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MP 8.01.23 Hematopoietic Stem Cell Transplantation for Epithelial Ovarian Cancer

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/11:2014


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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 



Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation (HSCT) 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 HSCT) or from a donor (allogeneic HSCT). 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 (GVHD). Cord blood is discussed in greater detail in policy No. 7.01.50.

HSCT 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 (GVT) 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 type. 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 2014 are estimated at 21,980 and 14,270, respectively.(1) Most ovarian cancer patients present with widespread disease, and annual mortality is approximately 65% of the incidence rate.

Current management of advanced epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy.(2) Approximately 75% of patients present with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer and are treated with the combination of paclitaxel plus a platinum analog, the preferred regimen for newly diagnosed advanced disease.(3,4) The use of platinum and taxanes has improved progression-free survival (PFS) and overall survival (OS) in advanced disease to 16 to 21 months and 32 to 57 months, respectively.(3) However, most of these women develop recurrences and die of the disease, as chemotherapy drug resistance leads to uncontrolled cancer growth.(4)

High-dose chemotherapy (HDC) has been investigated as a way to overcome drug resistance. However, limited data exist on this treatment approach; the ideal patient population and best treatment regimen remain to be established.(4) HSCT has been studied in a variety of patient groups with ovarian cancer as follows:

  • to consolidate remission after induction therapy
  • 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

Regulatory Status

HDC with stem-cell support is a procedure and, therefore, is not subject to U.S. Food and Drug Administration (FDA) regulations. However, cytotoxic drugs used in HDC do require, and generally have received, FDA approval. HDC is an off-label use of approved drugs.



Autologous or allogeneic hematopoietic stem-cell transplantation is considered investigational to treat epithelial ovarian cancer.

Policy Guidelines


Stem-cell transplantation to treat germ cell tumors of the ovary is considered separately in policy No. 8.01.35.

Benefit Application
BlueCard/National Account Issues


The following considerations may supersede this policy:

  • State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).
  • Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.
  • Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage. 


This policy was originally based on a 1998 TEC Assessment, “High-dose chemotherapy with autologous stem-cell support for epithelial ovarian cancer”(5) that reached the following conclusions:

  • Data were unavailable from randomized controlled trials for any of the patient groups studied (see Description). Thus, the Assessment was able to compare outcomes only indirectly, using separate studies of high-dose chemotherapy (HDC) and conventional dose regimens.(5 Although some results reported after HDC appeared encouraging, indirect comparisons did not permit conclusions.
  • In previously untreated patients, reported response rates suggested that HDC increased objective response rates compared with 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.(5) Treatment-related mortality was greater after HDC.
  • 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 (OS) after HDC. 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 ncluded in studies of high-dose or conventional chemotherapies.(5)

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 salvage therapy after a failed prior course of HDC with autologous stem-cell support (HDC/AuSCS).(6) There were no data regarding outcomes of this strategy as therapy for epithelial ovarian cancer.

This policy has been updated at regular intervals with literature searches of the MEDLINE database; the most recent update covered the period through October 20, 2014. Experience with hematopoietic stem-cell transplantation (HSCT) in epithelial ovarian cancer is primarily derived from registry data and phase 2 trials.(7-10) Over the last 20 years, more than 1000 patients have been entered on transplant registries in Europe and in the United States.(3,8,10) Many registry patients were treated after relapse and others in nonrandomized studies using HDC as first-line treatment. Case selection and retrospective review make interpretation of registry and nonrandomized data difficult.(3) Survival analyses from registry data and clinical trials suggested a possible benefit in treating ovarian cancer patients with HSCT.

However, as outlined here, no randomized trial has provided evidence that HSCT in ovarian cancer provides any outcome benefit.

In 2012, Sabatier et al reported on a retrospective review of 163 patients with advanced or metastatic (Federation of Gynecology and Obstetrics [FIGO] stage 3c/4) epithelial ovarian cancer who were treated at a single institution in France.(11) All patients received cytoreductive surgery and combination platinum/taxane chemotherapy. Investigators compared median progression-free survival (PFS) and OS between 60 patients who received subsequent HDC with autologous HSCT support and 103 patients who did not. HDC 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 HDC 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 HDC 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 HDC with autologous HSCT support in patients younger than 50 years.

In 2008, Papadimitriou et al reported on the use of HDC with stem-cell support as consolidation therapy in patients with advanced epithelial ovarian cancer (FIGO stage IIC-IV).(4) 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 80 patients were enrolled in the trial. Of 37 patients allocated to HDC, 11 (30%) did not receive the treatment either due to refusal or failure of peripheral blood stem-cell mobilization. In an intention-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).

In 2007, Mobus et al 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.(3) This was the first randomized trial comparing HDC with standard chemotherapy as first-line treatment of ovarian cancer, and investigators found no statistically significant difference in PFS or OS between the 2 treatments. Median patient age was 50 years (range, 20-65) and FIGO stage was 2b/2c in 4%, stage 3 in 78%, and stage 4 in 17%. Seventy-six percent of patients in the HDC arm received all 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 to 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 to 1.94; p=0.54).

In 2004, Curé et al reported on outcomes in advanced ovarian cancer patients randomly assigned after second-look surgery to receive either HDC with peripheral blood stem-cell support or conventional-dose maintenance chemotherapy.(12) Results were presented in abstract form and have yet to be published. Patients were younger than age 60 years with FIGO stage 3/4 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 survival or OS between the 2 treatment arms. Disease-free survival in the conventional- and high-dose groups was 12.2 months (95% CI, 7.3 to 17.1) and 17.5 months (95% CI, 5.2 to 29.9) (p=0.22), respectively. OS was 42.5 months (95% CI, 28.8 to 56.6) and 49.7 months (95% CI, 29.9 to 69.4), respectively (p=0.43).

Ongoing and Unpublished Clinical Trials

A search of found no trials of HSCT for epithelial ovarian cancer.

Summary of Evidence

Evidence for the use of hematopoietic stem-cell transplantation (HSCT) as an adjunct to high-dose chemotherapy in epithelial ovarian cancer is based on 3 published randomized trials and data from case series and registries. Currently, evidence is insufficient to recommend this intervention either as first-line therapy or for patients in whom epithelial ovarian cancer has relapsed after standard chemotherapy. Therefore, use of HSCT in epithelial ovarian cancer remains investigational.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Although authors of the current National Comprehensive Cancer Network guideline for ovarian cancer (version 3.2014) state, “For patients with definitive residual disease and with persistently elevated alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (beta-HCG) after first-line chemotherapy, recommendations include…high-dose chemotherapy with stem cell support,” a formal recommendation for this approach is not included in the guideline itself.(22)

U.S. Preventive Services Task Force Recommendations
Not applicable.

Medicare National Coverage
The Centers for Medicare and Medicaid Services currently have the following national noncoverage decision on autologous stem-cell transplantation: “Insufficient data exist to establish definite conclusions regarding the efficacy of AuSCT for the following condition[s]: Solid tumors (other than neuroblastoma).”


  1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, Ga: American Cancer Society; 2014. Accessed October 21, 2014.
  2. National Comprehensive Cancer Network NCCN). Clinical practice guidelines in oncology: ovarian cancer, version 3.2014. Accessed October 21, 2014.
  3. Mobus V, Wandt H, Frickhofen N, et al. 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):4187-4193.
  4. Papadimitriou C, Dafni U, Anagnostopoulos A, et al. High-dose melphalan and autologous stem cell transplantation as consolidation treatment in patients with chemosensitive ovarian cancer: results of a singleinstitution randomized trial. Bone Marrow Transplant. 2008;41(6):547-554.
  5. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). High-dose chemotherapy with autologous stem-cell support for epithelial ovarian cancer. TEC Assessments. 1998;Volume 13, Tab 6.
  6. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Salvage high-dose chemotherapy with allogeneic stem cell support for relapse following high-dose chemotherapy with autologous stem cell support for non-lymphoid solid tumors. TEC Assessments. 1999;Volume 14, Tab 11.
  7. Donato ML, Aleman A, Champlin RE, et al. Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation. Bone Marrow Transplant. 2004;33(12):1219-1224.
  8. Ledermann JA, Herd R, Maraninchi D, et al. High-dose chemotherapy for ovarian carcinoma: long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol. 2001;12(5):693-699.
  9. Stiff PJ, Bayer R, Kerger C, et al. High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol. 1997;15(4):1309-1317.
  10. Stiff PJ, Veum-Stone J, Lazarus HM, et al. 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):504-515.
  11. Sabatier R, Goncalves A, Bertucci F, et al. Are there candidates for high-dose chemotherapy in ovarian carcinoma? J Exp Clin Cancer Res. 2012;31:87. PMID 23072336
  12. Curé H, Battista C, Guastalla J et al. 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 for Clinical Oncology 40th Annual Meeting, 2004; New Orleans, Louisiana. Accessed October 21, 2014.






Management of recipient hematopoietic cell donor search and cell acquisition 



Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic 



Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection autologous 



Thawing of previously frozen harvest 



Washing of harvest 



Specific cell depletion with harvest, T-cell depletion 



Tumor cell depletion 



Red blood cell removal 



Platelet depletion 



Plasma (volume) depletion 



Cell concentration in plasma, mononuclear, or buffy coat layer 



Bone marrow, aspiration only 



Biopsy, needle or trocar 



Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic 



Bone marrow or blood-derived peripheral stem-cell transplantation; autologous 



Allogeneic donor lymphocyte infusions 

ICD-9 Procedure 


Autologous bone marrow transplant 

  41.02 Allogeneic bone marrow transplant with purging
  41.03 Allogeneic bone marrow transplant without purging



Autologous hematopoietic stem-cell transplant 

  41.05 Allogeneic hematopoietic stem-cell transplant without purging
  41.07 Autologous hematopoietic stem cell transplant with purging
  41.08 Allogeneic hematopoietic stem cell transplant with purging
  41.09 Autologous bone marrow transplant with purging



Aspiration of bone marrow from donor for transplant 



Other therapeutic apheresis (includes harvest of stem cells) 

ICD-9 Diagnosis 


Investigational for all codes


Q0083, Q0084, Q0085 

Chemotherapy, administration code range 



Chemotherapy drug code range 



Cord blood harvesting for transplantation, allogeneic 



Cord blood derived stem-cell transplantation, allogeneic 



Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care on the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services) 

ICD-10-CM (effective 10/1/15)   Investigational for all relevant diagnoses
  C56.0-C56.9 Malignant neoplasm of ovary code range
ICD-10-PCS (effective 10/1/15)    ICD-10-PCS codes are only used for inpatient services.
  30243G0, 30243X0, 30243Y0 Percutaneous transfusion, central vein, bone marrow or stem cells, autologous, code list
  30243G1, 30243X1, 30243Y1 Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list
  07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ Surgical, lymphatic and hemic systems, extraction, bone marrow, code list

Type of Service 


Place of Service 




High-dose Chemotherapy, Ovarian, Epithelial
Ovarian Cancer, Epithelial, High-dose Chemotherapy  

Policy History


Date Action Reason
12/01/99 Add to Therapy section New policy represents a revision of policy No. 8.01.15 to focus entirely on ovarian cancer. Policy statement changed
04/30/00 Replace policy Policy revised only to cross-reference to new policy 8.01.35
12/18/02 Replace policy Policy updated, references added; no change in policy statement. CPT codes updated
11/09/04 Replace policy Literature review update for the period of December 2002 through July 2004; referenced added. Policy statement unchanged
09/27/05 Replace policy Literature review update for the period of July 2004 through July 2005; no new clinical trial publications found. NCI and NCCN information updated. Policy statement unchanged
12/12/06 Replace policy Literature review updated for period of July 2005 through October 2006. No new relevant clinical trials publications noted. Policy statement unchanged
12/13/07 Replace policy Policy updated with literature review; policy statements unchanged.
12/11/08 Replace policy  Policy updated with literature review; policy statements unchanged. Rationale rewritten extensively; reference list extensively revised. “High-dose chemotherapy” removed from policy title
11/12/09 Replace policy Policy updated with literature review through October 2009; no new studies added. Term “hematopoietic” added to policy statement; otherwise, no changes. Policy reference 11 updated.
11/11/10 Replace policy Policy updated with literature review, reference numbers 1 and 11 updated, no change in policy statement
11/10/11 Replace policy Policy updated with literature review; no new references added; no change in policy statement.
11/08/12 Replace Policy Policy updated with literature review; no new references added; no change in policy statement. Need for policy affirmed.
11/14/13 Replace policy Policy updated with literature review through August 2013. Reference 11 added; references 1, 2, and 12 updated. No change in policy statement.
12/12/13 Replace policy - correction only next review date revised to November 2014
11/13/14 Replace policy Policy updated with literature review through October 20, 2014; no new references added; references 1-2 and 12 updated. No change in policy statement.


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