High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant 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, umbilical cord blood, or bone marrow stem-cells.
Initially, this policy was based on a 1998 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (5) that reached the following conclusions:
- Data was unavailable from randomized controlled trials for any of the patient groups studied. Thus, the Assessment was able to compare outcomes only indirectly, using separate studies of HDC and conventional dose regimens. Although some results reported after high-dose therapy appeared encouraging, the indirect comparisons did not permit conclusions.
- In previously untreated patients, reported response rates suggested that high-dose therapy increased the objective response rate compared to patients given conventional-dose chemotherapy. However, this comparison was flawed by age bias and by differences in performance status and other baseline characteristics of patients included in the two sets of studies. Response duration and survival data were unavailable for comparison. Treatment-related mortality was greater after high-dose therapy.
- In previously treated patients, objective response rates after HDC also were reportedly higher than after conventional-dose regimens. Subgroup analyses showed higher response rates among platinum-sensitive, optimally debulked patients. Minimum values of the ranges reported across studies for median response duration and survival after HDC were similar to those reported after conventional-dose chemotherapy. However, the maxima for these ranges suggested improved response duration and overall survival after high-dose therapy. In contrast, data from the Autologous Blood and Marrow Transplant Registry did not show similarly high survival for comparable subgroups. Comparison with conventional-dose chemotherapy was again biased due to differences in age distributions, performance status, and other baseline characteristics of patients included in studies of high-dose or conventional therapies.
The 1998 TEC Assessment did not identify any studies reporting outcomes of allogeneic transplants for patients with ovarian cancer. A separate 1999 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (6) evaluated the use of HDC with allogeneic stem-cell support (HDC/AlloSCS) as a salvage therapy after a failed prior course of HDC with autologous stem-cell support (HDC/AuSCS). There was no data regarding outcomes of this strategy as therapy for epithelial ovarian cancer.
Several uncontrolled studies were published after the 1998 TEC Assessment. These reported retrospective or prospective analyses on outcomes of high-dose regimens followed by AuSCS for ovarian cancer patients who were previously untreated (7, 8, 9) had residual disease or a responding relapse, (10, 11, 12) or for mixed groups of these patients. (13, 14, 15, 16) Registries in North America (17) and Europe (18, 19) also reported retrospective analyses that may include some of the same patients. Taken together, these data were judged inadequate to alter conclusions of the 1998 TEC Assessment. Recent reviews (20, 21) and an editorial (22) did not cite convincing evidence that benefits from high-dose therapy is superior to those of conventional-dose management for any group of patients with ovarian cancer.
The abstract by Cure and coworkers, (23) from the June 2004 meeting of the American Society for Clinical Oncology, reported on a Phase III randomized trial outcomes of women with advanced ovarian cancer randomly assigned after second-look surgery to receive either HDC with peripheral blood stem-cell support or conventional-dose maintenance chemotherapy, which included (10) either HDC with carboplatin-cyclophosphamide or three cycles of a conventional-dose maintenance regimen. These results were presented in abstract form and have yet to be published. Patients were younger than age 60 years with FIGO stage III-IV and disease sensitive to first-line chemotherapy. Enrolled were 110 patients (n=57 high-dose and n=53 conventional-dose chemotherapy). Median follow-up was 60 months. No difference was seen in disease-free or OS between the two arms. Disease-free survival in the conventional- versus the high-dose group was 12.2 months (95% CI: 7.3–17.1) versus 17.5 months (95% CI: 5.2–29.9) (p=0.22), respectively. OS was 42.5 months (95% CI: 28.8-56.6) and 49.7 months (95% CI: 29.9–69.4), respectively (p=0.43). The authors reported no significant differences in disease free-survival or overall survival in either treatment group. (23) These findings suggest HDC/AuSCS cannot be supported as a treatment of advanced ovarian cancer over conventional-dose maintenance.
National Comprehensive Cancer Network (NCCN) Guidelines:
In addition, the National Comprehensive Cancer Network clinical practice guidelines for ovarian cancer indicate that HDC/AuSCS is considered investigational for the treatment of ovarian cancer. (2)
National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
The National Cancer Institute (NCI) database of clinical trials (PDQ®) was searched for ongoing trials investigating high-dose therapy for patients with ovarian cancer. The PDQ® search identified only one open trial specifically focused on patients with ovarian cancer investigating HDC followed by hematopoietic stem-cell transplant:
- A Phase II trial using cyclophosphamide, carboplatin, and mitoxantrone followed by autologous bone marrow transplant for patients with refractory or relapsed ovarian cancer (NCI-V91-0058).
Additional Infusion Treatments for Epithelial Ovarian Cancer
Tandem or triple stem-cell transplant and donor leukocyte infusion (DLI) for ovarian cancer is 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 October 2012 was conducted. The following is a summary of the key literature to date.
Experience with SCS in epithelial ovarian cancer is primarily derived from registry data and Phase II trials. (17, 18, 24) Over the last 20 years, more than 1,000 patients have been entered on transplant registries in Europe and in the United States. (4, 17, 18) Many of the registry patients were treated following relapse and others in nonrandomized studies using HDC as first-line treatment. Case selection and retrospective review make the interpretation of the registries and nonrandomized data difficult. (4) Survival analyses from registry data and clinical trials suggested a possible benefit treating ovarian cancer patients with SCS.
However, as outlined here, none of the randomized trials that have been performed have provided evidence that HSCT in ovarian cancer provides any outcome benefit.
In 2007, Mobus and colleagues reported on a trial of 149 patients with untreated ovarian cancer who were randomly assigned, after debulking surgery, to standard chemotherapy or sequential HDC and peripheral blood stem-cell support. (4) This was the first randomized trial comparing HDC to standard chemotherapy as first-line treatment of ovarian cancer, and the investigators found no statistically significant difference in progression-free survival (PFS) or OS between the two treatment options. The median patient age was 50 years (range: 20–65) and International Federation of Gynecology and Obstetrics (FIGO) stage was IIb/IIc in 4%, III in 78%, and IV in 17%. Seventy-six percent of patients in the HDC arm received all of the scheduled chemotherapy cycles. After a median follow-up of 38 months, PFS was 20.5 months in the standard chemotherapy arm and 29.6 months in the HDC arm (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.56–1.26; p=0.40). Median OS was 62.8 months in the standard chemotherapy arm and 54.4 months in the HDC arm (HR: 1.17; 95% CI: 0.71–1.94; p=0.54).
In 2008, Papadimitriou and colleagues reported on the use of HDC with SCS as consolidation therapy in patients with advanced epithelial ovarian cancer (FIGO stage IIC-IV). (3) Patients who achieved first clinical complete remission after conventional chemotherapy were randomly assigned to receive or not receive high-dose melphalan and AuSCS. A total of 80 patients were enrolled in the trial. Of the 37 patients allocated to HDC, 11 did not receive the treatment either due to refusal or failure of peripheral blood stem-cell mobilization. In an intent-to-treat analysis, there were no significant differences between the two arms in time-to-disease progression (p=0.059) or OS (p=0.38).
Additional Infusion Treatments for Epithelial Ovarian Cancer Using Hematopoietic Progenitor Cell (HPC) Boost or Stem-Cell Boost (SCB)
As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS to treat hematological malignancies. (25) 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. (25, 26, 27, 28)
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. (29, 30) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of epithelial ovarian cancer, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (29, 30, 31, 32, 33, 34)
National Comprehensive Cancer Network (NCCN) Guidelines:
Current NCCN Guidelines for ovarian cancer did not indicate any type of HDC with SCS for the treatment of ovarian cancer at any stage or within any progression/recurrence of the disease. (2)
National Cancer Institute (NCI) Clinical Trials Database (PDQ®):
As of October 2012, no Phase III trials investigating HDC therapy for patients with ovarian epithelial cancer were identified in the 2012 National Cancer Institute database.
The evidence for the use of SCS as an adjunct to HDC epithelial ovarian cancer is based on 2 published randomized trials with conflicting outcomes, and data from case series and registries. At present, the evidence is insufficient to recommend this intervention in either first-line therapy or for patients in whom epithelial ovarian cancer has relapsed following standard chemotherapy, and therefore, the use of SCS in epithelial ovarian cancer remains experimental, investigational and unproven.
Based on a search of peer reviewed literature in the MedLine database, through October 2012, there were no new clinical trial publications or any additional information that would change our coverage position; therefore, tandem or triple stem-cell transplant and DLI remain experimental, investigational and unproven for the treatment of epithelial ovarian cancer.
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 epithelial ovarian cancer 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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