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    Testicular Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

    Testicular Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

    This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

    Testicular Cancer Treatment

    General Information About Testicular Cancer

    Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Incidence and Mortality

    Note: Estimated new cases and deaths from testicular cancer in the United States in 2012:[1]

    • New cases: 8,590.
    • Deaths: 360.

    Testicular cancer is a highly treatable, usually curable, cancer that most often develops in young and middle-aged men. Most testicular cancers are germ cell tumors. For treatment planning, germ cell tumors are broadly divided into seminomas and nonseminomas because they have different prognostic and treatment algorithms. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage seminoma or nonseminoma, the cure rate approaches 100%.[2,3,4,5,6]

    Risk Factors

    Risk factors for testicular cancer include the following:[7]

    • An undescended testis (cryptorchidism).
    • A family history of testis cancer (particularly in a father or brother).
    • A personal history of testis cancer.

    Surgical correction of an undescended testis (orchiopexy) before puberty appears to lower the risk of testis cancer, but this isn't certain.[8]

    Types of Testicular Germ Cell Tumors: Seminomas Versus Non-Seminomas

    The five histopathological subtypes of testicular germ cell tumors include:

    • Seminomas.
    • Embryonal carcinomas.
    • Teratomas.
    • Yolk sac tumors.
    • Choriocarcinomas.

    Tumors that are 100% seminoma are considered seminomas. All other tumors, including those that have a mixture of seminoma and nonseminoma components, are considered and should be managed as nonseminomas. Most nonseminomas consist of a mixture of the different germ-cell tumor subtypes. Tumors that appear to have a seminoma histology but are accompanied by an elevated serum level of alpha-fetoprotein (AFP) should be treated as nonseminomas because seminomas do not produce AFP.

    Serum Tumor Markers and Testis Cancer: AFP, Beta-HCG, and LDH

    Alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG), and lactase dehydrogenase (LDH) play an important role as serum tumor markers in the staging and monitoring of germ cell tumors and should be measured prior to removing the involved testicle.[9] For patients with nonseminomas, the degree of tumor-marker elevation after the cancerous testicular has been removed is one of the most significant predictors of prognosis.[10] Serum tumor markers are also very useful for monitoring all stages of nonseminomas and for monitoring metastatic seminomas because elevated marker levels are often the earliest sign of relapse.

    AFP: Elevation of serum AFP is seen in 40% to 60% of men with nonseminomas. Seminomas do not produce AFP. Men who have an elevated serum AFP should be considered to have a mixed germ cell tumor (i.e., nonseminomatous germ cell tumors [NSGCT]) even if the pathology shows a pure seminoma, unless there is a more persuasive explanation for the elevated AFP, such as liver disease.

    Beta-HCG: Elevation of the beta subunit of hCG is found in approximately 14% of the patients with stage I pure seminoma prior to orchiectomy and in about half of patients with metastatic seminoma.[11,12,13] Approximately 40% to 60% of men with nonseminomas have an elevated serum beta-hCG.

    Significant and unambiguously rising levels of AFP and/or hCG are an indication of relapsed germ cell tumor in most cases and are an indication for treatment even in the absence of radiological evidence of metastatic disease. Nonetheless, tumor-marker elevations do need to be interpreted with caution. For example, false-positive hCG levels can result from cross reactivity of the assay with luteinizing hormone, in which case an intramuscular injection of testosterone should result in normalization of hCG values. There are also clinical reports of marijuana use resulting in elevations of serum hCG and some experts recommend querying patients about drug use and retesting hCG levels after a period of abstinence from marijuana use. Similarly, AFP is chronically mildly elevated in some individuals for unclear reasons and can be substantially elevated by liver disease.

    LDH: Seminomas and nonseminomas alike may result in elevated lactate dehydrogenase (LDH) but such values are of less clear prognostic significance because LDH may be elevated in many different conditions unrelated to cancer. A study of the utility of LDH in 499 patients with testicular germ cell tumor undergoing surveillance after orchiectomy or after treatment of stage II or III disease reported that 7.7% of patient visits had elevations in LDH unrelated to cancer, whereas only 1.4% of visits had cancer-related increases in LDH.[14] Of 15 relapses, LDH was elevated in six and was the first sign of relapse in one. Over 9% of the men had a persistent false-positive increase in LDH. The positive predictive value for an elevated LDH was 12.8%.

    A second study reported that among 494 patients with stage I germ cell tumors who subsequently relapsed, 125 had an elevated LDH at the time of relapse. Of these 125, all had other evidence of relapse: 112 had a concurrent rise in AFP and/or hCG, one had CT evidence of relapse prior to the elevation in LDH, one had palpable disease on examination and one complained of back pain that led to imaging that revealed retroperitoneal relapse.[15] Measuring LDH thus appears to have little value during surveillance of germ cell tumors for relapse. On the other hand, for patients with metastatic NSGCT, large studies of prognostic models have found the LDH level to be a significant independent predictor of survival on multivariate analysis.[10,16]

    Staging and Risk Stratification

    There are two major prognostication models for testicular cancer: staging,[17] and for risk-stratification of men with distant and/or bulky retroperitoneal metastases, the International Germ Cell Cancer Consensus Group classification.[10] The prognosis of testicular germ cell tumors is determined by the following factors:

    1. Histology (seminoma vs. nonseminoma).
    2. The extent to which the tumor has spread (testis only vs. retroperitoneal lymph node involvement vs. pulmonary or distant nodal metastasis vs. nonpulmonary visceral metastasis).
    3. For nonseminomas, the degree to which serum tumor markers are elevated.[10]

    Thus, for men with disseminated seminomas, the main adverse prognostic variable is the presence of metastases to organs other than the lungs (e.g., bone, liver, or brain). For men with disseminated nonseminomas, the following variables are independently associated with poor prognosis:

    • Metastases to organs other than the lungs.
    • Highly elevated serum tumor markers.
    • Tumor that originated in the mediastinum rather than the testis.

    Nonetheless, even patients with widespread metastases at presentation, including those with brain metastases, may have curable disease and should be treated with this intent.[18]

    Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice in diagnosing and treating a malignant testicular mass.[19] As noted above, serum AFP, LDH, and hCG should be measured prior to orchiectomy. Transscrotal biopsy is not considered appropriate because of the risk of local dissemination of tumor into the scrotum or its spread to inguinal lymph nodes. A retrospective analysis of reported series in which transscrotal approaches had been used showed a small but statistically significant increase in local recurrence rates compared with the recurrence rates when the inguinal approach was used (2.9% vs. 0.4%).[20][Level of evidence: 3iiiDii] Distant recurrence and survival rates, however, were indistinguishable in the two approaches.

    Evaluation of the retroperitoneal lymph nodes, usually by CT scanning, is an important aspect of staging and treatment planning in adults with testicular cancer.[21,22] Patients with a negative result however, have a substantial chance of having microscopic involvement of the lymph nodes. Nearly 20% of seminoma patients and 30% of nonseminoma patients with normal CT scans and serum tumor markers will subsequently relapse if not given additional treatment after orchiectomy.[23,24,25] For nonseminoma patients, retroperitoneal lymph node dissection (RPLND) increases the accuracy of staging but as many as 10% of men with normal imaging, normal tumor markers, and benign pathology at RPLND will still go on to relapse.[26] About 25% of patients with clinical stage I nonseminomatous testicular cancer will be upstaged to pathologic stage II with RPLND, and about 25% of clinical stage II patients will be downstaged to pathologic stage I with RPLND.[26,27,28] In prepubertal children, the use of serial measurements of AFP has proven sufficient for monitoring response after initial orchiectomy. Lymphangiography and para-aortic lymph node dissection do not appear to be useful or necessary in the proper staging and management of testicular cancer in prepubertal boys.[29] (Refer to the Genital/Urinary Tumors section in the PDQ summary on Unusual Cancers of Childhood for more information.)

    Patients who have been cured of testicular cancer have approximately a 2% cumulative risk of developing a cancer in the opposite testicle during the 15 years after initial diagnosis.[30,31] Within this range, men with nonseminomatous primary tumors appear to have a lower risk of subsequent contralateral testis tumors than men with seminomas.

    HIV-infected men are reported to be at increased risk for developing testicular seminomas.[32] Depending on comorbid conditions such as active infection, these men are generally managed similarly to non-HIV-infected patients.

    Because the majority of testis cancer patients who receive chemotherapy are curable, it is necessary to be aware of possible long-term effects of platinum-based treatment, such as the following:

    1. Fertility: Many patients have oligospermia or sperm abnormalities prior to therapy, but semen analysis results generally become more normal after treatment. The impact of standard chemotherapy on fertility in testis cancer patients is not well defined, although it is well documented that most men can father children after treatment, often without the use of cryopreserved semen. In two large studies, roughly 70% of patients actually fathered children after treatment for testicular cancer.[33,34] The likelihood of recovering fertility is related to the type of treatment received. The children do not appear to have an increased risk of congenital malformations, but the existing data are not adequate to properly investigate this issue.[35,36] It is recommended that men wait at least 3 months after completing chemotherapy before conceiving a child (unless using cryopreserved sperm collected before chemotherapy was administered).[36]

    Radiation therapy, used to treat pure seminomatous testicular cancers, can cause fertility problems because of radiation scatter to the remaining testicle during radiation therapy to retroperitoneal lymph nodes (as evidenced in the SWOG-8711 trial, for example).[37] (For more information on fertility, refer to the Sexuality and Reproductive Issues summary.) Depending on scatter dose, sperm counts fall after radiation therapy but may recover over the course of 1 to 2 years. Shielding techniques can be used to decrease the radiation scatter to the remaining normal testicle. Because chemotherapy, retroperitoneal lymph node dissection, and radiation therapy can each result in infertility, men should be offered the opportunity to bank sperm before undergoing any treatment for testis cancer other than orchiectomy.

    2. Secondary leukemias: Several reports of elevated risk of secondary acute leukemia, primarily nonlymphocytic, have appeared.[38,39] An increased risk of leukemia has been associated with platinum-based chemotherapy and radiation therapy.[38] Etoposide-containing regimens are also associated with a risk of secondary acute leukemias, usually in the myeloid lineage, and with a characteristic 11q23 translocation.[40,41] Etoposide-associated leukemias typically occur sooner after therapy than alkylating agent-associated leukemias and often show balanced chromosomal translocations on the long arm of chromosome 11. Standard etoposide dosages (<2 g/m2 cumulative dose) are associated with a relative risk of 15 to 25, but this translates into a cumulative incidence of leukemia of less than 0.5% at 5 years. Preliminary data suggest that cumulative doses of more than 2 g/m2 of etoposide may confer higher risk.
    3. Renal function: Minor decreases in creatinine clearance occur (about a 15% decrease, on average) during platinum-based therapy, but these appear to remain stable in the long term and without significant deterioration.[42]
    4. Hearing: Bilateral hearing deficits occur with cisplatin-based chemotherapy, but the deficits generally occur at sound frequencies of 4 kHz to 8 kHz, which is outside the range of conversational tones; therefore, hearing aids are rarely required if standard doses of cisplatin are administered.[42]
    5. Lung function: A study of pulmonary function tests in 1,049 long-term survivors of testis cancer reported a cisplatin-dose-dependent increase in the incidence of restrictive lung disease.[43] Whereas men receiving up to 850 mg of cisplatin had a normal risk of restrictive lung disease, men who received over 850 mg of cisplatin had a three-fold increased risk. In absolute terms, patients who received no chemotherapy had an incidence of restrictive lung disease of less than 8%, whereas the incidence of restrictive lung disease among those receiving over 850 mg of cisplatin was nearly 18%. However, only 9.5% of those with pulmonary function testing indicative of restrictive lung disease reported dyspnea. Although cisplatin was more strongly associated with decreased lung function in this study, cumulative bleomycin dose was also associated with a decline in forced vital capacity and the 1-second forced expiratory volume (FEV1) but not with restrictive lung disease.

    Although acute bleomycin pulmonary toxic effects may occur, they are rarely fatal at total cumulative doses of less than 400 units. Because life-threatening pulmonary toxic effects can occur, the drug should be discontinued if early signs of pulmonary toxic effects develop. Although decreases in pulmonary function are frequent, they are rarely symptomatic and are reversible after the completion of chemotherapy. Survivors of testis cancer who were treated with chemotherapy have been reported to be at increased risk of death from respiratory diseases, but it is unknown whether this finding is related to bleomycin exposure.[44]

    Radiation therapy, often used in the management of pure seminomatous germ cell cancers, has been linked to the development of secondary cancers, especially solid tumors in the radiation portal, usually after a latency period of a decade or more.[45,46] These include melanoma and cancers of the stomach, bladder, colon, rectum, pancreas, lung, pleura, prostate, kidney, connective tissue, and thyroid. Chemotherapy has also been associated with an elevated risk of secondary cancers.

    Cardiovascular Disease in Testicular Cancer Survivors

    More recently, men with testis cancer who have been treated with radiation therapy and/or chemotherapy have been reported to be at increased risk of cardiovascular events.[47,48,49] Other studies have reported that chemotherapy for testis cancer is associated with an increased risk of developing metabolic syndrome and hypogonadism.[50,51] Moreover, an international population-based study reported that men treated with either radiation or chemotherapy were at increased risk of death from circulatory diseases.[44]

    In a retrospective series of 992 patients treated for testicular cancer at the Royal Marsden Hospital between 1982 and 1992, cardiac events were increased approximately 2.5-fold in patients treated with radiation therapy and/or chemotherapy compared with those who underwent surveillance after a median of 10.2 years. The actuarial risks of cardiac events were 7.2% for patients who received radiation therapy (92% of whom did not receive mediastinal radiation therapy), 3.4% for patients who received chemotherapy (primarily platinum-based), 4.1% for patients who received combined therapy, and 1.4% for patients who underwent surveillance management after 10 years of follow-up.[48]

    A population-based retrospective study of 2,339 testicular cancer survivors in the Netherlands, treated between 1965 and 1995 and followed for a median of 18.4 years, found that the overall incidence of coronary heart disease (i.e., myocardial infarction and/or angina pectoris) was increased 1.17 times (95% confidence interval [CI], 1.04?1.31) compared with the general population.[49] Patients who received radiation therapy to the mediastinum had a 2.5-fold (95% CI, 1.8?3.4) increased risk of coronary heart disease, and those who also received chemotherapy had an almost 3-fold (95% CI, 1.7?4.8) increased risk. Patients who were treated with infradiaphragmatic radiation therapy alone had no significantly increased risk of coronary heart disease. In multivariate Cox regression analyses, the older chemotherapy regimen of cisplatin, vinblastine, and bleomycin (PVB), used until the mid-1980s, was associated with a significant 1.9-fold (95% CI, 1.2?2.9) increased risk of cardiovascular disease (i.e., myocardial infarction, angina pectoris, and heart failure combined). The newer regimen of bleomycin, etoposide, and cisplatin (BEP) was associated with a borderline significant 1.5-fold (95% CI, 1.0?2.2) increased risk of cardiovascular disease. Similarly, an international pooled analysis of population-based databases reported that the risk of death from circulatory disease was increased in men treated with chemotherapy (standardized mortality ratio 1.58) or radiation therapy (SMR = 1.70).[44][Level of evidence: 3iiiDii]

    Although testicular cancer is highly curable, all newly diagnosed patients are appropriately considered candidates for clinical trials designed to decrease morbidity of treatment while further improving cure rates.

    Related Summary

    • Testicular Cancer Screening

    References:

    1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed September 26, 2013.
    2. Ries LAG, Melbert D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2005. Bethesda, Md: National Cancer Institute, 2007. Also available online. Last accessed April 04, 2013.
    3. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 53 (3): 478-96, 2008.
    4. Groll RJ, Warde P, Jewett MA: A comprehensive systematic review of testicular germ cell tumor surveillance. Crit Rev Oncol Hematol 64 (3): 182-97, 2007.
    5. Neill M, Warde P, Fleshner N: Management of low-stage testicular seminoma. Urol Clin North Am 34 (2): 127-36; abstract vii-viii, 2007.
    6. Tandstad T, Dahl O, Cohn-Cedermark G, et al.: Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program. J Clin Oncol 27 (13): 2122-8, 2009.
    7. Holzik MF, Rapley EA, Hoekstra HJ, et al.: Genetic predisposition to testicular germ-cell tumours. Lancet Oncol 5 (6): 363-71, 2004.
    8. Pettersson A, Richiardi L, Nordenskjold A, et al.: Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med 356 (18): 1835-41, 2007.
    9. Sturgeon CM, Duffy MJ, Stenman UH, et al.: National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 54 (12): e11-79, 2008.
    10. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.
    11. 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 (4): 745-52, 2003.
    12. 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 (9482): 293-300, 2005 Jul 23-29.
    13. Weissbach L, Bussar-Maatz R, Mann K: The value of tumor markers in testicular seminomas. Results of a prospective multicenter study. Eur Urol 32 (1): 16-22, 1997.
    14. Venkitaraman R, Johnson B, Huddart RA, et al.: The utility of lactate dehydrogenase in the follow-up of testicular germ cell tumours. BJU Int 100 (1): 30-2, 2007.
    15. Ackers C, Rustin GJ: Lactate dehydrogenase is not a useful marker for relapse in patients on surveillance for stage I germ cell tumours. Br J Cancer 94 (9): 1231-2, 2006.
    16. van Dijk MR, Steyerberg EW, Habbema JD: Survival of non-seminomatous germ cell cancer patients according to the IGCC classification: An update based on meta-analysis. Eur J Cancer 42 (7): 820-6, 2006.
    17. Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    18. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 53 (3): 497-513, 2008.
    19. Leibovitch I, Baniel J, Foster RS, et al.: The clinical implications of procedural deviations during orchiectomy for nonseminomatous testis cancer. J Urol 154 (3): 935-9, 1995.
    20. Capelouto CC, Clark PE, Ransil BJ, et al.: A review of scrotal violation in testicular cancer: is adjuvant local therapy necessary? J Urol 153 (3 Pt 2): 981-5, 1995.
    21. Sohaib SA, Koh DM, Husband JE: The role of imaging in the diagnosis, staging, and management of testicular cancer. AJR Am J Roentgenol 191 (2): 387-95, 2008.
    22. Leibovitch L, Foster RS, Kopecky KK, et al.: Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. J Urol 154 (5): 1759-63, 1995.
    23. Chung P, Warde P: Surveillance in stage I testicular seminoma. Urol Oncol 24 (1): 75-9, 2006 Jan-Feb.
    24. Segal R: Surveillance programs for stage I nonseminomatous germ cell tumors of the testis. Urol Oncol 24 (1): 68-74, 2006 Jan-Feb.
    25. 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 (22): 4448-52, 2002.
    26. Stephenson AJ, Bosl GJ, Motzer RJ, et al.: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 23 (12): 2781-8, 2005.
    27. Choueiri TK, Stephenson AJ, Gilligan T, et al.: Management of clinical stage I nonseminomatous germ cell testicular cancer. Urol Clin North Am 34 (2): 137-48; abstract viii, 2007.
    28. Donohue JP, Thornhill JA, Foster RS, et al.: Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer 31A (10): 1599-604, 1995.
    29. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
    30. Fosså SD, Chen J, Schonfeld SJ, et al.: Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst 97 (14): 1056-66, 2005.
    31. Theodore Ch, Terrier-Lacombe MJ, Laplanche A, et al.: Bilateral germ-cell tumours: 22-year experience at the Institut Gustave Roussy. Br J Cancer 90 (1): 55-9, 2004.
    32. Goedert JJ, Purdue MP, McNeel TS, et al.: Risk of germ cell tumors among men with HIV/acquired immunodeficiency syndrome. Cancer Epidemiol Biomarkers Prev 16 (6): 1266-9, 2007.
    33. Brydøy M, Fosså SD, Klepp O, et al.: Paternity following treatment for testicular cancer. J Natl Cancer Inst 97 (21): 1580-8, 2005.
    34. Huyghe E, Matsuda T, Daudin M, et al.: Fertility after testicular cancer treatments: results of a large multicenter study. Cancer 100 (4): 732-7, 2004.
    35. Babosa M, Baki M, Bodrogi I, et al.: A study of children, fathered by men treated for testicular cancer, conceived before, during, and after chemotherapy. Med Pediatr Oncol 22 (1): 33-8, 1994.
    36. Spermon JR, Kiemeney LA, Meuleman EJ, et al.: Fertility in men with testicular germ cell tumors. Fertil Steril 79 (Suppl 3): 1543-9, 2003.
    37. Gordon W Jr, Siegmund K, Stanisic TH, et al.: A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group. Int J Radiat Oncol Biol Phys 38 (1): 83-94, 1997.
    38. Travis LB, Andersson M, Gospodarowicz M, et al.: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 92 (14): 1165-71, 2000.
    39. van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, et al.: Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J Clin Oncol 11 (3): 415-24, 1993.
    40. Houck W, Abonour R, Vance G, et al.: Secondary leukemias in refractory germ cell tumor patients undergoing autologous stem-cell transplantation using high-dose etoposide. J Clin Oncol 22 (11): 2155-8, 2004.
    41. Kollmannsberger C, Hartmann JT, Kanz L, et al.: Therapy-related malignancies following treatment of germ cell cancer. Int J Cancer 83 (6): 860-3, 1999.
    42. Osanto S, Bukman A, Van Hoek F, et al.: Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol 10 (4): 574-9, 1992.
    43. Haugnes HS, Aass N, Fosså SD, et al.: Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol 27 (17): 2779-86, 2009.
    44. Fosså SD, Gilbert E, Dores GM, et al.: Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 99 (7): 533-44, 2007.
    45. Travis LB, Fosså SD, Schonfeld SJ, et al.: Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97 (18): 1354-65, 2005.
    46. 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 (28): 4370-8, 2007.
    47. Meinardi MT, Gietema JA, van der Graaf WT, et al.: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18 (8): 1725-32, 2000.
    48. Huddart RA, Norman A, Shahidi M, et al.: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21 (8): 1513-23, 2003.
    49. 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 (3): 467-75, 2006.
    50. Haugnes HS, Aass N, Fosså SD, et al.: Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol 18 (2): 241-8, 2007.
    51. 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 (16): 3718-25, 2005.

    Cellular Classification of Testicular Cancer

    The following histologic classification of malignant testicular germ cell tumors (testicular cancer) reflects the classification used by the World Health Organization (WHO).[1] Less than 50% of malignant testicular germ cell tumors have a single cell type, of which roughly 50% are seminomas. The rest have more than one cell type, and the relative proportions of each cell type should be specified. The cell type of these tumors is important for estimating the risk of metastases and the response to chemotherapy. Polyembryoma presents an unusual growth pattern and is sometimes listed as a single histologic type, though it might better be regarded as a mixed tumor.[1,2,3]

    1. Intratubular germ cell neoplasia, unclassified.
    2. Malignant pure germ cell tumor (showing a single cell type):
    1. Seminoma.
    2. Embryonal carcinoma.
    3. Teratoma.
    4. Choriocarcinoma.
    5. Yolk sac tumor.
    3. Malignant mixed germ cell tumor (showing more than one histologic pattern):
    1. Embryonal carcinoma and teratoma with or without seminoma.
    2. Embryonal carcinoma and yolk sac tumor with or without seminoma.
    3. Embryonal carcinoma and seminoma.
    4. Yolk sac tumor and teratoma with or without seminoma.
    5. Choriocarcinoma and any other element.
    4. Polyembryoma.

    References:

    1. Woodward PJ, Heidenreich A, Looijenga LHJ, et al.: Germ cell tumours. In: Eble JN, Sauter G, Epstein JI, et al.: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press, 2004, pp 221-49.
    2. Ulbright TM, Berney DM: Testicular and paratesticular tumors. In: Mills SE, Carter D, Greenson JK, et al., eds.: Sternberg's Diagnostic Surgical Pathology. Philadelphia, Pa: Lippincott Williams & Wilkins, 2010, pp 1944-2004.
    3. Bosi GJ, Feldman DR, Bajorin DE, et al.: Cancer of the testis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1280-1301.

    Stage Information for Testicular Cancer

    Note: This Stage Information section has been updated to include information from the 7th edition (2010) of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. The PDQ Adult Treatment Editorial Board, which is responsible for maintaining this summary, is currently reviewing the new staging categories to determine whether additional changes need to be made to other parts of the summary. Any necessary changes will be made as soon as possible.

    Definitions of TNM

    The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define testicular cancer.[1]

    Table 1. Primary Tumor (T)a, b, c

    a Reprinted with permission from AJCC: Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    b The extent of primary tumor is usually classified after radical orchiectomy, and for this reason, apathologic stage is assigned.
    c Except for pTis and pT4, extent of primary tumor is classified by radical orchiectomy. TX may be used for other categories in the absence of radical orchiectomy.
    pTX Primary tumor cannot be assessed.
    pT0 No evidence of primary tumor (e.g., histologic scar in testis).
    pTis Intratubular germ cell neoplasia (carcinoma in situ).
    pT1 Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis.
    pT2 Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis.
    pT3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion.
    pT4 Tumor invades the scrotum with or without vascular/lymphatic invasion.

    Table 2. Regional Lymph Nodes (N)a

    a Reprinted with permission from AJCC: Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    Clinical
    NX Regional lymph nodes cannot be assessed.
    N0 No regional lymph node metastasis.
    N1 Metastasis with a lymph node mass =2 cm in greatest dimension; or multiple lymph nodes, none >2 cm in greatest dimension.
    N2 Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension; or multiple lymph nodes, any one mass >2 cm but not >5 cm in greatest dimension.
    N3 Metastasis with a lymph node mass >5 cm in greatest dimension.
    Pathologic (pN)
    pNX Regional lymph nodes cannot be assessed.
    pN0 No regional lymph node metastasis.
    pN1 Metastasis with a lymph node mass =2 cm in greatest dimension and =5 nodes positive, none >2 cm in greatest dimension.
    pN2 Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension; or >5 nodes positive, none >5 cm; or evidence of extranodal extension of tumor.
    pN3 Metastasis with a lymph node mass >5 cm in greatest dimension.

    Table 3. Distant Metastasis (M)a

    a Reprinted with permission from AJCC: Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    M0 No distant metastasis.
    M1 Distant metastasis.
    M1a Nonregional nodal or pulmonary metastasis.
    M1b Distant metastasis other than to nonregional lymph nodes and lung.

    Table 4. Anatomic Stage/Prognostic Groupsa

    Group T N M S (Serum Tumor Markers)
    a Reprinted with permission from AJCC: Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    0 pTis N0 M0 S0
    I pT1?4 N0 M0 SX
    IA pT1 N0 M0 S0
    IB pT2 N0 M0 S0
    pT3 N0 M0 S0
    pT4 N0 M0 S0
    IS Any pT/Tx N0 M0 S1?3
    II Any pT/Tx N1?3 M0 SX
    IIA Any pT/Tx N1 M0 S0
    Any pT/Tx N1 M0 S1
    IIB Any pT/Tx N2 M0 S0
    Any pT/Tx N2 M0 S1
    IIC Any pT/Tx N3 M0 S0
    Any pT/Tx N3 M0 S1
    III Any pT/Tx Any N M1 SX
    IIIA Any pT/Tx Any N M1a S0
    Any pT/Tx Any N M1a S1
    IIIB Any pT/Tx N1?3 M0 S2
    Any pT/Tx Any N M1a S2
    IIIC Any pT/Tx N1?3 M0 S3
    Any pT/Tx Any N M1a S3
    Any pT/Tx Any N M1b Any S

    Table 5. Site-Specific Prognostic Factorsa

    Serum Tumor Markers (S) Required for Staging
    a Reprinted with permission from AJCC: Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    b AFP = alpha-fetoprotein; hCG = human chorionic gonadotropin; LDH = lactase dehydrogenase; N indicates the upper limit of normal for the LDH assay.
    SX Marker studies not available or not performed.
    S0 Marker study levels within normal limits.
    S1 LDH <1.5 × Nb and hCG (mIu/ml) <5,000and AFP (ng/ml) <1,000.
    S2 LDH 1.5?10 × Nor hCG (mIu/ml) 5,000?50,000or AFP (ng/ml) 1,000?10,000.
    S3 LDH >10 × Nor hCG (mIu/ml) >50,000or AFP (ng/ml) >10,000.

    In addition to the clinical stage definitions, surgical stage may be designated based on the results of surgical removal and microscopic examination of tissue.

    Stage I

    Stage I testicular cancer is limited to the testis. Invasion of the scrotal wall by tumor or interruption of the scrotal wall by previous surgery does not change the stage but does increase the risk of spread to the inguinal lymph nodes, and this must be considered in treatment and follow-up. Invasion of the epididymis tunica albuginea and/or the rete testis does not change the stage. Invasion of the tunica vaginalis or lymphovascular invasion signifies a T2 tumor, while invasion of the spermatic cord signifies a T3 tumor, and invasion of the scrotum signifies a T4. Increases in T stage are associated with increased risk of occult metastatic disease and recurrence. Men with stage I disease who have persistently elevated serum tumor markers after orchiectomy are staged as IS, but stage IS nonseminomas are treated as stage III. Elevated serum tumor markers in stage I or II seminoma are of unclear significance except that a persistently elevated or rising hCG usually indicates metastatic disease.

    Stage II

    Stage II testicular cancer involves the testis and the retroperitoneal or peri-aortic lymph nodes usually in the region of the kidney. Retroperitoneal involvement should be further characterized by the number of nodes involved and the size of involved nodes. The risk of recurrence is increased if more than five nodes are involved or if the size of one or more involved nodes is more than 2 cm. Bulky stage II disease (stage IIC) describes patients with extensive retroperitoneal nodes (>5 cm), which portends a less favorable prognosis.

    Stage III

    Stage III implies spread beyond the retroperitoneal nodes based on physical examination, imaging studies, and/or blood tests (i.e., patients with retroperitoneal adenopathy and highly elevated serum tumor markers are stage III). Stage III can be further stratified based on the location of metastasis and the degree of elevation of serum tumor markers. In the favorable group (IIIA), metastases are limited to lymph nodes and lung, and serum tumor markers are no more than mildly elevated. Stage IIIB patients have moderately elevated tumor markers, while stage IIIC patients have highly elevated markers and/or metastases to liver, bone, brain or some organ other than the lungs. These subclassifications of stage III correspond to the International Germ Cell Consensus Classification system for disseminated germ cell tumors.[2]

    References:

    1. Testis. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 469-78.
    2. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.

    Treatment Option Overview

    Testicular cancer is broadly divided into seminoma and nonseminoma for treatment planning because seminomatous types of testicular cancer are more sensitive to radiation therapy and chemotherapy and are less prone to distant metastases. Moreover, nonseminomas may include teratomatous elements, which tend to be resistant to chemotherapy and often require surgery for cure. By definition, pure seminomas do not contain elements of teratoma. Therefore, surgery plays a larger role in the management of nonseminomas than in the management of seminomas. Nonseminomatous testicular tumors include:

    • Embryonal carcinomas.
    • Yolk sac tumors.
    • Choriocarcinomas.
    • Teratomas.
    • Mixed germ cell tumors.

    An international germ cell tumor prognostic classification has been developed based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous and 660 patients with metastatic seminomatous germ cell tumors.[1] All patients received treatment with cisplatin- or carboplatin-containing therapy as their first chemotherapy course. The prognostic classification, shown below, was agreed on in 1997 by all major clinical trial groups worldwide. It should be used for reporting clinical trial results of patients with germ cell tumors.

    A meta-analysis of treatment outcomes for patients with advanced nonseminoma suggested that 5-year survival rates have improved for those patients with a poor prognosis during the period of 1989 to 2004.[2] In addition to improved therapy, the improvement seen in these survival rates could be the result of publication bias, changes in patient selection in reported clinical trials, or more sensitive staging methods that could migrate less-advanced stages to more-advanced stage categories (i.e., stage migration).

    Good Prognosis

    Nonseminoma:

    • Testis/retroperitoneal primary, and
    • No nonpulmonary visceral metastases, and
    • Good markers?all of:
      • Alpha-fetoprotein (AFP) less than 1,000 ng/mL, and
      • Human chorionic gonadotropin (hCG) less than 5,000 IU/mL (1,000 ng/mL), and
      • Lactate dehydrogenase (LDH) less than 1.5 × the upper limit of normal

      56%?61% of nonseminomas

      5-year progression-free survival (PFS) is 89%; 5-year survival is 92%?94%

    Seminoma:

    • Any primary site, and
    • No nonpulmonary visceral metastases, and
    • Normal AFP, any hCG, any LDH

      90% of seminomas

      5-year PFS is 82%; 5-year survival is 86%

    Intermediate Prognosis

    Nonseminoma:

    • Testis/retroperitoneal primary, and
    • No nonpulmonary visceral metastases, and
    • Intermediate markers?any of:
      • AFP 1,000 ng/mL or more and 10,000 ng/mL or less, or
      • hCG 5,000 IU/L or more and 50,000 IU/L or less, or
      • LDH 1.5 or more × N* and less than 10 × N*

      13%?28% of nonseminomas

      5-year PFS is 75%; 5-year survival is 80%?83%

      *N indicates the upper limit of normal for the LDH assay.

    Seminoma:

    • Any primary site, and
    • Nonpulmonary visceral metastases, and
    • Normal AFP, any hCG, any LDH

      10% of seminomas

      5-year PFS is 67%; 5-year survival is 72%

    Poor Prognosis

    Nonseminoma:

    • Mediastinal primary, or
    • Nonpulmonary visceral metastases, or
    • For markers?any of:
      • AFP more than 10,000 ng/mL, or
      • hCG more than 50,000 IU/mL (10,000 ng/mL), or
      • LDH more than 10 × the upper limit of normal

      16%?26% of nonseminomas

      5-year PFS is 41%; 5-year survival is 71%

    Seminoma:

    • No patients are classified as poor prognosis.

    References:

    1. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.
    2. van Dijk MR, Steyerberg EW, Habbema JD: Survival of non-seminomatous germ cell cancer patients according to the IGCC classification: An update based on meta-analysis. Eur J Cancer 42 (7): 820-6, 2006.

    Stage I Testicular Cancer

    Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage I Seminoma

    Stage I seminoma has a cure rate of greater than 95% regardless of whether or not postorchiectomy adjuvant therapy is given.

    Standard treatment options:

    1. Radical inguinal orchiectomy with no retroperitoneal node radiation therapy followed by periodic determination of serum markers, chest x-rays, and computed tomographic (CT) scans of the abdomen and pelvis (surveillance). These studies are typically performed every 4 months for the first 3 years, then every 6 months for 3 years, and then annually for an additional 4 years.

    Results of multiple clinical series, including more than 1,200 patients with stage I seminoma managed by postorchiectomy surveillance, have been reported.[1,2,3,4,5,6,7,8] The overall 10-year tumor recurrence rate is 15% to 20%, and nearly all patients whose disease recurred were cured by radiation therapy or chemotherapy. Thus, the overall cure rate is indistinguishable from that achieved with adjuvant radiation therapy or carboplatin chemotherapy. Relapses after 5 years are unusual but can occur in as many as 4% of patients.[5] Independent risk factors for relapse include tumor size greater than 4 cm and invasion of the rete testis.[1] The 5-year risk of relapse is about 10% without either risk factor, 16% with one risk factor, and 32% with both risk factors.

    2. Radical inguinal orchiectomy followed by either one or two doses of carboplatin adjuvant therapy.

    In a large randomized controlled equivalency trial comparing para-aortic (or dog-leg field, if clinically indicated) radiation to a single dose of carboplatin (concentration-versus-time curve [AUC] × 7) after radical inguinal orchiectomy, relapse-free survival (RFS) and overall survival (OS) rates were equivalent after a median follow-up of 4 years.[9][Level of evidence: 1iiA][10] Three-year RFS was 94.8% with carboplatin versus 95.9% with radiation therapy. In this trial, AUC dosing was based on radioisotope measurement of glomerular filtration rate; dosing based on calculations of creatinine clearance is not equivalent, has not been validated in this setting, and is discouraged.

    Phase II studies, including several with more than 4 years median follow-up, have consistently reported lower relapse rates (0%?3.3%) when two doses of carboplatin were administered either 3 or 4 weeks apart and dosed either at 400 mg/m2 or at an AUC of 7.[2,3,11,12,13,14,15] Administration of two doses of carboplatin has never been compared to a single dose nor to radiation therapy in a randomized trial.

    3. Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy is an approach that is associated with a 5-year relapse-free survival of 95% to 96% and a 5-year disease-specific survival in excess of 99% in multiple large series and randomized controlled trials.[16,17,18,19,20,21,22]

    Two treatment fields are commonly used: a para-aortic strip covering the retroperitoneal nodes or a dog-leg field that includes the ipsilateral iliac lymph nodes as well as the retroperitoneum. The dose ranges from 20 Gy to 26 Gy. Relapse rates and toxic effects were studied in a randomized comparison of para-aortic radiation therapy alone versus para-aortic radiation therapy with an added ipsilateral iliac lymph node field.[18] Three-year RFS rates were virtually identical (96% vs. 96.6%) as were OS rates (99.3% vs. 100%). Pelvic RFS rates were 98.2% versus 100%; the 95% confidence interval (CI) for the difference in pelvic RFS rates was 0% to 3.7%. A statistically significant increase was observed in leukopenia and diarrhea associated with the ipsilateral iliac radiation therapy. In a randomized trial (MRC-TE18), radiation to 20 Gy over 10 daily fractions was clinically equivalent to 30 Gy over 15 fractions after a median follow-up of 61 months in both RFS and OS. Patient-reported lethargy and ability to perform normal work were better in the lower-dose regimen.[19][Level of evidence: 1iiA]

    Stage I Nonseminoma

    Stage I nonseminoma is highly curable (>99%). Orchiectomy alone will cure about 70% of patients but the remaining 30% will relapse and require additional treatment. The relapses are highly curable, and thus post-orchiectomy surveillance is a standard treatment option, but some physicians and patients prefer to reduce the risk of relapse by having the patient undergo either a retroperitoneal lymph node dissection (RPLND) or one or two cycles of chemotherapy. Each of these three approaches has unique advantages and disadvantages, and none has been shown to result in longer survival or superior quality of life.

    Standard treatment options:

    1. Radical inguinal orchiectomy followed by a regular and frequent surveillance schedule.

    Typically, patients are seen monthly during the first year, every 2 months during the second year, every 3 months during the third year, every 4 months during the fourth year, every 6 months during the fifth year, and annually for the subsequent 5 years.[23,24,25] At each visit, the history is reviewed, a physical examination is given, determination of serum markers are performed, and a chest x-ray is obtained (sometimes at alternating visits). An additional key aspect of surveillance involves abdominal or abdominopelvic CT scans, but the preferred frequency of such scans is controversial.

    A randomized controlled trial (MRC-TE08) compared a schedule that used only two scans at 3 months and 12 months to a schedule that used five scans at 3, 6, 9, 12 and 24 months.[26] With over 400 randomly assigned patients and a median follow-up of 40 months, all relapsing patients had either good- or intermediate-risk disease, and there were no differences in the stage or extent of disease at relapse between the two arms. No deaths were reported. Nonetheless, some organizations recommend CT scans every 3 to 4 months during the first 3 years of follow-up and continuing but less-frequent CT scans thereafter. While this study would appear to indicate that scans at 3 and 12 months are adequate during the first year, longer follow-up will be needed to assess whether discontinuing scans after 12 months is safe.[26][Level of evidence: 1iiA] With regard to chest imaging, disease recurrence is rarely detected by chest x-ray alone, so chest x-ray may play little or no role in routine surveillance but is nonetheless included in the mainstream surveillance schedules.[23]

    The need for long-term follow-up has not been adequately investigated. Surveillance series with long follow-up have reported that fewer than 1% of clinical stage I patients relapse after 5 years.[27,28] Late relapses often occur in the retroperitoneum when they do occur. Hence, some schedules discontinue CT scans after 12 months, while others recommend at least annual scans for 10 years.

    The option of a radical inguinal orchiectomy followed by a regular and frequent surveillance schedule should be considered only if:

    1. CT scan and serum markers are negative.
    2. The patient accepts the need for and commits to frequent surveillance visits. Children are adequately followed by serum markers alpha-fetoprotein (AFP), chest x-rays, and clinical examination.[29]
    3. The physician accepts responsibility for seeing that a follow-up schedule is maintained as noted.
    2. Removal of the testicle through the groin followed (in adults) by RPLND.

    A nerve-sparing RPLND that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPLND.[30,31,32] Surgery should be followed by monthly determination of serum markers and chest x-rays for the first year and every other month determinations for the second year.[23]

    Men undergoing RPLND who are found to have pathological stage I disease have a roughly 10% risk of relapsing subsequently, whereas men with pathological stage II disease (i.e., those who are found to have lymph node metastases at RPLND) have as much as a 50% risk of relapse without further treatment.[33]Two cycles of post-RPLND chemotherapy using either bleomycin, etoposide, and cisplatin (BEP) or etoposide plus cisplatin (EP) lowers the risk of relapse in men with pathological stage II disease to about 1%.[34,35] The vast majority of reported patients in studies of RPLND underwent the operation at a center of excellence with a urological surgeon who had performed hundreds of such operations. The ability of less-experienced urologists to achieve similar results is unknown.

    In patients with pathologic stage I disease after RPLND, the presence of lymphatic or venous invasion or a predominance of embryonal carcinoma in the primary tumor appears to predict for relapse.[36,37,38] In a large Testicular Cancer Intergroup Study, the relapse rate among men with pathological stage I disease was 19% in those with vascular invasion versus 6% in those without vascular invasion. One study reported that the relapse rate for men with pathological stage I disease was 21.2% (18 of 85 men relapsed) if their tumors were predominantly embryonal carcinoma and 29% if there was a predominance of embryonal carcinoma plus lymphovascular invasion, versus 3% (5 of 141 men relapsed) if there was not a predominance of embryonal carcinoma.[36,37]

    Among pathological stage II patients, the relapse rate was 32% among men with embryonal carcinoma-predominant tumors compared with15.6% in the other stage II patients. The risk of metastatic disease (i.e., either pathological stage II disease or relapsed pathological stage I disease) in men with tumors showing a predominance of embryonal carcinoma plus lymphovascular invasion was 62% compared with 16% in men with neither risk factor.

    These data have shown that high-risk patients undergoing RPLND have a substantial risk of subsequently receiving chemotherapy. Data from one institution have shown that about half of men with stage I pure embryonal carcinoma undergoing RPLND will subsequently receive cisplatin-based chemotherapy.[39]

    Retroperitoneal dissection of lymph nodes is not helpful in the management of children, and potential morbidity of the surgery is not justified by the information obtained.[29] In men who have undergone RPLND, chemotherapy is employed immediately on first evidence of recurrence.

    3. Adjuvant therapy consisting of one or two courses of BEP chemotherapy in patients with clinical stage I disease.

    A randomized controlled trial compared a single cycle of BEP chemotherapy to RPLND in 382 patients. The 2-year recurrence-free survival rates were 99.5% with chemotherapy versus 91.9% with RPLND (absolute difference = 7.6%; 95% confidence interval, 3.1%?12.1%). There were no treatment-related or cancer-specific deaths in either arm of the study.[40]

    A Swedish and Norwegian study reported results of a risk-adapted therapy protocol in which patients with nonseminomas with lymphovascular invasion underwent postorchiectomy chemotherapy with one or two cycles of BEP chemotherapy, while those without lymphovascular invasion underwent either surveillance or a single cycle of BEP.[41] The study included 745 patients and, with a median follow-up of 4.7 years and 2-year follow-up of 89% of patients, there were no deaths from testicular cancer, although one patient died of a stroke immediately after completing chemotherapy for relapsed disease. Overall survival and cause-specific survival were 98.9% and 99.9%, respectively. Both of these studies were conducted at community-based hospitals and demonstrated that postorchiectomy chemotherapy could be delivered at a regional or national level without depending on centers of excellence.

    Several phase II studies and case series reporting the results after two cycles of BEP in intermediate- or high-risk patients have reported relapse rates ranging from 0% to 4% (average = 2.4%).[42] Fewer than 1% of patients in these series died of testicular cancer. While chemotherapy produces the lower relapse rate and a comparable disease-specific survival rate compared to RPLND or surveillance, it is unknown whether a brief course of chemotherapy results in late toxicity or an increased risk of late relapse. Longer follow-up is awaited.

    There is no consensus about the optimal management of men with stage I nonseminomas, but each of the three strategies above produces a disease-specific survival rate of about 99%. Some clinicians have advocated a risk-adapted approach such that low-risk patients undergo surveillance, while others undergo either RPLND or chemotherapy. The goal of such an approach is to minimize the side effects of treatment, but risk-adapted therapy has never been demonstrated to result in better outcomes. Some experts prefer a surveillance strategy generally so as to minimize unnecessary treatment. Others prefer RPLND to obtain more accurate staging, to reduce the risk of needing chemotherapy (and hence chemotherapy's side effects and toxicity) and to, theoretically, reduce the risk of late relapse. At the same time, many experts reject RPLND as insufficiently effective at lowering relapse rates and prefer chemotherapy. Surveillance and chemotherapy have been tested at the regional and national level with excellent results, whereas the limited data concerning RPLND in the regional setting have shown higher than expected in-field relapse rates but no deaths.[40,41]

    With regard to risk stratification, data suggest that relapse rates are higher in patients with histologic evidence of lymphatic or venous invasion or a predominance of embryonal carcinoma.[17,27,36,37,43] Tumors that consist of mature teratoma appear to have a lower relapse rate.[44]

    Current Clinical Trials

    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

    General information about clinical trials is also available from the NCI Web site.

    References:

    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 (22): 4448-52, 2002.
    2. Aparicio J, García del Muro X, Maroto P, et al.: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 14 (6): 867-72, 2003.
    3. Aparicio J, Germà JR, García 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 (34): 8717-23, 2005.
    4. Choo R, Thomas G, Woo T, et al.: Long-term outcome of postorchiectomy surveillance for Stage I testicular seminoma. Int J Radiat Oncol Biol Phys 61 (3): 736-40, 2005.
    5. Chung P, Parker C, Panzarella T, et al.: Surveillance in stage I testicular seminoma - risk of late relapse. Can J Urol 9 (5): 1637-40, 2002.
    6. Daugaard G, Petersen PM, Rørth M: Surveillance in stage I testicular cancer. APMIS 111 (1): 76-83; discussion 83-5, 2003.
    7. Horwich A, Alsanjari N, A'Hern R, et al.: Surveillance following orchidectomy for stage I testicular seminoma. Br J Cancer 65 (5): 775-8, 1992.
    8. von der Maase H, Specht L, Jacobsen GK, et al.: Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 29A (14): 1931-4, 1993.
    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 (9482): 293-300, 2005 Jul 23-29.
    10. Oliver RT, Mead GM, Rustin GJ, et al.: Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol 29 (8): 957-62, 2011.
    11. Dieckmann KP, Brüggeboes B, Pichlmeier U, et al.: Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient? Urology 55 (1): 102-6, 2000.
    12. Krege S, Kalund G, Otto T, et al.: Phase II study: adjuvant single-agent carboplatin therapy for clinical stage I seminoma. Eur Urol 31 (4): 405-7, 1997.
    13. Oliver RT, Boublikova L, Ong J, et al.: Fifteen year follow up of the Anglian Germ Cell Cancer Group adjuvant studies of carboplatin as an alternative to radiation or surveillance for stage I seminoma. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-780, 196a, 2001.
    14. Reiter WJ, Brodowicz T, Alavi S, et al.: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 19 (1): 101-4, 2001.
    15. Steiner H, Höltl L, Wirtenberger W, et al.: Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study. Urology 60 (2): 324-8, 2002.
    16. Bamberg M, Schmidberger H, Meisner C, et al.: Radiotherapy for stages I and IIA/B testicular seminoma. Int J Cancer 83 (6): 823-7, 1999.
    17. Classen J, Schmidberger H, Meisner C, et al.: Para-aortic irradiation for stage I testicular seminoma: results of a prospective study in 675 patients. A trial of the German testicular cancer study group (GTCSG). Br J Cancer 90 (12): 2305-11, 2004.
    18. 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 (4): 1146, 1999.
    19. 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 (6): 1200-8, 2005.
    20. Logue JP, Harris MA, Livsey JE, et al.: Short course para-aortic radiation for stage I seminoma of the testis. Int J Radiat Oncol Biol Phys 57 (5): 1304-9, 2003.
    21. Oliver RT, Mason M, Von der Masse H, et al.: A randomised comparison of single agent carboplatin with radiotherapy in the adjuvant treatment of stage I seminoma of the testis, following orchidectomy: MRC TE19/EORTC 30982. [Abstract] J Clin Oncol 22 (Suppl 14): A-4517, 386, 2004.
    22. Santoni R, Barbera F, Bertoni F, et al.: Stage I seminoma of the testis: a bi-institutional retrospective analysis of patients treated with radiation therapy only. BJU Int 92 (1): 47-52; discussion 52, 2003.
    23. van As NJ, Gilbert DC, Money-Kyrle J, et al.: Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse. Br J Cancer 98 (12): 1894-902, 2008.
    24. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 53 (3): 478-96, 2008.
    25. National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer. Version 2.2009. Fort Washington, PA: National Comprehensive Cancer Network, 2009. Available online. Last accessed January 18, 2012.
    26. Rustin GJ, Mead GM, Stenning SP, et al.: Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197--the National Cancer Research Institute Testis Cancer Clinical Studies Group. J Clin Oncol 25 (11): 1310-5, 2007.
    27. Colls BM, Harvey VJ, Skelton L, et al.: Late results of surveillance of clinical stage I nonseminoma germ cell testicular tumours: 17 years' experience in a national study in New Zealand. BJU Int 83 (1): 76-82, 1999.
    28. Shahidi M, Norman AR, Dearnaley DP, et al.: Late recurrence in 1263 men with testicular germ cell tumors. Multivariate analysis of risk factors and implications for management. Cancer 95 (3): 520-30, 2002.
    29. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
    30. Foster RS, McNulty A, Rubin LR, et al.: The fertility of patients with clinical stage I testis cancer managed by nerve sparing retroperitoneal lymph node dissection. J Urol 152 (4): 1139-42; discussion 1142-3, 1994.
    31. Donohue JP: Evolution of retroperitoneal lymphadenectomy (RPLND) in the management of non-seminomatous testicular cancer (NSGCT). Urol Oncol 21 (2): 129-32, 2003 Mar-Apr.
    32. Heidenreich A, Albers P, Hartmann M, et al.: Complications of primary nerve sparing retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumors of the testis: experience of the German Testicular Cancer Study Group. J Urol 169 (5): 1710-4, 2003.
    33. Williams SD, Stablein DM, Einhorn LH, et al.: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 317 (23): 1433-8, 1987.
    34. Behnia M, Foster R, Einhorn LH, et al.: Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer. the Indiana University experience. Eur J Cancer 36 (4): 472-5, 2000.
    35. Kondagunta GV, Sheinfeld J, Mazumdar M, et al.: Relapse-free and overall survival in patients with pathologic stage II nonseminomatous germ cell cancer treated with etoposide and cisplatin adjuvant chemotherapy. J Clin Oncol 22 (3): 464-7, 2004.
    36. Hermans BP, Sweeney CJ, Foster RS, et al.: Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 163 (6): 1721-4, 2000.
    37. Sweeney CJ, Hermans BP, Heilman DK, et al.: Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer. J Clin Oncol 18 (2): 358-62, 2000.
    38. Sesterhenn IA, Weiss RB, Mostofi FK, et al.: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: a report from the Testicular Cancer Intergroup Study. J Clin Oncol 10 (1): 69-78, 1992.
    39. Stephenson AJ, Bosl GJ, Bajorin DF, et al.: Retroperitoneal lymph node dissection in patients with low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol 174 (2): 557-60; discussion 560, 2005.
    40. Albers P, Siener R, Krege S, et al.: Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol 26 (18): 2966-72, 2008.
    41. Tandstad T, Dahl O, Cohn-Cedermark G, et al.: Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program. J Clin Oncol 27 (13): 2122-8, 2009.
    42. Choueiri TK, Stephenson AJ, Gilligan T, et al.: Management of clinical stage I nonseminomatous germ cell testicular cancer. Urol Clin North Am 34 (2): 137-48; abstract viii, 2007.
    43. Heidenreich A, Sesterhenn IA, Mostofi FK, et al.: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 83 (5): 1002-11, 1998.
    44. Alexandre J, Fizazi K, Mahé C, et al.: Stage I non-seminomatous germ-cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse. Eur J Cancer 37 (5): 576-82, 2001.

    Stage II Testicular Cancer

    Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage II Seminoma

    Stage II seminoma is divided into bulky and nonbulky disease for treatment planning and expression of prognosis. Bulky disease is generally defined as tumors larger than 5 cm on a computed tomographic (CT) scan (i.e., stage IIC disease). Nonbulky disease can be further subdivided into stage IIA, meaning no lymph node mass larger than 2 cm, and stage IIB, meaning a lymph node mass between 2 cm and 5 cm.

    Nonbulky stage II disease has a cure rate of about 90% to 95% with radiation alone at doses of 30 Gy to 36 Gy, [1,2,3,4] and most relapsing patients can be cured with chemotherapy. Cure rates are slightly higher for patients with stage IIA disease than for those with IIB disease, but the figures are within the range given above. Risk factors for relapse include multiple enlarged nodes.

    Results for patients with stage IIC disease have been less favorable. For example, one institution reported that 9 of 16 (56%) stage IIC patients relapsed following radiation therapy, while relapse occurred in only 1 of 23 (4%) IIC patients treated with chemotherapy.[3] A pooled analysis of earlier studies reported a 65% relapse-free survival for men receiving radiation therapy for bulky stage II seminoma.[5] Unfortunately, there are only sparse contemporary data on the use of radiation therapy to treat bulky stage II seminomas, and there are no randomized trials comparing radiation therapy with chemotherapy in this population. Combination chemotherapy with cisplatin is effective therapy in patients with bulky stage II seminomas and has become the most widely accepted treatment option.[6,7]

    Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric attempts to resect residual masses 3 cm or larger, while others advocate close surveillance, with intervention only if the residual mass increases in size. Postchemotherapy radiation therapy has fallen out of favor, in part because of a retrospective study of a consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers that reported that empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[4][Level of evidence: 3iiDiii]

    In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma who require additional therapy.[5] Nevertheless, other reports indicate that the size of the residual mass does not correlate well with active residual disease, most residual masses do not grow, and frequent marker and CT scan evaluation is a viable option even when the residual mass is 3 cm or larger.[6]

    A more recent approach has been to obtain an 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan following chemotherapy. A study of 56 patients reported that positron emission tomography (PET) scans correctly identified eight of ten patients with residual seminoma with no false positives among the 46 patients with benign masses.[8] In this study, PET scans were 100% accurate in patients with residual masses greater than 3 cm in greatest diameter whereas residual malignant masses less than 3 cm were only detected in one of three men. This study provides support for observing men with residual FDG-PET-negative masses greater than 3 cm and for performing a biopsy or resection of any FDG-PET-positive mass.

    Standard treatment options for patients with nonbulky tumors:

    1. Radical inguinal orchiectomy followed by radiation therapy to the retroperitoneal and ipsilateral pelvic lymph nodes. Prophylactic radiation therapy to the mediastinum is contraindicated because of cardiovascular toxicity, and prophylactic radiation to the supraclavicular fossa is not standard. Radiation therapy to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk.
    2. Systemic chemotherapy using three cycles of BEP or four cycles of etoposide and cisplatin. This approach is generally reserved for stage IIA and IIB patients who have multiple areas of adenopathy in the retroperitoneum or a contraindication to radiation therapy such as a horseshoe or pelvic kidney, or inflammatory bowel disease.[7,9,10,11]
    3. Retroperitoneal lymph node dissection (RPLND) may be performed in those rare men who have contraindications to radiation therapy and chemotherapy.

    Standard treatment options for patients with bulky tumors:

    1. Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen) using three cycles of BEP or four cycles of etoposide and cisplatin.[7,9,10,11]
    2. Radical inguinal orchiectomy followed by radiation therapy to the abdominal and pelvic lymph nodes. The recurrence rate is higher after radiation therapy for men with bulky stage II tumors than radiation therapy for nonbulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (=5 cm?10 cm).[3,12]

    Stage II Nonseminoma

    Stage II nonseminoma is highly curable (>95%). Men with stage II disease and persistently elevated serum tumor markers are generally treated as having stage III disease and receive chemotherapy. For men with normal markers after orchiectomy, nonseminomas are divided into stages IIA, IIB, and IIC for treatment purposes. In general, stage IIA patients undergo RPLND to confirm the staging. As many as 40% of clinical stage IIA patients will have benign findings at RPLND and will be restaged as having pathological stage I disease.[13] RPLND can thus prevent a significant number of clinical stage IIA patients from receiving unnecessary chemotherapy.

    In contrast, stage IIB and IIC patients are usually treated with systemic chemotherapy for disseminated disease because these patients have a higher relapse rate after RPLND. One study reported that by limiting RPLND to patients with earlier stage II disease and normal serum tumor markers, 5-year relapse-free survival (RFS) increased from 78% to 100% after RPLND, while RFS did not change significantly among stage II patients receiving chemotherapy (100% vs. 98%).[14] However, the question of whether to treat patients with stage II nonseminomas germ cell tumors with RPLND or chemotherapy has never been subjected to a randomized trial.

    Standard treatment options:

    1. For patients with clinical stage II disease and normal postorchiectomy serum tumor markers, radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving RPLND followed by monthly checkups, which include physical examination, chest x-ray, and serum marker tests (e.g., alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase).

    This option of surgery and careful follow-up, reserving chemotherapy for relapse, is particularly attractive for patients who have pathological stage I or IIA disease (fewer than six positive nodes at RPLND, none of which are larger than 2 cm in diameter). Such patients appear to have a relapse rate of about 10% if followed without chemotherapy, and most are curable with standard chemotherapy if they do relapse.[13,15] Presence of lymphatic or venous invasion and the proportion of the primary tumor that is embryonal carcinoma also help to predict which patients may relapse.[16,17,18] In one study, the relapse rate in men with pathological stage I disease was 3% in men with nonembryonal carcinoma-predominant tumors, 21% in men with embryonal carcinoma-predominant tumors, and 31% in those with embryonal carcinoma-predominant tumors and lymphovascular invasion.[17,18] In children, surgical resection of retroperitoneal nodes is generally not performed. Patients with clinical stage II disease are given chemotherapy.[19]

    2. For patients with clinical and pathological stage II disease and normal postorchiectomy serum tumor markers, radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by two cycles of chemotherapy (i.e., etoposide and cisplatin either with or without bleomycin) and then monthly checkups.

    This option of RPLND plus adjuvant chemotherapy applies to patients who have pathologically confirmed lymph node metastases as a result of RPLND and is most attractive for patients with pathological stage IIB or IIC disease. The results of a large study comparing the first treatment option with the second treatment option were published.[20] Two courses of cisplatin-based chemotherapy (either cisplatin, vinblastine, bleomycin [PVB] or vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin [VAB VI]) prevented a relapse in more than 95% of patients. A 49% relapse rate was seen in patients assigned to observation; however, the majority of these patients could be effectively treated, and no significant differences were found in overall survival. The study concluded that adjuvant therapy will most often prevent relapse in patients treated with optimal surgery, follow-up, and chemotherapy; however, observation with chemotherapy only for relapse will lead to a similar cure rate.

    3. Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups.

    This option is most attractive for patients with elevated serum tumor markers and/or clinical stage IIB or IIC disease. The combination of chemotherapy plus resection of residual masses in these patients results in cure in more than 95% of patients.[14,21]

    Chemotherapy regimens include:

    • BEP: bleomycin plus etoposide plus cisplatin for three courses.[22,23] A modified regimen has been used in children.[19]
    • EP: etoposide plus cisplatin for four courses in good-prognosis patients.[24]

    A randomized study has shown that bleomycin is an essential component of the BEP regimen when only three courses are administered.[25]

    Other regimens that appear to produce similar survival outcomes but are no longer considered standard include:

    • PVB: cisplatin plus vinblastine plus bleomycin.
    • VAB VI: vinblastine plus dactinomycin plus bleomycin plus cyclophosphamide plus cisplatin.[26]
    • VPV: vinblastine plus cisplatin plus etoposide.[27]

    In a randomized comparison of PVB versus BEP, equivalent anticancer activity was seen but with less toxic effects with the use of BEP.[20,28]

    If these patients do not achieve a complete response on chemotherapy, surgical removal of residual masses should be performed. The timing of such surgery requires clinical judgment but would occur most often after three or four cycles of combination chemotherapy and normalization or stabilization of serum markers. The presence of persistently elevated markers is not a contraindication to resection of residual masses, but patients with rising markers at the end of chemotherapy are generally treated with salvage chemotherapy. Despite numerous studies, no sufficiently accurate predictors of the histology of residual masses have been validated. Therefore, the standard of care is to resect all residual masses apparent on scans in patients who have normal or stable markers after responding to chemotherapy. The presence of persistent nonseminomatous germ-cell malignant elements in the resected specimen is a poor prognostic sign and is often a trigger for additional chemotherapy. However, men with only microscopic residual cancer have a much more favorable prognosis than men with more substantial residual disease.[29,30] Identifying which patients benefit from additional chemotherapy is not possible from existing data.

    In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. There is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[31]

    Current Clinical Trials

    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

    General information about clinical trials is also available from the NCI Web site.

    References:

    1. Bamberg M, Schmidberger H, Meisner C, et al.: Radiotherapy for stages I and IIA/B testicular seminoma. Int J Cancer 83 (6): 823-7, 1999.
    2. Bauman GS, Venkatesan VM, Ago CT, et al.: Postoperative radiotherapy for Stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 42 (2): 313-7, 1998.
    3. Chung PW, Gospodarowicz MK, Panzarella T, et al.: Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol 45 (6): 754-59; discussion 759-60, 2004.
    4. 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 (6): 1101-6, 2003.
    5. Thomas GM: Over 20 Years of Progress in Radiation Oncology: Seminoma. Semin Radiat Oncol 7 (2): 135-145, 1997.
    6. Krege S, Beyer J, Souchon R, et al.: European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 53 (3): 497-513, 2008.
    7. Warde P, Gospodarowicz M, Panzarella T, et al.: Management of stage II seminoma. J Clin Oncol 16 (1): 290-4, 1998.
    8. De Santis M, Becherer A, Bokemeyer C, et al.: 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol 22 (6): 1034-9, 2004.
    9. Mencel PJ, Motzer RJ, Mazumdar M, et al.: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12 (1): 120-6, 1994.
    10. 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 (4): 745-52, 2003.
    11. Culine S, Abs L, Terrier-Lacombe MJ, et al.: Cisplatin-based chemotherapy in advanced seminoma: the Institut Gustave Roussy experience. Eur J Cancer 34 (3): 353-8, 1998.
    12. Zagars GK, Pollack A: Radiotherapy for stage II testicular seminoma. Int J Radiat Oncol Biol Phys 51 (3): 643-9, 2001.
    13. Stephenson AJ, Bosl GJ, Motzer RJ, et al.: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 23 (12): 2781-8, 2005.
    14. Stephenson AJ, Bosl GJ, Motzer RJ, et al.: Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 25 (35): 5597-602, 2007.
    15. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 9 (8): 1393-6, 1991.
    16. Heidenreich A, Sesterhenn IA, Mostofi FK, et al.: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 83 (5): 1002-11, 1998.
    17. Hermans BP, Sweeney CJ, Foster RS, et al.: Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 163 (6): 1721-4, 2000.
    18. Sweeney CJ, Hermans BP, Heilman DK, et al.: Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer. J Clin Oncol 18 (2): 358-62, 2000.
    19. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
    20. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.
    21. Horwich A, Norman A, Fisher C, et al.: Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis. J Urol 151 (1): 72-7; discussion 77-8, 1994.
    22. de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001.
    23. Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989.
    24. Xiao H, Mazumdar M, Bajorin DF, et al.: Long-term follow-up of patients with good-risk germ cell tumors treated with etoposide and cisplatin. J Clin Oncol 15 (7): 2553-8, 1997.
    25. Loehrer PJ Sr, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 13 (2): 470-6, 1995.
    26. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4 (10): 1493-9, 1986.
    27. Wozniak AJ, Samson MK, Shah NT, et al.: A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study. J Clin Oncol 9 (1): 70-6, 1991.
    28. Stoter G, Koopman A, Vendrik CP, et al.: Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin. J Clin Oncol 7 (8): 1099-104, 1989.
    29. Fizazi K, Oldenburg J, Dunant A, et al.: Assessing prognosis and optimizing treatment in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT): results of the sCR2 international study. Ann Oncol 19 (2): 259-64, 2008.
    30. Spiess PE, Tannir NM, Tu SM, et al.: Viable germ cell tumor at postchemotherapy retroperitoneal lymph node dissection: can we predict patients at risk of disease progression? Cancer 110 (12): 2700-8, 2007.
    31. Leibovitch I, Little JS Jr, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. J Urol 155 (3): 952-4, 1996.

    Stage III Testicular Cancer

    Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Stage III seminoma and nonseminomas are usually curable but have different criteria for estimating prognosis.

    Patients with disseminated seminomas can be divided into good-risk and intermediate-risk groups based on whether nonpulmonary visceral metastases are present. Good-risk patients (i.e., those with metastases only to lymph nodes and/or lungs) have a 5-year progression-free survival (PFS) and overall survival (OS) of 82% and 86%, respectively. Intermediate-risk seminoma patients have a 5-year PFS and OS rate of 67% and 72%, respectively.[1]

    Patients with disseminated nonseminomas can be divided into good-, intermediate-, and poor-risk groups based on whether nonpulmonary visceral metastases are present, the site of the primary tumor (i.e., mediastinal vs. either gonadal or retroperitoneal), and the level of serum tumor markers.[1]

    • Poor-risk: Men with mediastinal primary tumors, nonpulmonary visceral metastases, or very highly elevated serum tumor markers (as detailed in the Stage Information for Testicular Cancer section) are considered to be at poor risk.
    • Intermediate-risk: Men with intermediate tumor markers levels are considered to be at intermediate risk.
    • Good-risk: Men with good-risk disease have a testis or retroperitoneal primary, metastases limited to lymph nodes and/or lungs, and tumor markers that are in the good-risk range.

    In the 1997 analysis that established these risk groups, 5-year OS was 92%, 80% and 48% in good-, intermediate-, and poor-risk groups while the figures for PFS were 89%, 75% and 41%. However, a 2006 pooled analysis of chemotherapy trials reported improved outcomes compared with the 1997 paper: survival in the good-, intermediate-, and poor-risk groups was 94%, 83% and 71%, respectively.[2]

    Clinical Trials of Chemotherapy for Disseminated Testis and Extragonadal Germ Cell Tumors

    Four cycles of bleomycin plus etoposide plus cisplatin (BEP) chemotherapy as a standard-of-care treatment option for patients with metastatic testicular germ cell tumors was established by a randomized trial showing that it produced similar outcomes with less toxicity in comparison with cisplatin, vinblastine, and bleomycin (PVB).[3] Two randomized trials comparing four courses of BEP with four courses of etoposide plus ifosfamide plus cisplatin (VIP) showed similar OS and time-to-treatment failure for the two regimens in patients with intermediate- and poor-risk advanced disseminated germ cell tumors who had not received prior chemotherapy.[4,5,6][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen. For good-risk patients, two randomized trials compared three versus four cycles of BEP and reported no significant benefit from longer treatment in that population.[7,8,9]

    Numerous attempts have been made to develop a regimen superior to BEP for poor-prognosis germ cell tumors but none have been successful. Most recently, four cycles of BEP was compared with two cycles of BEP followed by two cycles of high-dose cyclophosphamide, etoposide, and carboplatin, but there was no difference in survival between the two arms.[10] Earlier trials of higher dose cisplatin or long-term maintenance chemotherapy were similarly disappointing.

    For good-risk patients, the goal of clinical trials has been to minimize treatment toxicity without sacrificing the therapeutic effectiveness. As noted above, no difference in outcome was seen when comparing three versus four cycles of BEP chemotherapy. However, attempts to eliminate bleomycin produced more ambiguous and usually disappointing results. A randomized controlled trial comparing three cycles of BEP with three cycles of EP reported lower OS (95% vs. 86%, P = .01) in the EP arm.[11] Similarly, when three cycles of BEP was compared with four cycles of EP in a randomized trial in more than 260 patients, there were 6 relapses and 5 deaths in the bleomycin arm compared with 14 relapses and 12 deaths in the EP arm, but these differences were not statistically significant.[12] Several other studies have compared bleomycin-containing regimens to etoposide and cisplatin and in every trial, the trend in survival has favored the bleomycin arm, but the differences have not usually been statistically significant.[13,14,15] These results have led to some controversy as to whether three cycles of BEP is superior to four cycles of EP.

    Special Considerations During Chemotherapy

    In most patients, an orchiectomy is performed before starting chemotherapy. If the diagnosis has been made by biopsy of a metastatic site (or on the basis of highly elevated serum tumor markers and radiological imaging consistent with an advanced-stage germ cell tumor) and chemotherapy has been initiated, subsequent orchiectomy is generally performed because chemotherapy may not eradicate the primary tumor. Case reports illustrate that viable tumor has been found on postchemotherapy orchiectomy despite complete response of metastatic lesions.[16]

    Some retrospective data suggest that the experience of the treating institution may impact the outcome of patients with stage III nonseminoma. Data from 380 patients treated from 1990 to 1994 on the same study protocol at 49 institutions in the European Organization for Research and Treatment of Cancer and the Medical Research Council were analyzed.[17] Overall, 2-year survival for the 55 patients treated at institutions that entered fewer than 5 patients onto the protocol was 62% (95% confidence interval [CI], 48%?75%) versus 77% (95% CI, 72%?81%) in the institutions that entered 5 or more patients onto the protocol.

    Similarly, a population-based study of testis cancer in Japan in the 1990s reported a significant association between survival and the number of testis cancer patients treated. Relative 5-year survival was 98.8% at high-volume hospitals compared with 79.7% at low-volume hospitals. After adjusting for stage and age, the hazard ratio for death in a high-volume hospital was 0.11 (95% CI, 0.025?0.495).[18] Several other studies have reported similar findings.[19,20,21] As in any nonrandomized study design, patient selection factors and factors leading patients to choose treatment at one center versus another can make interpretation of these results difficult.

    Many patients with poor-risk nonseminomatous testicular germ cell tumors who have a serum beta human chorionic gonadotropin (beta-hCG) level higher than 50,000 IU/mL at the initiation of cisplatin-based therapy (BEP or PVB) will still have an elevated beta-hCG level at the completion of therapy, showing an initial rapid decrease in beta-hCG followed by a plateau.[22] In the absence of other signs of progressing disease, monthly evaluation with initiation of salvage therapy, if and when there is serologic progression, may be appropriate. Many patients, however, will remain disease-free without further therapy.[22][Level of evidence: 3iiDiv]

    Residual Masses After Chemotherapy in Men with Seminomas

    Residual radiologic abnormalities are common at the completion of chemotherapy. Such masses are not treated unless they grow or are histopathologically shown to contain viable cancer. In a combined retrospective consecutive series of 174 seminoma patients with postchemotherapy residual disease seen at ten treatment centers, empiric radiation was not associated with any medically significant improvement in PFS after completion of platinum-based combination chemotherapy.[23][Level of evidence: 3iiDiii] In some series, surgical resection of specific masses has yielded a significant number of patients with residual seminoma that require additional therapy.[24] Larger masses are more likely to harbor viable cancer, but there is no size criteria with high sensitivity and specificity. 18 fluorodeoxyglucose-positron emission tomography (FDG-PET) scans have been shown to be helpful in identifying patients who harbor viable cancers, but the false-positive rate is substantial in some series.[25,26,27] The strength of positron emission tomograph (PET) scans in residual seminoma masses is that they have a very high sensitivity and a low false-negative rate. Thus, for men with residual masses for whom resection is being planned, a negative PET scan provides evidence that surgery is not necessary.

    Although larger residual masses are more likely to harbor viable seminoma, the size of the residual mass is of limited prognostic value.[24,25,26] Most residual masses do not grow, and regular marker and computed tomographic (CT) scan evaluation is a viable management option for large or small masses.[28] An alternative approach is to operate on larger masses, to resect them when possible, and to perform biopsies of unresectable masses. Postchemotherapy masses are often difficult or impossible to resect because of a dense desmoplastic reaction. Historically, such surgery has been characterized by a high rate of complications or additional procedures such as nephrectomy or arterial or venous grafting.[29]

    Residual Masses After Chemotherapy in Men with Nonseminomas

    Residual masses following chemotherapy in men with nonseminomatous germ cell tumors often contain viable cancer or teratoma, and the standard of care is to resect all such masses when possible. However, there are no randomized controlled trials evaluating this issue. Instead, the practice is based on the fact that viable neoplasm is often found at surgery in these patients, and the presumption is that such tumors would progress if not resected. If serum tumor markers are rising, salvage chemotherapy is usually given, but stable or slowly declining tumor markers are not a contraindication to resection of residual masses.

    Case series of men undergoing postchemotherapy resections have reported that roughly 10% will have viable germ cell cancer, 45% will have teratoma, and 45% will have no viable tumor.[30] Numerous attempts have been made to identify the patients who need surgery and the patients who can be safely observed. Variables predictive of finding only necrosis or fibrosis at surgery are:[31]

    • Absence of any teratoma in the primary tumor.
    • Normal prechemotherapy serum alpha-fetoprotein, ß-human chorionic gonadotropin, and lactase dehydrogenase.
    • A small residual mass.
    • A large diminishment in mass size during chemotherapy.

    However, only a very small proportion of men have favorable enough features to have less than a 10% chance of having viable neoplasm in their residual masses, and thus the utility of current models has been questioned.[24,32]

    When multiple sites of residual disease are present, all residual masses are generally resected. If it is not surgically feasible, then resection is generally not performed. Some patients may have discordant pathologic findings (e.g., fibrosis/necrosis, teratoma, or carcinoma) in residual masses in the abdomen versus the chest. Some medical centers perform simultaneous retroperitoneal and thoracic operations to remove residual masses,[28,33] but most do not. Although the agreement among the histologies of residual masses found after chemotherapy above the diaphragm versus below the diaphragm is only moderate (kappa statistic = 0.42), some evidence exists that if retroperitoneal resection is performed first, results can be used to guide decisions about whether to perform a thoracotomy.[34]

    In a multi-institutional case series of surgery to remove postchemotherapy residual masses in 159 patients, necrosis only was found at thoracotomy in about 90% of patients who had necrosis only in their retroperitoneal masses. The figure was about 95% if the original testicular primary tumor had contained no teratomatous elements. Conversely, the histology of residual masses at thoracotomy did not predict nearly as well the histology of retroperitoneal masses.[34] Nonetheless, some centers continue to support resection of all residual masses, even if necrosis is found in the retroperitoneum.[35]

    The presence of persistent malignant elements in the resected specimen is considered by some clinicians to be an indication for additional chemotherapy.[36] However, there are no prospective trials investigating the benefit of such treatment. In some cases, chemotherapy is initiated before the orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation or completion of chemotherapy is advisable to remove the primary tumor. A physiologic blood-testis barrier seems to appear, and there is a higher incidence (approximately 50%) of residual cancer in the testicle than in remaining radiographically detectable retroperitoneal masses after platinum-based chemotherapy.[16] Some investigators have suggested that in children, 90% of whom have yolk sac tumors, radiation therapy should be given to residual masses after chemotherapy rather than surgery.[37]

    Standard treatment options for initial treatment for nonseminoma patients with good-risk disease:

    • Radical inguinal orchiectomy followed by multidrug chemotherapy.[38]

      Chemotherapy combinations include:

      • BEP: bleomycin plus etoposide plus cisplatin for three 21-day cycles. [7,8,9,11]
      • EP: etoposide plus cisplatin for four 21-day cycles.[13,39,40] Four cycles of EP should be considered for men with good-risk metastatic seminoma who have a contraindication to receiving bleomycin.

    Standard treatment options for initial treatment for nonseminoma patients with intermediate- and poor-risk disease:

    • Radical inguinal orchiectomy followed by multidrug chemotherapy.[38]

      Chemotherapy combinations include:

      • BEP: bleomycin plus etoposide plus cisplatin.[3,4,41,42]
      • VIP: etoposide plus ifosfamide plus cisplatin.[5,41] Four cycles of VIP should be considered for patients with intermediate-risk metastatic seminoma who have a contraindication to receiving bleomycin.

    Management of residual masses following chemotherapy for patients with seminoma

    • In seminoma patients, the residual masses after chemotherapy are usually fibrotic but may contain residual seminoma that requires additional therapy.[43,44] There are three standard management strategies:
      • Observation with no additional treatment or biopsies unless the residual mass(es) increase(s) in size.
      • Observation of masses smaller than 3 cm and surgical resection of masses larger than 3 cm.
      • FDG-PET scan 2 months after chemotherapy is completed with observation of PET-negative masses and resection of PET-positive masses.

    Management of residual masses following chemotherapy for patients with nonseminoma

    • In patients who have residual masses following chemotherapy, all such masses should be resected if technically feasible. If some, but not all, residual masses can be resected, surgery is not usually performed. The rationale for surgery in this setting is that about half of the masses will contain viable tumor, either teratoma or cancer.

    Current Clinical Trials

    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

    General information about clinical trials is also available from the NCI Web site.

    References:

    1. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.
    2. van Dijk MR, Steyerberg EW, Habbema JD: Survival of non-seminomatous germ cell cancer patients according to the IGCC classification: An update based on meta-analysis. Eur J Cancer 42 (7): 820-6, 2006.
    3. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.
    4. Nichols CR, Catalano PJ, Crawford ED, et al.: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 16 (4): 1287-93, 1998.
    5. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97 (8): 1869-75, 2003.
    6. de Wit R, Louwerens M, de Mulder PH, et al.: Management of intermediate-prognosis germ-cell cancer: results of a phase I/II study of Taxol-BEP. Int J Cancer 83 (6): 831-3, 1999.
    7. Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989.
    8. Saxman SB, Finch D, Gonin R, et al.: Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indiana University experience. J Clin Oncol 16 (2): 702-6, 1998.
    9. de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001.
    10. Motzer RJ, Nichols CJ, Margolin KA, et al.: Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 25 (3): 247-56, 2007.
    11. Loehrer PJ Sr, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 13 (2): 470-6, 1995.
    12. 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 (5): 917-24, 2007.
    13. Bosl GJ, Geller NL, Bajorin D, et al.: A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors. J Clin Oncol 6 (8): 1231-8, 1988.
    14. Levi JA, Raghavan D, Harvey V, et al.: The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J Clin Oncol 11 (7): 1300-5, 1993.
    15. de Wit R, Stoter G, Kaye SB, et al.: Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 15 (5): 1837-43, 1997.
    16. Leibovitch I, Little JS Jr, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. J Urol 155 (3): 952-4, 1996.
    17. Collette L, Sylvester RJ, Stenning SP, et al.: Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma. European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 91 (10): 839-46, 1999.
    18. Suzumura S, Ioka A, Nakayama T, et al.: Hospital procedure volume and prognosis with respect to testicular cancer patients: a population-based study in Osaka, Japan. Cancer Sci 99 (11): 2260-3, 2008.
    19. Aass N, Klepp O, Cavallin-Stahl E, et al.: Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol 9 (5): 818-26, 1991.
    20. Feuer EJ, Frey CM, Brawley OW, et al.: After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer. J Clin Oncol 12 (2): 368-77, 1994.
    21. Harding MJ, Paul J, Gillis CR, et al.: Management of malignant teratoma: does referral to a specialist unit matter? Lancet 341 (8851): 999-1002, 1993.
    22. Zon RT, Nichols C, Einhorn LH: Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels. J Clin Oncol 16 (4): 1294-7, 1998.
    23. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma--a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 33 (6): 829-35, 1997.
    24. Heidenreich A, Thüer D, Polyakov S: Postchemotherapy retroperitoneal lymph node dissection in advanced germ cell tumours of the testis. Eur Urol 53 (2): 260-72, 2008.
    25. De Santis M, Becherer A, Bokemeyer C, et al.: 2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial. J Clin Oncol 22 (6): 1034-9, 2004.
    26. Hinz S, Schrader M, Kempkensteffen C, et al.: The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma. J Urol 179 (3): 936-40; discussion 940, 2008.
    27. Lewis DA, Tann M, Kesler K, et al.: Positron emission tomography scans in postchemotherapy seminoma patients with residual masses: a retrospective review from Indiana University Hospital. J Clin Oncol 24 (34): e54-5, 2006.
    28. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.
    29. Mosharafa AA, Foster RS, Leibovich BC, et al.: Is post-chemotherapy resection of seminomatous elements associated with higher acute morbidity? J Urol 169 (6): 2126-8, 2003.
    30. Steyerberg EW, Keizer HJ, Fosså SD, et al.: Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups. J Clin Oncol 13 (5): 1177-87, 1995.
    31. Vergouwe Y, Steyerberg EW, Foster RS, et al.: Predicting retroperitoneal histology in postchemotherapy testicular germ cell cancer: a model update and multicentre validation with more than 1000 patients. Eur Urol 51 (2): 424-32, 2007.
    32. Vergouwe Y, Steyerberg EW, de Wit R, et al.: External validity of a prediction rule for residual mass histology in testicular cancer: an evaluation for good prognosis patients. Br J Cancer 88 (6): 843-7, 2003.
    33. Brenner PC, Herr HW, Morse MJ, et al.: Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis. J Clin Oncol 14 (6): 1765-9, 1996.
    34. Steyerberg EW, Donohue JP, Gerl A, et al.: Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group. J Urol 158 (2): 474-8, 1997.
    35. Katz MH, McKiernan JM: Management of non-retroperitoneal residual germ cell tumor masses. Urol Clin North Am 34 (2): 235-43; abstract x, 2007.
    36. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.
    37. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. J Pediatr Surg 25 (4): 406-10, 1990.
    38. 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 (4): 745-52, 2003.
    39. Bajorin DF, Geller NL, Weisen SF, et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67 (1): 28-32, 1991.
    40. Mencel PJ, Motzer RJ, Mazumdar M, et al.: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 12 (1): 120-6, 1994.
    41. de Wit R, Stoter G, Sleijfer DT, et al.: Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group. European Organization for Research and Treatment of Cancer. Br J Cancer 78 (6): 828-32, 1998.
    42. Culine S, Abs L, Terrier-Lacombe MJ, et al.: Cisplatin-based chemotherapy in advanced seminoma: the Institut Gustave Roussy experience. Eur J Cancer 34 (3): 353-8, 1998.
    43. Quek ML, Simma-Chiang V, Stein JP, et al.: Postchemotherapy residual masses in advanced seminoma: current management and outcomes. Expert Rev Anticancer Ther 5 (5): 869-74, 2005.
    44. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 157 (3): 860-2, 1997.

    Recurrent Testicular Cancer

    Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

    Deciding on further treatment depends on many factors, including the specific cancer, previous treatment, site of recurrence, and individual patient considerations. Salvage regimens consisting of ifosfamide, cisplatin, and either etoposide or vinblastine can induce long-term complete responses in about 25% of patients with disease that has persisted or recurred following other cisplatin-based regimens. Patients who have had an initial complete response to first-line chemotherapy and those without extensive disease have the most favorable outcomes.[1,2] This regimen is now the standard initial salvage regimen.[2,3] Few, if any, patients with recurrent nonseminomatous germ cell tumors of extragonadal origin, however, achieve long-term disease-free survival (DFS) using vinblastine, ifosfamide, and cisplatin if their disease recurred after they received an initial regimen containing etoposide and cisplatin.[2][Level of evidence: 3iiDii]

    High-dose chemotherapy with autologous marrow transplantation has also been used in uncontrolled case series in the setting of recurrent disease.[4,5,6,7,8,9,10,11] However, a randomized controlled trial comparing conventional doses of salvage chemotherapy with high-dose chemotherapy with autologous marrow rescue showed more toxic effects and treatment-related deaths in the high-dose arm without any improvement in response rate or overall survival.[12][Level of evidence: 1iiA] In some highly selected patients with chemorefractory disease confined to a single site, surgical resection may yield long-term DFS.[13,14] One case series suggests that a maintenance regimen of daily oral etoposide (taken 21 days out of 28 days) may benefit patients who achieve a complete remission after salvage therapy.[15]

    A special case of late relapse may include patients who relapse more than 2 years after achieving complete remission; this population represents less than 5% of patients who are in complete remission after 2 years. Results with chemotherapy are poor in this patient subset, and surgical treatment appears to be superior, if technically feasible.[16] Teratoma may be amenable to surgery at relapse, and teratoma also has a better prognosis than carcinoma after late relapse. Teratoma is a relatively resistant histologic subtype, so chemotherapy may not be appropriate.

    Clinical trials are appropriate and should be considered whenever possible, including phase I and phase II studies for those patients who do not achieve a complete remission with induction therapy, or for those who do not achieve a complete remission following etoposide and cisplatin for their initial relapse, or for patients who have a second relapse.[17]

    Current Clinical Trials

    Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

    General information about clinical trials is also available from the NCI Web site.

    References:

    1. Loehrer PJ Sr, Lauer R, Roth BJ, et al.: Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 109 (7): 540-6, 1988.
    2. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.
    3. Motzer RJ, Cooper K, Geller NL, et al.: The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors. Cancer 66 (12): 2476-81, 1990.
    4. Broun ER, Nichols CR, Kneebone P, et al.: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117 (2): 124-8, 1992.
    5. Droz JP, Pico JL, Ghosn M, et al.: Long-term survivors after salvage high dose chemotherapy with bone marrow rescue in refractory germ cell cancer. Eur J Cancer 27 (7): 831-5, 1991.
    6. Cullen MH: Dose-response relationships in testicular cancer. Eur J Cancer 27 (7): 817-8, 1991.
    7. Motzer RJ, Mazumdar M, Bosl GJ, et al.: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14 (4): 1098-105, 1996.
    8. Motzer RJ, Bosl GJ: High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. J Natl Cancer Inst 84 (22): 1703-9, 1992.
    9. Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000.
    10. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.
    11. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007.
    12. Pico JL, Rosti G, Kramar A, et al.: A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 16 (7): 1152-9, 2005.
    13. Murphy BR, Breeden ES, Donohue JP, et al.: Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 11 (2): 324-9, 1993.
    14. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11 (7): 1294-9, 1993.
    15. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. J Clin Oncol 13 (5): 1167-9, 1995.
    16. Baniel J, Foster RS, Gonin R, et al.: Late relapse of testicular cancer. J Clin Oncol 13 (5): 1170-6, 1995.
    17. Motzer RJ, Geller NL, Tan CC, et al.: Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989). Cancer 67 (5): 1305-10, 1991.

    Changes to This Summary (01 / 20 / 2012)

    The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

    General Information About Testicular Cancer

    Updated statistics with estimated new cancer cases and deaths for 2012 (cited American Cancer Society as reference 1).

    Cellular Classification of Testicular Cancer

    Updated Bosi et al. as reference 3.

    This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

    About This PDQ Summary

    Purpose of This Summary

    This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of testicular cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

    Reviewers and Updates

    This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

    Board members review recently published articles each month to determine whether an article should:

    • be discussed at a meeting,
    • be cited with text, or
    • replace or update an existing article that is already cited.

    Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

    The lead reviewer for Testicular Cancer Treatment is:

    • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)

    Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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    National Cancer Institute: PDQ® Testicular Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/testicular/HealthProfessional. Accessed <MM/DD/YYYY>.

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