Coverage Policy Manual
Policy #: 2000050
Category: Medicine
Initiated: October 2000
Last Review: May 2018
  HDC & Autologous or Allogeneic Cell Transplantation-Epithelial Ovarian Cancer

Description:
Hematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiation therapy. Bone marrow stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood is discussed in greater detail in policy No. 1998089.
 
SCT is an established treatment for certain hematologic malignancies, however, its use in solid tumors in adults continues to be largely experimental. Initial enthusiasm for the use of autologous transplant with the use of high-dose chemotherapy and stem cells for solid tumors has waned with the realization that dose intensification often fails to improve survival, even in tumors with a linear-dose response to chemotherapy. With the advent of reduced-intensity conditioning (RIC) allogeneic transplant, interest has shifted to exploring the generation of alloreactivity to metastatic solid tumors via a graft-versus-tumor effect of donor-derived T cells.
 
Epithelial Ovarian Cancer
Several different types of malignancies can arise in the ovary; epithelial carcinoma is the most common. Epithelial ovarian cancer is the fifth most common cause of cancer death in women. New cases and deaths from ovarian cancer in the United States for 2017 were estimated at 22,440 and 14,080, respectively (American Cancer Society, 2017). Most ovarian cancer patients present with widespread disease, and the National Cancer Institute Surveillance, Epidemiology and Results Program reported a 46.5% five-year survival for all cases between 2007 and 2013 (NCI, 2017).
 
The current management of advanced epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy.  Approximately 75% of patients present with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer, with the combination of paclitaxel and a platinum analog being the preferred regimen for newly diagnosed advanced disease. (2, 3) The use of platinum and taxanes has improved progression-free survival (PFS) and overall survival (OS) rates in advanced disease to 16–21 months and 32–57 months, respectively. However, most of these women develop recurrences and die of their disease as chemotherapy drug resistance leads to uncontrolled cancer growth.  
 
High-dose chemotherapy has been investigated as a way to overcome drug resistance. However, limited data exist on this treatment approach, and the ideal patient population and best regimen remain to be established. (2) Hematopoietic stem-cell transplantation has been studied in a variety of patient groups with ovarian cancer as follows:
    • to consolidate remission after initial treatment
    • to treat relapse after a durable response to platinum-based chemotherapy
    • to treat tumors that relapsed after less than 6 months
    • to treat refractory tumors

Policy/
Coverage:
High dose chemotherapy with autologous stem cell support for the treatment of epithelial ovarian cancer does not meet Primary Coverage Criteria and is not covered. The only two phase III clinical trials have shown no benefit over standard chemotherapy, and there are a number of ongoing studies of the use of hematopoietic stem cell support for the treatment of epithelial ovarian cancer.
 
High dose chemotherapy with autologous stem cell support for the treatment of epithelial ovarian cancer is considered investigational for contracts without Primary Coverage Criteria.   Investigational services are an exclusion in the member certificate of coverage.
 
High dose chemotherapy with allogeneic stem cell support for the treatment of epithelial ovarian cancer does not meet member certificate of benefit Primary Coverage Criteria as there are no studies indicating effectiveness of this treatment.
 
High dose chemotherapy with allogeneic stem cell support for the treatment of epithelial ovarian cancer is considered investigational for contracts without Primary Coverage Criteria.  Investigational services are an exclusion in member certificate of coverage.
 
Coverage of high dose chemotherapy and stem cell support for the much less common germ cell tumor of the ovary is addressed in the policy HDC & Autologous Stem &/or Progenitor Cell Support for Treatment of Germ Cell Tumors, #2000012.

Rationale:
This policy was originally developed in October 2000 following discussion of this therapy at a transplant meeting.   Blue Cross Blue Shield Association Technology Evaluation Center (TEC) Assessments in 1998 and 1999 were used as references in this policy:
Data were 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 high-dose chemotherapy (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 2 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 TEC Assessment evaluated the use of HDC with allogeneic stem-cell support (HDC/AlloSCS) as a salvage therapy after a failed prior course of HDC/AuSCS.  There were no data regarding outcomes of this strategy as therapy for epithelial ovarian cancer.
 
Updated literature searches in December 2002 and July 2004 identified only 1 abstract by Cure and colleagues that compared conventional-dose maintenance chemotherapy to HDC/AuSCS.  No other reports from randomized trials directly comparing high-dose and conventional therapies were identified.
 
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, had residual disease or a responding relapse or for mixed groups of these patients.  Registries in North America and Europe 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 or this policy. Recent reviews  and an editorial did not cite convincing evidence that benefits from high-dose therapy are superior to those of conventional-dose management for any group of patients with ovarian cancer.
 
The abstract by Cure and coworkers, from the June 2004 meeting of the American Society for Clinical Oncology, reported on a Phase III randomized trial of women with advanced ovarian cancer treated with either HDC with carboplatin-cyclophosphamide or 3 cycles of a conventional-dose maintenance regimen.  The authors reported no significant differences in disease free-survival or overall survival in either treatment group. These findings suggest HDC/AuSCS cannot be supported as a treatment of advanced ovarian cancer over conventional-dose maintenance. In addition, a 2005 National Comprehensive Cancer Network clinical practice guidelines for ovarian cancer indicate that HDC/AuSCS is considered investigational for the treatment of ovarian cancer.
 
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 1 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).
 
The European Phase III trial randomizing patients with optimally debulked stage III or IV ovarian cancer not previously exposed to chemotherapy to sequential high-dose therapy with paclitaxel/cyclophosphamide plus G-CSF, then paclitaxel/carboplatin plus G-CSF, followed by autologous peripheral blood stem-cell support, or to conventional-dose management with carboplatin/paclitaxel (EU-99040, NCT00004921) is no longer recruiting patients.
 
One additional trial is open for patients with various other solid tumors; it includes advanced ovarian cancer.
 
2006 Update
A literature review was conducted for the time period of July 2005 through October 2006. No reports of clinical trials were found that would alter the policy statement.
 
2007 Update
A literature review was conducted using MEDLINE for the period of October 2006 through October 2007.   No reports of clinical trials were found that would alter the policy statement.
 
2008 Update
Summary of the Literature Through 2008 on the Use of Stem-Cell Transplantation in Ovarian Cancer
Experience with HDC in ovarian cancer comes primarily from registry data and phase II trials.  Over the last 20 years, more than 1,000 patients have been entered on transplant registries in Europe and in the United States.  Many of the registry patients were treated in 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. Survival analyses from registry data and clinical trials suggested a possible benefit treating ovarian cancer patients with HDC.
 
However, as outlined here, none of the randomized trials that have been performed have provided evidence that HDC with stem-cell transplant in ovarian cancer provides any outcome benefit, whether used as part of initial therapy or as a consolidation strategy.
 
Initial therapy
Mobus et al (2007) 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.  This was the first randomized trial comparing HDC to standard CT as first-line treatment of ovarian cancer, and the investigators found no statistically significant difference in progression-free survival (PFS) or overall survival (OS) between the 2 treatment options. The median patient age was 50 years (range: 20–65) and 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% 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).
 
Consolidation therapy
Papadimitriou et al (2008) reported on the use of HDC with stem cell support as consolidation therapy in patients with advanced epithelial ovarian cancer (FIGO stage IIC-IV).  Patients who achieved first clinical complete remission after conventional chemotherapy were randomly assigned to receive or not receive high-dose melphalan and autologous stem-cell transplant. A total of 30 patients were enrolled into 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 2 arms in time-to-disease progression (p=0.059) or OS (p=0.38).
 
Cure et al reported on outcomes in advanced ovarian cancer patients randomized after second-look surgery to receive either HDC with peripheral blood stem-cell support or conventional-dose maintenance chemotherapy.  Patients were younger than 60 years old 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 2 arms. Disease-free survival in the conventional- versus 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). 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).
 
National Comprehensive Cancer Network (NCCN) Guidelines
National Comprehensive Cancer Network clinical practice guidelines for ovarian cancer indicate that HDC with peripheral blood stem-cell transplantation is considered investigational for the treatment of ovarian cancer.
 
There continue to be a number of clinical trials listed on www.clinicaltrials.gov investigating the treatment of epithelial ovarian cancer with high dose chemotherapy followed by stem cell support.
 
2011 Update
Since the last update, there is no additional evidence identified that would prompt a change in the coverage statement.  Two ongoing clinical trials assessing the use of high dose chemotherapy and stem cell support were identified on the clinicaltrials.gov website (NCT01177501) (NCT00583622).
 
National Comprehensive Cancer Network (NCCN) Guidelines
National Comprehensive Cancer Network clinical practice guidelines for ovarian cancer indicate that HDC with peripheral blood stem-cell transplantation is considered investigational for the treatment of ovarian cancer.
 
2014 Update
This policy is being updated with a search of the MEDLINE database. There was no new information identified that would prompt a change in the coverage statement.
 
In 2012, Sabatier et al. reported on a retrospective review of 163 patients with advanced or metastatic (Federation of Gynecology and Obstetrics [FIGO] stage IIIc-IV) epithelial ovarian cancer who were treated at a single institution in France (Sabatier, 2012). All patients received cytoreductive surgery and combination platinum/taxane chemotherapy. Investigators compared progression-free survival (PFS) and overall survival (OS) between 60 patients who received subsequent high-dose chemotherapy with autologous HSCT support and 103 patients who did not. High-dose chemotherapy regimens varied, but all contained alkylating agents. At a median follow-up of 47.5 months, PFS in the high-dose and standard chemotherapy groups was 20.1 and 18.1 months, respectively (p value not reported). OS was 47.3 and 41.3 months, respectively (p=0.29). In prespecified subgroup analyses, median PFS was significantly longer in women younger than age 50 years who received high-dose chemotherapy compared with women who received standard chemotherapy (81.7 months vs 11 months; p=0.02); in women older than 50 years, median PFS did not differ statistically between groups (17.9 months vs 18.3 months; p=0.81). Similarly, median OS was significantly longer in women younger than age 50 years who received high-dose chemotherapy compared with women who received standard chemotherapy (54.6 months vs. 36 months; p=0.05) but not in women older than 50 years (49.5 months vs 42 months; p value not reported). The authors recommended further study of high-dose chemotherapy with autologous HSCT support in patients younger than 50 years.
 
Several different types of malignancies can arise in the ovary; epithelial carcinoma is the most common. Epithelial ovarian cancer is the fifth most common cause of cancer death in women. New cases and deaths from ovarian cancer in the United States in 2013 are estimated at 22,240 and 14,030, respectively (ACS, 2013). Most ovarian cancer patients present with widespread disease, and yearly mortality is approximately 65% of the incidence rate.
 
National Comprehensive Cancer Network clinical practice guidelines for epithelial ovarian cancer do not address a role for HSCT (NCCN, 2013).
 
2015 Update
A literature search conducted through April 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through April 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2018. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
38240Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241Hematopoietic progenitor cell (HPC); autologous transplantation
38242Allogeneic lymphocyte infusions

References: American Cancer Society.(2013) Cancer Facts and Figures 2013. Atlanta, Ga: American Cancer Society, 2013. Available online at: http://www.cancer.org/research/cancerfactsstatistics/. Last accessed September 2013.

Atlanta, GA: American Cancer Society; 2017.(2017) American Cancer Society. Cancer Facts & Figures 2017. http://www.cancer.org/research/cancerfactsstatistics/. Accessed December 5, 2017.

Berticci F, Viens P, Delpero JR et al.(2000) High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 2000; 26(1):61-7.

Bertucci F, Viens P, Gravis G, et al.(1999) High-dose chemotherapy with hematopoietic stem cell support in patients with advanced epithelial ovarian cancer: analysis of 67 patients treated in a single institution. Anticancer Res 1999; 19(2B):1455-61.

Bevacizumab Plus Gemcitabine, Docetaxel, Melphalan, and Carboplatin in Ovarian Cancer Patients (NCT00583622). Available online at: http://www.clinicaltrials.gov/ct2/show/NCT00583622?term=NCT00583622&rank=1

Clinical Practice Guidelines in Oncology: Ovarian Cancer. National Comprehensive Cancer Network, v2, 2009.

Cook S, Penson R, Duska L, et al.(2000) Efficacy and hematologic toxicity of salvage chemotherapy following stem cell-supported high-dose chemotherapy in women with recurrent ovarian cancer. Gynecol Oncol 2000; 77(1):48-54.

Cure H, Battista C, Guastalla JP et al.(2004) Phase III randomized trial of high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support as consolidation in patients (pts) with advanced ovarian cancer (AOC): 5-year follow-up of a GINECO/FNCLCC?SFGM-TC study. Abstract No:5006. American Society of Clinical Oncology 40th Annual Meeting New Orleans LA June 5-8, 2004.

Donato ML, Aleman A, Champlin RE, et al.(2004) Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation. Bone Marrow Transplant 2004; 33(12):1219-24.

Donato ML, Gershenson DM, Wharton JT, et al.(2001) High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer. Gynecol Oncol 2001; 82(3):420-6.

HDC with Autologous item cell support for epithelial ovarian cancer. 1998 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 6.

Ledermann JA, Herd R, Maraninchi D, et al.(2001) High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumor Registry of the European Group for Blood and Marrow Transplantation (EBMT). An Oncol 2001; 12(5):693-9.

MobusV, WandtH, et al.(2007) Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol, 2007; 25(27):4187-93.

Morgan RJ, Dorosho JH, Leong L et al.(2001) Phase II trial of high-dose intravenous doxorubicin, etoposide, and cyclophosphamide with autologous stem cell support in patients with residual or responding recurrent ovarian cancer. Bone Marrow Transplant 2001; 28(9):859-63.

National Cancer Institute, Surveillance Epidemiology and End Results Program.(2017) Cancer Stat Facts: Ovarian Cancer. n.d.; https://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 20, 2017.

National Comprehensive Cancer Network(2013) Practice Guidelines in Oncology. Ovarian Cancer. Version 2.2013. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Last accessed September 2013.

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Ovarian Cancer. Version 2.2011. Available online at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Last accessed October 2011.

National Comprehensive Cancer Network.(2005) Clinical Practice Guidelines in Oncology. Ovarian Cancer. Version 1.2005.

PapadimitriouC, DafniU, et al.(2008) High-dose melphalan and autologous stem cell transplantation in patients with chemosensitive ovarian cancer: results of a single-institution randomized trial. Bone Marrow Transplant, 2008; 41(6):547-54.

Peethambaram PP, Long HJ.(2002) Second-line and subsequent therapy for ovarian carcinoma. Curr Oncol Rep 2002; 4(2):159-64.

Prince HM, Rischin D, Quinn M, et al.(2001) Repetitive high-dose topotecan, carboplatin, and paclitaxel with peripheral blood progenitor cell support in previously untreated ovarian cancer: results of a Phase I study. Gynecol Oncol 2001; 81(2):216-24.

Pujade-Lauraine E, Cure H, Battista C et al.(2001) High dose chemotherapy in ovarian cancer. Int J Gynecol Cancer 2001; 11(suppl 1):64-67.

Rosti G, Ferrante P, Ledermann J et al.(2002) High-dose chemotherapy for solid tumors: results of the EBMT. Crit Rev Oncol Hematol 2002; 41(2):129-40.

Sabatier R, Goncalves A, Bertucci F et al.(2012) Are there candidates for high-dose chemotherapy in ovarian carcinoma? J Exp Clin Cancer Res 2012; 31:87.

Salvage HDC/AutoSCS for relapse following HDC/Auscs for non-lymphoid solid tumors. 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 11.

Sarosy GA, Reed E.(2000) Autologous stem-cell transplantation in ovarian cancer: is more better. Ann Intern Med 2000; 122(7):555-6.

Shinozuka T, Miyamoto T, Muramatsu T, et al.(1999) High-dose chemotherapy with autologous stem cell support in the treatment of patients with ovarian carcinoma: long term results for 105 patients. Cancer 1999; 85(7):1555-64.

Stiff PJ, Shall EJ, Liu PY, et al.(2004) Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: a Southwest Oncology Group Study. Gynecol Oncol 2004; 94(1):98-106.

Stiff PJ, Veum-Stone J, Lazarus HM, et al.(2000) High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report. Ann Intern med 2000; 133(7):504-15.

Trial of High Dose Topotecan With Carboplatin in Patients With Relapsed Ovarian Carcinoma (ITOV04) (NCT01177501) Available online at: http://www.clinicaltrials.gov/ct2/show/NCT01177501?term=NCT01177501&rank=1

Wandt H, Birkmmann J, Denzel T, et al.(1999) Sequential cycles of high-dose chemotherapy with dose escalation of carboplatin with or without paclitaxel supported by G-CSF mobilized peripheral blood progenitor cells: a phase I/II study in advanced ovarian cancer. Bone Marrow Transplant 1999; 23(8):763-70.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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