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Stage IIA and IIB testicular seminoma treated post-orchiectomy with radiation therapy versus other approaches: a population-based analysis of 241 patients

Abstract

Objectives

To evaluate post-orchiectomy utilization of radiation therapy (RT) versus other management approaches in stage IIA and IIB testicular seminoma patients.

Materials and Methods

Two hundred and forty-one patients with stage IIA and IIB testicular seminoma were identified between 1988 and 2003 using the Surveillance, Epidemiology, and End Results (SEER) database.

Results

Median follow-up was 10 years. Patients with stage IIA disease underwent RT more frequently than those with stage IIB disease (72% vs. 46%, respectively; P<0.001). There was no significant change in RT utilization for stage IIA or IIB disease between 1988 and 2003 (P = 0.89).

Conclusions

Between 1988 and 2003, stage IIA patients underwent RT more often than stage IIB patients in the United States. There was no significant change in RT utilization for stage IIA or IIB disease during this time period. Based on reports describing excellent progression-free survival with cisplatin-based chemotherapy, this approach has increased in popularity since 2003 and may eventually become the most popular treatment approach for both stage IIA and IIB testicular seminoma.

Testicular Neoplasms; Seminoma; Radiotherapy; Antineoplastic Agents


INTRODUCTION

Testicular cancer is the most commonly-diagnosed malignancy in men between the ages of 20 and 45 years. The American Cancer Society estimates that there were 7,920 new cases and 370 deaths due to testicular cancer in the United States (U.S.) in 2013 (1Hoffman KE, Chen MH, Punglia RS, Beard CJ, D’Amico AV. Influence of year of diagnosis, patient age, and sociodemographic status on recommending adjuvant radiation treatment for stage I testicular seminoma. J Clin Oncol. 2008;26:3937-42.). Eighty percent of testicular seminoma patients present with stage I disease and 11% present with stage II disease (2Morton GC, Thomas GM. Testis. In: Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK, editors. Principles and Practice of Radiation Oncology. 4th ed. Philadelphia: Lippincott, Williams & Wilkins; 2004; pp. 1763-84.). Standard of care post-orchiectomy for stage IIA and IIB testicular seminoma is radiation therapy (RT) or cisplatin-based combination chemotherapy (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41., 4Warde P, Huddart R, Bolton D, Heidenreich A, Gilligan T, Fossa S. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S435-43.).

Prior studies of RT for stage IIA and IIB testicular seminoma have involved fewer than 130 patients (5Chung PW, Gospodarowicz MK, Panzarella T, Jewett MA, Sturgeon JF, Tew-George, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol. 2004;45:754-59; discussion 759-60.

Classen J, Schmidberger H, Meisner C, Souchon R, Sautter-Bihl ML, Sauer R, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol. 2003;21:1101-6.

Detti B, Livi L, Scoccianti S, Gacci M, Lapini A, Cai T, et al. Management of Stage II testicular seminoma over a period of 40 years. Urol Oncol. 2009;27:534-8.
-8Hallemeier CL, Pisansky TM, Davis BJ, Choo R. Long-term outcomes of radiotherapy for stage II testicular seminoma--the Mayo Clinic experience. Urol Oncol. 2013;31:1832-8.). The purpose of this study is to analyze utilization of RT vs. other management approaches for stage IIA or IIB testicular seminoma in a relatively large number of patients based upon an analysis of the Surveillance, Epidemiology and End Results (SEER) database.

MATERIALS AND METHODS

The SEER program created by the National Cancer Institute (NCI) includes population-based cancer registries from 20 selected geographic areas in the U.S., covering approximately 28% of the national population. Data is submitted to the NCI registry on an annual basis without “identifiable” private information, and the NCI makes the data available to the public for research purposes. As a result, this study was exempt from Institutional Review Board review. Patient data was obtained via a query of the SEER dataset (November 2012 edition). The population for this study consisted of patients diagnosed with stage IIA and stage IIB pure testicular seminoma. Patients treated between 1988 and 2003 were identified using the following extent of disease codes for the primary tumor: T1: 10, 20, 30, and 40; T2: 15 and 45; T3: 50; and T4 60 and 70. For regional lymph nodes, extent of disease code one was used for N1 disease and code two was used for N2 disease. In the SEER database, patients are listed simply as having received RT or not having received RT. The database does not state the management approach that was used post-orchiectomy in patients who did not undergo RT. Also, it does not state whether a particular treatment approach (RT vs. other) was based upon physician recommendation or patient preference. In addition, RT and chemotherapy details, including dosages, are not included in the SEER database. Moreover, initial volume of nodal disease, relapse-free survival including sites of relapse, and non-lethal toxicities are not included. Patients in whom the stage grouping was unknown were excluded. Stage IIC disease was excluded because cisplatin-based combination chemotherapy for good-risk patients as defined by the International Germ Cell Cancer Collaborative Group (IGCCCG) constitutes the standard of care (9International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997;15:594-603.), precluding a statistical analysis of RT vs. other management approaches. There is no consensus on the definition of educational level. A low educational level was defined in this study as a high school graduation rate of <75%, a moderate educational level was defined as a high school graduation rate of 75-85%, and a high educational level was defined as a high school graduation rate of >85%.

Statistical analysis was performed using SAS 9.2 and JMP 7 (SAS Institute Inc., Cary, NC). Survival analysis was carried out using Kaplan-Meier estimates. The log-rank test was used to test for differences in survival. A non-parametric test of medians was used to assess continuous variables. A P-value less than 0.05 was considered to be statistically significant. The Cox proportional hazard model was used for univariate and multivariate analyses to assess the effect of patient characteristics on outcomes.

RESULTS

Patient Characteristics

One hundred and forty-five of 241 (60%) patients had stage IIA testicular seminoma and 96/241 (40%) patients had stage IIB testicular seminoma in the SEER database between the years of 1988 and 2003. Patient characteristics are presented in Table-1.

Table 1
Characteristics of Stage IIA and IIB Testicular Seminoma Patients.

Stages IIA and IIB Combined

Median follow-up was 10 years. Twenty-two of 241 (9%) patients died. For stages IIA and IIB combined, the 5-, 10-, and 15-year overall survival (OS) rates were 95%, 91%, and 89%, respectively. The 5-, 10-, and 15-year cause-specific survival (CSS) rates were 98%, 97%, and 97% respectively.

Stage IIA vs. IIB

Race, age, educational level, and marital status did not correlate with patient selection for RT. Patients with T1 disease underwent RT more frequently than those with T3 disease (64% vs. 16%, respectively; P<0.001). Also, patients with stage IIA disease underwent RT more frequently than those with stage IIB disease (72% vs. 46%, respectively; P <0.001). There was no significant change in RT utilization for stage IIA or IIB disease between 1988 and 2003 (P = 0.89). Causes of death in stage IIA and IIB patients are presented in Table-2.

Table 2
– A) Causes of Death in Stage IIA Testicular Seminoma Patients, B) Causes of Death in Stage IIB Testicular Seminoma Patients.

Patients with stage IIA disease who received RT had a 5-, 10-, and 15-year OS rate of 96% compared with 88%, 77%, and 77%, respectively, for those who underwent other management approaches (P = 0.008; Figure-1). The 5-, 10-, and 15-year CSS rate for stage IIA disease was 97% for RT compared with 96%, 92%, and 92%, respectively, for other management approaches (P = 0.30).

Figure 1
Overall survival for stage IIA testicular seminoma patients managed with radiation therapy vs. other approaches.

Improved OS (P = 0.03; Figure-2) was noted in patients with stage IIB disease who received RT (5-, 10-, and 15-year OS rates of 98, 96%, and 88%, respectively) as opposed to no RT (5-, 10-, and 15-year OS rates of 90%, 86%, and 86%, respectively). The 5-, 10-, and 15-year CSS rate was 98% for stage IIB patients who received RT compared with 98%, 96%, and 96%, respectively, for those who underwent other management approaches (P = 0.60).

Figure 2
Overall survival for stage IIB testicular seminoma patients managed with radiation therapy vs. other approaches.

Univariate and Multivariate Analyses

On univariate analysis, race, educational level, marital status, treatment year, and T and N stage were not associated with OS or CSS. Increasing age was associated with worse OS (P = 0.009), but not CSS (P = 0.11). Age was associated with worse OS on multivariate analysis as well, adjusting for race, T and N stage, year of treatment, use of RT, marital status, and educational level. The use of RT correlated with improved OS (HR 0.30; 95% CI: 0.12-0.74; P = 0.008) but not CSS (P = 0.35) on univariate analysis. The use of RT correlated with improved OS on multivariate analysis as well (HR 0.40; 95% CI: 0.15-0.90; P = 0.02).

DISCUSSION

The bulk of retroperitoneal adenopathy is the most important prognostic factor in stage II disease (5Chung PW, Gospodarowicz MK, Panzarella T, Jewett MA, Sturgeon JF, Tew-George, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol. 2004;45:754-59; discussion 759-60.). There have been no prospective, randomized trials involving stage IIA or IIB testicular seminoma due to the rarity of such patients. As a result, treatment recommendations have commonly been guided by reports from single institutions (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41.).

One limitation of the SEER database is a lack of randomization with regards to treatment. Other limitations include a lack of treatment details in the no RT group such as chemotherapeutic agents and doses.

In a highly curable disease such as stage IIA and IIB testicular seminoma, prevention of long-term complications of treatment is a priority. Retroperitoneal RT increases the relative risk (RR) of second non-germ-cell malignancies, including gastric (RR 4.1), pancreatic (RR 3.8), and colon (RR 1.9) cancers (1010 Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354-65.). Also, several groups have reported that retroperitoneal RT results in a twofold or greater risk of cardiovascular disease beyond 15 years, particularly when prophylactic mediastinal/supraclavicular RT is added (1111 Haugnes HS, Wethal T, Aass N, Dahl O, Klepp O, Langberg CW, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol. 2010;28:4649-57.

12 Huddart RA, Norman A, Shahidi M, Horwich A, Coward D, Nicholls J, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol. 2003 Apr 15;21(8):1513-23.
-1313 Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol. 2004;22:640-7.). Late effects are less well-defined for chemotherapy than they are for RT (1010 Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354-65.). The deleterious effects of 3-4 cycles of cisplatin-based chemotherapy on fertility are transitory, reversible, and dose-dependent (1414 Huyghe E, Matsuda T, Daudin M, Chevreau C, Bachaud JM, Plante P, et al. Fertility after testicular cancer treatments: results of a large multicenter study. Cancer. 2004;100:732-7.). Huyghe et al. (1414 Huyghe E, Matsuda T, Daudin M, Chevreau C, Bachaud JM, Plante P, et al. Fertility after testicular cancer treatments: results of a large multicenter study. Cancer. 2004;100:732-7.) suggested that RT has a more deleterious effect on fertility than chemotherapy in testicular cancer patients. However, RT in that study was antiquated by today’s standards. Fertility can be preserved when the RT dose to the remaining testis is reduced to less than 2 Gy (1515 Malas S, Levin V, Sur RK, Donde B, Krawitz HE, Pacella JA. Fertility in patients treated with radiotherapy following orchidectomy for testicular seminoma. Clin Oncol (R Coll Radiol). 1994;6:377-80., 1616 Nalesnik JG, Sabanegh ES Jr, Eng TY, Buchholz TA. Fertility in men after treatment for stage 1 and 2A seminoma. Am J Clin Oncol. 2004;27:584-8.). The cumulative incidence of spermatogenesis as a function of time appears to be similar after modern RT and cisplatin-based chemotherapy (1616 Nalesnik JG, Sabanegh ES Jr, Eng TY, Buchholz TA. Fertility in men after treatment for stage 1 and 2A seminoma. Am J Clin Oncol. 2004;27:584-8.

17 Christensen TB, Daugaard G, Geertsen PF, von der Maase H. Effect of chemotherapy on carcinoma in situ of the testis. Ann Oncol. 1998;9:657-60.
-1818 Malas S, Levin V, Sur RK, Donde B, Krawitz HE, Pacella JA. Fertility in patients treated with radiotherapy following orchidectomy for testicular seminoma. Clin Oncol (R Coll Radiol). 1994;6:377-80.). A low but increased risk of development of acute myeloid leukemia is associated with chemotherapy, especially when etoposide is administered in high cumulative doses (1919 Travis LB, Andersson M, Gospodarowicz M, van Leeuwen FE, Bergfeldt K, Lynch CF, et al. Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst. 2000;92:1165-71.). Travis et al. (1010 Travis LB, Fosså SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97:1354-65.) observed significantly increased risks of solid cancers among testicular cancer patients treated with RT alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). Huddart et al. (1212 Huddart RA, Norman A, Shahidi M, Horwich A, Coward D, Nicholls J, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol. 2003 Apr 15;21(8):1513-23.) observed an increased incidence of cardiovascular events in germ cell tumor patients treated with cisplatin-based chemotherapy. van den Belt-Dusebout et al. (2020 van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. 2007;25:4370-8.) reported that retroperitoneal RT strongly increases the risk of second malignancies but not of cardiovascular disease, whereas chemotherapy increases the risks of both second malignancies and cardiovascular disease. In addition, cisplatin-based chemotherapy has been associated with nephrotoxicity, ototoxicity, and neuropathy (2121 Horwich A, Dearnaley DP, Sohaib A, Pennert K, Huddart RA. Neoadjuvant carboplatin before radiotherapy in stage IIA and IIB seminoma. Ann Oncol. 2013;24:2104-7.), especially when a large number of cycles of cisplatin is given. Fossa et al. (2222 Fosså SD, Gilbert E, Dores GM, Chen J, McGlynn KA, Schonfeld S, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst. 2007;99:533-44.) observed that men treated with chemotherapy (with or without RT) in 1975 or later had higher mortality from all non-cancer causes (standardized mortality ratio (SMR) = 1.34, 95% CI = 1.15 to 1.55), all circulatory diseases (SMR = 1.58, 95% CI = 1.25 to 2.01), all infections (SMR = 2.48, 95% CI = 1.70 to 3.50), and all respiratory diseases (SMR = 2.53, 95% CI = 1.26 to 4.53). Active surveillance is not a management option post-orchiectomy for stage IIA and IIB disease; however, it is the preferred approach for stage IA and IB disease (2323 Motzer RJ, Agarwal N, Beard C, Bhayani S, Bolger GB, Buyyounouski MK, et al. Testicular cancer. J Natl Compr Canc Netw. 2012;10:502-35.).

This report is the largest study of stage IIA and stage IIB testicular seminoma in the literature. The 5-year OS and CSS rates of 96-98% for RT are comparable with other reports (5Chung PW, Gospodarowicz MK, Panzarella T, Jewett MA, Sturgeon JF, Tew-George, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol. 2004;45:754-59; discussion 759-60., 8Hallemeier CL, Pisansky TM, Davis BJ, Choo R. Long-term outcomes of radiotherapy for stage II testicular seminoma--the Mayo Clinic experience. Urol Oncol. 2013;31:1832-8.). Based on a median follow-up of 10 years in this study, RT was associated with improved OS in stage IIA (Figure-1) and IIB (Figure-2) disease. Patients who underwent RT had similar known characteristics such as age to those who did not undergo RT (Table-1). However, this study was not randomized. As a result, the improved OS in patients who received RT may be due to selection bias. Also, patients in the RT group could have received a single cycle of neoadjuvant carboplatin chemotherapy prior to RT, which reduces the risk of relapse (2121 Horwich A, Dearnaley DP, Sohaib A, Pennert K, Huddart RA. Neoadjuvant carboplatin before radiotherapy in stage IIA and IIB seminoma. Ann Oncol. 2013;24:2104-7.). In addition, stage IIA and stage IIB testicular seminoma patients in the no RT group may have been treated with 4 cycles of single-agent carboplatin chemotherapy, which results in worse OS and progression-free survival than cisplatin-based chemotherapy (2424 Bokemeyer C, Kollmannsberger C, Stenning S, Hartmann JT, Horwich A, Clemm C, 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. 2004;91:683-7., 2525 Krege S, Boergermann C, Baschek R, Hinke A, Pottek T, Kliesch S, et al. Testicular Cancer Study Group (GTCSG). Single agent carboplatin for CS IIA/B testicular seminoma. A phase II study of the German Testicular Cancer Study Group (GTCSG). Ann Oncol. 2006;17:276-80.). In this report, no patients died of acute myeloid leukemia or infection in the RT group, whereas 2 patients died of these causes in the no RT group based on a median follow up of 10 years (Table-2). Most second malignancies and major cardiac events occur more than 15 years after RT (8Hallemeier CL, Pisansky TM, Davis BJ, Choo R. Long-term outcomes of radiotherapy for stage II testicular seminoma--the Mayo Clinic experience. Urol Oncol. 2013;31:1832-8., 1313 Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol. 2004;22:640-7.). As a result, longer follow-up is necessary to assess late toxicity and OS. Only 7 of 22 (32%) deaths in this study were due to testicular seminoma (Table-2). Consequently, statistical power was limited for the assessment of CSS.

Chung et al. (5Chung PW, Gospodarowicz MK, Panzarella T, Jewett MA, Sturgeon JF, Tew-George, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol. 2004;45:754-59; discussion 759-60.) reported 5-year relapse-free survival rates of 92% and 90%, respectively, for stage IIA and stage IIB testicular seminoma patients who underwent RT. Similarly, Classen et al. (6Classen J, Schmidberger H, Meisner C, Souchon R, Sautter-Bihl ML, Sauer R, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol. 2003;21:1101-6.) reported 6-year relapse-free survival rates of 95% and 89%, respectively, for stage IIA and stage IIB patients who were treated with RT.

Modified dog-leg RT to 30 Gy in 15 fractions remains the preferred approach by most investigators for stage IIA testicular seminoma in the absence of a horseshoe kidney, inflammatory bowel disease, or a history of RT (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41., 4Warde P, Huddart R, Bolton D, Heidenreich A, Gilligan T, Fossa S. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S435-43., 2626 Schmoll HJ, Jordan K, Huddart R, Pes MP, Horwich A, Fizazi K, et al. Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v140-6., 2727 Wilder RB, Buyyounouski MK, Efstathiou JA, Beard CJ. Radiotherapy treatment planning for testicular seminoma. Int J Radiat Oncol Biol Phys. 2012;83:e445-52.). If one of these 3 contraindications to RT is present, then cisplatin-based combination chemotherapy is recommended (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41., 4Warde P, Huddart R, Bolton D, Heidenreich A, Gilligan T, Fossa S. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S435-43., 2626 Schmoll HJ, Jordan K, Huddart R, Pes MP, Horwich A, Fizazi K, et al. Testicular seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v140-6., 2727 Wilder RB, Buyyounouski MK, Efstathiou JA, Beard CJ. Radiotherapy treatment planning for testicular seminoma. Int J Radiat Oncol Biol Phys. 2012;83:e445-52.). Prophylactic mediastinal/supraclavicular RT is no longer given for stage II testicular seminoma due to its late toxicity (1313 Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol. 2004;22:640-7., 2828 Chung PW, Warde PR, Panzarella T, Bayley AJ, Catton CN, Milosevic MF, et al. Appropriate radiation volume for stage IIA/B testicular seminoma. Int J Radiat Oncol Biol Phys. 2003;56:746-8.).

In most studies, more than 80% of stage IIA patients received RT (5Chung PW, Gospodarowicz MK, Panzarella T, Jewett MA, Sturgeon JF, Tew-George, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol. 2004;45:754-59; discussion 759-60., 7Detti B, Livi L, Scoccianti S, Gacci M, Lapini A, Cai T, et al. Management of Stage II testicular seminoma over a period of 40 years. Urol Oncol. 2009;27:534-8., 2929 Tandstad T, Smaaland R, Solberg A, Bremnes RM, Langberg CW, Laurell A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. J Clin Oncol. 2011;29:719-25.). Similarly, 82% of stage IIA patients in this report received RT. Nevertheless, cisplatin-based chemotherapy for good-risk testicular seminoma patients as defined by the IGCCCG (9International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 1997;15:594-603.) has gained in popularity over the past decade (3030 Garcia-del-Muro X, Maroto P, Gumà J, Sastre J, López Brea M, Arranz JA, 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. 2008;26:5416-21.). One advantage of cisplatin-based chemotherapy is that it can eradicate carcinoma in situ in the remaining testis and prevent or postpone the development of an invasive cancer in some patients (1717 Christensen TB, Daugaard G, Geertsen PF, von der Maase H. Effect of chemotherapy on carcinoma in situ of the testis. Ann Oncol. 1998;9:657-60.).

The Spanish Germ Cell Cancer Group conducted the first study of cisplatin-based chemotherapy as frontline therapy in stage IIA testicular seminoma patients (3030 Garcia-del-Muro X, Maroto P, Gumà J, Sastre J, López Brea M, Arranz JA, 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. 2008;26:5416-21.). None of the 19 stage IIA patients relapsed. Also, in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) study (2929 Tandstad T, Smaaland R, Solberg A, Bremnes RM, Langberg CW, Laurell A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. J Clin Oncol. 2011;29:719-25.), none of the 6 stage IIA patients who received cisplatin-based chemotherapy relapsed. Based on the impressive progression-free survival in these two studies, the European Society for Medical Oncology (3131 Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi125-32.) recommends cisplatin-based chemotherapy or modified dog-leg RT to 30 Gy in 15 fractions, with no preference for one treatment option over another, for stage IIA testicular seminoma.

Cisplatin-based chemotherapy used to be reserved for stage IIB patients with high-volume disease, e.g., multiple lymph nodes measuring 3.1-5.0 cm (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41., 4Warde P, Huddart R, Bolton D, Heidenreich A, Gilligan T, Fossa S. Management of localized seminoma, stage I-II: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009. Urology. 2011;78(4 Suppl):S435-43.). The Spanish Germ Cell Cancer Group conducted a study that included 54 patients with low-volume, e.g., a solitary retroperitoneal node measuring 2.1-3.0 cm, or high-volume stage IIB disease. Patients were treated with three cycles of cisplatin, etoposide, and bleomycin (PEB) or four cycles of cisplatin and etoposide (PE) (3030 Garcia-del-Muro X, Maroto P, Gumà J, Sastre J, López Brea M, Arranz JA, 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. 2008;26:5416-21.). Median follow up was 72 months. The 5-year progression-free survival rate for stage IIB patients was 87%. The SWENOTECA study included 67 stage IIB patients with low-volume or high-volume disease who were treated with cisplatin-based chemotherapy (2929 Tandstad T, Smaaland R, Solberg A, Bremnes RM, Langberg CW, Laurell A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish norwegian testicular cancer study group. J Clin Oncol. 2011;29:719-25.). None of them relapsed based on a median follow-up of 5.2 years. Based on the excellent progression-free survival in the SWENOTECA study, version 1.2014 of the National Comprehensive Cancer Network Clinical Practice Guidelines (3232 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Testicular Cancer, Version 1.2014. Retrieved on April 22, 2014. Available at: http://www.cus.cz/wp-content/uploads/2012/10/NCCN-C62-2014.pdf.
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) and the European Society for Medical Oncology (3131 Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi125-32.) recommend three cycles of PEB chemotherapy for all stage IIB patients, regardless of tumor burden. If there is a contraindication to bleomycin such as a reduction in lung capacity, emphysema, current or a history of heavy smoking, or poor renal function, then four cycles of PE may be used (3131 Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi125-32.). Modified dog-leg RT to 36 Gy in 18 fractions also constitutes a treatment option for stage IIB patients in whom chemotherapy would be unsuitable (3131 Oldenburg J, Fosså SD, Nuver J, Heidenreich A, Schmoll HJ, Bokemeyer C. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi125-32.) or who have a solitary retroperitoneal node measuring 2.1-3.0 cm (3232 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Testicular Cancer, Version 1.2014. Retrieved on April 22, 2014. Available at: http://www.cus.cz/wp-content/uploads/2012/10/NCCN-C62-2014.pdf.
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).

One treatment that has been investigated for stage IIA and IIB testicular seminoma is a single course of neoadjuvant carboplatin chemotherapy followed by para-aortic RT to 30-35 Gy. In a series involving 51 patients, there have been no relapses after a median follow up of 55 months (2121 Horwich A, Dearnaley DP, Sohaib A, Pennert K, Huddart RA. Neoadjuvant carboplatin before radiotherapy in stage IIA and IIB seminoma. Ann Oncol. 2013;24:2104-7.). Eight per cent of patients experienced grade 3 hematological toxicity and 2% developed grade 3 nausea. These results are promising; however, additional investigation is needed (3Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25:529-41., 3030 Garcia-del-Muro X, Maroto P, Gumà J, Sastre J, López Brea M, Arranz JA, 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. 2008;26:5416-21.).

CONCLUSIONS

Stage IIA testicular seminoma patients in the U.S. underwent RT more often than stage IIB patients between 1988 and 2003. There was no significant change in RT utilization for stage IIA or IIB disease during this time period. Cisplatin-based chemotherapy has produced excellent progression-free survival and, as a result, may eventually become the most popular treatment approach for both stage IIA and IIB testicular seminoma.

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    » http://www.cus.cz/wp-content/uploads/2012/10/NCCN-C62-2014.pdf

Publication Dates

  • Publication in this collection
    jan-feb 2015

History

  • Received
    23 Oct 2013
  • Accepted
    05 May 2014
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