Medical Policies - Surgery
Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors
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Single autologous hematopoietic stem-cell transplantation (HSCT) may be considered medically necessary as salvage therapy for germ-cell tumors:
• In patients with favorable prognostic factors (see NOTE 1) that have failed a previous course of conventional-dose salvage chemotherapy; or
• In patients with unfavorable prognostic factors (see NOTE 2) as initial treatment of first relapse (i.e., without a course of conventional-dose salvage chemotherapy) and in patients with platinum-refractory disease.
NOTE 1: Patients with favorable prognostic factors include those with a testis or retroperitoneal primary site, a complete response (CR) to initial chemotherapy, low levels of serum markers, and low volume disease.
NOTE 2: Patients with unfavorable prognostic factors are those with an extratesticular primary site, an incomplete response to initial therapy, high levels of serum markers, high-volume disease, or relapsing mediastinal nonseminomatous germ-cell tumors.
Tandem sequential autologous HSCT or transplant with sequential high-dose chemotherapy may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.
Autologous HSCT is considered experimental, investigational and/or unproven as a component of first-line treatment for germ-cell tumors.
Allogeneic HSCT is considered experimental, investigational and/or unproven to treat germ-cell tumors, including, but not limited to its use as therapy after a prior failed autologous HSCT.
NOTE 3: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.
Hematopoietic Stem-Cell Transplantation (HSCT)
HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).
Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).
Therapy for germ-cell tumors is generally dictated by several factors, including disease stage, tumor histology, site of tumor primary and response to chemotherapy. Patients with unfavorable prognostic factors may be candidates for HSCT.
Germ-cell tumors are composed primarily of testicular neoplasms as well as ovarian and extragonadal germ-cell tumors (no primary tumor in either testis or ovary). Germ-cell tumors are classified by their histology, stage, prognosis, and response to chemotherapy.
The most common testicular germ-cell tumors are seminomas; all other histologic types are collectively referred to as nonseminomatous tumors. Nonseminomatous tumor types include embryonal cell tumor, yolk sac tumor, and teratomas. Malignant germ-cell tumors of ovarian origin are classified as dysgerminomas or nondysgerminomas. Similarly, nondysgerminomas include immature teratomas, embryonal cell tumors, yolk sac tumor, polyembryoma, and mixed germ-cell tumors.
Stage depends on location and extent of the tumor, using the American Joint Committee on Cancer’s TNM system (T describes the size of the original [primary] tumor and whether it has invaded nearby tissue; N describes nearby[regional] lymph nodes that are involved; and, M describes distant metastasis [spread of cancer from one part of the body to another]). TNM stages, modified by serum concentrations of markers for tumor burden (S0-3) when available, are grouped by similar prognoses. Markers used for germ-cell tumors include human β-chorionic gonadotropin, lactate dehydrogenase, and α-fetoprotein. However, most patients with pure seminoma have normal α-fetoprotein concentrations. For testicular tumors, stages IA to B tumors are limited to the testis (no involved nodes or distant metastases) and no marker elevations (S0); stages IIA to C have increasing size and number of tumor-involved lymph nodes, and at least 1 marker moderately elevated above the normal range (S1); and stages IIIA to C have distant metastases and/or marker elevations greater than specified thresholds (S2-3).
Germ-cell tumors also are divided into good-, intermediate-, or poor-risk categories based on histology, site, extent of primary tumor, and serum marker levels. Good-risk pure seminomas can be at any primary site but are without nonpulmonary visceral metastases or marker elevations. Intermediate-risk pure seminomas have nonpulmonary visceral metastases with or without elevated human chorionic gonadotropin and/or lactate dehydrogenase. There are no poor-risk pure seminomas, but mixed histology tumors and seminomas with elevated α-fetoprotein (due to mixture with nonseminomatous components) are managed as nonseminomatous germ-cell tumors. Good- and intermediate-risk nonseminomatous germ-cell tumors have testicular or retroperitoneal tumors without nonpulmonary visceral metastases, and either S1 (good-risk) or S2 (intermediate-risk) levels of marker elevations. Poor-risk tumors have mediastinal primary tumors, or nonpulmonary visceral metastases, or the highest level (S3) of marker elevations.
Therapy for germ-cell tumors is generally dictated by stage, risk subgroup, and tumor histology. Testicular cancer is divided into seminomatous and nonseminomatous types for treatment planning because seminomas are more sensitive to radiotherapy. Stage I testicular seminomas may be treated by orchiectomy with or without radiation or single-dose carboplatin adjuvant therapy. Nonseminomatous stage I testicular tumors may be treated with orchiectomy with or without retroperitoneal lymph node dissection. Higher stage disease typically involves treatment that incorporates chemotherapy. First-line chemotherapy for good- and intermediate-risk patients with higher stage disease is usually 3 or 4 cycles of a regimen combining cisplatin and etoposide, with or without bleomycin depending on histology and risk group. Chemotherapy is often followed by surgery to remove residual masses. Second-line therapy often consists of combined therapy with ifosfamide/mesna and cisplatin, plus vinblastine, paclitaxel, or etoposide (if not used for first-line treatment). Patients whose tumors are resistant to cisplatin may receive carboplatin-containing regimens. The probability of long-term continuous complete remission diminishes with each successive relapse.
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (19) Hematopoietic stem-cells are included in these regulations.
This policy was originally created in 1990, moved to this current policy in 2010. The policy has been updated with reviews of the MedLine database. The most recent literature review was performed through July 2018. While the coverage of this policy does not address myeloablative (MA) (also known as high-dose chemotherapy [HDC]) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes may be influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date for preparative conditioning, allogeneic or autologous HSCT.
Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
The majority of evidence describes the diagnosis and management of seminomatous and nonseminomatous germ-cell tumors.
Autologous HSCT as First Line Therapy of Germ-Cell Tumors
Daugaard et al. (2011) reported on the outcomes of a randomized phase 3 study comparing standard-dose cisplatin, etoposide, and bleomycin (BEP) with sequential high-dose cisplatin, etoposide, and ifosfamide plus stem-cell support in previously untreated males with poor-prognosis germ-cell cancer. (1) The trial aimed to recruit 222 patients but closed with 137 patients from 27 European oncology centers due to slow accrual. Patients were ages 15 to 50 years and had previously untreated metastatic poor-prognosis nonseminomatous germ-cell tumor of testicular or extragonadal origin. Median follow-up was 4.4 years; 66 patients in the BEP group and 65 patients in the transplant group were included in the analysis. Toxicity was more severe in patients who received HDC, and toxicity-related deaths were reported for 2 patients who received HDC and in 1 patient in the BEP arm. There was no improvement in complete response (CR) rate in the HDC arm (44.6%) versus the standard-dose arm (33.3%; p=0.18). There was no difference in failure-free survival between the 2 groups. At 2 years, failure-free survival rates were 44.8% (95% confidence interval [CI], 32.5% to 56.4%) and 58.2% (95% CI, 48.0% to 71.9%), respectively, for the standard- and high-dose arms. The difference was not statistically significant (p=0.06). Overall survival (OS) did not differ between groups (p>0.1). The authors concluded that HDC given as part of first-line therapy does not improve outcomes in patients with poor-prognosis germ-cell tumor.
Motzer et al. (2007) reported on a phase 3 prospective, randomized, multicenter trial of 219 previously untreated patients with poor-prognosis germ-cell tumors. (2) Median patient age was 28 years. Patients were randomized to conventional chemotherapy (4 cycles of BEP; n=111) or 2 cycles of BEP followed by 2 cycles of HDC with autologous HSCT. Median follow-up was 51 months. The 1-year durable CR rate was 52% after BEP plus HDC with HSCT, and 48% after BEP alone (p=0.53). There was no survival difference at 106 months for patients treated with HDC and HSCT (68%) compared with patients treated with conventional chemotherapy (69%).
Droz et al. (2007) assessed the impact of HDC plus HSCT on the survival of patients with high-volume, previously untreated, metastatic nonseminomatous germ-cell tumors. (3) Patients were randomized to 4 cycles every 21 days of vinblastine, etoposide, cisplatin, and bleomycin (n=57) or a slightly modified regimen followed by HDC plus autologous HSCT (n=57). In an intention-to-treat analysis, the CR rates were 56% and 42% for the conventional and HDC groups, respectively (p=0.099). Median follow-up was 9.7 years, and no significant difference in OS between groups (p=0.167).
Section Summary: Autologous HSCT as First Line Therapy of Germ-Cell Tumors
The evidence from several randomized trials found that autologous HSCT as first-line therapy for germ-cell tumors did not significantly improve outcomes compared with alternative therapy (e.g., standard-dose chemotherapy). However, study sample sizes were relatively small and might have been underpowered to detect differences between groups.
Autologous HSCT for Relapsed or Refractory Germ-Cell Tumors
One RCT was identified. In 2005, Pico et al. reported on a randomized trial comparing 4 cycles of conventional-dose chemotherapy with 3 cycles of the same regimen followed by carboplatin-based HDC plus autologous HSCT in 280 patients who had relapsed after a complete or partial remission following first-line therapy with a cisplatin-based regimen. (4) The authors reported no significant differences between treatment arms in 3-year event-free survival (EFS) or OS. However, the trial began before international consensus (5) had established the current risk group definitions; thus, Pico et al. likely included patients now considered to have good prognosis at relapse. Furthermore, while 77% and 86% of patients in the control and experimental arms, respectively, had at least 1 elevated serum tumor marker, they did not report how highly elevated rates were or compare arms with respect to the marker thresholds that presently determine risk level (S1-3). Finally, HDC in the experimental arm followed 3 cycles of conventional-dose chemotherapy, which differs from most current practice in the U.S., in which a single cycle is used before HDC. As a consequence, 38 (28%) of 135 patients randomized to the HDC arm did not receive HDC because of progression, toxicity, or withdrawal of consent.
In addition, several case series were identified. Seftel et al. (2011) conducted a multicenter study of consecutive patients undergoing a single autologous HSCT for germ-cell tumor between 1986 and 2004. (6) For 71 subjects, median follow-up was 10.1 years. Median age was 31 years (range, 16-58 years). Sixty-seven patients had nonseminomatous germ-cell tumors and 4 had seminomatous germ-cell tumors. Fifty-seven patients had primary gonadal disease and 14 had primary extragonadal disease. Of the latter, 11 patients presented with primary mediastinal disease, 2 presented with primary central nervous system (CNS) disease, and 1 presented with retroperitoneal disease. In all, 28 patients underwent autologous HSCT for relapsed disease after achieving an initial CR. Of these, 24 patients underwent autologous HSCT after a first relapse and 4 underwent transplant after a second relapse. An additional 36 patients achieved only an incomplete response after initial therapy and proceeded to autologous HSCT after salvage chemotherapy for active residual disease. The OS rate at 5 years was 44.7% (95% CI, 32% to 56.5%) and the EFS rate was 43.5% (95% CI, 31.4% to 55.1%). There were 7 (10%) treatment-related deaths within 100 days of transplant. Three (4.2%) patients developed secondary malignancies. Of 33 relapses, 31 occurred within 2 years of the transplant. Two very late relapses occurred 13 and 11 years after transplant. In a multivariate analysis, a favorable outcome was associated with International Germ-Cell Consensus Classification good prognosis disease at diagnosis, primary gonadal disease, and response to salvage chemotherapy.
Agarwal et al. (2009) reported on their experience at a single center in treating 37 consecutive patients who received HDC and autologous HSCT between 1995 and 2005 for relapsed germ-cell tumors. (7) Median patient age was 28 years (range, 9-59 years), with 34 males and 3 females. Primary tumor sites included 24 testes/adnexal, 10 chest/neck/retroperitoneal, and 3 CNS. Twenty-nine patients had received prior standard salvage chemotherapy. The 3-year OS rate was 57% (95% CI, 41% to 71%), and the 3-year progression-free survival (PFS) rate was 49% (95% CI, 33% to 64%).
Baek et al. (2013) reported on results of a small feasibility study of HDC followed by HSCT for patients with relapsed or progressed CNS germ-cell tumors. (8) Investigators enrolled 11 patients with nongerminomatous (i.e., nonseminomatous) germ-cell tumors and 9 patients with germinomatous stem-cell tumors, all of whom had received conventional chemotherapy with or without radiotherapy before HSCT. Sixteen patients received an initial course of HDC with carboplatin, thiopental, and etoposide followed by HSCT, and 9 of them received a second course of HDC with cyclophosphamide-melphalan followed by a second HSCT (see the tandem and sequential HSCT for germ-cell tumors section next). Twelve patients remained alive at a median follow-up of 47 months (range, 22-90 months), with a 3-year OS probability estimate of 59.1%.
Nieto et al. (2015) reported on 43 male patients with poor-risk relapsed or refractory germ-cell tumors with received HDC and autologous HSCT. (9) Primary tumors were testicular in 32 patients, mediastinal in 7 patients, and retroperitoneal in 4 patients. Median follow-up was 46 months (range, 9-84 months). At follow-up, the relapse-free survival (RFS) rate was 55.8% and the OS rate was 58.1%. RFS rates were 66% in patients with testicular primaries, 28.5% in patients with mediastinal primaries, and 25% in patients with retroperitoneal primaries.
Section Summary: Autologous HSCT for Relapsed or Refractory Germ-Cell Tumors
The single published RCT did not find improved outcomes with HDC and autologous HSCT compared with standard-dose HSCT. Case series had sample sizes ranging between 11 and 71 patients each. Three-year OS rates in these case series ranged between 55% and 60%.
Tandem Autologous HSCT and Sequential HSCT for Germ-Cell Tumors
There is ongoing research into the role of tandem autologous HSCT and sequential HDC for germ-cell tumors, with a variety of specific chemotherapy regimens.
Lorch et al. (2007) compared single with sequential HDC plus autologous HSCT as first or subsequent salvage treatment in patients with relapsed or refractory germ-cell tumors. (10) Patients were randomized to 2 different HDC regimens (arm A, arm B). Most tumors were gonadal primaries; 10% of patients in arm A had retroperitoneal, mediastinal, or CNS primaries, and 11% of patients in arm B had retroperitoneal or mediastinal primaries. This represented the first salvage therapy received for 86% of the patients in arm A and 85% in arm B, whereas 14% in arm A and 15% in arm B had received one or more previous salvage regimens before randomization. A total of 111 (51%) of 216 patients were randomized to sequential HDC, and 105 (47%) of 216 patients were randomized to single HDC. The trial was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B (sequential). There was a planned interim analysis after the inclusion of 50% of the required total number of patients. Survival analyses were performed on an intention-to-treat basis.
At a median follow-up of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression-free. At 1 year, EFS, PFS, and OS rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (p>0.05 for all comparisons). Survival rates were not reported separately by primary tumor site. No difference in survival probabilities was found between the single and sequential high-dose regimens; however, sequential HDC was better tolerated and resulted in fewer treatment-related deaths. Treatment-related deaths, mainly from sepsis and cardiac toxicity, were less frequent in arm A (4/108 [4%] patients) than in arm B (16/103 [16%] patients; p<0.01). The authors attributed the higher rate of treatment-related deaths in arm B to the higher dosages per HSCT cycle in the arm B regimen compared with arm A, as well as the toxic renal and cardiac effects of cyclophosphamide used in arm B.
Lorch et al. (2012) reported long-term results from this trial; 5-year PFS rates were 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; p=0.454). (11) Five-year OS rates were 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR=1.42; 95% CI, 0.99 to 2.05; p=0.057). The authors concluded that patients with relapsed or refractory germ-cell tumors could achieve durable long-term survival after single as well as tandem HSCT plus sequential HDC and that fewer early deaths related to toxicity translated into superior long-term OS after HSCT plus sequential HDC.
Lazarus et al. (2007) reported on the results of autologous HSCT for relapsed testicular/germ-cell cancer using registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR). (12) Patients with mediastinal primaries were excluded. Data included 300 patients from 76 transplant centers in 8 countries who received a single or a tandem autologous HSCT between 1989 and 2001. Of the 300 patients, 102 received tandem and 198 received single planned autologous HSCT. PFS and OS rates at 1, 3, and 5 years were similar for both groups. The probability of PFS at 5 years for the tandem transplant group was 34% (95% CI, 25% to 44%) versus 38% (95% CI, 31% to 45%) for the single transplant group (p=0.50). The probability of 5-year OS was 35% (95% CI, 25% to 46%) versus 42% (95% CI, 35% to 49%), respectively (p=0.29).
Lotz et al. (2005) reported on the results of a phase 2 study on 3 consecutive cycles of HDC regimens supported by autologous HSCT in 45 poor-prognosis patients with relapsed germ-cell tumors. (13) From 1998 to 2001 (median follow-up, 31.8 months), 45 patients (median age, 28 years) were enrolled. Most patients (76%) had testicular primaries; 13% had mediastinal primaries; 11% had retroperitoneal, hepatic, or unknown. Of all patients, 22 received the complete course. Twenty-five patients died from disease progression and 5 from treatment toxicity. The overall response rate was 37.7%, including an 8.9% CR rate. Median OS was 11.8 months. The 3-year OS and PFS rates were both 23.5%. Authors used the Beyer prognostic score to predict the outcome of HDC and concluded that patients with a Beyer score greater than two did not benefit from this approach, confirming that highly refractory patients and particularly patients with resistant or refractory primary mediastinal germ-cell tumors do not benefit from HDC.
Einhorn et al. (2007) reported retrospectively on a series of 184 patients, treated between 1996 and 2004, with 2 consecutive cycles of HDC for metastatic testicular cancer that had progressed (relapsed) after receiving cisplatin-containing combination chemotherapy. (14) Patients with primary mediastinal nonseminomatous germ-cell tumors or tumors with late relapse (≥2 years after previous therapy) were excluded. The patient population included those with initial International Germ-Cell Consensus Classification stage defined as low-risk (39%), intermediate-risk (21%), and high-risk (41%) and both platinum-sensitive and refractory disease at the beginning of HDC. Results from this experienced center showed that, of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months. Of the 135 patients who received the treatment as second-line therapy (i.e., first salvage setting), 94 (70%) were disease-free during follow-up; 22 (45%) of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer refractory to standard-dose platinum, 18 (45%) were disease-free. Caveats to the Einhorn study included the lack of a validation set for the prognostic scoring system used; the unanswered question of the role of high-dose versus conventional-dose chemotherapy in the first salvage setting; and the lack of a universally accepted prognostic scoring system in this setting.
In a subsequent study from the same center as the Einhorn study, Suleiman et al. (2013) evaluated outcomes for 12 patients with recurrent primary mediastinal nonseminomatous germ-cell tumors after initial treatment with cisplatin-containing combination chemotherapy, a population excluded from their previous study, who were treated with tandem HSCT. (15) Patients received 2 consecutive courses of HDC (carboplatin and etoposide) followed by HSCT. Overall outcomes were poor, with a median survival of 11 months (range, 4-52 months), but 3 of 12 patients achieved a CR. One patient remained disease-free at 50 months of follow-up, and one remained disease-free after tandem HSCT and subsequent mediastinal surgery at 52 months of follow-up.
Pal et al. (2013) reported on 5-year follow-up results for 48 patients with relapsed germ-cell tumors enrolled in a retrospective case series to evaluate the effectiveness of 2 sequential cycles of chemotherapy with paclitaxel, etoposide, and carboplatin in the first cycle, high-dose paclitaxel, ifosfamide, and carboplatin in the second, followed by HSCT. (16) Forty-three (91.5%) patients had nonseminomatous histology. Most patients (n=39) had received 2 prior chemotherapy regimens; 6 patients had received 3 prior regimens. Thirty-four patients had intermediate-risk classification by the Beyer score and the remainder had high-risk classification. Of the 48 patients enrolled, 17 received only 1 course of paclitaxel, etoposide, and carboplatin, 11 due to progressive disease, 5 due to toxicities, and 1 due to a severe fungal infection. Seventeen of the 48 patients enrolled were alive and progression-free at a median of 123.2 months (range, 51.6-170.2 months); 25 died, most (n=23) due to disease progression. Of the 23 patients alive after receiving per-protocol therapy, 18 were contacted for interviews at a median 115.6 months (range, 38.9-185.9 months) post-enrollment and underwent a cancer-related quality-of-life assessment with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire?Core 30. The overall average score on the questionnaire was 87.04; the authors compared quality-of-life scores in this cohort with a separate cohort of 150 patients who had germ-cell tumors who received chemotherapy; authors reported that patients in their cohort had significantly higher global health scores (87.04 versus 75.62, p=0.02), but lower physical functioning scores (68.9 versus 92.7, p<0.001). The authors concluded that tandem HDC followed by HSCT would be a reasonable treatment option for relapsed germ-cell tumors, with long-term survivors demonstrating a reasonable quality of life.
A 2012 comparative effectiveness review, conducted for the Agency for Healthcare Research and Quality (AHRQ), on the use of HSCT in the pediatric population concluded that, for germ-cell tumors, the body of evidence on OS with tandem HSCT compared with single HSCT was insufficient to draw conclusions. (17)
Section Summary: Tandem Autologous HSCT and Sequential for Germ-Cell Tumors
One RCT compared tandem HSCT with single versus sequential HDC for germ-cell tumors. This RCT showed higher treatment-related mortality with sequential HDC than with single HDC. Five-year survival outcomes, however, did not show significant differences between groups. Observational studies have included heterogeneous patient populations, in different salvage treatment settings (i.e., first versus subsequent salvage therapy), and lacked a universally accepted prognostic scoring system to risk-stratify patients.
Allogeneic HSCT for Germ-Cell Tumors
No RCTs or nonrandomized comparative studies evaluating allogeneic HSCT for germ-cell tumors were identified. One 2007 case report has described successful treatment of a refractory mediastinal germ-cell tumor with allogeneic HSCT. (18)
Section Summary: Allogeneic HSCT for Germ-Cell Tumors
There is a lack of comparative studies evaluating allogeneic HSCT for germ-cell tumors. Only a single case report was identified.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed in Table 1.
Table 1. Summary of Key Trials
Autologous Peripheral Blood Stem-Cell Transplant for Germ-Cell Tumors
High-dose Chemotherapy for Poor-prognosis Relapsed Germ-cell Tumors
Standard Dose Chemotherapy or High-Dose Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ-cell Tumors
NCT: National Clinical Trial.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In 2010, Blue Cross Blue Shield Association requested and received clinical input from various physician specialty societies and academic medical centers.
In response to requests, input was received from 3 physician specialty societies, 3 academic medical centers, and 5 Blue Distinction Centers for Transplants while this policy was under review. There was general agreement with the policy statements regarding the use of single autologous HSCT as salvage therapy, the use of autologous HSCT as first-line treatment, and the use of allogeneic HSCT.
Seven of the reviewers felt that:
• Tandem or sequential HSCT is medically necessary for patients as salvage therapy or with platinum-refractory disease;
• 2 reviewers felt that tandem or sequential HSCT was investigational; and
• 2 stated that commenting on this was beyond his/her area of expertise.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN)
Current NCCN guidelines on testicular cancer (v.2.2018) state that for patients with unfavorable prognostic features (including incomplete response to first-line treatment, high levels of serum markers, high-volume disease, and presence of extratesticular primary tumor), HDC followed by autologous HSCT is a treatment option. (19) The guidelines do not address the use of tandem transplant with sequential HSCT in the treatment of testicular tumors.
American Society for Blood and Marrow Transplantation (ASBMT)
In 2015, guidelines by the ASBMT were published on indications for autologous and allogeneic HSCT. Recommendations were intended to describe the current consensus on use of HSCT within and outside of the clinical trial setting. (20) Recommendations on germ-cell tumors are listed in Table 2.
Table 2. Recommendations on Allogeneic and Autologous HSCT
Germ-cell tumor, relapse
Germ-cell tumor, refractory
Germ-cell tumor, relapse
Germ-cell tumor, refractory
HSCT: hematopoietic stem-cell transplantation;
C: clinical evidence available, standard of care;
D: developmental (i.e. promising);
N: not generally recommended.
Summary of Evidence
For individuals who have previously untreated germ-cell tumors who receive autologous hematopoietic stem-cell transplantation (HSCT) as first-line therapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. Results from the RCTs have shown that autologous HSCT as initial therapy for germ-cell tumors did not significantly improve outcomes compared with alternative therapy (e.g., standard-dose chemotherapy). Study sample sizes were relatively small and might have been underpowered to detect differences between groups. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have relapsed or refractory germ-cell tumors who receive autologous HSCT, the evidence includes an RCT and several case series. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The RCT did not find significant differences in outcomes between autologous HSCT plus HDC and standard-dose chemotherapy. Case series found 3-year overall survival rates that ranged from 55% to 60%; these studies lacked comparison groups. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have germ-cell tumors who receive tandem autologous transplantation and sequential HDC, the evidence includes an RCT, several retrospective cohort studies, and a comparative effectiveness review. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The RCT reported a higher rate of treatment-related mortality with sequential HDC compared with single HDC. However, 5-year survival outcomes did not differ significantly between groups. Overall, the available studies have included heterogeneous patient populations, in different salvage treatment settings (i.e., first versus subsequent salvage therapy), and have lacked a universally accepted prognostic scoring system to risk-stratify patients. Tandem autologous transplant or transplant with sequential HDC has not shown a benefit in patients with primary mediastinal germ-cell tumors. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have germ-cell tumors who receive allogeneic HSCT, the evidence includes a case report. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. There were no RCTs or nonrandomized comparative studies evaluating allogeneic HSCT for germ-cell tumors. One 2007 case report has described successful treatment of a refractory mediastinal gem-cell tumor with allogeneic HSCT. The evidence is insufficient to determine the effects of the technology on health outcomes.
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The following codes may be applicable to this Medical policy and may not be all inclusive.
36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241
S2140, S2142, S2150
ICD-9 Diagnosis Codes
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ICD-10 Diagnosis Codes
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ICD-10 Procedure Codes
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.
A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. Daugaard G, Skoneczna I, Aass N, et al. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974). Ann Oncol. May 2011; 22:1054-61. PMID 21059637
2. Motzer RJ, Nichols CJ, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ-cell tumors. J Clin Oncol. Jan 20 2007; 25(3):247-56. PMID 17235042
3. Droz JP, Kramar A, Biron P, et al. Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: mature results of a randomized trial. Eur Urol. Mar 2007; 51(3):739-48. PMID 17084512
4. Pico JL, Rosti G, et al. A randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ-cell tumors. Ann Oncol. Jul 2005; 16(7):1152-9. PMID 15928070
5. International Germ-cell Cancer Collaborative Group. International Germ-cell Consensus Classification: a prognostic factor-based staging system for metastatic germ-cell cancers. J Clin Oncol. Feb 1997; 15(2):594-603. PMID 9053482
6. Seftel MD, Paulson K, Doocey R, et al. Long-term follow-up of patients undergoing auto-SCT for advanced germ-cell tumour: a multicentre cohort study. Bone Marrow Transplant. Jun 2011; 46(6):852-7. PMID 21042312
7. Agarwal R, Dvorak CC, Stockerl-Goldstein KE, et al. High-dose chemotherapy followed by stem cell rescue for high-risk germ-cell tumors: the Standard experience. Bone Marrow Transplant. Apr 2009; 43(7):547-52. PMID 18997833
8. Baek HJ, Park HJ, Sung KW, et al. Myeloablative chemotherapy and autologous stem cell transplantation in patients with relapsed or progressed central nervous system germ-cell tumors: results of Korean Society of Pediatric Neuro-Oncology (KSPNO) S-053 study. J Neurooncol. Sep 2013; 114(3):329-38. PMID 23824533
9. Nieto Y, Tu SM, Bassett R, et al. Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors. Ann Oncol. Dec 2015; 26(12):2507-8. PMID 26487577
10. Lorch A, Kollmannsberger C, Hartmann JT, et al. Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ-cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. J Clin Oncol. Jul 1 2007; 25(19):2778-84. PMID 17602082
11. 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. Mar 10 2012; 30(8):800-5. PMID 22291076
12. 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. Jul 2007; 13(7):778-9. PMID 17580256
13. Lotz JP, Bui B, Gomez F, et al. Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ-cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation. Results of the phase II multicentric TAXIF trial. Ann Oncol. Mar 2005; 16(3):411-8. PMID 15659420
14. Einhorn LH, Williams SD, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. Jul 26 2007; 357(4):340-8. PMID 17652649
15. Suleiman Y, Siddiqui BK, Brames, MJ et al. Salvage therapy with high-dose chemotherapy and peripheral blood stem cell transplant in patients with primary mediastinal nonseminomatous germ-cell tumors. Biol Blood Marrow Transplant. Jan 2013; 19(1):161-3. PMID 22892555
16. Pal SK, Yamzon J, Sun V, et al. Paclitaxel-based high-dose chemotherapy with autologous stem cell rescue for relapsed germ-cell tumor: clinical outcome and quality of life in long-term survivors. Clin Genitourin Cancer. Jun 2013; 11(2):121-7. PMID 23062817
17. Ratko TA, Belinson SE, Brown HM, et al. Hematopoietic Stem-Cell Transplantation in the Pediatric Population. Comparative Effectiveness Review, No. 48. Agency for Healthcare Research and Quality (AHRQ): Rockville (MD.), February 2012. Available at <http://www.ncbi.nlm.nih.gov> (Accessed May 12, 2016).
18. Goodwin A, Gurney H, Gottlieb D. Allogeneic bone marrow transplant for refractory mediastinal germ-cell tumour: possible evidence of graft-versus-tumour effect. Intern Med J. Feb 2007; 37(2):127-9. PMID 17229257
19. NCCN – Testicular Cancer. Clinical Practice Guidelines in Oncology (Version 2.2018). National Comprehensive Cancer Network. Available at <http://www.nccn.org> (accessed July 20, 2018).
20. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-9. PMID 26256941
21. FDA – Tissue and Tissue Products (Parts 1270 and 1271) (February 23, 2016). Food and Drug Administration – Center for Biologics Evaluation and Research. Available at <http://fda.gov> (accessed on 2016 April 12).
22. Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 February) Therapy 8.01.35.
|10/1/2018||Document updated with literature review. Revised coverage statement for content clarification on tandem sequential autologous hematopoietic stem-cell transplantation for testicular tumors; intent of coverage statement remains unchanged. Information on unfavorable prognostic factors added to NOTE 2. References 9 and 20 added; one reference removed.|
|6/1/2017||Reviewed. No changes.|
|7/15/2016||Document updated with literature review. Coverage unchanged.|
|2/1/2015||Document updated with literature review. Coverage language modified, without change to coverage position. CPT/HCPCS code(s) updated. Title changed from: Stem-Cell Transplant for Germ-Cell Tumors (GCTs).|
|10/15/2013||Document updated with literature review. The following was added: 1) AutoSCS may be considered medically necessary for treatment of germ-cell tumors (GCTs) in patients with a) favorable prognostic factors that have failed a previous course of conventional-dose salvage chemotherapy; or b) unfavorable prognostic factors as initial treatment of first relapse (i.e., without a course of conventional-dose salvage chemotherapy); 2) tandem or sequential AutoSCS for testicular tumors may be considered medically necessary; and 3) any other sequence or combination of tandem AutoSCS and AlloSCS, or triple SCS are considered experimental, investigational and unproven; 4) hematopoietic progenitor cell boost is considered experimental, investigational and unproven; and 5) Any related services, other than AutoSCS and/or tandem or sequential AutoSCS for testicular tumors determined to be medically necessary, for the treatment of GCT’s, such as short tandem repeat (STR) markers, are considered experimental, investigational and unproven.|
|4/1/2010||New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies. Stem cell transplant continues to be medically necessary when stated criteria are met. NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): • Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; • Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; • Cord Blood as a Source of Stem Cells; • Donor Leukocyte Infusion (DLI); and • Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.|
|Title:||Effective Date:||End Date:|
|Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors||10-01-2018||05-31-2019|
|Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors||06-01-2017||09-30-2018|
|Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors||07-15-2016||05-31-2017|
|Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors||02-01-2015||07-14-2016|
|Stem-Cell Transplant for Germ-Cell Tumors (GCTs)||10-15-2013||01-31-2015|
|Stem-Cell Transplant for Germ Cell Tumors||04-01-2010||10-14-2013|