Pending Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Epithelial Ovarian Cancer

Number:SUR703.034

Effective Date:05-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Autologous or allogeneic hematopoietic stem-cell transplantation (HSCT) is considered experimental, investigational and/or unproven to treat epithelial ovarian cancer.

NOTE 1: For stem-cell transplantation to treat germ-cell tumors of the ovary see Medical Policy SUR703.045, “Hematopoietic Stem-Cell Transplantation for Germ-Cell Tumors (GCTs)”.

NOTE 2: 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.

Description:

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).

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.

Background

Several 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 2016 were estimated at 22,280 and 14,240, respectively. (1) Most ovarian cancer patients present with widespread disease, and annual mortality is approximately 65% of the incidence rate.

Epithelial Ovarian Cancer

Current management for advanced epithelial ovarian cancer is cytoreductive surgery with chemotherapy. (2) Approximately 75% of patients present with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer and are treated with paclitaxel plus a platinum analogue, the preferred regimen for newly diagnosed advanced disease. (3, 4) Use of platinum and taxanes has improved progression-free survival and overall survival in advanced disease to between 16 and 21 months and 32 and 57 months, respectively. (3) However, cancer recurs in most women and they die of the disease, because chemotherapy drug resistance leads to uncontrolled cancer growth. (4)

HSCT has been investigated as a therapy 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 tested in various patient groups with ovarian cancer:

To consolidate remission after induction therapy;

To treat relapse after a durable response to platinum-based chemotherapy;

To treat tumors that relapse after less than 6 months;

To treat refractory tumors.

Regulatory Status

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 (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (12) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was originally created in 1990, moved to this policy in 2010, which has been updated with reviews of the MedLine database and Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments of 1998 and 1999. (5, 6) The most recent literature review was performed through April 17, 2017. The following is a summary of the key literature to date.

The 1998 BCBSA TEC Assessment reached the following conclusions (5):

Data were unavailable from randomized controlled trials (RCTs) 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 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. (5) 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 (OS) 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. (5)

The 1998 BCBSA TEC Assessment did not identify any studies reporting outcomes of allogeneic transplants for patients with ovarian cancer. A separate 1999 BCBSA TEC Assessment evaluated the use of HDC with allogeneic HSCT as salvage therapy after a failed prior course of HDC with autologous hematopoietic stem-cell transplantation (HSCT). (6) There were no data on outcomes of this strategy as therapy for epithelial ovarian cancer.

Experience with HSCT in epithelial ovarian cancer is primarily derived from registry data and phase 2 trials. (7-10) Many registry patients were treated after relapse and others in nonrandomized trials 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 have suggested a possible benefit in treating ovarian cancer patients with HSCT.

Randomized Controlled Trials (RCTs)

In 2007, Mobus et al. reported on a randomized, phase 3 trial that included 149 patients with untreated ovarian cancer who were randomized, 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 differences in progression-free survival (PFS) or OS between the 2 treatments. The study was powered such that a sample of 208 patients would be needed to detect an absolute improvement of 15% in PFS with a power of 80% and a 1-sided α of 5%. Median patient age was 50 years (range, 20-65 years) and International Federation of Gynecology and Obstetrics (FIGO) stage was IIB or IIC in 4%, stage III in 78%, and stage IV 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 2008, Papadimitriou et al. reported on an RCT comparing 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 complete remission after conventional chemotherapy were randomized to receive or not high-dose melphalan and autologous HSCT. Eighty 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).

Observational Comparative Studies

In 2012, Sabatier et al. retrospectively reviewed 163 patients with advanced or metastatic (FIGO stage IIIC or IV) epithelial ovarian cancer who were treated at a single institution in France. (11) All patients received cytoreductive surgery and combination platinum plus taxane chemotherapy. Investigators compared median 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 the standard chemotherapy groups was 20.1 and 18.1 months, respectively (p 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 (81.7 months) than in women who received standard chemotherapy (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, respectively; p=0.81). Similarly, median OS was significantly longer in women younger than age 50 years who received HDC (54.6 months) than in women who received standard chemotherapy (36 months; p=0.05), but not in women older than 50 years (49.5 months versus 42 months, respectively; p not reported). The authors recommended further study of HDC with autologous HSCT support in patients younger than 50 years.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in January 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

Practice Guidelines and Policy Statements

National Comprehensive Cancer Network (NCCN) Guidelines

Current NCCN guidelines (v.1.2017) do not address HSCT for ovarian cancer for patients either with newly diagnosed or with relapsed or refractory disease. (2)

Summary of Evidence

For individuals who have advanced-stage epithelial ovarian cancer who receive HSCT, the evidence includes RCTs and data from case series and registries. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment related mortality and morbidity. Although some observational studies have reported longer survival in subsets of women with advanced epithelial ovarian cancer than in women treated with standard chemotherapy, none of the randomized trial evidence has shown a benefit from HSCT in this population. Overall, the evidence has not shown that HSCT improves health outcomes in treating epithelial ovarian cancer, including survival, compared with conventional standard doses of chemotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

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

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

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.

OR

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed or changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. American Cancer Society: Cancer Facts and Figures 2016. Atlanta, GA: American Cancer Society, 2013. Available at <http://www.cancer.org> (accessed on April 17, 2017).

2. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology. Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 1.2017). Available at <http://www.nccn.org> (accessed on April 17, 2017).

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. Sep 20 2007; 25(27):4187-93. PMID 17698804

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 single-institution randomized trial. Bone Marrow Transplant. Mar 2008; 41(6):547-54. PMID 18026148

5. High-Dose Chemotherapy with Autologous Stem-Cell Support for Epithelial Ovarian Cancer. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Assessments. 1998; Volume 13, Tab 6.

6. 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. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (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. Jun 2004; 33(12):1219-24. PMID 15122311

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. May 2001; 12(5):693-9. PMID 11432630

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. Apr 1997; 15(4):1309-17. PMID 9193322

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. Oct 3 2000; 133(7):504-15. PMID 11015163

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. Food and Drug Administration (FDA). Tissue and Tissue Products (December 29, 2016). Available at http://www.fda.gov> (accessed April 14, 2017).

13. Hematopoietic Stem-Cell Support for Epithelial Ovarian Cancer. Chicago Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 January) Therapy 8.01.23.

Policy History:

Date Reason
5/15/2018 Reviewed. No changes.
6/1/2017 Document updated with literature review. Coverage unchanged.
6/1/2016 Reviewed. No changes.
6/1/2015 Document updated with literature review. Coverage unchanged. Title changed from Stem-Cell Transplant for Epithelial Ovarian Cancer.
12/1/2014 Document updated with literature review. Coverage language modified, without change to coverage position.
10/15/2013 Document updated with literature review. The following was added: 1) Donor leukocyte infusion and hematopoietic progenitor cell boost are considered experimental, investigational and 2) Any related services for the treatment of epithelial ovarian cancer, such as short tandem repeat (STR) markers are considered experimental, investigational and unproven. . Otherwise, coverage unchanged. Description and Rationale significantly revised.
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 remains experimental, investigational and unproved when used to treat epithelial ovarian cancer. [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.

Archived Document(s):

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