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Clinical Policy Bulletin:
Hematopoietic Cell Transplantation for Testicular Cancer
Number: 0617


Policy

  1. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of persons with testicular cancer who do not attain a complete remission after an initial course of standard-dose chemotherapy, i.e., those with refractory (less than 50 % reduction in tumor burden) testicular cancer or those exhibiting a partial response (at least a 50 % reduction in tumor burden).

  2. Aetna considers autologous hematopoietic cell transplantation as consolidation therapy medically necessary for persons with testicular cancer who relapse after an initial course of standard-dose chemotherapy.

  3. Aetna considers tandem autologous hematopoietic cell transplantation medically necessary for persons with testicular cancer who have relapsed.

  4. Aetna considers autologous hematopoietic cell transplantation experimental and investigational as initial treatment (i.e., instead of an initial course of standard-dose chemotherapy with Food and Drug Administration-approved drugs) of persons with testicular cancer because the effectiveness of this approach has not been established.

  5. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of persons with testicular cancer because its effectiveness for this indication has not been established.

See also CPB 0352 - Tumor Markers, and CPB 0532 - Scrotal Ultrasonography.



Background

Testicular cancer, a highly treatable, commonly curable cancer, accounts for only 1 % of all male malignancy.  It usually develops in young and middle-age men in the 20- to 40- year old age group.  Testicular cancer is one type of germ cell tumors, which can be classified according to their histology, stage, prognosis, or response to chemotherapy.  Histology includes seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor, and mixed germ cell tumors.  Seminomas are the most common and can be subdivided into typical, spermatocytic, and anaplastic varieties.  All other types of germ cell tumors may be collectively referred to as non-seminomatous germ cell tumors.  Seminoma accounts for 40 % of all germ cell tumors, while non-seminoma germ cell tumors account for 60 %.  Testicular palpation is useful in differentiating the type of tumor involved.  Seminomas are usually felt throughout the entire testicle, whereas non-seminomas tend to be small hard masses.

Differentiation between seminoma and non-seminoma germ cell tumors is important because the staging, evaluation and management in the two are different.  Seminomas are generally characterized by an indolent clinical course, and are more sensitive to radiation therapy than non-seminomas for patients with early-stage disease.  Furthermore, seminomas frequently exhibit a predictable pattern of metastatic spread via the regional lymphatics to the retroperitoneal nodes of the abdomen and/or to the mediastinal and supraclavicular lymph nodes before gaining access to other visceral structures.  In contrast, patients with non-seminomas are generally radio-resistant, with pulmonary and other hematogenous metastases more common than for patients with seminomas.

Once the histologic diagnosis is made, the patient must be staged.  The stage of the disease is dependent on the location (extent) of the tumor:

  • Stage I is limited to the testis, epididymis, or spermatic cord
  • Stage II is limited to retroperitoneal (regional) lymph nodes
  • Stage III is disease outside the retroperitoneum, involving supradiaphragmatic nodal sites or viscera.

Ultrasonography as well as laboratory tests are used to confirm the diagnosis and stage of disease.  In addition to blood cell counts and urine analysis, there are 2 serum tumor markers present in testicular cancer, (i) human chorionic gonadotropin (HCG) and (ii) alpha-fetal protein (AFP).  Studies have reported that 40 % of patients diagnosed with disseminated non-seminomas will have an elevated AFP, 75 % will have an elevated HCG, and 85 % will have one or both markers elevated.  In contrast, these markers are only present in 10 % of patients with seminoma, although 50 % of patients with stage III seminomas will have elevated HCG levels.  Staging is also confirmed by laparotomy and CT scan.

For patients with Stage I disease, radiation therapy (for seminomas) or retroperitoneal lymph node resection (for non-seminomas) has been shown to result in cure rates of greater than 90 %.  Additionally, for patients with Stage I non-seminomas, surveillance (after orchiectomy) is another generally accepted alternative.  For patients with Stage II, Stage III disease or extragonadal site of origin, treatment with cisplatin-based chemotherapy has been shown to be very effective in achieving a complete remission.  The results of treatment of non-seminomatous germ cell tumors have been improved significantly by cisplatin-containing chemotherapy regimens.  The literature indicates that first-line therapy generally entails 3 to 4 cycles of the combination regimen of cisplatin, bleomycin, and etoposide.  Under established guidelines, patients whose tumors are resistant to cisplatin may proceed to regimens containing carboplatin.  Chemotherapy is often followed by surgery to remove residual masses.  Regimens used for relapsed disease include cisplatin plus ifosfamide, combined with either etoposide or vinblastine (salvage therapy).

Salvage therapy has been shown to 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 outcome.  However, the literature states that few, if any, patients with recurrent non-seminomatous 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.  High-dose chemotherapy with autologous bone marrow transplantation (ABMT) has been used with some success in the setting of refractory disease.  Durable complete remissions may be attainable in 10 to 20 % of patients with disease resistant to standard cisplatin-based regimens who are treated with high-dose carboplatin and etoposide with ABMT.

A review by Ayash et al (2001) stated that patients with relapsed/refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse.  Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression before ABMT, and/or markedly elevated beta-HCG at ABMT.  New treatment modalities are needed for the latter group.  This observation is in accordance with the view of Flechon and associates (2001) that new strategies are needed to improve the survival rate of poor prognosis germ cell tumor patients.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
38206 - 38232 Bone marrow or stem cell services/procedures (excluding allogenic)
38241 Hematopoietic progenitor cell (HPC); autologous transplantation
96401 - 96549 Chemotherapy administration
CPT codes not covered for indications listed in the CPB:
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogenic
38230 Bone marrow harvesting for transplantation; allogenic
38240 Bone marrow or blood-derived peripheral stem cell transplantation; allogenic
HCPCS codes covered if selection criteria are met:
S2150 Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
ICD-9 codes covered if selection criteria are met:
186.0 - 186.9 Malignant neoplasm of testis
233.6 Carcinoma in situ of other and unspecified male genital organs


The above policy is based on the following 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. 1988;109(7):540-546.
  2. 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. 1990;66(12):2476-2481.
  3. 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. 1991;27(7):831-835.
  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. 1992;117(2):124-128.
  5. Motzer RJ, Bosl GJ. High-dose chemotherapy for resistant germ cell tumors: Recent advances and future directions. J Natl Cancer Inst. 1992;84(22):1703-1709.
  6. Lotz JP, Andre T, Donsimoni R, et al. High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults. Cancer. 1995;75(3):874-885.
  7. Margolin BK, Doroshow JH, Ahn C, et al. Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. J Clin Oncol. 1996;14(10):2631-2637.
  8. 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. 1996;14(4):1098-1105.
  9. Mandanas RA, Saez RA, Epstein RB, et al. Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors. Bone Marrow Transplant. 1998;21(6):569-576.
  10. Takahashi A, Miyao N, Masumori N, et al. Treatment for advanced testicular cancer with high-dose chemotherapy and autologous blood stem cell transplantation. Int J Urol. 1998;5(1):67-72; discussion 73.
  11. 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. 1998;16(7):2500-2504.
  12. Hara I, Yamada Y, Miyake H, et al. Clinical outcome of high-dose chemotherapy combined with peripheral blood stem cell transplantation for male germ cell tumors. Anticancer Drugs. 1999;10(8):711-718.
  13. Sobecks RM, Vogelzang NJ. High dose chemotherapy with autologous stem-cell support for germ cell tumors. A critical review. Semin Oncol. 1999;26:106-118.
  14. Simnett S J, Stewart LA, Sweetenham J, et al. Autologous stem cell transplantation for malignancy: A systematic review of the literature.  Clin Lab Haematol. 2000;22(2):61-72.
  15. Miyazaki J, Miyanaga N, Kawai K, et al. High-dose chemotherapy with peripheral blood stem cell transplantation for advanced testicular cancer. Int J Urol. 2000;7(7):258-262.
  16. Bhatia S, Abonour R, Porcu P, et al. High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol. 2000;18(19):3346-3351.
  17. Flechon A, Culine S, Droz JP. Intensive and timely chemotherapy, the key of success in testicular cancer. Crit Rev Oncol Hematol. 2001;37(1):35-46.
  18. Ayash LJ, Clarke M, Silver SM, et al. Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: The University of Michigan experience and literature review. Bone Marrow Transplant. 2001;27(9):939-947.
  19. Roeleveld TA, Horenblas S, Meinhardt W, et al. Surveillance can be the standard of care for stage I nonseminomatous testicular tumors and even high risk patients. J Urol. 2001;166(6):2166-2170.
  20. Motzer RJ, Bosl GJ. Testicular cancer. In: Harrison's Principles of Internal Medicine. 15th ed. Vol. 1. E Braunwald, et al., eds. New York, NY: McGraw-Hill; 2001; Ch. 96: 616-620.
  21. Vuky J, Tickoo SK, Sheinfeld J, et al. Salvage chemotherapy for patients with advanced pure seminoma. J Clin Oncol. 2002;20(1):297-301.
  22. Shelley MD, Burgon K, Mason MD. Treatment of testicular germ-cell cancer: A Cochrane evidence-based systematic review. Cancer Treat Rev. 2002;28(5):237-253.
  23. Bojko P, Akca A, Seeber S. Outcome of 67 patients with solid tumors relapsed after high-dose chemotherapy and peripheral blood stem cell transplantation. Bone Marrow Transplant. 2003;31(11):995-1000.
  24. Jones RH, Vasey PA. Part II: Testicular cancer--management of advanced disease. Lancet Oncol. 2003;4(12):738-747.
  25. Schmoll HJ, Kollmannsberger C, Metzner B, et al.; German Testicular Cancer Study Group. Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: An extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol. 2003;21(22):4083-4091.
  26. Schmoll HJ, Souchon R, Krege S, et al. European consensus on diagnosis and treatment of germ cell cancer: A report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol. 2004;15(9):1377-1399.
  27. Miki T, Mizutani Y, Akaza H, et al; Japan Blood Cell Transplantation Study Group for Testicular Germ Cell Tumor. Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor. Int J Urol. 2007;14(1):54-59.
  28. Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340-348.
  29. Sonpavde G, Hutson TE, Roth BJ. Management of recurrent testicular germ cell tumors. Oncologist. 2007;12(1):51-61.
  30. Lazarus HM, Stiff PJ, Carreras J, et al. Utility of single versus tandem autotransplants for advanced testes/germ cell cancer: A center for international blood and marrow transplant research (CIBMTR) analysis. Biol Blood Marrow Transplant. 2007;13(7):778-789.
  31. Lorch A, Kleinhans A, Kramar A, et al. Sequential versus single high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: Long-term results of a prospective randomized trial. J Clin Oncol. 2012;30(8):800-805.
  32. Haugnes HS, Laurell A, Stierner U, et al. High-dose chemotherapy with autologous stem cell support in patients with metastatic non-seminomatous testicular cancer - a report from the Swedish Norwegian Testicular Cancer Group (SWENOTECA). Acta Oncol. 2012;51(2):168-176.
  33. Alberta Provincial Genitourinary Tumour Team. Testicular germ cell tumours. Clinical Practice Guideline No. GU-001. Edmonton, EB: Alberta Health Services, Cancer Care; February 2012.
  34. De Blasio A, Rossi L, Zappone E, et al. Plerixafor and autologous stem cell transplantation: Impressive result in a chemoresistant testicular cancer patient treated with high-dose chemotherapy. Anticancer Drugs. 2013;24(6):653-657.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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