High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, bone marrow, or umbilical cord blood stem-cells.
This policy is based on a 1991 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (1) that was updated with literature published between 1991 and April 2000. The 1991 TEC Assessment offered the following conclusions:
- Data were insufficient to permit conclusions about the outcomes of HDC and autologous stem-cell support as a component of initial therapy in patients with poor-risk tumors, or after a first relapse following initial standard-dose chemotherapy.
- Data demonstrated that, compared with conventional chemotherapy, outcomes after HDC and autologous stem-cell support were improved in patients with germ-cell tumors in second or subsequent relapse.
The literature published from 1991 through April 2000 did not change these conclusions. The most thorough review, published in 1999, was that of Sobecks and Vogelzang. (2) This review pooled results of six studies focusing on high-dose therapy in first-line treatment of GCTs. Only two studies reported survival, and it was unclear whether long-term survival was better than after conventional-dose therapy for comparable patients. Sobecks and Vogelzang also pooled results of five small studies focusing on HDC to treat GCTs at first relapse. The rate of continuous complete response (CR) was 56%, with an estimated median duration of 29 months. Treatment-related mortality (TRM) was 5%. In contrast, conventional-dose chemotherapy achieves five year disease-free survival (DFS) of 30% and TRM of 2% or less. Since HDC carries a higher risk of initial TRM, it is important to compare the long-term survival after conventional therapy with long-term survival after HDC.
The data published from 1991 through April 2000 also confirmed the beneficial effect of HDC and autologous stem-cell support (AutoSCS) in patients with GCTs in second or subsequent relapse, as concluded by the 1991 TEC Assessment. (1)
There were scattered reports on use of tandem courses of HDC. (3) However, there were no controlled studies demonstrating that outcomes of tandem transplants were superior to those of a single course of HDC.
A 1999 TEC Assessment evaluated outcomes of HDC and allogeneic stem-cell support (AlloSCS) as salvage therapy for GCTs after a failed prior course of AutoSCS. A thorough review of the published literature identified no references reporting outcomes of this approach to HDC. (4)
The only randomized controlled trial among the new studies from 2002 tested the impact of amifostine on peripheral blood mobilization prior to HDC. (5) Other recent studies reported outcomes of HDC as upfront (i.e., initial) treatment for poor prognosis or high-risk GCTs, primary salvage therapy of relapsed GCT, salvage therapy for second or later relapse, or to treat refractory GCTs. These were uncontrolled clinical series enrolling small numbers of patients, or retrospective reviews of larger cohorts treated at one or several institutions. None of the studies compared outcomes of HDC to outcomes of conventional-dose chemotherapy in a randomized or nonrandomized trial, and many included patients in multiple prognostic or risk categories. As such, these studies do not permit conclusions regarding health outcomes of HDC and do not support a change in current policy; recent reviews on the status of HDC reach similar conclusions. (6, 7, 8, 9)
In 2005, Pico and colleagues (10) reported on a randomized trial comparing four cycles of conventional-dose chemotherapy to three cycles of the same regimen followed by carboplatin-based HDC plus AutoSCS in 280 patients who had relapsed after a complete or partial remission following first-line therapy with a cisplatin-based regimen. The authors reported no significant differences between treatment arms in three year event-free survival (EFS) and overall survival (OS). However, the study began before international consensus (11) established the current risk group definitions; thus, Pico and colleagues likely included some 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 one elevated serum tumor marker, they did not report how highly elevated these were and did not compare arms with respect to the marker thresholds that presently determine risk level (S1-3). Finally, HDC in the experimental arm followed three cycles of conventional-dose chemotherapy, which differs from most current practice in the United States, where a single cycle is used prior to HDC. As a consequence, 38 of 135 (28%) randomized to the HDC arm did not receive HDC because of progression, toxicity, or withdrawal of consent. For all these reasons, the Pico study does not alter conclusions or current policy on HDC as a component of therapy for poor-risk relapse.
An Intergroup Phase III trial on HDC as part of first-line therapy for poor prognosis GCT was presented at a 2006 ASCO (American Society of Clinical Oncology) annual national meeting. (12) The trial compared four cycles of conventional dose chemotherapy (n=111) versus two cycles of the same regimen followed by two cycles of HDC and AutoSCS (n=108). Investigators reported HDC did not significantly increase the proportion with a durable complete remission at one year, EFS, or OS. These outcomes support current coverage on HDC for first-line therapy of poor-risk GCT.
A Phase II study on three cycles of tandem HDC regimens in 45 refractory, poor-prognosis patients by Lotz and coworkers was identified. (13) The authors reported some patients (with a Beyer score >2) did not benefit from tandem HDC and suggested that further study is needed. A randomized trial presented at the ASCO 2006 meeting one cycle of HDC after three cycles of conventional-dose therapy versus three cycles of HDC after one cycle of conventional-dose therapy. (14) Conventional-dose therapy was etoposide (VP16), ifosfamide, and cisplatin (the VIP regimen), while HDC was carboplatin and etoposide. The trial was stopped early because of excess toxicity in the arm given three cycles of VIP before HDC. Investigators reported no significant differences between arms in OS or EFS.
Motzer and colleagues (15) reported on a randomized trial of chemotherapy with or without HDC in 219 previously untreated patients with poor-prognosis GCTs. In this trial, patients received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP), or two cycles of BEP followed by two cycles of HDC with autologous stem-cell rescue. The one year durable complete response rate was 52% after BEP and HDC, and 48% after BEP alone (p=0.53). This study is consistent with the current policy statements.
Einhorn and colleagues (16) reported on a series of 184 patients, treated between 1996 and 2004, with two consecutive cycles of HDC for metastatic testicular cancer that had progressed (relapsed) after receiving cisplatin-containing combination chemotherapy. 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, 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 that was refractory to standard-dose platinum, 18 (45%) were disease-free. These results from this highly-specialized center are quite encouraging. However, until similar results are reported from other centers, the coverage statement concerning tandem treatments is unchanged.
Clinical Guidelines and Trials
National Comprehensive Cancer Network (NCCN) Guidelines:
The National Comprehensive Cancer Network (NCCN) guidelines (17) on testicular cancer recommend HDC when there is an incomplete response to first-line therapy or in second relapse when there is an incomplete response or subsequent relapse. The NCCN guidelines are consistent with current coverage.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®):
A search of the National Cancer Institute’s Physician Data Query database identified one open Phase III randomized study of standard cisplatin, etoposide, and ifosfamide (VIP) followed by sequential high-dose VIP and SCS versus bleomycin, etoposide, and cisplatin (BEP) in chemotherapy-naive men ages 16–50 years with poor-prognosis germ-cell cancer (protocols EORTC-30974, NCT00003941). This trial is organized by the European Organization for Research and Treatment of Cancer and expects to accrue 222 patients within two years.
Additional Infusion Treatments for GCTs
Donor leukocyte infusion (DLI) for GCTs are considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
A search of peer reviewed literature through November 2012 was completed. The following is the key literature to date.
AutoSCS as Front-line Therapy of GCTs
Daugaard and colleagues reported the outcomes of a randomized Phase III study comparing standard-dose BEP (cisplatin, etoposide, and bleomycin) to sequential high-dose VIP (cisplatin, etoposide, and ifosfamide) plus SCS in previously untreated males with poor-prognosis germ-cell cancer. (18) The study aimed to recruit 222 patients but closed with 137 patients from 27 European oncology centers due to slow accrual. Patients were age 15-50 years and had previously untreated metastatic poor-prognosis nonseminomatous GCT of either testicular or extragonadal origin. Median follow-up was 4.4 years. Toxicity was more severe in the patients who received HDC, and toxic death was reported in 2 patients who received HDC and one in the BEP arm. There was no improvement in CR rate in the HDC arm versus the standard-dose arm (44.6% vs. 33.3%, respectively, p=0.18). There was no difference in failure-free survival (FFS) between the two groups. At 2 years, FFS was 44.8% (95% confidence interval [CI]: 32.5-56.4) and 58.2% (95% CI: 48.0-71.9), respectively, for the standard and high-dose arms. The difference was not statistically significant (p=0.06). OS did not differ between the two groups (log-rank p>0.1). The authors concluded that HDC given as part of first-line therapy does not improve outcomes in patients with poor-prognosis GCT.
Droz and colleagues assessed the impact of HDC with SCS on the survival of patients with high-volume, previously untreated, metastatic nonseminomatous GCTs. (19) Patients were randomized to four cycles every 21 days of vinblastine, etoposide, cisplatin and bleomycin (n=57) or a slightly modified regimen followed by HDC and AutoSCS (n=57). In an intention-to-treat (ITT) analysis, there were 56% and 42% CRs in the conventional and HDC groups, respectively (p=0.099). Median follow-up was 9.7 years, and no significant difference between OS was observed (p=0.167).
AutoSCS for Relapsed or Refractory GCTs
Agarwal and colleagues reported their experience at Stanford in treating 37 consecutive patients who received HDC and AutoSCS between 1995 and 2005 for relapsed GCTs. (20) The 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 central nervous system (CNS). Twenty-nine of the patients had received prior standard salvage chemotherapy. Three-year OS was 57% (95% CI: 41-71%), and 3-year PFS was 49% (95% CI: 33–64%).
Seftel and colleagues conducted a multicenter cohort study of consecutive patients undergoing a single AutoSCS for GCTs between January 1986 and December 2004. (21) Of 71 subjects, median follow-up was 10.1 years. The median age was 31 years (range 16–58 years). A total of 67 of the patients had nonseminomatous GCTs and 4 had seminomatous germ-cell tumors. A total of 57 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 CNS disease, and 1 presented with retroperitoneal disease. In all, 28 patients underwent AutoSCS for relapsed disease after achieving an initial CR. Of these, 24 patients underwent AutoSCS after a first relapse, whereas 4 patients underwent transplant after a second relapse. An additional 36 patients achieved only an incomplete response after initial therapy and proceeded to AutoSCS after salvage chemotherapy for active residual disease. OS at 5 years was 44.7% (95% CI: 32.9–56.5%) and EFS 43.5% (95% CI: 31.4–55.1%). 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 (IGCCC) good prognosis disease at diagnosis, primary gonadal disease, and response to salvage chemotherapy.
Tandem and Sequential SCS for GCTs
Lazarus and colleagues reported the results of AutoSCS in relapsed testicular or germ-cell cancer from registry data from the Center for International Blood and Marrow Transplant Research. (23) Patients with mediastinal primaries were excluded. Data included 300 patients from 76 transplant centers in 8 countries who received either a single transplant or tandem AutoSCS between 1989 and 2001. Of the 300 patients, 102 received tandem, and 198 single planned AutoSCS. PFS and OS at 1, 3, and 5 years was similar for both groups. The probability of PFS at 5 years for the tandem transplant group was 34% (95% CI: 25–44%) versus 38% (95% CI: 31–45%) in the single transplant group; p=0.50. The probability of 5-year OS was 35% (95% CI: 25–46%) versus 42% (95% CI: 35–49%), respectively; p=0.29.
Further review of the Lorch and colleagues study comparing a single versus sequential HDC with AutoSCS as first or subsequent salvage treatment in patients with relapsed or refractory germ-cell tumors was completed. (14) Between November 1999 and November 2004, patients planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin, etoposide, and ifosfamide (VIP) plus 3 cycles of high-dose carboplatin and etoposide (CE; arm A) versus 3 cycles of VIP plus one cycle of high-dose carboplatin, etoposide and cyclophosphamide (CEC; arm B). The majority of the tumors were gonadal primaries; ten percent 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 in 86% of the patients in arm A and 85% in arm B, whereas 14% (arm A) and 15% (arm B) had received one or more previous salvage regimens prior to randomization. One-hundred-eleven (51%) of 216 patients were randomly assigned to sequential high-dose therapy, and 105 (47%) of 216 patients were randomly assigned to single high-dose therapy. The study was stopped prematurely after recruitment of 216 patients as a result of excess TRM in arm B. There was a planned interim analysis after the inclusion of 50% of the required total number of patients. Survival analyses were performed on an ITT basis.
With a median follow-up time 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 site of the tumor. No difference in survival probabilities was found between the single and sequential high-dose regimens; however, sequential high-dose therapy was better tolerated and resulted in fewer treatment-related deaths (TRDs). TRDs, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (4 of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; p<0.01). The authors state that the higher TRDs observed in arm B likely were due to the higher dosages per SCS cycle in the arm B regimen compared to arm A, and the toxic renal and cardiac effects of cyclophosphamide used in arm B. The authors conclude that sequential treatment at submaximal doses of carboplatin and etoposide might be less toxic and safer to deliver SCS in pretreated patients with GCTs than single SCS.
Lotz and colleagues reported the results of a Phase II study on 3 consecutive cycles of HDC regimens supported by autologous transplant in 45 poor-prognosis patients with relapsed GCTs. (24) From March 1998 to September 2001 (median follow-up, 31.8 months), 45 patients (median age, 28 years) were enrolled. Most of the patients (76%) had testicular primaries; 13% had mediastinal primaries; 11% retroperitoneal, hepatic, or unknown. Of all patients, 22 received the complete course. Twenty-five patients died from progression and five from toxicity. The overall response rate was 37.7%, including an 8.9% CR rate. The median OS was 11.8 months. The 3-year survival and PFS rate was 23.5%. The authors used the “Beyer” prognostic score to predict the outcome of HDC and concluded that patients with a Beyer score greater than 2 did not benefit from this approach, confirming that highly refractory patients and particularly patients with resistant or refractory primary mediastinal GCTs do not benefit from HDC. The authors also state that better selection criteria have to be fulfilled in forthcoming studies.
A comparative effectiveness review conducted for the Agency for Healthcare Research and Quality (AHRQ) on the use of SCS in the pediatric population concluded that, for GCTs, the body of evidence on OS with tandem SCS compared to single SCS for the treatment of relapsed pediatric GCTs was insufficient to draw conclusions. (25)
Clinical Guidelines and Trials
National Comprehensive Cancer Network (NCCN) Practice Guidelines:
The NCCN 2012 (v.1.2012) guidelines (26) for the treatment of testicular cancer state that if a patient with favorable prognostic factors (defined as testicular primary site, prior CR to first-line therapy, low levels of serum markers and low volume disease) has disease recurrence after prior chemotherapy, HDC is an option, or if a patient with disease recurrence undergoes conventional-dose chemotherapy and experiences an incomplete response or relapses, HDC with AutoSCS is category 2A recommendation. Patients with unfavorable prognostic factors (e.g., an incomplete response to prior chemotherapy, high levels of serum markers, high-volume disease, extratesticular primary or late relapse) and disease recurrence are considered for treatment with HDC plus AutoSCS (category 2B). These definitions are in agreement with those from DeVita, Hellman, and Rosenberg’s textbook Cancer: Principles and Practice of Oncology. (27) The NCCN guidelines do not address the use of tandem or sequential SCS in the treatment of testicular tumors.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®):
A search of the National Cancer Institute’s Physician Data Query database identified the following Phase III randomized study, Salvage Using Cisplatin, Etoposide, and Ifosfamide (PEI) or Vinblastine, Ifosfamide, and Cisplatin (VeIP) With or Without High-Dose Carboplatin, Etoposide, and Cyclophosphamide, Followed by Autologous Bone Marrow and/or Peripheral Blood Stem-Cell Transplantation in Male Patients With Germ-Cell Tumors in Relapse or First Partial Remission (NCT00002566). Expected enrollment is 280 patients. Trial status is unknown.
Additional Infusion Treatments for GCTs
There are scant data in the literature to support the use of AlloSCS in the treatment of GCTs. (28) Thus, the use AlloSCS remains experimental, investigational and unproven.
Donor leukocyte infusion (DLI) for GCT is considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
As with DLI, hematopoietic progenitor cell (HPC) boost has a positive response rate for relapse following AlloSCS. (29) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (29, 30, 31, 32)
Short Tandem Repeat (STR) Markers
Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (33, 34) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of GCTs, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (33, 34, 35, 36, 37, 38)
Salvage therapy plays a role in patients with GCTs who are either refractory to cisplatin or who relapse after initial treatment. (20) The timing for the use of HDC and SCS instead of standard salvage chemotherapy is less well-defined, with patient heterogeneity playing a role in the overall outcome. (20) Studies have been limited trying to stratify patients into various prognostic groups to identify those who are high-risk, as only 30% of patients with GCTs require salvage treatment. (20) The use of HDC and SCS as first-line therapy has not been shown to be superior to standard chemotherapy; SCS remains the treatment of choice for patients who fail standard salvage therapy. (20)
The role of tandem or sequential autologous transplants in relapsed disease has been investigated in one Phase II study, one randomized study, two retrospective series (one single-center experience and one registry data from multiple centers), and a comparative effectiveness review for AHRQ. Tandem or sequential SCS may provide survival benefit, and the randomized study showed lower TRM with sequential SCS compared to single SCS. However, studies have included heterogeneous patient populations, in different salvage treatment settings (i.e., first versus subsequent salvage therapy) and have suffered from the lack of a universally accepted prognostic scoring system to risk-stratify patients. Tandem or sequential SCS has not shown benefit in patients with primary mediastinal GCTs.
Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of GCTs are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
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