Testicular cancer

Table of Contents
GENERAL INFORMATION CELLULAR CLASSIFICATION STAGE INFORMATION AJCC stage groupings Stage 0 Stage I Stage IA Stage IB Stage IS Stage II Stage IIA Stage IIB Stage IIC Stage III Stage IIIA Stage IIIB Stage IIIC Stage I Stage II Stage III TREATMENT OPTION OVERVIEW STAGE I TESTICULAR CANCER Stage I seminoma Stage I nonseminoma STAGE II TESTICULAR CANCER Stage II seminoma Stage II nonseminoma STAGE III TESTICULAR CANCER Stage III seminoma Stage III nonseminoma RECURRENT TESTICULAR CANCER

GENERAL INFORMATION
(A separate summary containing information on screening for testicular cancer is also available in PDQ.) 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 levels of evidence summary for more information. Testicular cancer is a highly treatable, often curable cancer that usually develops in young and middle-aged men. Testicular cancer is broadly divided into seminoma and nonseminoma types for treatment planning because seminomas are more sensitive to radiation therapy. For patients with seminoma (all stages combined), the cure rate exceeds 90%. For patients with low-stage disease, the cure rate approaches 100%.[1] Tumors which have a mixture of seminoma and nonseminoma components should be managed as nonseminoma. Nonseminoma includes embryonal carcinoma, teratoma, yolk sac carcinoma and choriocarcinoma, and various combinations of these cell types. Tumors that appear to have a seminoma histology but that have elevated serum

levels of alpha fetoprotein (AFP) should be treated as nonseminomas. Elevation of the beta subunit of human chorionic gonadotropin (HCG) alone is found in approximately 10% of patients with pure seminoma. Risk of metastases is lowest for teratoma and highest for choriocarcinoma, with the other cell types being intermediate. A number of prognostic classification schema are in use for metastatic nonseminomatous testicular cancer and for primary extragonadal nonseminomatous germ cell cancers treated with chemotherapy.[2-4] Most incorporate some or all of the following factors which may independently predict worse prognosis: 1) presence of liver, bone, or brain metastases; 2) very high serum markers; 3) primary mediastinal nonseminoma; and 4) large number of lung metastases. It is important to note that even patients with widespread metastases at presentation, including those with brain metastases, may still be curable and should be treated with this intent.[5] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice in diagnostically evaluating a testicular mass.[6] Transscrotal biopsy is not considered appropriate because of the risk of local dissemination of tumor into the scrotum or 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 to the inguinal approach (2.9% versus 0.4%).[7][Level of evidence: 3iiiDi] However, distant recurrence and survival rates were indistinguishable in the 2 approaches. Local recurrence was similar in patients who did not have scrotal violation, regardless of whether or not additional treatments, such as hemiscrotal radiation, hemiscrotal resection, or inguinal lymph node dissection, were used. An important aspect of the diagnosis and follow-up of testicular cancer is the use of serum markers. Serum markers include AFP, HCG (measurement of the beta subunit reduces luteinizing hormone (LH) crossreactivity), and lactate dehydrogenase (LDH). They may detect a tumor which is too small to be detected on physical examination or x-rays. Below the age of 15, about 90% of testicular germ cell cancers are yolk sac tumors. In virtually all of these patients, the AFP is elevated at diagnosis and is an excellent indicator of response to therapy and disease status.[8] Serum markers plus chest x-rays are important parts of the monthly checkups for patients after definitive therapy of testicular cancer as well as periodic abdominal computed tomographic (CT) scans for 2 to 3 years. The absence of markers does not mean the absence of tumor. Patients typically receive follow-up monthly for the first year and every other month for the second year after diagnosis and treatment. While the majority of tumor recurrences appear within 2 years, late relapse has been reported and lifelong marker, radiologic, and physical examination is recommended.[9] Evaluation of the retroperitoneal lymph nodes is an important aspect of treatment planning in adults with testicular cancer. These nodes are usually evaluated by CT scanning.[10,11] However, patients with a negative result have a 25% to 30% chance of having microscopic involvement of the lymph nodes. For seminoma, some physicians think that knowing the results of both the lymphangiogram and the CT scan is important for treatment planning. However, for nonseminoma, the inaccuracy of both is a problem and frequently surgical staging is required. About a quarter of patients with clinical stage I nonseminomatous testicular cancer will be upstaged to pathologic stage II with retroperitoneal lymph node dissection (RPLND), and about a quarter of clinical stage II patients will be downstaged to pathologic stage I with RPLND.[12] In children, the use of serial measurements of AFP has proven sufficient for monitoring response after initial orchiectomy. Lymphangiography and paraaortic lymph node dissection do not appear to be useful or necessary in the proper staging and management of these patients.[8] Patients who have been cured of testicular cancer have approximately a 2% to 5% cumulative risk of developing a cancer in the opposite testicle over the 25 years after initial diagnosis.[13,14] However, in a single series, the risk of a second cancer in the opposite testicle was not increased in patients who had been treated with chemotherapy for their original tumor.[15] There have been reports that HIV-infected men are at increased risk of developing testicular germ cell cancer.[16] Depending on co-morbid conditions such as active infection, these men are generally managed similarly to non-HIV-infected patients.

Since the majority of testis cancer patients who receive chemotherapy are curable, it is important to be aware of possible long-term effects of platinum-based treatment: 1. Fertility: Many patients have oligospermia or sperm abnormalities prior to therapy. Virtually all become oligospermic during chemotherapy. However, many recover sperm production and can father children. The children do not appear to have an increased risk of congenital malformations.[17-20] 2. Secondary leukemias: Several reports of elevated risk of secondary acute leukemia, primarily nonlymphocytic, have appeared.[21] In some cases, they were associated with the prolonged use of alkylating agents or with the use of radiation.[22] Etoposide-containing regimens are also associated with a risk of secondary acute leukemias, usually in the myeloid lineage, and with a characteristic 11q23 translocation.[23-26] Etoposideassociated leukemias typically occur earlier after therapy than alkylating agent-associated leukemias and often show balanced chromosomal translocations on the long arm of chromosome 11.[23] Standard etoposide dosages (<2 grams per square meter 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 greater than 2 grams per square meter of etoposide may confer higher risk. The risk of secondary leukemia after treatment with cisplatin, vinblastine, and bleomycin (PVB) may only be minimally elevated.[15] 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, without significant deterioration.[27] 4. Hearing: Bilateral hearing deficits occur with cisplatin-based chemotherapy, but they generally occur at sound frequencies of 4 to 8 kilohertz, outside the range of conversational tones.[27] Therefore, hearing aids are rarely required at standard doses of cisplatin. Although bleomycin pulmonary toxic effects may occur, it is rarely fatal at total cumulative doses below 400 units. However, 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. There has been a report that men treated curatively for germ cell tumors with cisplatin-based regimens have had elevations in total serum cholesterol.[28] However, this could not be confirmed in another study.[29] No clear long-term effects on coronary artery disease have been shown. 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.[21,23] These include cancers of the stomach, the bladder, and possibly the pancreas. Many patients have oligospermia or sperm abnormalities prior to therapy. Radiation therapy, used to treat pure seminomatous testicular cancers, can cause fertility problems due to radiation scatter to the remaining testicle during radiation to retroperitoneal lymph nodes.[30] Depending on scatter dose, sperm counts fall after radiation, 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. As with treatment with chemotherapy, some men have been reported to father children after radiation treatment of seminoma, and the children do not appear to have a high risk of congenital malformations.[30][Level of evidence: 3iiiD] Though 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. References: 1. Bosl GJ, Bajorin DF, Sheinfeld J, et al.: Cancer of the testis. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1397-1425.

2. Bajorin DF, Bosl GJ.: The use of serum tumor markers in the prognosis and treatment of germ cell tumors. Cancer: Principles and Practice of Oncology Updates 6(1): 1-11, 1992. 3. Mead GM, Stenning SP, Parkinson MC, et al.: The second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumors. Journal of Clinical Oncology 10(1): 85-94, 1992. 4. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. Journal of Clinical Oncology 15(2): 594-603, 1997. 5. Spears WT, Morphis JG, Lester SG, et al.: Brain metastases and testicular tumors: long-term survival. International Journal of Radiation Oncology, Biology, Physics 22(1): 17-22, 1992. 6. Leibovitch I, Baniel J, Foster RS, et al.: The clinical implications of procedural deviations during orchiectomy for nonseminomatous testis cancer. Journal of Urology 154(3): 935-939, 1995. 7. Capelouto CC, Clark PE, Ransil BJ, et al.: A review of scrotal violation in testicular cancer: is adjuvant local therapy necessary? Journal of Urology 153(3 Pt 2): 981-985, 1995. 8. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. Journal of Pediatric Surgery 25(4): 406-410, 1990. 9. Gerl A, Clemm C, Schmeller N, et al.: Late relapse of germ cell tumors after cisplatin-based chemotherapy. Annals of Oncology 8(1): 41-47, 1997. 10. Socinski MA, Stomper PC: Radiologic evaluation of nonseminomatous germ cell tumor of the testis. Seminars in Urology 6(3): 203-215, 1988. 11. National Institutes of Health: National Institutes of Health Consensus Development Conference: magnetic resonance imaging. Journal of the American Medical Association 259(14): 2132-2138, 1988. 12. Donohue JP, Thornhill JA, Foster RS, et al.: The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: the Indiana University experience (1965 to 1989). Journal of Urology 153(1): 8589, 1995. 13. Osterlind A, Berthelsen JG, Abildgaard N, et al.: Risk of bilateral testicular germ cell cancer in Denmark: 1960-1984. Journal of the National Cancer Institute 83(19): 1391-1395, 1991. 14. Colls BM, Harvey VJ, Skelton L, et al.: Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978-1994. Journal of Clinical Oncology 14(7): 2061-2065, 1996. 15. 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. Journal of Clinical Oncology 11(3): 415-424, 1993. 16. Foster RS, Donohue JP: Surgical treatment of clinical stage A nonseminomatous testis cancer. Seminars in Oncology 19(2):166-170, 1992. 17. Drasga RE, Einhorn LH, Williams SD, et al.: Fertility after chemotherapy for testicular cancer. Journal of Clinical Oncology 1(3): 179-183, 1983. 18. Nijman JM, Koops HS, Kremer J, et al.: Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors. Journal of Clinical Oncology 5(4): 651-656, 1987. 19. Hansen PV, Trykker H, Helkjoer PE, et al.: Testicular function in patients with testicular cancer treated with orchiectomy alone or orchiectomy plus cisplatin-based chemotherapy. Journal of the National Cancer Institute 81(16): 1246-1250, 1989. 20. Stephenson WT, Poirier SM, Rubin L, et al.: Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin. Journal of Clinical Oncology 13(9): 2278-2280, 1995. 21. Travis LB, Curtis RE, Storm H, et al.: Risk of second malignant neoplasms among long-term survivors of testicular cancer. Journal of the National Cancer Institute 89(19): 1429-1439, 1997. 22. Redman JR, Vugrin D, Arlin ZA, et al.: Leukemia following treatment of germ cell tumors in men. Journal of Clinical Oncology 2(10): 1080-1087, 1984. 23. Bokemeyer C, Schmoll H: Treatment of testicular cancer and the development of secondary malignancies. Journal of Clinical Oncology 13(1): 283-292, 1995. 24. Pedersen-Bjergaard J, Daugaard G, Hansen SW, et al.: Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet 338(8736): 359-363, 1991. 25. Nichols CR, Breeden ES, Loehrer PJ, et al.: Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols. Journal of the National Cancer Institute 85(1): 3640, 1993.

26. Bajorin DF, Motzer RJ, Rodriguez E, et al.: Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. Journal of the National Cancer Institute 85(1): 60-62, 1993. 27. Osanto S, Bukman A, Van Hoek F, et al.: Long-term effects of chemotherapy in patients with testicular cancer. Journal of Clinical Oncology 10(4): 574-579, 1992. 28. Raghavan D, Cox K, Childs A, et al.: Hypercholesterolemia after chemotherapy for testis cancer. Journal of Clinical Oncology 10(9): 1386-1389, 1992. 29. Ellis PA, Fitzharris BM, George PM, et al.: Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors. Journal of Clinical Oncology 10(10): 1609-1614, 1992. 30. Gordon W, Siegmund K, Stanisic TH, et al.: A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). International Journal of Radiation Oncology, Biology, Physics 38(1): 83-94, 1997.

CELLULAR CLASSIFICATION
The World Health Organization histologic classification of testicular germ cell tumors is shown below along with their distribution in a study of over 1,000 cases from the Armed Forces Institute of Pathology (AFIP):[1]
A. Tumor showing single cell type 1. Seminoma 2. Embryonal carcinoma 3. Teratoma 4. Choriocarcinoma 5. Yolk sac tumor

26.9% 3.1% 2.7% 0.03% 2.4%

The majority of nonseminomas have more than 1 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 response to chemotherapy. B. Tumor showing more than 1 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 References: 1. Mostofi FK, Sesterhenn IA, Davis CJ: Developments in histopathology of testicular germ cell tumors. Seminars in Urology 6(3): 171-188, 1988.

STAGE INFORMATION
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

-- TNM definitions -Primary tumor (T) The extent of primary tumor is classified after radical orchiectomy. pTX: Primary tumor cannot be assessed (if no radical orchiectomy has been performed, TX is used.) pT0: No evidence of primary tumor (e.g., histologic scar in testis) pTis: Intratubular germ cell neoplasia (carcinoma in situ) pT1: Tumor limited to testis and epididymis without lymphatic/vascular invasion pT2: Tumor limited to 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 Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension N3: Metastasis in a lymph node more than 5 cm in greatest dimension Distant metastasis (M) MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis M1a: Non-regional nodal or pulmonary metastasis M1b: Distant metastasis other than to non-regional nodes and lungs Serum tumor markers (S) SX: Marker studies not available or not performed S0: Marker study levels within normal limits S1: LDH < 1.5 X N AND HCG (mIu/ml) < 5000 AND AFP (ug/ml) < 1000 S2: LDH 1.5-10 X N OR HCG (mIu/ml) 5000-50,000 OR AFP (ug/ml) 1000-10,000 S3: LDH > 10 X N OR HCG (mIu/ml) > 50,000 OR AFP (ug/ml) > 10,000 N: indicates the upper limit of normal for the LDH assay

AJCC stage groupings Stage 0 pTis, N0, M0, S0 Stage I pT1-4, N0, M0, SX Stage IA pT1, N0, M0, S0 Stage IB

pT2, N0, M0, S0 pT3, N0, M0, S0 pT4, N0, M0, S0 Stage IS Any pT/Tx, N0, M0, S1-3 Stage II Any pT/Tx, N1-3, M0, SX Stage IIA Any pT/Tx, N1, M0, S0 Any pT/Tx, N1, M0, S1 Stage IIB Any pT/Tx, N2, M0, S0 Any pT/Tx, N2, M0, S1 Stage IIC Any pT/Tx, N3, M0, S0 Any pT/Tx, N3, M0, S1 Stage III Any pT/Tx, Any N, M1, SX Stage IIIA Any pT/Tx, Any N, M1a, S0 Any pT/Tx, Any N, M1a, S1 Stage IIIB Any pT/Tx, N1-3, M0, S2 Any pT/Tx, Any N, M1a, S2 Stage IIIC Any pT/Tx, N1-3, M0, S3 Any pT/Tx, Any N, M1a, S3 Any pT/Tx, Any N, M1b, Any S 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 spermatic cord also does not change the stage but does increase the risk of retroperitoneal nodal involvement and the risk of recurrence. This stage corresponds to AJCC stages I and II.

Stage II Stage II testicular cancer involves the testis and the retroperitoneal or para-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 5 nodes are involved, if the size of 1 or more involved nodes is larger than 2 centimeters, or if there is extranodal fat involvement. Bulky stage II disease describes patients with extensive retroperitoneal nodes (>5 centimeters) who require primary chemotherapy and who have a less favorable prognosis. This stage corresponds to AJCC stages III and IV (no distant metastasis).

Stage III Stage III implies spread beyond the retroperitoneal nodes based on physical examination, x-rays, and/or blood tests. Stage III is subdivided into nonbulky stage III versus bulky stage III. In nonbulky stage III, metastases are limited to lymph nodes and lung with no mass larger than 2 centimeters in diameter. Bulky stage III includes extensive retroperitoneal nodal involvement, plus lung nodules or spread to other organs such as liver or brain. This stage corresponds to AJCC stage IV (distant metastasis). References: 1. Testis. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 225-230.

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. Nonseminomatous testicular tumors include yolk sac 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 early 1997 by all major clinical trial groups worldwide. It should be used for reporting of clinical trials results of patients with germ cell tumors.
-- Good Prognosis -Nonseminoma: testis/retroperitoneal primary and no non-pulmonary visceral metastases and good markers - all of: AFP < 1000 ug/ml and HCG < 5000 iu/l (1000 ug/ml) and LDH < 1.5 x upper limit of normal 56% of nonseminomas 5 year progression-free survival (PFS) 89% 5 year survival 92% Seminoma: Any primary site and no non-pulmonary visceral metastases and normal AFP, any HCG, any LDH 90% of seminomas 5 year PFS 82% 5 year survival 86% -- Intermediate Prognosis --

Nonseminoma: testis/retroperitoneal primary and no non-pulmonary visceral metastases and intermediate markers - any of: AFP >/= 1000 and </= 10,000 ug/ml or HCG >/= 5000 iu/l and </= 50,000 iu/l or LDH >/= 1.5 x N and </= 10 x N 28% of nonseminomas 5 year PFS 75% 5 year survival 80% Seminoma: any primary site and non-pulmonary visceral metastases and normal AFP, any HCG, any LDH 10% of seminomas 5 year PFS 67% 5 year survival 72% -- Poor Prognosis -Nonseminoma: mediastinal primary or non-pulmonary visceral metastases or poor markers - any of: AFP > 10,000 ug/ml or HCG > 50,000 iu/l (10,000 ug/ml) or LDH > 10 x upper limit of normal 16% of nonseminomas 5 year PFS 41% 5 year survival 48% Seminoma: No patients classified as poor prognosis.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations. References: 1. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. Journal of Clinical Oncology 15(2): 594-603, 1997.

STAGE I TESTICULAR CANCER

(Corresponds to AJCC stages I and II, T1-4, N0, M0.) 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 levels of evidence summary for more information.

Stage I seminoma Stage I seminoma has a cure rate of greater than 95%.

Treatment options: Removal of the testicle via radical inguinal orchiectomy followed by radiation therapy. Many radiation therapists recommend prophylactic irradiation of the retroperitoneal nodes even with a negative lymphangiogram and/or computed tomographic (CT) scan because approximately 15% will have occult nodal spread that can be cured with irradiation.[1,2] Only doses of 25 Gy are required. 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.[3] Three-year relapse-free survival rates were virtually identical (96% versus 96.6%), as were overall survival rates (99.3% versus 100%). Pelvic relapse-free survival rates were 98.2% versus 100%; the 95% confidence interval for the difference in pelvic relapse-free rates was 0% to 3.7%. There was a statistically significant increase in leukopenia and diarrhea associated with the ipsilateral iliac radiation therapy. Patients with tumors with vascular invasion seem at higher risk for nodal metastases.[4] Radical inguinal orchiectomy with no retroperitoneal node irradiation followed by frequent determination of serum markers, chest x-rays, and CT scans (surveillance). Results of at least 8 clinical series, with a total of 800 patients with stage I seminoma managed by post-orchiectomy surveillance, have been reported.[5] The overall tumor recurrence rate is about 15%, 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. In a single case series of 201 patients with clinical stage I seminoma managed this way, there was an actuarial relapse rate at 5 years of 15%, primarily in retroperitoneal nodes. The 5-year overall actuarial survival was 97% and the cause-specific survival was 99.5%.[6][Level of evidence: 3iiiA] All patients but 1 were successfully salvaged by radiation or chemotherapy. Prolonged surveillance is indicated for seminoma as about 20% of relapses (5 patients) occurred 4 or more years after diagnosis. The size of the primary tumors may be a prognostic factor, as the patients with tumors larger than 6 centimeters have a higher risk of relapse.[6]

Stage I nonseminoma Stage I nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, a surgical technique for sparing sympathetic ganglia and chains should be used. This technique is associated with postoperative fertility in most patients and appears to be as effective as non-nerve-sparing procedures in preventing retroperitoneal relapse.[7] 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.[8] Treatment options: Standard: 1. Removal of the testicle through the groin followed (in adults) by retroperitoneal lymph node dissection. A nerve-sparing retroperitoneal lymphadenectomy (RPL) that preserves ejaculation in virtually every patient has been described in clinical stage I patients and appears to be as effective as the standard RPL dissection.[7,9] Surgery should be followed by monthly determination of serum markers

and chest x-rays for the first year and 1 to 2 month determinations the second year.[10,11] In patients with pathologic stage I disease after RPL, the presence of lymphatic or venous invasion in the primary tumor appears to predict for relapse.[12] In a large Testicular Cancer Intergroup Study, the relapse rate was 19% in those with vascular invasion versus 6% in those without vascular invasion. 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.[8] In a large study, 27% of clinical stage I tumors had metastatic involvement of removed lymph nodes and were upstaged to pathological stage II.[13] Chemotherapy is employed immediately on first evidence of recurrence. In a large study, 15% of patients with a negative lymph node dissection experienced recurrence, usually pulmonary and usually within 18 months.[13] 2. Radical inguinal orchiectomy with no retroperitoneal node dissection followed by monthly determination of serum markers, chest x-rays, and, during the first year, abdominal CT scan every 2 months (surveillance). Careful follow-up is important, since relapses have been reported more than 5 years after the orchiectomy in patients who did not undergo a retroperitoneal dissection.[14-16] This option should be considered only if: a. CT scan and serum markers are negative. Lymphangiography, when CT scan and serum markers are negative, does not appear to significantly add to patient management.[17] b. The patient and physician accept the need for repeat CT scans as necessary to continue the periodic monitoring of the retroperitoneal lymph nodes. Children are adequately followed by serum markers alpha fetoprotein (AFP), chest x-rays, and clinical examination.[8] c. The patient will diligently follow a program of monthly checkups for 2 years which includes physical examination, chest x-ray, x-ray of abdominal lymph nodes, and determination of serum markers. d. Physician accepts responsibility for seeing that a follow-up schedule is maintained as noted for 2 years and then periodically beyond 2 years. Data suggest that relapse rates are higher in patients with histologic evidence of lymphatic or venous invasion. Some investigators have reported higher relapse rates in patients with embryonal cell histology and recommend RPL for such patients.[13,18] Other investigators have not found a higher relapse rate for this subgroup.[19] Additionally, some investigators recommend RPL in patients with a normal pre-orchiectomy AFP [13,18] because they feel the marker cannot be used as an indicator of relapse during follow-up. Since marker-negative patients may be marker-positive at relapse, and marker-positive patients may be marker-negative at relapse, some investigators do not view a negative AFP as a contraindication to a surveillance policy.[19] Adjuvant therapy consisting of 2 courses of cisplatin, bleomycin, and etoposide has been given to patients with clinical stage I disease who were considered at high risk of relapse (about 50% predicted relapse rate based on presence of vascular invasion and histologic type).[20] In 114 such patients, the relapse-free survival at 2 years was 98% (lower bound of 95% confidence interval=95%). Another study of high-risk clinical stage I patients treated with 2 adjuvant courses of cisplatin, etoposide, and bleomycin (PEB) has been reported.[21] Relapse rates after chemotherapy are less than 5%, compared with about 50% in historical series of high-risk patients followed without adjuvant chemotherapy. However, in the historical series, cure rates have been 95% and greater after chemotherapy for relapse. It is unclear which approach is superior in outcome. The adjuvant chemotherapy series is too small to draw

conclusions about the risk of chemotherapy-induced secondary malignancies, impact on fertility, or risk of late relapse. References: 1. Stutzman RE, McLeod DG: Radiation therapy: a primary treatment modality for seminoma. Urologic Clinics of North America 7(3): 757-764, 1980. 2. Duchesne GM, Horwich A, Dearnaley DP, et al.: Orchidectomy alone for stage I seminoma of the testis. Cancer 65(5): 1115-1118, 1990. 3. Fossa SD, Horwich A, et al., for the Medical Research Council Testicular Tumor Working Party: Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. Journal of Clinical Oncology 17(4): 1146-1154, 1999. 4. Marks LB, Rutgers JL, Shipley WU, et al.: Testicular seminoma: clinical and pathological features that may predict para-aortic lymph node metastases. Journal of Urology 143(3): 524-527, 1990. 5. Gospodarowicz MK, Sturgeon JF, Jewett MA: Early stage and advanced seminoma: role of radiation therapy, surgery, and chemotherapy. Seminars in Oncology 25(2): 160-173, 1998. 6. Warde P, Gospodarowicz MK, Banerjee D, et al.: Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. Journal of Urology 157(5): 1705-1710, 1997. 7. 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. Journal of Urology 152(4): 1139-1143, 1994. 8. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. Journal of Pediatric Surgery 25(4): 406-410, 1990. 9. Foster RS, Donohue JP: Surgical treatment of clinical stage A nonseminomatous testis cancer. Seminars in Oncology 19(2):166-170, 1992. 10. Lange PH, Narayan P, Fraley EE: Fertility issues following therapy for testicular cancer. Seminars in Oncology 2(4): 264-274, 1984. 11. Williams SD, Einhorn LH: Clinical stage I testis tumors: the medical oncologists' view. Cancer Treatment Reports 66(1): 15-18, 1982. 12. 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. Journal of Clinical Oncology 10(1): 69-78, 1992. 13. Klepp O, Olsson AM, Henrikson H, et al.: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Journal of Clinical Oncology 8(3): 509-518, 1990. 14. Rorth M, Jacobsen GK, Von der Masse H, et al.: Surveillance alone versus radiotherapy after orchiectomy for clinical stage I nonseminomatous testicular cancer. Journal of Clinical Oncology 9(9): 1543-1548, 1991. 15. Sujka SK, Huben RP: Clinical stage I nonseminomatous germ cell tumors of testis: observation vs. retroperitoneal lymph node dissection. Urology 38(1) 29-31, 1991. 16. Sturgeon JF, Jewett MA, Alison RE, et al.: Surveillance after orchidectomy for patients with clinical stage I nonseminomatous testis tumors. Journal of Clinical Oncology 10(4): 564-568, 1992. 17. Wishnow KI, Johnson DE, Tenney D: Are lymphangiograms necessary before placing patients with nonseminomatous testicular tumors on surveillance? Journal of Urology 141(5): 1133-1135, 1989. 18. Read G, Stenning SP, Cullen MH, et al.: Medical Research Council prospective study of surveillance for stage I testicular teratoma. Journal of Clinical Oncology 10(11): 1762-1768, 1992. 19. Colls BM, Harvey VJ, Skelton L, et al.: Results of the surveillance policy of stage I non-seminomatous germ cell testicular tumours. British Journal of Urology 70(4): 423-428, 1992. 20. Cullen MH, Stenning SP, Parkinson MC, et al.: Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. Journal of Clinical Oncology 14(4): 1106-1113, 1996. 21. Pont J, Albrecht W, Postner G, et al.: Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. Journal of Clinical Oncology 14(2): 441-448, 1996.

STAGE II TESTICULAR CANCER

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 levels of evidence summary for more information. (Corresponds to AJCC stages III and IV with no distant metastasis, T1-4, N1-3, M0.)

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 greater than 5 centimeters on a computed tomographic (CT) scan. Nonbulky stage II disease has a cure rate of greater than 90% with radiation alone. While earlier studies reported that bulky stage II seminoma had a cure rate of 70% with radiation alone, studies using improved treatment planning and equipment as well as careful selection of patients (including the use of tumor markers) have reported an improvement in the results of radiation in the treatment of patients with bulky stage II seminoma.[1,2] Combination chemotherapy with cisplatin is also effective therapy in bulky stage II seminomas. Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric radiation of residual persistent abnormalities or attempts to resect residual masses 3 centimeters or more in size. Either approach is controversial. In a combined retrospective consecutive series of 174 seminoma patients with post-chemotherapy residual disease seen at 10 treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[3][Level of evidence: 3iiDii] In some series, surgical resection of specific masses has yielded a significant number with residual seminoma that require additional therapy.[4] Nevertheless, other reports indicate that 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 centimeters or more.[5] Treatment options: Standard: For patients with nonbulky tumor: Radical inguinal orchiectomy followed by radiation to the retroperitoneal lymph nodes. Evidence favors the omission of prophylactic radiation therapy to the mediastinum and neck.[6] Radiation to inguinal nodes is not standard unless there has been some damage to the scrotum to put inguinal lymph nodes at risk. Treatment of ipsilateral iliac lymph nodes may also not be necessary. For patients with bulky tumor masses: Radical inguinal orchiectomy followed by combination chemotherapy (with a cisplatin-based regimen), or by radiation to the abdominal and pelvic lymph nodes.[1,2,7-9] Recurrence rate is higher after radiation for bulky stage II tumors than radiation for non-bulky tumors, leading some authors to recommend primary chemotherapy for patients with bulky disease (>/= 5-10 centimeters).[10] There is controversy over whether any residual masses present at the completion of chemotherapy should be empirically

irradiated, or whether masses greater than 3 centimeters should be resected.[4,5] Stage II nonseminoma Stage II nonseminoma is highly curable (>95%). If preservation of fertility is an important consideration, surgical techniques for sparing sympathetic ganglia and chains without compromising the total removal of all involved nodes are available, although this technique may not be feasible in many patients. This technique is associated with postoperative preservation of ejaculation in a large number of patients.[11-13] In most patients, an orchiectomy is performed prior to starting chemotherapy. However, if the diagnosis has been made by biopsy of a metastatic site and chemotherapy has been initiated, subsequent orchiectomy is generally performed, due to the fact that chemotherapy may not eradicate the primary cancer. This is illustrated by case reports in which viable tumor was found on post-chemotherapy orchiectomy despite complete response of metastatic lesions.[14] Treatment options: Standard: 1. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes with or without fertility-preserving RPL followed by monthly checkups, which include physical examination, chest x-ray, and serum marker tests (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 less than 6 positive nodes at retroperitoneal lymph node dissection, none of which are greater than 2 centimeters in diameter, and no extracapsular lymph node invasion. Such patients appear to have a relapse rate of only about 20% to 30% if followed without chemotherapy, and most are curable with standard chemotherapy if they do relapse.[15] Patients whose markers do not return to normal following the removal of retroperitoneal lymph node should be treated with chemotherapy.[11,16] Presence of lymphatic or venous invasion also helps to predict which patients may relapse. In a large Testicular Cancer Intergroup Study, the relapse rate after RPL was 64% in those who had microscopic evidence of vascular invasion in the primary tumor versus 24% in those who did not.[17] In children, surgical resection of retroperitoneal nodes is generally not performed. Patients with clinical stage II disease are given chemotherapy.[18] 2. Radical inguinal orchiectomy followed by removal of retroperitoneal lymph nodes followed by chemotherapy and then monthly checkups. The results of a large study comparing option #1 and #2 were published. Two courses of cisplatin-based chemotherapy (either cisplatin, vinblastine, bleomycin (PVB) or vinblastine, dactinomycin, bleomycin, cyclophosphamide, cisplatin (VAB VI)) prevented a relapse in greater than 95% of patients. There was a 49% relapse rate in patients assigned to observation; however, almost all of these patients could be effectively treated. The study concluded that although adjuvant therapy will almost always prevent relapse with optimal surgery, follow-up, and chemotherapy, observation only for relapse will lead to an equivalent cure rate.[19,20] 3. Radical inguinal orchiectomy followed by chemotherapy with delayed surgery for removal of residual masses (if present) followed by monthly checkups. This option would be considered for patients in whom clinical examination, lymphangiogram, or CT scan show large enough retroperitoneal masses that there are concerns about resectability. Chemotherapy regimens include: BEP: bleomycin + etoposide + cisplatin for 3 courses.[21] A modified regimen has been used in children.[18] EP: etoposide + cisplatin for 4 courses in good-prognosis patients.[9]

A randomized study has shown that bleomycin is an essential component of the BEP regimen when only 3 courses are administered.[22] Other regimens appear to produce similar survival outcomes but are in less common use. PVB: cisplatin + vinblastine + bleomycin VAB VI: vinblastine + dactinomycin + bleomycin + cyclophosphamide + cisplatin [19] VPV: vinblastine + cisplatin + etoposide [23] In a randomized comparison of PVB versus BEP, there was equivalent anticancer activity but less toxic effects with BEP.[21,24] 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 3 or 4 cycles of combination chemotherapy and normalization of serum markers. The probability of finding residual teratoma or carcinoma after chemotherapy may be dependent on the histology of the primary tumor. Patients whose primary tumor contained teratomatous elements have a higher probability of having residual teratoma or carcinoma in the retroperitoneal nodes than do patients whose primary tumor contains only embryonal cancer. One study has reported that irrespective of initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Some investigators think that neither size of the initial tumor nor degree of shrinkage while on therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some to recommend surgery with resection of all residual masses apparent on scans in patients who have normal markers after responding to chemotherapy. Some investigators recommend surgery for patients who have initial masses of 3 centimeters or more [25] on CT scan and after chemotherapy have a normal CT scan. This approach remains controversial, and there is no evidence that such an approach improves survival. The presence of persistent nonseminomatous germ cell malignant elements in the resected specimen is an indication for additional chemotherapy.[26] In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation of or completion of chemotherapy is advisable in order 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.[27] Under clinical evaluation: Primary chemotherapy has been administered in some clinical trials to patients with small volume retroperitoneal disease in an effort to avoid retroperitoneal node dissections. Although randomized comparison has not been performed, it appears that primary chemotherapy, when compared to primary retroperitoneal node dissection, may produce similar survival in clinical stage II testicular cancer patients.[28,29] Refer to PDQ and to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with testicular cancer. References: 1. Smalley SR, Evans RG, Richardson RL, et al.: Radiotherapy as initial treatment for bulky stage II testicular seminomas. Journal of Clinical Oncology 3(10): 1333-1338, 1985. 2. Friedman EL, Garnick MB, Stomper PC, et al.: Therapeutic guidelines and results in advanced seminoma. Journal of Clinical Oncology 3(10): 1325-1332, 1985. 3. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma: a diminishing role. European Journal of Cancer 33(6): 829-835, 1997. 4. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. Journal of Urology 157(3): 860-862, 1997.

5. Schultz SM, Einhorn LH, Conces DJ, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. Journal of Clinical Oncology 7(10): 14971503, 1989. 6. Stutzman RE, McLeod DG: Radiation therapy: a primary treatment modality for seminoma. Urologic Clinics of North America 7(3): 757-764, 1980. 7. Ball ED, Barrett A, Peckham MJ: The management of metastatic seminoma testes. Cancer 50(11): 22892294, 1982. 8. Loehrer PJ, Birch R, Williams SD, et al.: Chemotherapy of metastatic seminoma: The Southeastern Cancer Study Group experience. Journal of Clinical Oncology 5(8): 1212-1220, 1987. 9. Bajorin DF, Geller NL, Weisen SF et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67(1): 28-32, 1991. 10. Mason BR, Kearsley JH: Radiotherapy for stage 2 testicular seminoma: the prognostic influence of tumor bulk. Journal of Clinical Oncology 6(12): 1856-1862, 1988. 11. Lange PH, Narayan P, Fraley EE: Fertility issues following therapy for testicular cancer. Seminars in Oncology 2(4): 264-274, 1984. 12. Jewett MA, Kong YS, Goldberg SD, et al.: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. Journal of Urology 139(6): 1220-1224, 1988. 13. Donohue JP, Foster RS, Rowland RG, et al.: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. Journal of Urology 144(2, Part 1): 287-292, 1990. 14. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. Journal of Urology 155(6): 1938-1942, 1996. 15. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? Journal of Clinical Oncology 9(8): 1393-1396, 1991. 16. Donohue JP, Einhorn LH, Williams SD: Is adjuvant chemotherapy necessary following retroperitoneal lymph node dissection for nonseminomatous testicular cancer. Urologic Clinics of North America 7(3): 747-756, 1980. 17. 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. Journal of Clinical Oncology 10(1): 69-78, 1992. 18. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. Journal of Pediatric Surgery 25(4): 406-410, 1990. 19. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. Journal of Clinical Oncology 4(10): 1493-1499, 1986. 20. Williams SD, Stablein DM, Einhorn LH, et al.: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. New England Journal of Medicine 317(23): 1433-1438, 1987. 21. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. New England Journal of Medicine 316(23): 1435-1440, 1987. 22. Loehrer PJ, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group Trial. Journal of Clinical Oncology 13(2): 470-476, 1995. 23. 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. Journal of Clinical Oncology 9(1): 70-76, 1991. 24. Stoter G, Koopman A, Vendrik CP, et al.: Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin. Journal of Clinical Oncology 7(8): 1099-1104, 1989. 25. Toner GC, Panicek DM, Heelan RT, et al.: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. Journal of Clinical Oncology 8(10): 1683-1694, 1990. 26. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. Journal of Clinical Oncology 11(7): 1294-1299, 1993.

27. Leibovitch I, Little JS, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. Journal of Urology 155(3): 952-954, 1996. 28. Logothetis CJ, Swanson DA, Dexeus F, et al.: Primary chemotherapy for clinical stage II nonseminomatous germ cell tumors of the testis: a follow-up of 50 patients. Journal of Clinical Oncology 5(6): 906-911, 1987. 29. Socinski MA, Garnick MB, Stomper PC, et al.: Stage II nonseminomatous germ cell tumors of the testis: an analysis of treatment options in patients with low volume retroperitoneal disease. Journal of Urology 140(6): 1437-1441, 1988.

STAGE III TESTICULAR CANCER

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 levels of evidence summary for more information. (Corresponds to AJCC stage IV with distant metastasis, T1-4, N1-3, M1.)

Stage III seminoma Stage III seminoma is usually curable. Treatment options: Standard: Radical inguinal orchiectomy followed by multidrug chemotherapy.[1] In seminoma patients, the residual masses after chemotherapy are often fibrotic, although persistent, discrete (large) masses (>/= 3 centimeters) may contain residual seminoma that would require additional therapy.[2] Nevertheless, it has been reported that the size of the residual mass does not correlate well with active residual disease, that most residual masses do not grow, and that frequent marker and computed tomographic (CT) scan evaluation is a viable option even when the residual mass is larger than or equal to 3 centimeters.[3] In some patients, fertility has been returned following the use of bleomycin, etoposide, and cisplatin (BEP).[4] In a randomized trial, treatment with 4 courses of etoposide + cisplatin (EP) has shown equal efficacy and less toxic effects than vinblastine, dactinomycin, bleomycin, cyclophosphamide, and cisplatin (VAB VI) in the treatment of good-risk patients.[5] Chemotherapy combinations include: BEP: bleomycin + etoposide + cisplatin.[6,7] A modified regimen has been used in children.[8] EP: etoposide + cisplatin for 4 courses in good-prognosis patients [5] Other regimens appear to produce similar survival outcomes but are in less common use: PVB: cisplatin + vinblastine + bleomycin [9,10] VIP: etoposide + ifosfamide + cisplatin

A randomized study comparing 4 courses of BEP to 4 courses of VIP showed equivalent overall survival and time-to-treatment failure for the 2 regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects were substantially worse with the VIP regimen. Residual radiologic abnormalities are common at the completion of chemotherapy. Many abnormalities gradually regress over a period of months. Some clinicians advocate empiric radiation of residual persistent abnormalities or attempts to resect residual masses 3 centimeters or more in size. Either approach is controversial. In a combined retrospective consecutive series of 174 seminoma patients with post-chemotherapy residual disease seen at 10 treatment centers, empiric radiation was not associated with any medically significant improvement in progression-free survival after completion of platinum-based combination chemotherapy.[12][Level of evidence: 3iiDii] In some series, surgical resection of specific masses has yielded a significant number with residual seminoma that require additional therapy.[2] Nevertheless, other reports indicate that 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 centimeters or more.[3] Under clinical evaluation: Patients are usually eligible for the same chemotherapy clinical trials as those patients with nonseminomatous germ cell tumors. Stage III nonseminoma Stage III nonseminoma is usually curable (70%) with standard chemotherapy. In some patients fertility has returned following the use of chemotherapy. The 30% of patients who are not cured with standard chemotherapy usually have widespread visceral metastases, high tumor markers, or mediastinal primary tumors at presentation. In most patients, an orchiectomy is performed prior to starting chemotherapy. However, if the diagnosis has been made by biopsy of a metastatic site and chemotherapy has been initiated, subsequent orchiectomy is generally performed, due to the fact that chemotherapy may not eradicate the primary cancer. This is illustrated by case reports in which viable tumor was found on post-chemotherapy orchiectomy despite complete response of metastatic lesions.[13] The results of a large cooperative group randomized study of PVB versus BEP have been reported.[6] The BEP regimen produced less neuromuscular toxic effects and was more effective in patients with advanced disease, which makes it the preferable regimen of these 2 combinations. In addition, 3 courses of BEP have been shown to be equivalent to 4 courses in patients with minimal or moderate extent of disseminated germ cell tumors.[7] A randomized study has shown that bleomycin is an essential component of the BEP regimen when only 3 courses are administered.[14] Although another randomized study in good-prognosis patients treated with 4 courses of cisplatin plus vinblastine with or without bleomycin (PV+/-B) has shown better tumor-specific survival with PVB, this was offset by more toxic deaths. Overall survival rates were not significantly different between 4 courses of PV versus PVB.[15] In patients with poor-risk germ cell tumors, the standard-dose cisplatin regimen has been shown to be the equivalent of high-dose cisplatin in terms of complete response, cure rates, and survival; moreover, patients in the high-dose cisplatin regimen experienced significantly more toxic effects.[16] Many patients with poor-risk nonseminomatous testicular germ cell tumors who have a serum beta human chorionic gonadotropin (BHCG) level greater than 50,000 international units per milliliter at the initiation of cisplatin-based therapy (BEP or PVB) will still have an elevated BHCG level at the completion of therapy, showing an initial rapid decrease in BHCG followed by a plateau.[17] 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.[17][Level of evidence: 3iiD] Patients who present with brain metastases should be treated with chemotherapy and simultaneous whole brain irradiation (5,000 cGy/25 fractions).[18] Treatment options: Standard: 1. Chemotherapy: BEP: bleomycin + etoposide + cisplatin.[6,7] A modified regimen has been used in children.[8] EP: etoposide + cisplatin for 4 courses in good-prognosis patients [5] Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use. PVB: cisplatin + vinblastine + bleomycin [19] POMB/ACE: platinum + vincristine + methotrexate + bleomycin + dactinomycin + cyclophosphamide + etoposide [20] VIP: etoposide + ifosfamide + cisplatin A randomized study comparing 4 courses of BEP to four courses of VIP showed equivalent overall survival and time-to-treatment failure for the 2 regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[11][Level of evidence: 1iiA] Hematologic toxic effects was substantially worse with the VIP regimen. 2. In selected cases surgery should be used after chemotherapy to remove residual masses to determine if viable tumor cells remain, since such a finding is an indication for further chemotherapy. Surgical removal of residual masses is also necessary to prevent regrowth of teratomas and growth of non-germ cell elements present in some of these masses.[21,22] A study has reported that irrespective of initial histology, there is a significant risk of residual teratoma or carcinoma in residual masses after chemotherapy. Neither size of the initial tumor nor degree of shrinkage while on therapy appears to accurately identify patients with residual teratoma or carcinoma. This has led some to recommend surgery with resection of all residual masses apparent on scans in patients who have normal markers after responding to chemotherapy.[23] Some patients may have discordant pathologic findings (fibrosis/necrosis, teratoma, or carcinoma) in residual masses in the abdomen versus the chest; some medical centers therefore perform simultaneous retroperitoneal and thoracic operations to remove residual masses.[3,24] However, most centers do not perform simultaneous retroperitoneal and thoracic resections. Although the agreement among the histologies of residual masses found after chemotherapy above, versus below, the diaphragm is only moderate (kappa statistic=0.42), there is some evidence that if retroperitoneal resection is performed first, results can be used to guide decisions about whether to perform a thoracotomy.[25] In a multiinstitutional case series of surgery to remove post-chemotherapy 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 was not nearly as good a predictor of the histology of retroperitoneal masses.[25] Even patients who have initial masses of 3 centimeters or more on CT scan and after chemotherapy have normal CT scan and markers may have residual teratoma or carcinoma. This approach remains

controversial, and there is no evidence that such an approach improves survival. The presence of persistent malignant elements in the resected specimen is an indication for additional chemotherapy.[26] In some cases, chemotherapy is initiated prior to orchiectomy because of life-threatening metastatic disease. When this is done, orchiectomy after initiation of or completion of chemotherapy is advisable in order to remove the primary tumor. This is because there appears to be a physiologic blood-testis barrier 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.[27] 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.[8] Patients who relapse with brain metastases after a complete initial response to chemotherapy require further chemotherapy, with simultaneous whole brain irradiation and consideration of surgical excision of solitary lesions.[18] Under clinical evaluation: 1. Clinical trials. 2. High-dose chemotherapy with autologous bone marrow transplantation in selected patients with bulky disease.[28] References: 1. Ball ED, Barrett A, Peckham MJ: The management of metastatic seminoma testes. Cancer 50(11): 22892294, 1982. 2. Herr HW, Sheinfeld J, Puc HS, et al.: Surgery for a post-chemotherapy residual mass in seminoma. Journal of Urology 157(3): 860-862, 1997. 3. Schultz SM, Einhorn LH, Conces DJ, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. Journal of Clinical Oncology 7(10): 14971503, 1989. 4. Drasga RE, Einhorn LH, Williams SD, et al.: Fertility after chemotherapy for testicular cancer. Journal of Clinical Oncology 1(3): 179-183, 1983. 5. Bajorin DF, Geller NL, Weisen SF et al.: Two-drug therapy in patients with metastatic germ cell tumors. Cancer 67(1): 28-32, 1991. 6. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. New England Journal of Medicine 316(23): 1435-1440, 1987. 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. Journal of Clinical Oncology 7(3): 387-391, 1989. 8. Huddart SN, Mann JR, Gornall P, et al.: The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988. Journal of Pediatric Surgery 25(4): 406-410, 1990. 9. Einhorn LH, Williams SD: Chemotherapy of disseminated seminoma. Cancer Clinical Trials 3(4): 307313, 1980. 10. Loehrer PJ, Birch R, Williams SD, et al.: Chemotherapy of metastatic seminoma: The Southeastern Cancer Study Group experience. Journal of Clinical Oncology 5(8): 1212-1220, 1987. 11. 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. Journal of Clinical Oncology 16(4): 1287-1293, 1998. 12. Duchesne GM, Stenning SP, Aass N, et al.: Radiotherapy after chemotherapy for metastatic seminoma: a diminishing role. European Journal of Cancer 33(6): 829-835, 1997. 13. Leibovitch I, Baniel J, Rowland RG, et al.: Malignant testicular neoplasms in immunosuppressed patients. Journal of Urology 155(6): 1938-1942, 1996.

14. Loehrer PJ, Johnson D, Elson P, et al.: Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group Trial. Journal of Clinical Oncology 13(2): 470-476, 1995. 15. Levi JA, Raghavan D, Harvey V, et al.: The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Journal of Clinical Oncology 11(7): 1300-1305, 1993. 16. Nichols CR, Williams SD, Loehrer PJ, et al.: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and a Southwest Oncology Group protocol. Journal of Clinical Oncology 9(7): 1163-1172, 1991. 17. Zon RT, Nichols C, Einhorn LH: Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels. Journal of Clinical Oncology 16(4): 1294-1297, 1998. 18. Spears WT, Morphis JG, Lester SG, et al.: Brain metastases and testicular tumors: long-term survival. International Journal of Radiation Oncology, Biology, Physics 22(1): 17-22, 1992. 19. Einhorn LH, Williams SD: Chemotherapy of disseminated testicular cancer: a random prospective study. Cancer 46(6): 1339-1344, 1980. 20. Newlands ES, Bagshawe KD, Begent RH, et al.: Current optimum management of anaplastic germ cell tumours of the testis and other sites. British Journal of Urology 58(3): 307-314, 1986. 21. Einhorn LH, Williams SD, Mandelbaum I, et al.: Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer 48(4): 904-908, 1981. 22. Loehrer PJ, Hui S, Clark S, et al.: Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. Journal of Urology 135(6): 11831189, 1986. 23. Toner GC, Panicek DM, Heelan RT, et al.: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. Journal of Clinical Oncology 8(10): 1683-1694, 1990. 24. 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. Journal of Clinical Oncology 14(6): 1765-1769, 1996. 25. 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. Journal of Urology 158(2): 474-478, 1997. 26. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. Journal of Clinical Oncology 11(7): 1294-1299, 1993. 27. Leibovitch I, Little JS, Foster RS, et al.: Delayed orchiectomy after chemotherapy for metastatic nonseminomatous germ cell tumors. Journal of Urology 155(3): 952-954, 1996. 28. Motzer RJ, Memorial Sloan-Kettering Cancer Center: Phase III Randomized Study of BEP (BLEO/VP16/CDDP) Alone vs BEP Followed by High-Dose CBDCA/VP-16/CTX with Hematopoietic Rescue in Males with Previously Untreated Poor and Intermediate Risk Germ Cell Tumors (Summary Last Modified 05/1997), MSKCC-94076, clinical trial, active, 09/08/1994.

RECURRENT TESTICULAR CANCER

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 levels of evidence summary for more information. Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, site of recurrence, as well as individual patient considerations. Salvage regimens consisting of ifosfamide, cisplatin, and either etoposide or vinblastine can induce long-term complete responses in about one-quarter 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

outcome.[1,2] This regimen is now the standard initial salvage regimen.[3,2] However, few, if any, patients with recurrent nonseminomatous germ cell tumors of extragonadal origin achieve long-term disease-free survival using vinblastine, ifosfamide, and cisplatin if their disease recurred after they received an initial regimen containing etoposide and cisplatin.[2][Level of evidence: 3iiDi] High-dose chemotherapy with autologous marrow transplantation has also been used with some success in the setting of refractory disease.[4-7] Durable complete remissions may be achievable in 10% to 20% of patients with disease resistant to standard cisplatinbased regimens who are treated with high-dose carboplatin and etoposide with autologous bone marrow transplantation.[7,8] In general, patients with progressive tumors during frontline or salvage treatment and those with refractory mediastinal germ cell tumors do not appear to benefit as much from high-dose chemotherapy with autologous marrow transplantation as do those who relapse after a response.[9] In some highly selected patients with chemorefractory disease confined to a single site, surgical resection may yield long-term diseasefree survival.[10,11] The choice of salvage surgery versus autologous bone marrow transplantation for refractory disease is based on resectability, the number of sites of metastatic disease, and the degree to which the tumor is refractory to cisplatin. One case series suggests that maintenance daily oral etoposide (21 days out of 28) may benefit patients who achieve a complete remission after salvage therapy.[12] A special case of late relapse may be 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.[13] This may be because teratoma may be amenable to surgery at relapse and also has a better prognosis after late relapse than carcinoma. 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 II studies for those patients not achieving a complete remission with induction therapy or who do not achieve a complete remission following etoposide and cisplatin for their initial relapse or for patients who have a second relapse.[14] References: 1. Loehrer PJ, Lauer R, Roth BJ, et al.: Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Annals of Internal Medicine 109(7): 540-546, 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. Journal of Clinical Oncology 16(7): 2500-2504, 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): 2476-2481, 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. Annals of Internal Medicine 117(2): 124-128, 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. European Journal of Cancer 27(7): 831-835, 1991. 6. Cullen MH: Dose-response relationships in testicular cancer. European Journal of Cancer 27(7): 817-818, 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. Journal of Clinical Oncology 14(4): 1098-1105, 1996. 8. Motzer RJ, Bosl GJ: High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions. Journal of the National Cancer Institute 84(22): 1703-1709, 1992. 9. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. Journal of Clinical Oncology 14(10): 2638-2645, 1996. 10. Murphy BR, Breeden ES, Donohue JP, et al.: Surgical salvage of chemorefractory germ cell tumors. Journal of Clinical Oncology 11(2): 324-329, 1993.

11. Fox EP, Weathers TD, Williams SD, et al.: Outcome analysis for patients with persistent nonteratomatous germ cell tumor in postchemotherapy retroperitoneal lymph node dissections. Journal of Clinical Oncology 11(7): 1294-1299, 1993. 12. Cooper MA, Einhorn LH: Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors. Journal of Clinical Oncology 13(5): 1167-1169, 1995. 13. Baniel J, Foster RS, Gonin R, et al.: Late relapse of testicular cancer. Journal of Clinical Oncology 13(5): 1170-1176, 1995. 14. 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): 1305-1310, 1991. 15. Munshi NC, Loehrer PJ, Roth BJ, et al.: Vinblastine, ifosfamide and cisplatin (VeIP) as second line chemotherapy in metastatic germ cell tumors (GCT). Proceedings of the American Society of Clinical Oncology 9: A-520, 134, 1990.