| Medical Policy |
| Subject: Hematopoietic Stem Cell Transplantation for Germ Cell Tumors | |
| Document #: TRANS.00030 | Publish Date: 01/30/2025 |
| Status: Reviewed | Last Review Date: 11/14/2024 |
| Description/Scope |
This document addresses hematopoietic stem cell transplantation (HSCT) as a treatment of germ cell tumors (testicular, mediastinal, retroperitoneal, ovarian). Germ cell tumors are neoplasms developed from the reproductive germ cell line.
Note: For hematopoietic stem cell transplantation as a treatment of epithelial ovarian carcinoma, see:
| Position Statement |
Medically Necessary:
A single autologous hematopoietic stem cell transplantation is considered medically necessary as a treatment of primary germ cell tumors* in individuals treated with standard chemotherapy who had one of the following results:
A planned tandem autologous hematopoietic stem cell transplantation is considered medically necessary as a treatment of primary testicular cancer in individuals treated with standard chemotherapy who had one of the following results:
*Note: Ovarian germ cell tumors must be distinguished from the far more common epithelial ovarian cancers. For epithelial ovarian carcinoma, please refer to TRANS.00031 Hematopoietic Stem Cell Transplantation for Autoimmune Disease and Miscellaneous Solid Tumors.
A repeat autologous hematopoietic stem cell transplantation due to primary graft failure or failure to engraft is considered medically necessary.
Investigational and Not Medically Necessary:
A single autologous hematopoietic stem cell transplantation, in lieu of a course of standard chemotherapy, is considered investigational and not medically necessary as initial treatment of poor prognosis germ cell tumors.
A planned tandem autologous hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of all other non-testicular germ cell tumors.
Allogeneic (ablative and non-myeloablative [mini transplant]) hematopoietic stem cell transplantation is considered investigational and not medically necessary as a treatment of germ cell tumors, including but not limited to, use as a therapy after a prior failed high-dose chemotherapy with autologous hematopoietic stem cell support.
A second or repeat autologous hematopoietic transplant due to persistent, progressive or relapsed disease is considered investigational and not medically necessary.
Hematopoietic stem cell harvesting for a future but unscheduled transplant is considered investigational and not medically necessary.
| Rationale |
Germ cell tumors comprise the vast majority of primary testicular neoplasms, although germ cell tumors can arise in the ovary and in extragonadal locations such as the retroperitoneum or mediastinum. Germ cell tumors can be classified according to their histology, stage, prognosis, or response to chemotherapy. Testicular germ cell tumors are classified as either seminoma or nonseminoma. Histologies of nonseminomatous tumors include embryonal cell carcinoma, teratoma, choriocarcinoma, yolk sac tumor, and mixed germ cell tumors.
According to the International Germ Cell Cancer Collaborative Group (IGCCCG) consensus, risk classification of testicular germ cell tumors are separated by nonseminoma and seminoma diagnosis. There is no poor-risk disease in the seminoma category. In nonseminoma, poor prognosis or poor-risk disease is indicated by one of the following: mediastinal primary tumor, nonpulmonary visceral metastases, or elevation of any one post-orchiectomy marker (alpha fetal protein [AFP] greater than 10,000 ng/mL, human choriogonadotropin [hCG] greater than 50,000 IU/L, or lactate dehydrogenase [LDH] greater than 10 times the upper limit of normal) (National Comprehensive Cancer Network® [NCCN], 2024).
Autologous HSCT as Front-Line Therapy of Germ Cell Tumors
Motzer and colleagues (2007) reported results from a Phase III, multicenter, randomized trial of 219 individuals with poor-prognosis, metastatic germ cell tumors. Participants were assigned to conventional-dose chemotherapy (bleomycin, etoposide and cisplatin [BEP]) (n=111) or randomized to BEP plus high-dose chemotherapy (HDCT) with autologous HSCT (n=108) as first-line therapy. The 1-year durable complete response (CR) rate was 52% after BEP + HDCT and 48% after BEP alone (p=0.53). The median time-to-treatment failure (TTF) was 23.2 months and 11.3 months for individuals in the BEP + HDCT and BEP alone cohorts (p=0.40). With a median follow-up of 51 months, there was no difference in survival for individuals treated with BEP + HDCT versus BEP alone (p=0.94). Survival rate was 83% at 1 year and 71% at 2 years. The authors concluded that the routine inclusion of HDCT after two cycles of BEP in first-line treatment for germ cell tumors with metastases and poor predicted outcome to chemotherapy did not improve survival over four cycles of BEP alone. In addition, the authors noted that four cycles of BEP remains the standard of care for intermediate- and poor-risk germ cell tumors.
Droz and colleagues (2007) reported mature results from a randomized controlled trial of treatment naïve individuals with high-volume, metastatic nonseminomatous germ cell tumors. A total of 115 participants were randomized to receive either double-dose cisplatin with vinblastine and bleomycin (PVeBV) in Arm A compared to PVeBV with high dose chemotherapy followed by autologous bone marrow transplantation in Arm B. Both cohorts were equally balanced with 57 participants after 1 individual was deemed ineligible. There was no statistical significance in complete response (57% and 52%) and non-progressive disease (75% and 67%) in all evaluable participants in Arm A and Arm B, respectively. At a median follow-up of 9.7 years, 31 participants (Arm A) and 27 participants (Arm B) showed no evidence of disease. Five-year survival rates were 75% and 61% with 14 and 18 individuals still alive at 10-year follow-up in Arms A and B, respectively. Based on the results of the trial, the authors concluded that a clinical outcome benefit of high dose chemotherapy with autologous HSCT as front-line therapy was unproven.
Daugaard and colleagues (2011) reported the outcomes of a randomized Phase III study comparing standard-dose BEP with sequential high-dose VIP (cisplatin, etoposide, and ifosfamide) plus autologous stem-cell support in previously untreated males with poor-prognosis germ-cell cancer. The study aimed to recruit 222 natal males but closed with 137 natal males from 27 European oncology centers due to slow accrual. Participants were age 15-50 years and had previously untreated metastatic poor-prognosis nonseminomatous germ-cell tumor of either testicular or extragonadal origin. The median follow-up was 4.4 years. Toxicity was more severe for those