MEDICAL POLICY

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RATIONALE
REFERENCES
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APPENDIX
HISTORY

Hematopoietic Stem-Cell Transplantation for Epithelial Ovarian Cancer

Number 8.01.23

Effective Date January 28, 2015

Revision Date(s) 01/13/15; 01/13/14; 01/14/12; 01/06/12; 01/11/11; 01/12/10; 02/10/09; 04/08/08; 03/13/07; 01/10/06; 12/14/04; 08/12/03; 05/13/03; 02/26/01; 02/01/00

Replaces N/A

Policy

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

Related Policies

7.01.50

Placental and Umbilical Cord Blood as a Source of Stem-Cells

Policy Guidelines

N/A

Description

Use of hematopoietic stem-cell transplantation (HSCT) 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.

HSCT

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 radiotherapy. 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. Cord blood is discussed in greater detail in a separate medical policy. (see Related Policies)

HSCT is an established treatment for certain hematologic malignancies; however, its use in solid tumors in adults is largely experimental. Initial enthusiasm for the use of autologous transplantation with the use of HDC 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 determinants 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 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 between 16- and 21 months and 32 and 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)

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.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

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.

Rationale

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 two 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 included 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 II trials. (7-10) Over the last 20 years, more than 1,000 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 IIIc-IV) 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 two 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 IIb/IIc in 4%, III in 78%, and 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, progression-free survival (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) 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 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 online site ClinicalTrials.gov 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 Guidelines

Although authors of the current NCCN 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

Stem-cell transplantation is not a preventive service.

Medicare National Coverage

The Centers for Medicare and Medicaid Services currently have the following national non-coverage 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).”

References

  1. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, Ga: American Cancer Society; 2014. http://www.cancer.org/research/cancerfactsstatistics/. Accessed October 21, 2014.
  2. National Comprehensive Cancer Network NCCN). Clinical Practice Guidelines in Oncology: ovarian cancer, version 3.2014. http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. 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. PMID
  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. 2008; 41(6):547-554. PMID
  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. PMID
  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. PMID
  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. PMID
  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. PMID
  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. PMID
  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. PMID
  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. http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/5006. Accessed October 21, 2014.

Coding

Codes

Number

Description

CPT

38205

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

 

38206

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

 

38207

Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage

 

38208

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing

 

38209

thawing of previously frozen harvest, with washing

 

38210

Specific cell depletion with harvest, T cell depletion

 

38211

Tumor cell depletion

 

38212

Red blood cell removal

 

38213

Platelet depletion

 

38214

Plasma (volume) depletion

 

38215

Cell concentration in plasma, mononuclear, or buffy coat layer

 

38220

Bone marrow, aspiration only

 

38221

Bone marrow, Biopsy, needle or trocar

 

38232

Bone marrow harvesting for transplantation; autologous

 

38240

Bone marrow or blood derived peripheral stem cell transplantation; allogeneic

 

38241

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

 

38242

Bone marrow or blood-derived peripheral stem cell transplantation, allogeneic donor lymphocyte infusions

 

86825

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); first serum sample or dilution

 

86826

Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); each additional serum sample or sample dilution (List separately in addition to primary procedure)

ICD-9 Procedure

41.01

Autologous bone marrow transplant without purging

 

41.02

Allogeneic bone marrow transplant with purging

 

41.03

Allogeneic bone marrow transplant without purging

 

41.04

Autologous hematopoietic stem cell transplant without purging

 

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

 

41.91

Aspiration of bone marrow from donor for transplant

 

99.79

Other therapeutic apheresis (includes harvest of stem cells)

ICD-10-PCS
(effective 10/01/15)

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

HCPCS

S2140

Cord blood harvesting for transplantation, allogeneic

 

S2142

Cord blood derived stem cell transplantation, allogeneic

 

S2150

Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications including pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

Type of Service

Therapy

 

Place of Service

Inpatient
Outpatient

 

Appendix

N/A

History

Date

Reason

02/01/00

Add to Therapy Section - New Policy — replaces 8.01.15, original master policy on HDC for miscellaneous malignancies. However, policy statement is unchanged.

02/26/01

Replace Policy - Policy revised no criteria changes.

05/13/03

Replace Policy - Policy updated, references added; no change in policy statement. CPT codes updated.

08/12/03

Replace Policy - Reviewed and recommended for adoption without any changes by Company Oncology Advisory Panel 7/22/03

12/14/04

Replace Policy - Policy reviewed with literature search; references added. Policy statement unchanged.

01/10/06

Replace Policy - Policy reviewed with literature search; NCI and NCCN information updated; no change to policy statement. Reviewed by OAP 04/21/05.

06/02/06

Disclaimer and Scope updates - No other changes.

03/13/07

Replace Policy - Policy updated with literature review; policy statement unchanged. Reviewed and recommended by OAP February 22, 2007.

10/9/07

Cross References Updated - No other changes.

04/08/08

Replace Policy - Policy updated with literature search; no change to the policy statement. Reviewed and recommended for adoption by the Oncology Advisory Panel, February 21, 2008.

05/13/08

Cross Reference Update - No other changes

02/10/09

Replace Policy - Policy updated with literature search; no change to the policy statement. Rational section extensively revised. HDC removed from title and reflected on the body of the policy. References added.

01/12/10

Replace Policy - Policy updated with literature search. Minor addition to the policy statement “hematopoietic” added; no other changes.

02/09/10

Code Update - New 2010 codes added.

01/11/11

Replace Policy - Policy updated with literature review; references 1 and 11 updated. No change in policy statement. Reviewed and recommended for adoption by Oncology Advisory Panel, May 20, 2010.

12/6/11

Related Policy Titles Updated.

01/06/12

Replace Policy – Policy updated with literature review; no new references added; no change in policy statement. ICD-10 codes added to policy.

01/24/12

Code 38232 added.

02/10/12

The CPT code 38204 was removed from the policy.

06/20/12

Minor update: Related Policies updated; 8.01.17 replaced 8.01.507 effective June 12, 2012.

07/31/12

Updates to Related Policy titles: 8.01.17, 8.01.30, 8.01.31, 8.01.35, and 8.01.520. Removed 8.01.38 as it was archived.

10/08/12

Update Coding Section – ICD-10 codes are now effective 10/01/2014.

01/29/13

Replace policy. Policy updated with literature review; no new references added; no change in policy statement. Codes 38220 and 38221 removed; they do not apply to this policy. Change title to 8.01.21 in Related Policies section.

03/20/13

The following codes were removed from the policy, as they were not suspending and just informational: HCPCS J9000-J9999 and Q0083 – Q0085.

09/30/13

Update Related Policies. Change title to 8.01.31.

10/18/13

Update Related Policies. Change title to 8.01.17.

01/21/14

Replace policy. Policy updated with literature review through August 2013. Reference 11 added; references 1, 2, and 12 updated. No change in policy statement.

03/21/14

Update Related Policies. Delete 8.01.514.

04/18/14

Update Related Policies. Remove 8.01.20, 8.01.35 and 8.01.54, then add 8.01.529, 8.01.531 and 8.01.532.

12/03/14

Update Related Policies. Remove 8.01.17.

01/28/15

Annual Review. Policy updated with literature review through October 20, 2014; no new references added; references 1-2 and 12 updated. No change in policy statement. ICD-9 and ICD-10 diagnosis codes removed; these are not utilized in policy adjudication.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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