Pending Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Miscellaneous Solid Tumors in Adults

Number:SUR703.035

Effective Date:05-15-2018

Coverage:

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

Autologous or allogeneic hematopoietic stem-cell transplant is considered experimental, investigational and/or unproven for miscellaneous solid tumors in adults, including but not limited to the following malignancies:

Bile duct cancer,

Cervical cancer,

Colon cancer,

Esophageal cancer,

Fallopian tube(s) cancer,

Gallbladder cancer,

Lung cancer, any histology,

Malignant melanoma.

Nasopharyngeal cancer,

Neuroendocrine tumors,

Pancreas cancer,

Paranasal sinus cancer,

Prostate cancer,

Rectal cancer,

Renal cell cancer,

Soft tissue sarcomas,

Stomach cancer,

Thyroid tumors,

Tumors of the thymus,

Tumors of unknown primary origin,

Uterine cancer.

NOTE 1: For stem-cell transplantation to treat germ-cell tumors of the ovary see Medical Policy SUR703.045, “Hematopoietic Stem-Cell Transplantation in the Treatment of 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

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. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT; auto-HSCT) or from a donor (allogeneic HSCT; allo-HSCT). They can be harvested from bone marrow, peripheral blood, or from umbilical cord blood 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).

Immunologic compatibility between infused stem-cells and the recipient is not an issue in auto- HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allo-HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the Class I and Class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Background

HSCT is an established treatment for certain hematologic malignancies. Its use in solid tumors is less well established, although it has been investigated for a variety of solid tumors. With the advent of nonmyeloablative 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. (1)

Miscellaneous Solid Tumors in Adults

HSCT as a treatment for breast cancer, ovarian cancer, germ cell tumors, ependymoma, or malignant glioma is addressed in separate policies. This policy collectively addresses other solid tumors of adults for which HSCT has been investigated, including lung cancer, malignant melanoma, tumors of the gastrointestinal tract (affecting the colon, rectum, pancreas, stomach, esophagus, gallbladder, or bile duct), male and female genitourinary systems (e.g., renal cell carcinoma, prostate cancer, cervical cancer, uterine cancer, fallopian tube cancer), tumors of the head and neck, soft tissue sarcoma, thyroid tumors, tumors of the thymus, and tumors of unknown primary origin.

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. (2) 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 a 1995 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment. The most recent literature review was performed through March 28, 2018. The following is a summary of the key literature to date.

The medical policy assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are 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 to 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 a technology, 2 domains are examined: the relevance and the 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.

This policy was initially based on a 1995 BCBSA TEC Assessment that focused on adult solid tumors other than breast cancer, epithelial ovarian cancer, germ cell tumors, and glial cell?derived brain cancers. (3) Literature on solid tumors identified in the BCBSA TEC Assessment included lung cancers, melanoma, tumors of gastrointestinal organs, genitourinary system tumors, tumors of the head and neck, soft tissue sarcomas of the extremities and torso, thyroid tumors, tumors of the thymus, undifferentiated tumors, and tumors of unknown primary. The BCBSA TEC Assessment offered the following conclusions:

While 125 articles were identified that reported on the results of autologous hematopoietic stem-cell transplantation (HSCT; auto-HSCT) in a variety of solid tumors, only 17 included survival data from groups of patients with the same cancer. These studies reported on 4 indications: advanced small cell lung cancer (SCLC), advanced colorectal cancer, malignant melanomas, and inoperable gastric cancer.

The evidence did not permit conclusions on the effect of auto-HSCT on patient survival.

A 1999 BCBSA TEC Assessment evaluated the use of allogeneic HSCT (allo-HSCT) as a salvage therapy after a failed auto-HSCT for solid tumors. (4) The evidence was inadequate to permit conclusions.

Auto-HSCT in Solid Tumors of Adults

The evidence on the use of auto-HSCT for the solid tumors of adults addressed in this policy consists primarily of small series.

Adult Soft Tissue Sarcomas

The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a median survival of 1-year and a 5-year survival estimate of less than 10%. (5) A variety of single-agent and combination regimens are used for treatment, with targeted therapies available for some subtypes. (6) Based on initial observations that patients who achieved complete remission (CR) had longer survival, several phase 1 and 2 trials using auto-HSCT were conducted in the 1990s in an attempt to improve outcomes. (5) These trials were composed of small numbers of patients (range, 2-55 patients), yielding overall response rates (ORRs) from 20% to 65%, with CR ranging from 10% to 43%. The longest reported 5-year progression-free survival (PFS) rate was 21%, and 5-year overall survival (OS) rate was 32%. (5) One study (2007) of 21 patients with soft tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease prior to HSCT. (7) In another phase 2 study (2006), 21 (38%) of 55 patients responded to doxorubicin-based induction chemotherapy, but estimated OS did not differ statistically between those who did (14%) and did not (3%) receive an auto-HSCT (p=0.003). (8)

In 2017, a Cochrane systematic review evaluated the use of auto-HSCT following high-dose chemotherapy (HDC) for non-rhabdomyosarcoma soft tissue sarcomas. (9) One RCT (2012) assessing 83 patients was identified. (10) In the RCT, OS did not differ statistically between auto-HSCT following HDC and standard-dose chemotherapy (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.70 to 2.29; p=0.44), and the point estimate for survival at 3 years was 32.7% compared with 49.4%. In 2014, Peinemann and Labeit conducted another systematic review that included an RCT (described above) and 61 single-arm studies. (11) The pooled treatment-related mortality rate across 61 single-arm studies was 15 (5.1%) of 294.

A small number of studies not included in the Cochrane review have described outcomes after HSCT for soft tissue sarcoma. Kasper et al. (2010) reported the results of a prospective, single-institution phase 2 study that enrolled 34 patients with advanced and/or metastatic soft tissue sarcoma. (12) After 4 courses of chemotherapy, 9 patients with at least a partial response underwent HDC and auto-HSCT. All other patients continued chemotherapy for 2 more cycles. Median PFS for patients treated with HSCT was 11.6 months (range, 8-15 months) and 5.6 months for patients treated with standard chemotherapy (p=0.047); median OS for the 2 groups was 23.7 months (range, 12-34 months) and 10.8 months (range 0-39 months; p=0.027), respectively.

Hartmann et al. (2013) reported on results from a phase 2 study of HDC with ifosfamide, carboplatin, and etoposide followed by peripheral blood stem-cell transplantation in patients with grade 2 or 3 histologically proven soft tissue sarcoma considered unresectable or marginally resectable. (13) After a median follow-up of 50 months (range, 26-120 months) in surviving patients, median PFS for all patients was 21 months (range, 1-94 months) and median OS was 37 months (range, 3-120 months), corresponding to 5-year PFS and OS rates of 39% and 48%, respectively.

A 2014 case report on the use of auto-HSCT for treatment of an adult histiocytic sarcoma was identified, in which the patient was alive with no evidence of disease 30 months posttreatment. (14)

Section Summary: Adult Soft Tissue Sarcomas

Overall, 1 RCT and several small phase 2 studies have reported outcomes after auto-HSCT in adults with soft tissue sarcoma. Although 1 small phase 2 study reported longer survival for patients treated with HSCT than with standard chemotherapy, the available RCT did not show a survival benefit with auto-HSCT.

Small-Cell Lung Carcinoma (SCLC)

The interest in treating SCLC with auto-HSCT stems from the extremely high chemosensitivity and poor prognosis of this tumor type. A phase 3 trial (2005) randomized 318 patients with SCLC to standard chemotherapy or to HSCT. (15) No statistically significant difference in response rates was seen between the 2 groups (response rate, 80% in standard arm group versus 88% in HSCT group; difference, 8%; 95% CI, -1% to 17%; p=0.09). There was no statistically significant difference in OS between groups, with a median OS of 13.9 months in the standard arm (95% CI, 12.1 to 15.7 months) and 14.4 months in the HSCT arm (95% CI, 13.1 to 15.4 months; p=0.76). One smaller, randomized study and several single-arm studies of HSCT and auto-HSCT for SCLC are summarized in a 2007 review article. (16) Overall, most of the data from these studies, including the randomized study, showed no increased in OS with auto-HSCT.

Jiang et al. (2009) performed a meta-analysis of English-language studies through October 2008 using intensified chemotherapy with autologous hematopoietic progenitors to treat SCLC. (17) The meta-analysis consisted of 5 RCTs (3 phase 3 trials, 2 phase 2), with a total of 641 patients. Reviewers found no significant increase in the odds ratio for response rate with autologous transplant versus control chemotherapy (odds ratio, 1.29; 95% CI, 0.87 to 1.93; p=0.206). No statistically significant increase in OS was seen among the autologous transplant patients compared with control regimens (HR=0.94; 95% CI, 0.80 to 1.10; p=0.432). Reviewers concluded that current evidence did not support the use of intensified chemotherapy and autologous HSCT for treating SCLC.

Section Summary: SCLC

Treatment of SCLC with auto-HSCT has been studied in a meta-analysis, RCTs, and small series. None of these studies showed a survival benefit with auto-HSCT.

Other Tumors

Uncontrolled pilot studies of auto-HSCT for patients with refractory urothelial carcinoma (18) and recurrent or advanced nasopharyngeal carcinoma (19) have not demonstrated adequate evidence of improved outcomes to alter previous conclusions. In a 2014 small series (n=8) of bilateral retinoblastoma survivors with secondary osteosarcoma, 2 patients (of 7 treated with multimodal chemotherapy) received HDC with autologous peripheral blood stem-cell support. (20) The 2 HSCT-treated patients were alive with no evidence of disease at 33.4 and 56.4 months of follow-up.

Allo-HSCT in Solid Tumors of Adults

The evidence base for the treatment of patients with types of solid tumors using allo-HSCT consists of single-case reports and small series. (1, 22, 23)

Renal-Cell Carcinoma (RCC)

Metastatic RCC has an extremely poor prognosis, with a median survival of less than 1 year and a 5-year survival of less than 5%. (23) RCC is relatively resistant to chemotherapy but is susceptible to immune therapy, and interleukin-2 and/or interferon-α have induced responses and long-term PFS rates of in 4% to 15% of patients. (22) In addition, 7 targeted therapies are approved by the U.S. Food and Drug Administration (FDA) for treatment of advanced RCC: sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, everolimus, and bevacizumab. (24) Based on the susceptibility of RCC to immune therapies, the immune-based strategy of a graft-versus-tumor effect possible with an allogeneic transplant has led to an interest in its use in RCC. In 2000, Childs et al. published on the first series of patients with RCC treated with nonmyeloablative allo-HSCT. (23) The investigators showed tumor regression in 10 (53%) of 19 patients with cytokine-refractory, metastatic RCC who received a human leukocyte antigen (HLA)-identical sibling allo-HSCT. Three patients had a CR and remained in remission 16, 25, and 27 months after transplant. Four of 7 patients with a partial response were alive without disease progression 9 to 19 months after transplantation. Other pilot trials have demonstrated the graft-versus-tumor effect of allo-HSCT in metastatic RCC, but most have not shown as high a response rate as the Childs study. ORRs in these pilot trials have been approximately 25%, with CR rates of approximately 8%. (21) Prospective, randomized trials are needed to assess the net impact of this technique on the survival of patients with cytokine-refractory RCC. (21)

Bregni et al. (2009) assessed the long-term benefit of allografting in 25 patients with cytokine-refractory metastatic RCC who received reduced-intensity conditioning (RIC) with allo-HSCT from a sibling who was HLA-identical. (25) All patients received the same conditioning regimens. Response to allograft was available in 24 patients, with a CR in 1 patient and partial response in 4 patients. Twelve patients had a minor response or stable disease, and 7 had progressive disease. ORR (complete plus partial) was 20%. Six patients died because of transplant-related mortality. Median survival was 336 days (range, 12-2332+ days). The 1-year OS rate was 48% (95% CI, 28% to 68%) and the 5-year OS rate was 20% (95% CI, 4% to 36%). The authors concluded that allografting can induce long-term disease control in a small fraction of cytokine-resistant patients with RCC but that with the availability of novel targeted therapies for RCC, future treatment strategies should consider incorporating these therapies into the transplant regimen.

Section Summary: Allo-HSCT in RCC

Evidence on use of allo-HSCT for RCC is based on a BCBSA TEC Assessment and multiple case series. The BCBSA TEC Assessments found that HSCTs did not meet the criteria for treatment of RCC or other solid tumors. In absence of RCTs, current evidence is insufficient to conclude whether allo-HSCT results in improved OS among RCC patients.

Colorectal Cancer (CRC)

Aglietta et al. (2009) reported on their experience with 39 patients with metastatic CRC who underwent RIC allo-HSCT between 1999 and 2004 at 9 European Group for Blood and Marrow Transplantation (EBMT) centers. (26) Patients were treated with 1 of 5 RIC regimens. End points assessed were achievement of mixed chimerism, incidence of graft-versus-host disease (GVHD), treatment-related mortality, and toxicities, OS, and time to treatment failure (in patients who responded to the therapy). Patient population characteristics were heterogeneous; pre-transplant disease status was partial response in 2 patients, stable disease in 6 patients, and progressive disease in 31. Thirty-eight (97%) patients had had previous treatment, some with only chemotherapy and others with surgery, chemotherapy, or both. After transplant, tumor responses were complete and partial in 2% and 18% of patients, respectively, and 26% of patients had stable disease, for overall disease control in 46% of patients. Transplant-related mortality was 10%. Median overall follow-up was 202 days (range, 6-1020 days), after which time 33 patients had died and 6 were still alive. Tumor progression was the cause of death in 74% of patients. An assessment of OS of patients was performed after stratifying by potential prognostic factors. Achievement of response after transplantation was associated with a difference in OS, with the 18 patients who had a response having a median OS of approximately 400 days versus approximately 120 days for those who had no response (p<0.001). The authors concluded that the allo-HSCT approach should be reserved for patients with a partial response or stable disease after second-line therapy for metastatic CRC and that second-generation clinical trials in these patients would be warranted.

Section Summary: Allo-HSCT in CRC

Evidence on use of allo-HSCT for CRC is based on a BCBSA TEC Assessment and a case series. The BCBSA TEC Assessment concluded that allo-HSCT did not meet the criteria for treatment of solid tumors. In absence of RCTs, current evidence is insufficient to conclude whether allo-HSCT improves OS among colorectal carcinoma patients.

Pancreatic Cancer

Kanda et al. (2008) reported on the efficacy of RIC allo-HSCT for advanced pancreatic cancer in 22 patients from 3 transplantation centers in Japan. (27) RIC regimens differed across centers, and the patient population was fairly heterogeneous, with 15 patients having metastatic disease and 7 having locally advanced disease. All but 1 patient received chemotherapy of various combinations before transplant, and 10 patients received localized radiotherapy. After allo-HSCT, 1 patient achieved CR, 2 had partial response, 2 had minor response, and 8 had stable disease, with an ORR of 23%. Median survival was 139 days, and the major cause of death was tumor progression (median duration of survival in advanced pancreatic cancer in the non-transplant setting is less than 6 months, even in patients treated with gemcitabine). Only 1 patient survived longer than 1 year after transplantation. The authors concluded that a tumor response was observed in 25% of patients with advanced pancreatic cancer who underwent allo-HSCT and that the response was not durable. However, based on their observation of a relation between longer survival and the infusion of a higher number of CD34-positive cells or the development of chronic GVHD, they recommended additional study to evaluate the immunologic effect on pancreatic cancer.

Abe et al. (2009) reported on outcomes for 5 patients with chemotherapy-resistant, unresectable pancreatic adenocarcinoma who received a nonmyeloablative conditioning with allo-HSCT. (28) Median age was 54 years (range, 44-62 years). All patients had advanced disease, either with metastases or peritonitis, and had received at least 1 course of chemotherapy including gemcitabine. After allo-HSCT, tumor response was only observed in 2 patients (1 had complete disappearance of the primary tumor and the other had a 20% reduction in tumor size); the remaining patients had progressive disease (n=2) or stable disease (n=1). Four patients died of progressive disease (median, 96 days; range, 28-209 days post-transplant). One patient died at day 57 secondary to rupture of the common bile duct from rapid tumor regression. The authors concluded that findings showed a graft-versus-tumor effect, but, to obtain durable responses, an improved conditioning regimen and new strategies to control tumor growth after nonmyeloablative allo-HSCT would be needed.

Omazic et al. (2017) reported on outcomes for 2 patients who received allo-HSCT from HLA-identical sibling donors following resection of pancreatic ductal adenocarcinoma. (29) These patients were compared with 6 controls who underwent radical surgery for pancreatic ductal adenocarcinoma but did not receive HSCT. Both patients receiving HSCT were tumor free after 9 years following diagnosis, whereas all the patients in the control group died within 4 years of diagnosis.

Section Summary: Allo-HSCT in Pancreatic Cancer

Evidence on use of allo-HSCT for pancreatic cancer is based on a BCBSA TEC Assessment, multiple case series, and a small comparative study. The BCBSA TEC Assessment concluded that allo-HSCT did not meet the criteria for treatment of solid tumors. In absence of RCTs, current evidence is insufficient to conclude whether allo-HSCT improves OS among pancreatic cancer patients.

Nasopharyngeal Cancer

Toh et al. (2011) reported on outcomes of a phase 2 trial of 21 patients with pretreated metastatic nasopharyngeal cancer. (30) Median patient age was 48 years (range, 34-57 years), and patients had received a median of 2 previous chemotherapy regimens (range, 1-8 regimens). All patients had extensive metastases. Patients underwent a nonmyeloablative allo-HSCT with sibling allografts. Seven (33%) patients showed a partial response and 3 (14%) achieved stable disease. Four patients were alive at 2 years, and 3 showed prolonged disease control of 344, 525, and 550 days. After a median follow-up of 209 days (range, 4-1147 days), the median PFS was 100 days (95% CI, 66 to 128 days) and the median OS was 209 days (95% CI, 128 to 236 days). One- and 2-year OS rates were 29% and 19%, respectively, comparable to the median 7- to 14-month OS rates reported in the literature for metastatic nasopharyngeal patients treated with salvage chemotherapy without HSCT.

Section Summary: Allo-HSCT in Nasopharyngeal Cancer

Evidence on use of allo-HSCT for nasopharyngeal cancer is based on a BCBSA TEC Assessment and a phase 2 trial. The BCBSA TEC Assessment concluded that allo-HSCT did not meet the criteria for treatment of solid tumors. In absence of RCTs, current evidence is insufficient to conclude whether allo-HSCT improves OS among nasopharyngeal cancer patients.

Mixed Tumor Types

In 2016, Omazic et al. reported on long-term follow-up for 61 patients with a variety of solid tumor types considered incurable with conventional therapies who were treated with allo-HSCT from 1999 to 2012. (31) Tumors included metastatic renal carcinoma (n=22), cholangiocarcinoma (n=17), colon cancer (n=15), prostate cancer (n=3), pancreatic adenocarcinoma (n=3), and breast cancer (n=1). Most patients (n=59) had undergone surgical debulking of the primary tumor, and 31 patients had previously undergone additional therapy with cytotoxic chemotherapy, radiotherapy, or immunotherapy. Conditioning was myeloablative in 23 patients, RIC in 36 patients, and nonmyeloablative in 2 patients. Over a median follow-up of 8 years, OS rates at 5 and 10 years were 15% and 9%, respectively.

Ongoing and Unpublished Clinical Trials: Autologous and Allogeneic HSCT in Solid Tumors of Adults

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT03236883

Phase I Study of Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Pancreatic Cancer

30

Apr 2019

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements: Autologous and Allogeneic HSCT in Solid Tumors of Adults

National Comprehensive Cancer Network (NCCN) Guidelines

Current NCCN guidelines (2017-2018) on the tumors addressed in this policy do not discuss HSCT as a treatment option. (24, 32)

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015, the ASBMT issued guidelines related to indications for auto- and allo-HSCT. (33) The tumors addressed herein for which the Society has provided recommendations are listed in Table 2.

Table 2. Recommendations for Use of Auto- and Allo-HSCT

Condition

Treatment Option

Recommendation

Ewing sarcoma, high risk

Allo-HSCT

Not generally recommended

Auto-HSCT

Standard of care, clinical evidence available

Renal cancer, metastatic

Allo-HSCT

Developmental

Auto-HSCT

Not generally recommended

Table Key:

Allo: allogeneic;

Auto: autologous;

HSCT: hematopoietic stem-cell transplantation.

Summary of Evidence: Autologous- (Auto-) and Allogeneic- (Allo-) Hematopoietic Stem-Cell Transplantation (HSCT) in Solid Tumors of Adults

Auto-HSCT

For individuals who have adult soft tissue sarcomas who receive auto-HSCT, the evidence includes 2 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments, a randomized controlled trial (RCT), and a number of phase 2 single-arm studies, some of which have been summarized in a systematic review. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related morbidity and mortality. The 1995 and 1999 BCBSA TEC Assessments, focusing on auto-HSCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of HSCT on patient survival. Although a small phase 2 RCT reported longer survival for patients treated with auto-HSCT than with standard chemotherapy, this trial did not show a survival benefit with HSCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have small cell lung cancer (SCLC) who receive auto-HSCT, the evidence includes 2 BCBSA TEC Assessments, several RCTs, and systematic reviews of these studies. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity and mortality. The 1995 and 1999 BCBSA TEC Assessments, focusing on auto-HSCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of HSCT on patient survival. Studies published since the BCBSA TEC Assessments have not reported increased OS for patients with SCLC treated with auto-HSCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

Allo-HSCT

For individuals who have renal cell carcinoma (RCC), colorectal cancer (CRC), pancreatic cancer, or nasopharyngeal cancer who receive allo-HSCT, the evidence includes a BCBSA TEC Assessment and small single-arm series. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity and mortality. The 1995 and 1999 BCBSA TEC Assessments, focusing on allo-HSCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of allo-HSCT on patient survival. Since the publication of the BCBSA TEC Assessments, the evidence for allo-HSCT to treat RCC, CRC, pancreatic cancer, and nasopharyngeal cancer has been limited to small case series. 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 versus. 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 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 since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Carnevale-Schianca F, Ricchiardi A, Capaldi A, et al. Allogeneic hemopoietic stem cell transplantation in solid tumors. Transplant Proc. Jul-Aug 2005; 37(6):2664-6. PMID 16182778

2. FDA – Tissue and Tissue Products (Parts 1270 and 1271) (February 23, 2016). Food and Drug Administration – Center for Biologics Evaluation and Research. Available at <http://www.fda.gov> (accessed on April 12, 2016).

3. High-Dose Chemotherapy with Autologous Stem-Cell Support for Miscellaneous Solid Tumors in Adults. Chicago, Illinois: Blue Cross and Blue Shield Association - Technology Evaluation Center (TEC) Assessments 1995; Volume 10, Tab 4.

4. Salvage HDC/AlloSCS for Relapse Following HDC/AuSCS for Non-Lymphoid Solid Tumors. Chicago, Illinois: Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) Assessments 1999; Volume 14, Tab 11.

5. Pedrazzoli P, Ledermann JA, Lotz JP, et al. High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. Ann Oncol. Oct 17 2006; 17(10):1479- 88. PMID 16547069

6. NCCN – Soft Tissue Sarcoma (Version 2.2018). National Comprehensive Cancer Network Practice Guidelines. Available at <http://www.nccn.org> (accessed on March 28, 2018).

7. Kasper B, Dietrich S, Mechtersheimer G, et al. Large institutional experience with dose-intensive chemotherapy and stem cell support in the management of sarcoma patients. Oncology. 2007; 73(1- 2):58-64. PMID 18334832

8. Schlemmer M, Wendtner CM, Falk M, et al. Efficacy of consolidation high-dose chemotherapy with ifosfamide, carboplatin and etoposide (HD-ICE) followed by autologous peripheral blood stem cell rescue in chemosensitive patients with metastatic soft tissue sarcomas. Oncology. 2006; 71(1-2):32- 9. PMID 17344669

9. Peinemann F, Enk H, Smith LA. Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for nonrhabdomyosarcoma soft tissue sarcomas. Cochrane Database Syst Rev. Apr 13 2017; 4:CD008216. PMID 28407197

10. Bui-Nguyen B, Ray-Coquard I, Chevreau C, et al. High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial. Ann Oncol. Mar 2012; 23(3):777-784. PMID 21652583

11. Peinemann F, Labeit AM. Autologous haematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas: a Cochrane systematic review. BMJ Open. 2014; 4(7):e005033. PMID 25079925

12. Kasper B, Scharrenbroich I, Schmitt T, et al. Consolidation with high-dose chemotherapy and stem cell support for responding patients with metastatic soft tissue sarcomas: prospective, single- institutional phase II study. Bone Marrow Transplant. Jul 2010; 45(7):1234-8. PMID 19935728

13. Hartmann JT, Horger M, Kluba T, et al. A non-comparative phase II study of dose intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult type soft tissue sarcomas. Invest New Drugs. Dec 2013; 31(6):1592-601. PMID 24091981

14. Tsujimura H, Miyaki T, Yamada S, et al. Successful treatment of histiocytic sarcoma with induction chemotherapy consisting of dose-escalated CHOP plus etoposide and upfront consolidation auto-transplantation. Int J Hematol. Nov 2014; 100(5):507-10. PMID 25062797

15. Lorigan P, Woll PJ, O’Brien ME, et al. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst. May 4 2005; 97(9):666-74. PMID 15870437

16. Crivellari G, Monfardini S, Stragliotto S, et al. Increasing chemotherapy in small-cell lung cancer: from dose intensity and density to megadoses. Oncologist. Jan 2007; 112(1):79-89. PMID 17227903

17. Jiang J, Shi HZ, Deng JM, et al. Efficacy of intensified chemotherapy with hematopoietic progenitors in small-cell lung cancer: a meta-analysis of the published literature. Lung Cancer. Aug 2009; 65(2):214-8. PMID 19118919

18. Nishimura M, Nasu K, Ohta H, et al. High dose chemotherapy for refractory urothelial carcinoma supported by peripheral blood stem cell transplantation. Cancer. Nov 1 1999; 86(9):1827-31. PMID 10547557

19. Airoldi M, De Crescenzo A, Pedani F, et al. Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma. Head Neck. Sep 2001; 23(9):799- 803. PMID 11505492

20. Lee JA, Choi SY, Kang HJ, et al. Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases. Br J Ophthalmol. Oct 2014; 98(10):1355-9. PMID 24795337

21. Imanguli MM, Childs RW. Hematopoietic stem cell transplantation for solid tumors. Update Cancer Ther. 2006; 1(3):343-52.

22. Demirer T, Barkholt L, Blaise D, et al. Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. Nat Clin Pract Oncol. May 2008; 5(5):256-67. PMID 18398414

23. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal cell carcinoma after nonmyeloablative allogeneic peripheral blood stem cell transplantation. N Engl J Med. Sep 14 2000; 343(11):750-8. PMID 10984562

24. NCCN – Kidney Cancer (Version 3.2018). National Comprehensive Cancer Network Practice Guidelines. Available at <http://www.nccn.org> (accessed on March 28, 2018).

25. Bregni M, Bernardi M, Servida P, et al. Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting. Bone Marrow Transplant. Aug 2009; 44(4):237-42. PMID 19234510

26. Aglietta M, Barkholt L, Schianca FC, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adaptive cell therapy approach. The European Group for Blood and Marrow Transplantation experience. Biol Blood Marrow Transplant. Mar 2009; 15(3):326-35. PMID 19203723

27. Kanda Y, Omuro Y, Baba E, et al. Allo-SCT using reduced-intensity conditioning against advanced pancreatic cancer: a Japanese survey. Bone Marrow Transplant. Jul 2008; 42(2):99-103. PMID 18391987

28. Abe Y, Ito T, Baba E, et al. Nonmyeloablative allogeneic hematopoietic stem cell transplantation as immunotherapy for pancreatic cancer. Pancreas. Oct 2009; 38(7):815-9. PMID 19696692

29. Omazic B, Ayoglu B, Lohr M, et al. A preliminary report: radical surgery and stem cell transplantation for the treatment of patients with pancreatic cancer. J Immunother. Mar 23 2017. PMID 28338506

30. Toh HC, Chia WK, Sun L, et al. Graft-versus-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation. Bone Marrow Transplant. Apr 2011; 46(4):573-9. PMID 20661236

31. Omazic B, Remberger M, Barkholt L, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for solid cancer. Biol Blood Marrow Transplant. Apr 2016; 22(4):676-681. PMID 26740375

32. NCCN – Clinical Practice Guidelines in Oncology, Treatment of Cancer by Site. National Comprehensive Cancer Network Practice Guidelines. Available at: < http://www.nccn.org> (accessed on March 28, 2018).

33. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Bone Blood Marrow Transplant. Nov 2015; 21(11):1863-9. PMID 26256941

34. Hematopoietic Cell Transplantation for Miscellaneous Solid Tumors in Adults. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 January) Therapy: 8.01.24.

Policy History:

Date Reason
5/15/2018 Document updated with literature review. Coverage unchanged. Rationale and references reorganized; references 9, 10, 29, 31 added, none removed.
6/1/2017 Reviewed. No changes.
7/1/2016 Document updated with literature review. Coverage unchanged.
1/1/2015 Document updated with literature review. Coverage language modified, without change to coverage position. CPT/HCPCS code(s) updated. Title changed from: Stem-Cell Transplant for Miscellaneous Solid Tumors in Adults.
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 unproven; and 2) Any related services for the treatment of solid tumors in adults, 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 miscellaneous solid tumors in adults. 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.

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