadelmuro{at}iconcologia.net
Purpose To assess the long-term efficacy and toxicity of front-line cisplatin-based chemotherapy in patients with stage IIA or IIB testicular seminoma. Patients and Methods Untreated patients with pure seminoma of the testis after orchiectomy, with clinical stage IIA or IIB, were considered eligible for this prospective observational study. Chemotherapy consisted of either four cycles of cisplatin and etoposide or three cycles of cisplatin, etoposide, and bleomycin. Results Between April 1994 and March 2003, 72 patients were entered onto the study at 26 participating centers. Eighteen patients had stage IIA disease, and 54 patients had stage IIB disease. Eighty-three percent of patients achieved complete response, and 17% achieved partial response with residual mass. After a median follow-up time of 71.5 months, six patients with stage IIB disease experienced relapse, and one of these patients died as a result of seminoma. Three patients experienced non–seminoma-related deaths (two died from a further esophageal carcinoma, and one died from an upper digestive hemorrhage). The estimated 5-year progression-free survival rates for patients with stage IIA or IIB disease were 100% and 87% (95% CI, 77.5% to 97%), respectively. Five-year progression-free and overall survival rates for the whole group were 90% (95% CI, 82% to 98%) and 95% (95% CI, 89% to 100%), respectively. Severe granulocytopenia and thrombocytopenia were observed in eight and two patients, respectively. Mild to moderate emesis, stomatitis, and diarrhea were the most common nonhematologic effects. Conclusion Chemotherapy is a highly effective and well-tolerated treatment for patients with stage IIA or IIB seminoma and represents an available alternative that could avoid some of the serious late effects associated with radiotherapy. Further studies focusing on long-term toxicities of different treatment modalities are needed.
Testicular seminoma affects mainly young men in the third and fourth decades of their lives. Most patients have stage I disease on diagnosis (disease confined to testis) and have an excellent prognosis by management with orchidectomy followed by surveillance, radiotherapy, or carboplatin.1-3 Nevertheless, a small percentage of the patients will experience relapse during the follow-up period. For these patients and those who are diagnosed with more advanced disease, testicular seminoma is characterized by a tendency to spread primarily to lymph nodes and later hematogenously to the lung and other viscera. Given the exquisite sensitivity of seminoma to radiotherapy, this modality has long been considered the standard treatment for stage IIA and IIB seminoma. Radiotherapy, using different doses and target volumes, produces excellent results in these patients, with long-term relapse-free rates of greater than 85%.4-8 In patients with more advanced stages and in postradiotherapy relapses, cisplatin-based chemotherapy has demonstrated high activity, leading to high cure rates.9-13 Its efficacy seems to be greater than that of radiotherapy in bulky stage II disease.4,8 Therefore, cisplatin-based chemotherapy is now being widely used as a standard treatment for advanced seminoma stages. Consequently, the majority of patients, even those with advanced metastatic disease, are cured now by applying available therapies. However, several recent series showed that an increased risk of development of secondary malignancies, often arising in the previous irradiation ports, exists in long-term survivors after radiotherapy for stage I or II seminoma.14-17 Concern about this infrequent but extremely serious late effect has led to investigation of new alternatives for the management of these patients. The Spanish Germ Cell Cancer Group launched a prospective protocol of treatment with frontline cisplatin-based chemotherapy as an alternative to radiotherapy in stage IIA and IIB testicular seminoma. The purpose of the present study was to assess the long-term results and toxicity of this treatment modality in a large population of patients treated in a wide multicenter setting.
Patient Selection Patients with a histologic diagnosis of pure seminoma of the testis and clinical stage IIA (retroperitoneal lymph node metastases < 2 cm) or IIB (retroperitoneal lymph node metastases of 2 to 5 cm) disease were included in the study. Results concerning 34 of these patients were previously reported within a wider series of patients with stages II to IV seminoma,11 and their data are reviewed here with an updated follow-up. A central review of pathology was not performed in this study.
Patients had undergone prior inguinal orchidectomy. Staging procedures consisted of clinical examination; computed tomography scan of chest, abdomen, and pelvis; pre- and postoperative measurement of serum
Treatment
Outcome Evaluation and Statistical Analysis Response was determined by computed tomography scan, tumor marker assay, and histopathology findings at postchemotherapy surgery. Progression-free survival was defined as the time from the start of chemotherapy to the date of tumor relapse or progression. Overall survival was defined as the time from the start of chemotherapy to the date of death from any cause. Actuarial survival curves were calculated using the Kaplan-Meier method. The 5-year survival rate and its 95% CI were calculated using actuarial nonparametric method.
Patient Characteristics Between April 1994 and March 2003, 72 patients, who represented all of the patients treated at each of the 26 participating centers who were eligible and consented to participate, were enrolled onto the study. Median age was 32 years (range, 23 to 66 years). All patients underwent prior inguinal orchiectomy, and all presented with classical seminoma histology. Eighteen patients had stage IIA disease, and 54 had stage IIB disease. Thirteen of 72 patients had experienced a relapse of previous stage I disease on surveillance. In eight patients, prechemotherapy β-human chorionic gonadotropin serum levels were increased. The chemotherapy schedule administered consisted of E400P in 60 patients and BE500P in 12 patients. Nine patients received a total of three cycles, 60 patients received four cycles, and three patients received more than four cycles. Main patient characteristics are listed in Table 1. One patient with concomitant schizophrenia was lost to follow-up after chemotherapy. The median follow-up duration of the series was 71.5 months.
Response and Survival There were 60 (83%) complete responses with chemotherapy alone and 12 (17%) partial responses with residual mass and normal markers. No treatment failures to first-line chemotherapy were documented. In one patient, the residual mass was larger than 3 cm; in three patients, it was between 2 and 3 cm; and in eight patients, it was  2 cm. Two patients underwent resection of residual masses. Histologic findings of necrosis and fibrosis were found in both patients. No additional treatment was administered to any patient. After treatment, no patient with stage IIA seminoma but six patients with stage IIB seminoma experienced disease relapse. In these six patients, who had been treated in five different centers, the median time to relapse was 11.6 months (range, 5 to 35 months). One of the patients who experienced relapse had required a dose reduction from the original E400P regimen as a result of comorbidity, whereas the remaining five patients received full doses without dose reductions or significant delays. Relapses were seen in the retroperitoneum only in four patients and in the retroperitoneum, lung, and mediastinum in two patients. Initial chemotherapy had been E400P in all patients. Two patients were treated effectively with salvage second-line chemotherapy, and one additional patient was treated successfully with chemotherapy and radiotherapy. The other three patients experienced a further relapse. One of these patients was treated successfully with salvage surgery and radiotherapy, and another patient was treated successfully with chemotherapy; the third patient had progressive disease after radiotherapy and chemotherapy and died. Three patients experienced non–seminoma-related deaths during the follow-up. Two patients, one with stage IIA and one with stage IIB disease, developed an esophageal squamous cell carcinoma 4 and 2 years after seminoma treatment. The third patient, who had stage II disease, died as a consequence of an upper digestive hemorrhage 4 years after salvage chemotherapy for a relapse after E400P treatment. In these three patients, there was no evidence of seminoma at the time of death. The estimated 5-year progression-free survival rates for patients with stage IIA and IIB disease were 100% and 87% (95% CI, 77.5% to 97%; Fig 1), respectively. Five-year progression-free and overall survival rates for the whole group were 90% (95% CI, 82% to 98%) and 95% (95% CI, 89% to 100%), respectively (Fig 2).
Toxicity Severe toxicities were uncommon and primarily hematologic. There were no toxic deaths. Table 2 lists the maximum grade of common toxicities observed in each patient. Grade 3 or 4 granulocytopenia was seen in nine patients, and eight of these patients experienced at least one episode of febrile neutropenia. Grade 3 thrombocytopenia occurred in two patients. One patient experienced grade 3 anemia. Nonhematologic toxicity was, in general, of mild to moderate intensity. Emesis, stomatitis, and diarrhea were the most commonly reported adverse effects. One patient treated with E400P experienced reversible grade 3 pneumonitis. Grade 2 neurotoxicity was observed in four patients, and grade 1 ototoxicity occurred in two patients. Alopecia was universal. As yet, after a median follow-up time of close to 6 years, no significant late toxicity has been reported.
Over the last decade, several studies have demonstrated that cisplatin-based chemotherapy yields high cure rates in patients with bulky advanced seminoma and in patients who experience relapse after prior radiotherapy.9-13 However, in early stage II disease, the availability of radiotherapy has precluded the development of chemotherapy, until now. Radiotherapy has long been used for the treatment of stage IIA and IIB seminoma, and numerous series have shown excellent results with this treatment. The radiation dose administered is usually between 25 and 40 Gy, and the treatment volume includes the para-aortic and the ipsilateral pelvic lymph nodes. The long-term relapse-free survival rate is usually between 85% and 90% and seems to be superior for stage IIA compared with stage IIB disease.4-7 Nevertheless, the occurrence of relapses in a few patients, usually localized outside the radiation port, makes it necessary to have a long follow-up.4 Furthermore, radiotherapy is usually an acceptably well-tolerated treatment.5,18,19 To our knowledge, this study is the first to assess the activity of cisplatin-based combination chemotherapy as frontline treatment in early stage II seminoma. The study was performed as an observational study that included all consecutive nonselected patients seen in a wide multicenter setting, and therefore, it provides reliable information on the effectiveness of this treatment in routine clinical practice. The results showed that chemotherapy is, as expected, highly active in the treatment of these patients, producing complete or partial response with negative tumor markers in 100% of the patients and providing excellent progression-free and overall survival figures that compare favorably with those classically reported after radiotherapy. In addition, chemotherapy was, in general, well tolerated. Severe toxicity was infrequent, and it was manageable and reversible. The only previously reported experience of first-line chemotherapy treatment in early stage II seminoma used a single agent, carboplatin. Results were disappointing, showing a failure rate of 18%, with many patients requiring salvage treatment.20 This finding is not surprising and is consistent with the results of two randomized studies that demonstrated that cisplatin-based combination chemotherapy is more active than carboplatin alone in advanced seminoma patients.21,22 Another new approach that has been investigated is the combination of radiotherapy with a single course of carboplatin in stage IIA and IIB seminoma. In a series of 30 patients, the 5-year progression-free survival rate was 97%.23 These results are promising when compared with radiotherapy alone, but additional investigation is needed, particularly regarding toxicity of the combination. In our study, 60 patients received E400P, a modified regimen that included 400 mg/m2 of etoposide per cycle, and 12 patients received the standard BE500P regimen with 500 mg/m2 of etoposide per cycle. When the study was initiated in 1994, the E400P regimen was proposed with the intention of reducing the toxicity of chemotherapy by avoiding bleomycin and limiting the dose of etoposide because seminoma is a particularly sensitive subtype of germ cell tumor. Our first results in advanced seminoma showed promising activity and acceptable tolerance.11 Lately, a large randomized phase III trial established the benefit, in terms of survival, of the BE500P regimen versus another regimen with lower doses of etoposide and bleomycin for germ cell tumors (BE360P).24 Additionally, subsequent large studies have suggested that four cycles of E500P, with 500 mg/m2 of etoposide, could be an alternative to three cycles of BE500P for good-risk germ cell tumors.25,26 Therefore, nowadays, the recommended regimen of chemotherapy for stage IIA or IIB seminoma patients should be three cycles of BE500P or four cycles of E500P, instead of the E400P regimen. Furthermore, in our study, all relapses were observed after treatment with the E400P regimen, and none were observed after BE500P treatment. Although the number of patients treated with E400P was much larger, we cannot rule out a potential impact of lower dose etoposide on the relapse rate. In a highly curable disease such as stage IIA and IIB testicular seminoma, prevention of long-term sequelae of treatment is a priority, especially when these sequelae might compromise the life of the patient. Recently, consistent data from several clinical series with long follow-up and studies based on cancer registries have revealed the existence of an increased incidence of secondary malignancies in long-term survivors of stage I and II seminoma treated with radiotherapy.15,17,27-31 These tumors are usually located in radiotherapy fields and are commonly GI and genitourinary tract cancers, pancreatic cancer, and sarcoma.29,30 The occurrence of this rare but severe late complication, in patients who are usually young and otherwise cured, resulted in the need to investigate new management alternatives that minimize this risk. In stage IIA and IIB seminoma, primary treatment with chemotherapy, as is done in more advanced stages, could be a reasonable option. The results of our study showed that this approach is feasible, yielding excellent efficacy results with an acceptable tolerance. Reduction in radiation volumes and doses5 is another potential option that has been more extensively studied in stage I seminoma.32,33 In the study of Zagars et al,14 however, no differences were found in mortality as a result of secondary malignancies between patients receiving less than 25 Gy and those receiving more than 25 Gy. Therefore, further studies are needed to elucidate this issue. In our study, two patients who had not received radiotherapy developed an esophageal cancer during the follow-up period. An increased risk of occurrence of this type of cancer in testicular cancer survivors was recently described, but it had been initially interpreted as possibly related to radiotherapy.29,30 However, our observation suggests that the possible influence of other factors, such as chemotherapy, or the existence of shared risk factors cannot be ruled out and need further investigation. Indeed, a low but increased risk of development of acute myeloid leukemia associated with chemotherapy, especially when etoposide is administered in high cumulative doses, has been well established in testicular cancer survivors.34,35 Furthermore, recent large studies showed that survivors of testicular cancer have a consistently significant increased risk of secondary malignancies when compared with the general population.29-31,35-37 A collaborative study that included a large population of 40,576 long-term testicular cancer survivors showed that this risk persisted for at least 35 years and may be higher for younger patients.30 In this study, a significant risk of solid secondary tumors in patients treated with chemotherapy alone was observed, and this risk increased when radiotherapy and chemotherapy were combined. Although the number of analyzed patients treated with chemotherapy was low and the follow-up was short, this observation is particularly concerning and indicates that further studies are needed. Also, the potential occurrence of late noncancer toxicities in survivors of testicular cancer treated with different modalities should be considered. In particular, cisplatin-based chemotherapy has been associated with some known late effects in these patients. Nephrotoxicity, ototoxicity, and neuropathy can persist to some degree in a small percentage of patients,38 especially when a large number of cycles of cisplatin was administered. Infertility is not uncommon after chemotherapy, although many of these patients already had prior abnormalities in semen analysis. However, 50% to 80% of the patients recover normal sperm counts within 5 years from treatment.39 Radiotherapy seemed to have a more deleterious effect on fertility than chemotherapy in testicular cancer patients in one study.40 Of particular concern, several studies have recently reported an increased incidence of cardiovascular events in patients treated with cisplatin-based chemotherapy for germ cell tumors.41,42 The development of metabolic syndrome,43 a known cardiovascular risk factor, in some patients could contribute to this complication. Radiotherapy has also been associated with an increased risk of cardiac disease, mainly when prophylactic mediastinal irradiation had been administered.14,44 Furthermore, a recent large study showed that mortality as a result of noncancer causes, such as infection, digestive diseases, and circulatory diseases, is slightly increased in testicular cancer survivors.44 A recent study compared the long-term risks of second malignant neoplasms and cardiovascular diseases in a nationwide cohort of 2,707 testicular cancer survivors with a median follow-up time of 17 years.31 In this study, the risk of second malignancy was increased by 2.6-fold after subdiaphragmatic radiotherapy and by 2.1-fold after chemotherapy. The risk of cardiovascular disease was increased by 1.7-fold after chemotherapy, whereas it was not significantly increased after subdiaphragmatic radiotherapy. All of these data concerning long-term toxicities indicate that studies to better determine their causes and to quantify specific risks of the treatments are critical to assess the advantages and inconveniences of different treatment modalities. In conclusion, our study shows that chemotherapy is a highly effective and well-tolerated treatment for patients with stage IIA or IIB seminoma that yields excellent progression-free and overall survival rates. These results indicate that chemotherapy is an available alternative to radiotherapy in the treatment of these patients and could avoid some of the serious late effects associated with radiotherapy. Nevertheless, future studies focused on long-term toxicities of different treatment modalities are strongly recommended.
The author(s) indicated no potential conflicts of interest.
Conception and design: Xavier Garcia-del-Muro, Pablo Maroto, Josep R. Germà-Lluch Administrative support: Xavier Garcia-del-Muro, Josep R. Germà-Lluch Provision of study materials or patients: Xavier Garcia-del-Muro, Pablo Maroto, Josep Gumà, Javier Sastre, Marta López Brea, José A. Arranz, Nuria Lainez, Diego Soto de Prado, Jorge Aparicio, José M. Piulats, Josep R. Germà-Lluch Collection and assembly of data: Xavier Garcia-del-Muro, Pablo Maroto, Josep Gumà, Javier Sastre, Marta López Brea, José A. Arranz, Nuria Lainez, Diego Soto de Prado, Jorge Aparicio, José M. Piulats Data analysis and interpretation: Xavier Garcia-del-Muro, Xavier Pérez Manuscript writing: Xavier Garcia-del-Muro Final approval of manuscript: Xavier Garcia-del-Muro, Pablo Maroto, Josep Gumà, Javier Sastre, Marta López Brea, José A. Arranz, Nuria Lainez, Diego Soto de Prado, Jorge Aparicio, José M. Piulats, Xavier Pérez, Josep R. Germà-Lluch
The following investigators also contributed to this study: Agustí Barnadas, Hospital Trias I Pujol, Badalona; Jordi Alfaro, Hospital de Terrassa; Anna Balil, Hospital Arnau de Vilanova, Lleida; María José Mendez, Hospital Reina Sofia, Córdoba; Joan Carles, Hospital del Mar, Barcelona; Daniel Almenar, Hospital Dr Peset, Valencia; Joan Dorca, ICO Girona; Miguel Angel Climent, IVO Valencia; Amalia Velasco, Hospital la Princesa, Madrid; Javier Dorta, Hospital N.S. Candelaria, Tenerife; Jesús Montesinos, Hospital Parc Taulí, Sabadell; María Lomas, Hospital Infanta Cristina, Badajoz; Severina Dominguez, Hospital Txagorritxu, Vitoria; Antonio Colmenarejo, Hospital Central de la Defensa, Madrid; Sergio Vazquez, Hospital Xeral, Lugo; Miguel Sánchez, Hospital de Donostia; and David Olmos, Hospital Clínico de Málaga, Spain.
We thank Gema Berenguer and Ron Clapp for their contribution to this study.
published online ahead of print at www.jco.org on October 20, 2008. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis. J Clin Oncol 20:4448-4452, 2002 2. 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] 3. Aparicio J, Germa JR, Garcia del Muro X, et al: Risk-adapted management for patients with clinical stage I seminoma: The Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 23:8717-8723, 2005 4. Warde P, Gospodarowicz M, Panzarella T, et al: Management of stage II seminoma. J Clin Oncol 16:290-294, 1998 5. Classen J, Schmidberger H, Meisner C, et al: Radiotherapy for stages IIA/B testicular seminoma: Final report of a prospective multicenter clinical trial. J Clin Oncol 21:1101-1106, 2003 6. Chung PW, Gospodarowicz MK, Panzarella T, et al: Stage II testicular seminoma: Patterns of recurrence and outcome of treatment. Eur Urol 45:754-759, 2004[CrossRef][Medline] 7. Zagars GK, Pollack A: Radiotherapy for stage II testicular seminoma. Int J Radiat Oncol Biol Phys 51:643-649, 2001[CrossRef][Medline] 8. Mason BR, Kearsley JH: Radiotherapy for stage II testicular seminoma: The prognostic influence of tumor bulk. J Clin Oncol 6:1856-1862, 1988[Medline] 9. Gholam D, Fizazi K, Terrier-Lacombe MJ, et al: Advanced seminoma: Treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: A single-institution experience in 145 patients. Cancer 98:745-752, 2003[Medline] 10. Fosså SD, Oliver RT, Stenning SP, et al: Prognostic factors for patients with advanced seminoma treated with platinum-based chemotherapy. Eur J Cancer 33:1380-1387, 1997[Medline] 11. Arranz Arija JA, Garcia del Muro X, Guma J, et al: E400P in advanced seminoma of good prognosis according to the international germ cell cancer collaborative group (IGCCCG) classification: The Spanish Germ Cell Cancer Group experience. Ann Oncol 12:487-491, 2001 12. Loehrer PJ Sr, Birch R, Williams SD, et al: Chemotherapy of metastatic seminoma: The Southeastern Cancer Study Group experience. J Clin Oncol 5:1212-1220, 1987 13. Mencel PJ, Motzer RJ, Mazumdar M, et al: Advanced seminoma: Treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12:120-126, 1994[Abstract] 14. Zagars GK, Ballo MT, Lee AK, et al: Mortality after cure of testicular seminoma. J Clin Oncol 22:640-647, 2004 15. 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] 16. 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Horwich A, Oliver RT, Wilkinson PM, et al: A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma: MRC Testicular Tumour Working Party. Br J Cancer 83:1623-1629, 2000[CrossRef][Medline] 22. Bokemeyer C, Kollmannsberger C, Stenning S, et al: Metastatic seminoma treated with either single agent carboplatin or cisplatin-based combination chemotherapy: A pooled analysis of two randomised trials. Br J Cancer 91:683-687, 2004[Medline] 23. 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] 24. Toner GC, Stockler MR, Boyer MJ, et al: Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: A randomised trial—Australian and New Zealand Germ Cell Trial Group. Lancet 357:739-745, 2001[CrossRef][Medline] 25. Culine S, Kerbrat P, Kramar A, et al: Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-cell tumors: A randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP). Ann Oncol 18:917-924, 2007 26. Kondagunta GV, Bacik J, Bajorin D, et al: Etoposide and cisplatin chemotherapy for metastatic good-risk germ cell tumors. J Clin Oncol 23:9290-9294, 2005 27. Bokemeyer C, Schmoll HJ: Secondary neoplasms following treatment of malignant germ cell tumors. J Clin Oncol 11:1703-1709, 1993 28. Hanks GE, Peters T, Owen J: Seminoma of the testis: Long-term beneficial and deleterious results of radiation. Int J Radiat Oncol Biol Phys 24:913-919, 1992[Medline] 29. Richiardi L, Scelo G, Boffetta P, et al: Second malignancies among survivors of germ-cell testicular cancer: A pooled analysis between 13 cancer registries. Int J Cancer 120:623-631, 2007[Medline] 30. 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 31. 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 32. Jones WG, Fossa SD, Mead GM, et al: Randomized trial of 30 versus 20 Gy in the adjuvant treatment of stage I testicular seminoma: A report on Medical Research Council Trial TE18, European Organisation for the Research and Treatment of Cancer Trial 30942 (ISRCTN18525328). J Clin Oncol 23:1200-1208, 2005 33. Fosså SD, Horwich A, Russell JM, et al: Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial—Medical Research Council Testicular Tumor Working Group. J Clin Oncol 17:1146, 1999 34. Travis LB, Andersson M, Gospodarowicz M, et al: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 92:1165-1171, 2000 35. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89:1429-1439, 1997 36. Robinson D, Moller H, Horwich A: Mortality and incidence of second cancers following treatment for testicular cancer. Br J Cancer 96:529-533, 2007[CrossRef][Medline] 37. Schairer C, Hisada M, Chen BE, et al: Comparative mortality for 621 second cancers in 29356 testicular cancer survivors and 12420 matched first cancers. J Natl Cancer Inst 99:1248-1256, 2007 38. Bokemeyer C, Berger CC, Kuczyk MA, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-2932, 1996[Abstract] 39. Lampe H, Horwich A, Norman A, et al: Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 15:239-245, 1997 40. Huyghe E, Matsuda T, Daudin M, et al: Fertility after testicular cancer treatments: Results of a large multicenter study. Cancer 100:732-737, 2004[CrossRef][Medline] 41. 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 42. 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 43. Nuver J, Smit AJ, Wolffenbuttel BH, et al: The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 23:3718-3725, 2005 44. Fosså SD, Gilbert E, Dores GM, et al: Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 99:533-544, 2007 Submitted December 21, 2007; accepted July 8, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
-fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase; and ultrasonography of the contralateral testis. Patients were required to have stage IIA or IIB disease either at diagnosis or as a relapse of a previous stage I seminoma, no previous treatment with radiotherapy or chemotherapy, and normal 
60 mL/min. Patients with history of prior malignant disease and patients with significant cardiac or hepatic disease were not eligible for this study. The study was approved by the institutional review board of the coordinator center, acting as a central institutional review board. All patients gave informed consent according to the recommendations of the participating institutions. 
