Description
The use of hematopoietic cell transplantation (HCT) has been investigated for treatment of patients with epithelial ovarian cancer. Hematopoietic stem cells are infused to restore bone marrow function after cytotoxic doses of chemotherapeutic agents with or without whole body radiotherapy.

For individuals who have advanced-stage epithelial ovarian cancer who receive HCT, the evidence includes randomized trials and data from case series and registries. Relevant outcomes are overall survival, 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 HCT in this population. Overall, the evidence has not shown that HCT 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. 

Background 
Epithelial Ovarian Cancer
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 2017 were estimated at 22,440 and 14,080, respectively.¹ 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 2013.²

Treatment
Current management for advanced epithelial ovarian cancer is cytoreductive surgery with chemotherapy.³ 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 the newly diagnosed advanced disease.^4,5 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.⁴ However, cancer recurs in most women, and they die of the disease because chemotherapy drug resistance leads to uncontrolled cancer growth.⁵

Hematopoietic Cell Transplantation
HCT is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs with or without whole body radiotherapy. Bone marrow stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT). 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 “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood transplantation is discussed in detail in evidence review 70150.

HCT is an established treatment for certain hematologic malignancies; however, its use in solid tumors in adults is largely experimental.    

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

Related Policies
80135 Hematopoietic Cell Transplantation in the Treatment of Germ-Cell Tumors
80124 Hematopoietic Cell Transplantation for Miscellaneous Solid Tumors in Adults

Policy
Autologous and allogeneic hematopoietic cell transplantation are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY to treat epithelial ovarian cancer.

Policy Guidelines
Stem cell transplantation to treat germ cell tumors of the ovary is considered separately in evidence review 80135.

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.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Hematopoietic Cell Transplantation for Epithelial Ovarian Cancer
Clinical Context and Therapy Purpose
The purpose of autologous or allogeneic stem cell transplantation in patients who have epithelial ovarian cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does autologous or allogeneic stem cell transplantation used as part of the treatment of ovarian cancer improve net health outcomes?

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest are patients with advanced epithelial ovarian cancer who have undergone debulking surgery and first-line chemotherapy.

Interventions
The therapy being considered is autologous or allogeneic stem cell transplantation. HCT has been investigated as a therapy to overcome drug resistance. HCT 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.

Comparators
The following practices are currently being used to make decisions about the treatment of advanced epithelial ovarian cancer: guideline-based clinical pathways for debulking surgery and platinum-based chemotherapy.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival, change in disease status, treatment-related mortality.

This evidence review was informed by a 1998 TEC Assessment that reached the following conclusions:⁵

Data were unavailable from RCTs 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 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 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 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 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 included in studies of high-dose or conventional chemotherapies.

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

Experience with HCT in epithelial ovarian cancer is primarily derived from registry data and phase 2 trials.^7,8,9,10 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 HCT.

Review of Evidence
Randomized Controlled Trials
Mobus et al. (2007) reported on a 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 treatments. The trial 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 αof 5%. Median patient age was 50 years (range, 20 – 65 years) and International Federation of Gynecology and Obstetrics 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, 0.84; 95% confidence interval, 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 (hazard ratio, 1.17; 95% confidence interval, 0.71 to 1.94; p = 0.54).

Papadimitriou et al. (2008) reported on an RCT comparing the use of HDC with stem cell support as consolidation therapy in patients with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stage IIC-IV).⁴ Patients who achieved first complete remission after conventional chemotherapy were randomized to receive or not, high-dose melphalan and autologous HCT. 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 arms in time-to-disease progression (p = 0.059) or OS (p = 0.38).

Observational Comparative Studies
Sabatier et al. (2012) retrospectively reviewed 163 patients with advanced or metastatic (International Federation of Gynecology and Obstetrics 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 among 60 patients who received subsequent HDC with autologous HCT 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 months and 18.1 months, respectively (p not reported). OS was 47.3 months 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 vs 42 months, respectively; p not reported). The authors recommended further study of HDC with autologous HCT support in patients younger than 50 years.

Summary of Evidence
For individuals who have advanced-stage epithelial ovarian cancer who receive HCT, the evidence includes randomized trials and data from case series and registries. Relevant outcomes are overall survival, 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 HCT in this population. Overall, the evidence has not shown that HCT improves health outcomes in treating epithelial ovarian cancer, including survival, compared with conventional standard doses of chemotherapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (NCCN) guidelines on ovarian cancer including fallopian tube cancer and primary peritoneal cancer (v. 3.2021) do not address hematopoietic cell transplantation (HCT) for epithelial ovarian cancer for patients either with newly diagnosed or with relapsed or refractory disease.¹²

Accordingly, NCCN guidelines on HCT (5.2021) do not reference epithelial ovarian cancer as an indication for HCT.¹³

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in November 2021 did not identify any ongoing or unpublished trials that would likely influence this review.

References 

1. American Cancer Society. Cancer Facts & Figures 2021. Atlanta, GA: American Cancer Society; 2021. http://www.cancer.org/research/cancerfactsstatistics/. Accessed November 22, 2021.
2. National Cancer Institute, Surveillance Epidemiology and End Results Program. Cancer Stat Facts: Ovarian Cancer. n.d.; https://seer.cancer.gov/statfacts/html/ovary.html. Accessed November 22, 2021.
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 18026149
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. 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 03 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. Oct 16 2012; 31: 87. PMID 23072336
12. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 3.2021. https://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed November 22, 2021.
13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hematopoietic Cell Transplantation (HCT): Pre-Transplant Recipient Evaluation and Management of Graft-Versus-Host Disease. Version 5.2021. https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf. Accessed November 22, 2021
14. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation (110.23, formerly 110.8.1). 2016: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=366. Accessed November 22, 2021.

Coding Section

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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