Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Hematopoietic cell transplantation (HCT) is an established treatment for certain hematologic malignancies and has been investigated for a variety of adult solid tumors. Interest continues in exploring nonmyeloablative allogeneic HCT (allo-HCT) for a graft-versus-tumor effect of donor-derived T-cells in metastatic solid tumors.

Though cancer incidence along with overall mortality has been declining in the United States, certain population groups continue to have an increased risk of cancer progression and mortality due to social, economic, and environmental disadvantages (NCI, 2022). The National Cancer Institute has published statistics on cancer disparities in relation to various criteria including specific racial and ethnic groups, gender, and geography. Some key incidence and mortality statistics in the United States are as follows: incidence rates of lung, colorectal, and cervical cancers are increased in rural Appalachia compared to urban areas; American Indians/Alaska Natives have increased mortality rates from kidney, liver, and intrahepatic bile duct cancer compared to other racial and ethnic groups; Black men are twice as likely to die of prostate cancer than White men.

Hematopoietic Cell Transplantation

Hematopoietic -cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous. HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA A, B, and DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect in of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative.

Hematopoietic Cell Transplantation Solid Tumors in Adults

HCT 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 (Carnevale-Schianca, 2005).

Miscellaneous Solid Tumors in Adults

This policy collectively addresses solid tumors of adults for which SCT has been investigated, including lung cancer; malignant melanoma; tumors of the gastrointestinal tract (include colon, rectum, pancreas, stomach, esophagus, gallbladder, and bile duct); male and female genitourinary systems (e.g., renal cell carcinoma, cervical carcinoma, cancer of the uterus, fallopian tubes, and prostate gland); 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 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 (USFDA, 2015). Hematopoietic stem cells are included in these regulations.

Effective April 15, 2023

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:

· Lung cancer, any histology

· Pancreatic cancer

· Esophageal cancer

· Gall bladder cancer

· Cancer of the bile duct

· Renal cell carcinoma

· Cancer of the fallopian tubes

· Nasopharyngeal cancer

· Paranasal sinus cancer

· Neuroendocrine tumors

· Soft tissue sarcomas

· Tumors of the thymus

· Tumors of unknown primary origin

· Malignant melanoma. .

For contracts without primary coverage criteria language, high dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies is considered investigational for:

· Lung cancer, any histology

· Pancreatic cancer

· Esophageal cancer

· Gall bladder cancer

· Cancer of the bile duct

· Renal cell carcinoma

· Cancer of the fallopian tubes

· Nasopharyngeal cancer

· Paranasal sinus cancer

· Neuroendocrine tumors

· Soft tissue sarcomas

· Tumors of the thymus

· Tumors of unknown primary origin

· Malignant melanoma.

Investigational services are an exclusion in the member certificate of coverage.

Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective March 2021 through April 14, 2023

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Investigational services are an exclusion in the member certificate of coverage.

Effective April 2000 to March 2021

High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies does not meet primary coverage criteria for effectiveness:

Investigational services are an exclusion in the member certificate of coverage.

Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is not covered.

This policy was initially based on a 1995 TEC Assessment that focused on the malignancies listed in the Policy section. The Assessment offered the following conclusions:

A 1999 TEC Assessment evaluated the use of HDC with allogeneic stem-cell support as a salvage therapy after a failed prior course of HDC with autologous stem-cell support for solid tumors. Data were inadequate to permit conclusions.

A review by Nieto and Shpall and a report from the European Group for Bone Marrow Transplantation's Solid Tumors Working Party agreed that evidence was still insufficient to establish a definite role for HDC and autologous transplantation in small-cell lung cancer. Nieto and Shpall also concluded that evidence was inadequate to demonstrate a survival benefit from HDC for melanoma or sarcoma. Other malignancies listed in the Policy section of this document were not considered in either of these reviews. Uncontrolled pilot studies on HDC with hematopoietic stem-cell transplantation for patients with refractory urothelial carcinoma and recurrent or advanced nasopharyngeal carcinoma also provide inadequate evidence of improved outcomes to alter previous conclusions.

Autologous SCT in Solid Tumors of Adults

Data on the use of autologous transplant for the solid tumors of adults addressed in this policy consists mainly of anecdotal reports and small series, and the number of randomized trials is limited.

Adult soft tissue sarcomas

The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a median survival of about 1 year, and less than 10% 5-year survival. In general, dose-intensive doxorubicin and ifosfamide-based regimens have yielded higher response rates and prolonged disease-free survival, but not overall survival. However, as it was shown that patients who achieved complete remission (CR) had longer survival, several phase I and II trials were conducted in the 1990s in an attempt to improve outcomes. These trials were composed of small numbers of patients (ranging from 2–55), with HDC yielding overall response rates from 20%–65% with CR from 10%–43%. The longest reported 5-year progression-free survival (PFS) rate was 21%, and 5-year overall survival (OS) was 32%. One study of 21 patients with soft tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease before receiving HDC. The data from these small trials are insufficient to support the use of autologous SCT in adult patients with soft tissue sarcoma. In 1 additional phase ll study, 21 of 55 (38%) patients responded to doxorubicin-based induction chemotherapy (14% vs. 3%; p=0.003), but estimated OS was not statistically different between those that received HDC and those that did not. The authors felt that their results warranted a phase lll trial examining the role of HDC as consolidation therapy in these patients. No phase lll trials involving SCT for first line therapy of advanced or metastatic adult soft tissue sarcoma compared to conventional standard-dose chemotherapy were found in a systematic review.

Small cell lung carcinoma (SCLC)

The interest in treating SCLC with SCT stems from its extremely high chemosensitivity and poor prognosis. A phase III trial of 318 patients with SCLC randomly assigned patients to standard chemotherapy or HDC with stem-cell transplantation. No statistically significant difference in response rates was seen between the two groups (80% response rate in the standard arm vs. 88% in the HDC group [difference=8%, 95% confidence interval of -1% to 17%; p=.09]). There was no statistically significant difference in OS between the two groups, with a median OS of 13.9 months in the standard arm (95% confidence interval of 12.1 to 15.7 months) versus 14.4 months in the HDC arm (95% CI 13.1 to 15.4); p=.76. One smaller, randomized study and several single-arm studies of HDC and autologous SCT for SCLC are summarized in a review article. Overall, the majority of the data from these studies, including the randomized study, showed no increased OS with HDC and SCT.

Review articles summarize the most recent data from studies of HDC with autologous SCT for solid tumors in adults. (5,11)

Allogeneic SCT in Solid Tumors of Adults

Single-case reports and small series of patients with various types of solid tumors have been treated with allogeneic hematopoietic SCT, including some of the tumor types addressed in this policy. (1, 2, 12)

Renal cell carcinoma

Metastatic renal cell carcinoma (RCC) has an extremely poor prognosis, with a median survival of less than 1 year and a 5-year survival of less than 5%. (13) RCC is relatively resistant to chemotherapy, but is susceptible to immune therapy, and interleukin-2 (IL-2) and/or interferon alpha have induced responses and long-term progression-free survival in 4%–15% of patients. Therefore, 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 and coworkers published the first series of patients with RCC treated with nonmyeloablative allogeneic SCT. The investigators showed regression of the tumor in 10 of 19 (53%) patients with cytokine-refractory, metastatic RCC who received an HLA-identical sibling allogeneic SCT. Three patients had a complete response, 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 to19 months after transplantation. Other pilot trials have demonstrated the graft-versus-tumor effect of allogeneic transplant in metastatic RCC, but most have not shown as high a response rate as the Childs’ study. Overall response rates in these pilot trials have been about 25%, with complete response rates of about 8%. (1) Prospective, randomized trials are needed to assess the net impact of this technique on the survival of patients with cytokine-refractory RCC.

Clinical Trials and Guidelines

To date, no clinical trials have been published that would alter the policy statement. An August 2008 search of the National Cancer Institute (NCI) database of ongoing clinical trials (Physician Data Query [PDQ] database) shows a phase III clinical trial of chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with small-cell lung cancer (NCT00011921) is still ongoing. Also ongoing is a phase II/III study of disease-specific high-dose conditioning regimens followed by autologous SCT (single or tandem) in patients with hematologic malignancies or solid tumors (NCT00536601). No additional ongoing phase III clinical trials of chemotherapy followed by SCT in treating adults with miscellaneous solid tumors listed in this policy were identified.

In addition, the National Comprehensive Cancer Network (NCCN) guidelines on the tumors addressed in this policy has not indicated SCT as a treatment option.

The following is a summary of the key literature published since the last policy update.

Autologous HSCT in Solid Tumors of Adults

Jiang and colleagues performed a meta-analysis of the medical literature through October 2008 of English language studies using intensified chemotherapy with autologous hematopoietic progenitors to treat SCLC (Jiang, 2009). The meta-analysis consisted of 5 randomized, controlled trials (3 were Phase III trials and 2 were Phase II), for a total of 641 patients. They found no significant increase in the odds ratio for response rate with autologous transplant versus control chemotherapy (odds ratio, 1.29; 95% CI: 0.87–1.93; p=.206). No statistically significant increase in OS was seen among the autologous transplant patients compared to control regimens (hazard ratio, 0.94; 95% CI: 0.80–1.10; p=0.432). The authors concluded that current evidence does not support the use of intensified chemotherapy and autologous HSCT for treating SCLC.

Allogeneic HSCT in Solid Tumors of Adults

Aglietta and colleagues reported their experience with 39 patients with metastatic colorectal cancer who underwent reduced-intensity conditioning (RIC) allogeneic HSCT between 1999 and 2004 at 9 European Group for Blood and Marrow Transplantation (EBMT) centers (Aglietta, 2009). Patients were treated with one of five different RIC regimens. Endpoints that were assessed were achievement of mixed chimerism, incidence of graft-versus-host disease, treatment-related mortality and toxicities, OS, and time to treatment failure (in patients who responded to the therapy). Patient population characteristics were heterogeneous; pretransplant disease status was partial response in 2 patients, stable disease in 6 patients, and progressive disease in 31. Thirty-eight patients (97%) had been previously treated, some with only chemotherapy and others with surgery and/or chemotherapy. After transplant, tumor responses were complete in 2% of patients, partial in 18%, 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: 6–1,020), after which time 33 patients had died and 6 were still alive. Tumor progression was the cause of death in 74% of patients. A comparison of OS of patients was performed after stratifying by some 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=0.00018). The authors concluded that the HSCT approach should probably be reserved for patients with a partial response or stable disease after second-line therapy for metastatic colorectal cancer, and that second-generation clinical trials in these patients are warranted.

Bregni and colleagues assessed the long-term benefit of allografting in 25 patients with cytokine-refractory metastatic RCC who received an RIC allograft from a sibling who is human leukocyte antigen (HLA) identical (Bregni, 2009). All patients received the same conditioning regimens. Response to allograft was available in 24 patients, with a complete response in 1 patient and partial response in 4 patients. Twelve patients had minor response or stable disease, and 7 reported progressive disease. Overall response rate (complete plus partial) was 20%. Six patients died because of transplant-related mortality. Median survival was 336 days (12–2,332+). One-year OS was 48% (95% CI: 28–68), and 5-year OS was 20% (95% CI: 4–36). The authors concluded that allografting is able to 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 the incorporation of these therapies into the transplant regimen.

Kanda and colleagues reported on the efficacy of RIC allogeneic HSCT against advanced pancreatic cancer in 22 patients from three transplantation centers in Japan (Kanda, 2008). The RIC regimens differed among the centers, and the patient population was fairly heterogeneous, with 15 patients having metastatic disease and 7 locally advanced disease. All but 1 patient received chemotherapy of various combinations before transplant, and 10 patients received local radiation. After HSCT, 1 patient achieved complete response, 2 patients had partial response, 2 had minor response, and 8 had stable disease, with an overall response rate 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 nontransplant 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 one-fourth of patients with advanced pancreatic cancer who underwent HSCT and that the response was not durable. However, they felt that their observation of a relationship between longer survival and the infusion of a higher number of CD34-positive cells or the development of chronic graft-versus-host disease warrant future studies to enhance the immunologic effect against pancreatic cancer.

Abe and colleagues reported the outcomes for 5 patients with chemotherapy-resistant, unresectable pancreatic adenocarcinoma who received a nonmyeloablative allogeneic peripheral blood HSCT (Abe, 2009). The conditioning regimen consisted of fludarabine and low-dose total-body irradiation. The median patient age was 54 years (range: 44–62 years). All patients had advanced disease, either with metastases or peritonitis, and had received at least one course of chemotherapy including gemcitabine. After HSCT, tumor response was only observed in 2 patients—one had complete disappearance of the primary tumor and one 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, ranging from post-transplant day 28 to day 209 (median: 96 days). One patient died at day 57 secondary to rupture of the common bile duct from rapid tumor regression. The authors concluded that their study showed a graft-versus-tumor effect, but that in order to obtain durable responses, an improved conditioning regimen and new strategies to control tumor growth after nonmyeloablative allogeneic HSCT are needed.

A search of the online site Clinicaltrials.gov showed a Phase III trial of sequential, high-dose chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with SCLC (NCT00011921); the recruitment status is unknown. No additional ongoing Phase III clinical trials of chemotherapy followed by HSCT in treating adults with miscellaneous solid tumors listed in this policy were identified.

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network (NCCN) guidelines on the tumors addressed in this policy do not indicate HSCT as a treatment option (NCCN, 2012).

A search of the MEDLINE database through November 2013 did not reveal any new literature that would prompt a change in the coverage statement.

A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Hartmann et al reported results from a phase 2 study of high-dose chemotherapy with ifosfamide, carboplatin, and etoposide followed by peripheral blood stem-cell transplantation in patients with grade 2 or 3 histologically proven soft tissue sarcoma that were considered unresectable or marginally resectable (Hartmann, 2013). Thirty patients were enrolled, 14 of whom did not receive all allocated interventions due to progressive disease (N=5), ifosfamide-related neurotoxicity (N=6), withdrawal of consent (N=1), CR to induction chemotherapy (N=1), and insufficient stem-cell harvest (N=1). Eighteen patients underwent radiation, preoperatively in 5, postoperatively in 12, and with palliative intent in 1. Twenty-four of 30 (80%) patients underwent surgery with macroscopically complete tumor resection. In the subgroup of patients who underwent consolidation high-dose chemotherapy, surgery revealed R0-margins (microscopically margin-negative resection) in 12 patients (75%), while 4 patients had R1-margins (macroscopically margin-negative but microscopically margin-positive resection). In the subgroup of patients treated without HD-ICE consolidation, 7/8 patients had R1-margins. Severe hematologic toxicity occurred in most patients, and 8 patients developed febrile neutropenia. One patient developed myelodysplastic syndrome after 25 months of follow-up. After a median follow-up period of 50 months (range, 26–120 months) in surviving patients, the median PFS of all patients was 21 months (range, 1–94) and median OS was 37 months (range, 3–120 months), corresponding to 5-year PFS and OS rates of 39 % and 48 %, respectively. The authors conclude that induction chemo-/ radiotherapy and the role of dose intensification should be further studied until potential alternatives of targeted therapies become available for further distinct subtypes of adult type sarcomas. One case report of the use of allogeneic HSCT for treatment of an adult histiocytic sarcoma was identified, in which the patient was alive with no evidence of disease 30 months post-treatment (Tsujimura, 2014).

No phase 3 trials involving HSCT for first-line therapy of advanced or metastatic adult soft tissue sarcoma compared with conventional standard-dose chemotherapy were identified in a 2008 systematic review.

In 2014, a Cochrane systematic review evaluated the use of autologous HSCT following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas (Peinemann. 2014). The authors included 62 studies reporting on 294 transplanted patients, with a variety of soft tissue sarcomas. One randomized controlled trial (RCT), including 83 patients, was identified; the remaining studies were single-arm studies. In the RCT, OS was not statistically significantly different between autologous HSCT following high-dose chemotherapy compared with 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%. The pooled treatment-related mortality rate across the single-arm studies was 15/294 (5.1%). Overall, the available evidence from small phase 2 studies is insufficient to support the use of autologous HSCT in adult patients with soft tissue sarcoma.

A search of the database ClinicalTrials.gov in September 2014 identified 1 Phase 3 trial of sequential, high-dose chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with SCLC (NCT00011921). Enrollment is planned for 430 subjects; the estimated study completion date is not listed and the recruitment status is unknown. No additional ongoing phase 3 clinical trials of chemotherapy followed by HSCT in treating adults with miscellaneous solid tumors listed in this policy were identified.

Hematopoietic stem-cell transplantation (HSCT) has been investigated for a variety of adult solid tumors.

Assessments in 1995 and 1999 focusing on 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. The largest body of evidence for HSCT in solid tumors has been for small-cell lung cancer (SCLC), including 1 phase 2 randomized trial. Overall, autologous HSCT has not been associated with increased overall survival for SCLC. For other solid tumors, including adult soft tissue sarcomas, renal cell carcinoma, colorectal cancer, pancreatic cancer, and nasopharyngeal cancer, the evidence is limited to small case series. The available evidence is insufficient to demonstrate improved patient outcomes with allogeneic or autologous HSCT for the solid tumors listed in the policy statement.

A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

HSCT is an established treatment for certain hematologic malignancies. Its use in solid tumors in adults 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 (Carnevale, 2005).

In a small series (n=8) of bilateral retinoblastoma survivors with secondary osteosarcoma, 2 patients (of 7 treated with multimodal chemotherapy) received high-dose chemotherapy with autologous peripheral blood stem cell support (Lee, 2014). The 2 HSCT-treated patients were alive with no evidence of disease at 33.4 and 56.4 months of follow up.

A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Omazic and colleagues reported on long-term follow-up for 61 patients with a variety of solid tumor types considered incurable with any conventional therapy who were treated with allo-HCT from 1999 to 2012 (Omazic, 2016). 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, reduced-intensity 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.

A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

AUTOLOGOUS HCT IN SOLID TUMORS OF ADULTS

In 2017, a Cochrane systematic review evaluated the use of autologous HCT following high-dose chemotherapy (HDC) for nonrhabdomyosarcoma soft tissue sarcomas (Peinemann, 2017). One RCT assessing 83 patients was identified (Bui-Nguyen, 2012). In the RCT, OS did not differ statistically between autologous HCT 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. The pooled treatment-related mortality rate across 61 single-arm studies was 15 (5.1%) of 294.

Pancreatic Cancer

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

Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.

A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through February 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

A 2019 RCT evaluated the use of autologous HCT following high-dose chemotherapy for Ewing Sarcoma in patients younger than 50 years of age with only pulmonary or pleural metastases (Dirksen, 2019). The median age of patients was 14.2 years (range, 1.0 to 47.8 years). Induction chemotherapy for all patients consisted of 6 chemotherapy courses combining vincristine, ifosfamide, doxorubicin, and etoposide and 1 course of vincristine, dactinomycin, and ifosfamide. Patients were then randomized to receive either high-dose chemotherapy with autologous HCT without whole-lung irradiation (n=144) or standard-dose chemotherapy with whole-lung irradiation (n=143). Median follow-up was 8.1 years. No significant differences in survival outcomes between treatment groups were observed. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for standard-dose chemotherapy and high-dose chemotherapy with autologous HCT, respectively (hazard ratio, 0.79; 95% CI, 0.56 to 1.10; p=.16). The hazard ratio for OS was 1.00 (95% CI, 0.70 to 1.44; p=.99). Four patients died as a result of toxicity from high-dose chemotherapy with autologous HCT, and none died after standard-dose chemotherapy. Investigators concluded there is no clear benefit from high-dose chemotherapy with autologous HCT compared with standard-dose chemotherapy.

The American Society for Blood and Marrow Transplantation (now referred to as the American Society for Transplantation and Cellular Therapy) updated the guidelines related to indications for autologous and allogeneic HCT in 2020 (Kanate, 2020). The tumors for which the Society has provided recommendations are listed below.

2020 Recommendations for Use of Autologous and Allogeneic Hematopoietic Cell Transplantation

Annual policy review completed with a literature search using the MEDLINE database through February 2023. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

In general, the 5-year survival rate for soft-tissue sarcomas is over 65%. The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a 5-year survival estimate of 17 % (ASCO, 2023). A variety of single-agent and combination regimens are used for treatment, with targeted therapies available for some subtypes (NCCN, 2023). Based on initial observations that patients who achieved complete remission (CR) had longer survival, several phase 1 and 2 trials using autologous HCT were conducted in the 1990s to improve outcomes (Pedrazzoli, 2006). These trials were composed of sample size ranging from 2 to 55, 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 the 5-year OS rate was 32% (Pedrazzoli, 2006). One study of 21 patients with soft tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease prior to HCT (Kasper, 2007). In another phase 2 study, 21 (38%) of 55 patients responded to doxorubicin-based induction chemotherapy but estimated 5-year OS did not differ statistically between those who did (14%) and did not (3%) receive an autologous HCT (p=.08) (Schlemmer, 2006).

Few studies not included in the Cochrane review have described outcomes after HCT 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 (Kasper, 2010). After 4 courses of chemotherapy, 9 patients with at least a partial response underwent high-dose chemotherapy and autologous HCT. All other patients continued chemotherapy for 2 more cycles. Median PFS for patients treated with HCT was 11.6 months (range, 8 to 15 months) and 5.6 months for patients treated with standard chemotherapy (p=.047); median OS for the 2 groups was 23.7 months (range, 12 to 34 months) and 10.8 months (range, 0 to 39 months; p=.027), respectively.

A 2020 registry study retrospectively evaluated the effectiveness of autologous HCT in the treatment of soft tissue sarcoma using data from the European Society for Blood and Marrow Transplantation database between 1996 and 2016 (N=338) (Heilig, 2020). The PFS and OS were 8.3 and 19.8 months, respectively. The PFS and OS at 5 years were 13% and 25%, respectively. Predictors of favorable benefit with HCT were younger age, better remission status before transplantation, and melphalan-based preparative regimens. The authors concluded that autologous HCT should not be performed on patients with soft tissue sarcoma in routine clinical practice without further investigation.

A phase 3 trial randomized 318 patients with SCLC to standard chemotherapy or to HCT (Lorigan, 2005). No statistically significant difference in response rates was seen between the 2 groups (response rate, 80% in standard arm group vs. 88% in the HCT group; difference, 8%; 95% CI, -1% to 17%; p=.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 HCT arm (95% CI, 13.1 to 15.4 months; p=.76). One randomized study and several single-arm studies of HCT and autologous HCT for SCLC are summarized in a 2007 review article (Crivellari, 2007). Overall, most of the data from these studies, including the randomized study, showed no increase in OS with autologous HCT.

Outcomes of a phase 2 trial were reported of 21 patients with pretreated metastatic nasopharyngeal cancer (Toh, 2011). Median patient age was 48 years (range, 34 to 57 years), and patients had received a median of 2 previous chemotherapy regimens (range, 1 to 8 regimens). All patients had extensive metastases. Patients underwent a nonmyeloablative allo-HCT 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 to 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 HCT.

	HDC & Hematopoietic Stem Cell Support-Miscellaneous Solid Tumors in Adults

Description:	Hematopoietic cell transplantation (HCT) is an established treatment for certain hematologic malignancies and has been investigated for a variety of adult solid tumors. Interest continues in exploring nonmyeloablative allogeneic HCT (allo-HCT) for a graft-versus-tumor effect of donor-derived T-cells in metastatic solid tumors. Though cancer incidence along with overall mortality has been declining in the United States, certain population groups continue to have an increased risk of cancer progression and mortality due to social, economic, and environmental disadvantages (NCI, 2022). The National Cancer Institute has published statistics on cancer disparities in relation to various criteria including specific racial and ethnic groups, gender, and geography. Some key incidence and mortality statistics in the United States are as follows: incidence rates of lung, colorectal, and cervical cancers are increased in rural Appalachia compared to urban areas; American Indians/Alaska Natives have increased mortality rates from kidney, liver, and intrahepatic bile duct cancer compared to other racial and ethnic groups; Black men are twice as likely to die of prostate cancer than White men. Hematopoietic Cell Transplantation Hematopoietic -cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous. HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA A, B, and DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci. Conditioning for Hematopoietic Cell Transplantation Conventional Conditioning The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect in of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections. The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD. Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative. Hematopoietic Cell Transplantation Solid Tumors in Adults HCT 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 (Carnevale-Schianca, 2005). Miscellaneous Solid Tumors in Adults This policy collectively addresses solid tumors of adults for which SCT has been investigated, including lung cancer; malignant melanoma; tumors of the gastrointestinal tract (include colon, rectum, pancreas, stomach, esophagus, gallbladder, and bile duct); male and female genitourinary systems (e.g., renal cell carcinoma, cervical carcinoma, cancer of the uterus, fallopian tubes, and prostate gland); 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 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 (USFDA, 2015). Hematopoietic stem cells are included in these regulations.

Policy/ Coverage:	Effective April 15, 2023 Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for: · Lung cancer, any histology · Colon cancer · Rectal cancer · Pancreatic cancer · Stomach cancer · Esophageal cancer · Gall bladder cancer · Cancer of the bile duct · Renal cell carcinoma · Cervical cancer · Uterine cancer · Cancer of the fallopian tubes · Prostate cancer · Nasopharyngeal cancer · Paranasal sinus cancer · Neuroendocrine tumors · Soft tissue sarcomas · Thyroid tumors · Tumors of the thymus · Tumors of unknown primary origin · Malignant melanoma. . For contracts without primary coverage criteria language, high dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies is considered investigational for: · Lung cancer, any histology · Colon cancer · Rectal cancer · Pancreatic cancer · Stomach cancer · Esophageal cancer · Gall bladder cancer · Cancer of the bile duct · Renal cell carcinoma · Cervical cancer · Uterine cancer · Cancer of the fallopian tubes · Prostate cancer · Nasopharyngeal cancer · Paranasal sinus cancer · Neuroendocrine tumors · Soft tissue sarcomas · Thyroid tumors · Tumors of the thymus · Tumors of unknown primary origin · Malignant melanoma. Investigational services are an exclusion in the member certificate of coverage. Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage. Effective March 2021 through April 14, 2023 Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for: Lung cancer, any histology; Colorectal cancer; Cervical cancer; Pancreas cancer; Uterine cancer; Stomach cancer; Cancer of fallopian tubes; Esophageal cancer; Prostate cancer; Gall bladder cancer; Thyroid tumors; Cancer of the bile duct; Tumors of thymus; Nasopharyngeal cancer; Paranasal sinus cancer; Neuroendocrine tumors; Soft tissue sarcomas; Tumors of unknown primary origin. For contracts without primary coverage criteria language, high dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies is considered investigational for: Lung cancer, any histology; Colorectal cancer; Cervical cancer; Pancreas cancer; Uterine cancer; Stomach cancer; Cancer of fallopian tubes; Esophageal cancer; Prostate cancer; Gall bladder cancer; Thyroid tumors; Cancer of the bile duct; Tumors of thymus; Nasopharyngeal cancer; Paranasal sinus cancer; Neuroendocrine tumors; Soft tissue sarcomas; Tumors of unknown primary origin. Investigational services are an exclusion in the member certificate of coverage. Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage. Effective April 2000 to March 2021 High dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies does not meet primary coverage criteria for effectiveness: Lung cancer, any histology; Colorectal cancer; Cervical cancer; Pancreas cancer; Uterine cancer; Stomach cancer; Cancer of fallopian tubes; Esophageal cancer; Prostate cancer; Gall bladder cancer; Thyroid tumors; Cancer of the bile duct; Tumors of thymus; Nasopharyngeal cancer; Paranasal sinus cancer; Neuroendocrine tumors; Soft tissue sarcomas; Tumors of unknown primary origin. For contracts without primary coverage criteria language, high dose chemotherapy with allogeneic or autologous stem cell support for the treatment of the following malignancies is considered investigational and not covered: Lung cancer, any histology; Colorectal cancer; Cervical cancer; Pancreas cancer; Uterine cancer; Stomach cancer; Cancer of fallopian tubes; Esophageal cancer; Prostate cancer; Gall bladder cancer; Thyroid tumors; Cancer of the bile duct; Tumors of thymus; Nasopharyngeal cancer; Paranasal sinus cancer; Neuroendocrine tumors; Soft tissue sarcomas; Tumors of unknown primary origin. Investigational services are an exclusion in the member certificate of coverage. Tandem transplants are not covered based on a specific exclusion in the member benefit contract. Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is not covered.

Rationale:	This policy was initially based on a 1995 TEC Assessment that focused on the malignancies listed in the Policy section. The Assessment offered the following conclusions: While 125 articles were identified that reported on the results of high-dose chemotherapy (HDC) 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, advanced colorectal cancer, malignant melanomas, and inoperable gastric cancer. The evidence did not permit conclusions as to the effect of HDC on patient survival. A 1999 TEC Assessment evaluated the use of HDC with allogeneic stem-cell support as a salvage therapy after a failed prior course of HDC with autologous stem-cell support for solid tumors. Data were inadequate to permit conclusions. A review by Nieto and Shpall and a report from the European Group for Bone Marrow Transplantation's Solid Tumors Working Party agreed that evidence was still insufficient to establish a definite role for HDC and autologous transplantation in small-cell lung cancer. Nieto and Shpall also concluded that evidence was inadequate to demonstrate a survival benefit from HDC for melanoma or sarcoma. Other malignancies listed in the Policy section of this document were not considered in either of these reviews. Uncontrolled pilot studies on HDC with hematopoietic stem-cell transplantation for patients with refractory urothelial carcinoma and recurrent or advanced nasopharyngeal carcinoma also provide inadequate evidence of improved outcomes to alter previous conclusions. 2008 Update Autologous SCT in Solid Tumors of Adults Data on the use of autologous transplant for the solid tumors of adults addressed in this policy consists mainly of anecdotal reports and small series, and the number of randomized trials is limited. Adult soft tissue sarcomas The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a median survival of about 1 year, and less than 10% 5-year survival. In general, dose-intensive doxorubicin and ifosfamide-based regimens have yielded higher response rates and prolonged disease-free survival, but not overall survival. However, as it was shown that patients who achieved complete remission (CR) had longer survival, several phase I and II trials were conducted in the 1990s in an attempt to improve outcomes. These trials were composed of small numbers of patients (ranging from 2–55), with HDC yielding overall response rates from 20%–65% with CR from 10%–43%. The longest reported 5-year progression-free survival (PFS) rate was 21%, and 5-year overall survival (OS) was 32%. One study of 21 patients with soft tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease before receiving HDC. The data from these small trials are insufficient to support the use of autologous SCT in adult patients with soft tissue sarcoma. In 1 additional phase ll study, 21 of 55 (38%) patients responded to doxorubicin-based induction chemotherapy (14% vs. 3%; p=0.003), but estimated OS was not statistically different between those that received HDC and those that did not. The authors felt that their results warranted a phase lll trial examining the role of HDC as consolidation therapy in these patients. No phase lll trials involving SCT for first line therapy of advanced or metastatic adult soft tissue sarcoma compared to conventional standard-dose chemotherapy were found in a systematic review. Small cell lung carcinoma (SCLC) The interest in treating SCLC with SCT stems from its extremely high chemosensitivity and poor prognosis. A phase III trial of 318 patients with SCLC randomly assigned patients to standard chemotherapy or HDC with stem-cell transplantation. No statistically significant difference in response rates was seen between the two groups (80% response rate in the standard arm vs. 88% in the HDC group [difference=8%, 95% confidence interval of -1% to 17%; p=.09]). There was no statistically significant difference in OS between the two groups, with a median OS of 13.9 months in the standard arm (95% confidence interval of 12.1 to 15.7 months) versus 14.4 months in the HDC arm (95% CI 13.1 to 15.4); p=.76. One smaller, randomized study and several single-arm studies of HDC and autologous SCT for SCLC are summarized in a review article. Overall, the majority of the data from these studies, including the randomized study, showed no increased OS with HDC and SCT. Review articles summarize the most recent data from studies of HDC with autologous SCT for solid tumors in adults. (5,11) Allogeneic SCT in Solid Tumors of Adults Single-case reports and small series of patients with various types of solid tumors have been treated with allogeneic hematopoietic SCT, including some of the tumor types addressed in this policy. (1, 2, 12) Renal cell carcinoma Metastatic renal cell carcinoma (RCC) has an extremely poor prognosis, with a median survival of less than 1 year and a 5-year survival of less than 5%. (13) RCC is relatively resistant to chemotherapy, but is susceptible to immune therapy, and interleukin-2 (IL-2) and/or interferon alpha have induced responses and long-term progression-free survival in 4%–15% of patients. Therefore, 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 and coworkers published the first series of patients with RCC treated with nonmyeloablative allogeneic SCT. The investigators showed regression of the tumor in 10 of 19 (53%) patients with cytokine-refractory, metastatic RCC who received an HLA-identical sibling allogeneic SCT. Three patients had a complete response, 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 to19 months after transplantation. Other pilot trials have demonstrated the graft-versus-tumor effect of allogeneic transplant in metastatic RCC, but most have not shown as high a response rate as the Childs’ study. Overall response rates in these pilot trials have been about 25%, with complete response rates of about 8%. (1) Prospective, randomized trials are needed to assess the net impact of this technique on the survival of patients with cytokine-refractory RCC. Clinical Trials and Guidelines To date, no clinical trials have been published that would alter the policy statement. An August 2008 search of the National Cancer Institute (NCI) database of ongoing clinical trials (Physician Data Query [PDQ] database) shows a phase III clinical trial of chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with small-cell lung cancer (NCT00011921) is still ongoing. Also ongoing is a phase II/III study of disease-specific high-dose conditioning regimens followed by autologous SCT (single or tandem) in patients with hematologic malignancies or solid tumors (NCT00536601). No additional ongoing phase III clinical trials of chemotherapy followed by SCT in treating adults with miscellaneous solid tumors listed in this policy were identified. In addition, the National Comprehensive Cancer Network (NCCN) guidelines on the tumors addressed in this policy has not indicated SCT as a treatment option. 2012 Update The following is a summary of the key literature published since the last policy update. Autologous HSCT in Solid Tumors of Adults Jiang and colleagues performed a meta-analysis of the medical literature through October 2008 of English language studies using intensified chemotherapy with autologous hematopoietic progenitors to treat SCLC (Jiang, 2009). The meta-analysis consisted of 5 randomized, controlled trials (3 were Phase III trials and 2 were Phase II), for a total of 641 patients. They found no significant increase in the odds ratio for response rate with autologous transplant versus control chemotherapy (odds ratio, 1.29; 95% CI: 0.87–1.93; p=.206). No statistically significant increase in OS was seen among the autologous transplant patients compared to control regimens (hazard ratio, 0.94; 95% CI: 0.80–1.10; p=0.432). The authors concluded that current evidence does not support the use of intensified chemotherapy and autologous HSCT for treating SCLC. Allogeneic HSCT in Solid Tumors of Adults Aglietta and colleagues reported their experience with 39 patients with metastatic colorectal cancer who underwent reduced-intensity conditioning (RIC) allogeneic HSCT between 1999 and 2004 at 9 European Group for Blood and Marrow Transplantation (EBMT) centers (Aglietta, 2009). Patients were treated with one of five different RIC regimens. Endpoints that were assessed were achievement of mixed chimerism, incidence of graft-versus-host disease, treatment-related mortality and toxicities, OS, and time to treatment failure (in patients who responded to the therapy). Patient population characteristics were heterogeneous; pretransplant disease status was partial response in 2 patients, stable disease in 6 patients, and progressive disease in 31. Thirty-eight patients (97%) had been previously treated, some with only chemotherapy and others with surgery and/or chemotherapy. After transplant, tumor responses were complete in 2% of patients, partial in 18%, 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: 6–1,020), after which time 33 patients had died and 6 were still alive. Tumor progression was the cause of death in 74% of patients. A comparison of OS of patients was performed after stratifying by some 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=0.00018). The authors concluded that the HSCT approach should probably be reserved for patients with a partial response or stable disease after second-line therapy for metastatic colorectal cancer, and that second-generation clinical trials in these patients are warranted. Bregni and colleagues assessed the long-term benefit of allografting in 25 patients with cytokine-refractory metastatic RCC who received an RIC allograft from a sibling who is human leukocyte antigen (HLA) identical (Bregni, 2009). All patients received the same conditioning regimens. Response to allograft was available in 24 patients, with a complete response in 1 patient and partial response in 4 patients. Twelve patients had minor response or stable disease, and 7 reported progressive disease. Overall response rate (complete plus partial) was 20%. Six patients died because of transplant-related mortality. Median survival was 336 days (12–2,332+). One-year OS was 48% (95% CI: 28–68), and 5-year OS was 20% (95% CI: 4–36). The authors concluded that allografting is able to 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 the incorporation of these therapies into the transplant regimen. Kanda and colleagues reported on the efficacy of RIC allogeneic HSCT against advanced pancreatic cancer in 22 patients from three transplantation centers in Japan (Kanda, 2008). The RIC regimens differed among the centers, and the patient population was fairly heterogeneous, with 15 patients having metastatic disease and 7 locally advanced disease. All but 1 patient received chemotherapy of various combinations before transplant, and 10 patients received local radiation. After HSCT, 1 patient achieved complete response, 2 patients had partial response, 2 had minor response, and 8 had stable disease, with an overall response rate 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 nontransplant 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 one-fourth of patients with advanced pancreatic cancer who underwent HSCT and that the response was not durable. However, they felt that their observation of a relationship between longer survival and the infusion of a higher number of CD34-positive cells or the development of chronic graft-versus-host disease warrant future studies to enhance the immunologic effect against pancreatic cancer. Abe and colleagues reported the outcomes for 5 patients with chemotherapy-resistant, unresectable pancreatic adenocarcinoma who received a nonmyeloablative allogeneic peripheral blood HSCT (Abe, 2009). The conditioning regimen consisted of fludarabine and low-dose total-body irradiation. The median patient age was 54 years (range: 44–62 years). All patients had advanced disease, either with metastases or peritonitis, and had received at least one course of chemotherapy including gemcitabine. After HSCT, tumor response was only observed in 2 patients—one had complete disappearance of the primary tumor and one 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, ranging from post-transplant day 28 to day 209 (median: 96 days). One patient died at day 57 secondary to rupture of the common bile duct from rapid tumor regression. The authors concluded that their study showed a graft-versus-tumor effect, but that in order to obtain durable responses, an improved conditioning regimen and new strategies to control tumor growth after nonmyeloablative allogeneic HSCT are needed. Clinical Trials A search of the online site Clinicaltrials.gov showed a Phase III trial of sequential, high-dose chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with SCLC (NCT00011921); the recruitment status is unknown. No additional ongoing Phase III clinical trials of chemotherapy followed by HSCT in treating adults with miscellaneous solid tumors listed in this policy were identified. Practice Guidelines and Position Statements The National Comprehensive Cancer Network (NCCN) guidelines on the tumors addressed in this policy do not indicate HSCT as a treatment option (NCCN, 2012). 2013 Update A search of the MEDLINE database through November 2013 did not reveal any new literature that would prompt a change in the coverage statement. 2014 Update A literature search conducted through November 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below. Hartmann et al reported results from a phase 2 study of high-dose chemotherapy with ifosfamide, carboplatin, and etoposide followed by peripheral blood stem-cell transplantation in patients with grade 2 or 3 histologically proven soft tissue sarcoma that were considered unresectable or marginally resectable (Hartmann, 2013). Thirty patients were enrolled, 14 of whom did not receive all allocated interventions due to progressive disease (N=5), ifosfamide-related neurotoxicity (N=6), withdrawal of consent (N=1), CR to induction chemotherapy (N=1), and insufficient stem-cell harvest (N=1). Eighteen patients underwent radiation, preoperatively in 5, postoperatively in 12, and with palliative intent in 1. Twenty-four of 30 (80%) patients underwent surgery with macroscopically complete tumor resection. In the subgroup of patients who underwent consolidation high-dose chemotherapy, surgery revealed R0-margins (microscopically margin-negative resection) in 12 patients (75%), while 4 patients had R1-margins (macroscopically margin-negative but microscopically margin-positive resection). In the subgroup of patients treated without HD-ICE consolidation, 7/8 patients had R1-margins. Severe hematologic toxicity occurred in most patients, and 8 patients developed febrile neutropenia. One patient developed myelodysplastic syndrome after 25 months of follow-up. After a median follow-up period of 50 months (range, 26–120 months) in surviving patients, the median PFS of all patients was 21 months (range, 1–94) and median OS was 37 months (range, 3–120 months), corresponding to 5-year PFS and OS rates of 39 % and 48 %, respectively. The authors conclude that induction chemo-/ radiotherapy and the role of dose intensification should be further studied until potential alternatives of targeted therapies become available for further distinct subtypes of adult type sarcomas. One case report of the use of allogeneic HSCT for treatment of an adult histiocytic sarcoma was identified, in which the patient was alive with no evidence of disease 30 months post-treatment (Tsujimura, 2014). No phase 3 trials involving HSCT for first-line therapy of advanced or metastatic adult soft tissue sarcoma compared with conventional standard-dose chemotherapy were identified in a 2008 systematic review. In 2014, a Cochrane systematic review evaluated the use of autologous HSCT following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas (Peinemann. 2014). The authors included 62 studies reporting on 294 transplanted patients, with a variety of soft tissue sarcomas. One randomized controlled trial (RCT), including 83 patients, was identified; the remaining studies were single-arm studies. In the RCT, OS was not statistically significantly different between autologous HSCT following high-dose chemotherapy compared with 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%. The pooled treatment-related mortality rate across the single-arm studies was 15/294 (5.1%). Overall, the available evidence from small phase 2 studies is insufficient to support the use of autologous HSCT in adult patients with soft tissue sarcoma. A search of the database ClinicalTrials.gov in September 2014 identified 1 Phase 3 trial of sequential, high-dose chemotherapy followed by peripheral stem-cell or bone marrow transplant compared with chemotherapy alone in treating patients with SCLC (NCT00011921). Enrollment is planned for 430 subjects; the estimated study completion date is not listed and the recruitment status is unknown. No additional ongoing phase 3 clinical trials of chemotherapy followed by HSCT in treating adults with miscellaneous solid tumors listed in this policy were identified. Hematopoietic stem-cell transplantation (HSCT) has been investigated for a variety of adult solid tumors. Assessments in 1995 and 1999 focusing on 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. The largest body of evidence for HSCT in solid tumors has been for small-cell lung cancer (SCLC), including 1 phase 2 randomized trial. Overall, autologous HSCT has not been associated with increased overall survival for SCLC. For other solid tumors, including adult soft tissue sarcomas, renal cell carcinoma, colorectal cancer, pancreatic cancer, and nasopharyngeal cancer, the evidence is limited to small case series. The available evidence is insufficient to demonstrate improved patient outcomes with allogeneic or autologous HSCT for the solid tumors listed in the policy statement. 2016 Update A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below. HSCT is an established treatment for certain hematologic malignancies. Its use in solid tumors in adults 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 (Carnevale, 2005). In a small series (n=8) of bilateral retinoblastoma survivors with secondary osteosarcoma, 2 patients (of 7 treated with multimodal chemotherapy) received high-dose chemotherapy with autologous peripheral blood stem cell support (Lee, 2014). The 2 HSCT-treated patients were alive with no evidence of disease at 33.4 and 56.4 months of follow up. 2017 Update A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below. Omazic and colleagues reported on long-term follow-up for 61 patients with a variety of solid tumor types considered incurable with any conventional therapy who were treated with allo-HCT from 1999 to 2012 (Omazic, 2016). 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, reduced-intensity 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. 2018 Update A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below. AUTOLOGOUS HCT IN SOLID TUMORS OF ADULTS In 2017, a Cochrane systematic review evaluated the use of autologous HCT following high-dose chemotherapy (HDC) for nonrhabdomyosarcoma soft tissue sarcomas (Peinemann, 2017). One RCT assessing 83 patients was identified (Bui-Nguyen, 2012). In the RCT, OS did not differ statistically between autologous HCT 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. The pooled treatment-related mortality rate across 61 single-arm studies was 15 (5.1%) of 294. Pancreatic Cancer Omazic et al reported on outcomes for 2 patients who received allo-HCT from human leukocyte antigen-identical sibling donors following resection of pancreatic ductal adenocarcinoma (Omazic, 2017). These patients were compared with 6 controls who underwent radical surgery for pancreatic ductal adenocarcinoma but did not receive HCT. Both patients receiving HCT were tumor free after 9 years following diagnosis, whereas all the patients in the control group died within 4 years of diagnosis. 2019 Update Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement. 2020 Update A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement. 2022 Update Annual policy review completed with a literature search using the MEDLINE database through February 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. A 2019 RCT evaluated the use of autologous HCT following high-dose chemotherapy for Ewing Sarcoma in patients younger than 50 years of age with only pulmonary or pleural metastases (Dirksen, 2019). The median age of patients was 14.2 years (range, 1.0 to 47.8 years). Induction chemotherapy for all patients consisted of 6 chemotherapy courses combining vincristine, ifosfamide, doxorubicin, and etoposide and 1 course of vincristine, dactinomycin, and ifosfamide. Patients were then randomized to receive either high-dose chemotherapy with autologous HCT without whole-lung irradiation (n=144) or standard-dose chemotherapy with whole-lung irradiation (n=143). Median follow-up was 8.1 years. No significant differences in survival outcomes between treatment groups were observed. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for standard-dose chemotherapy and high-dose chemotherapy with autologous HCT, respectively (hazard ratio, 0.79; 95% CI, 0.56 to 1.10; p=.16). The hazard ratio for OS was 1.00 (95% CI, 0.70 to 1.44; p=.99). Four patients died as a result of toxicity from high-dose chemotherapy with autologous HCT, and none died after standard-dose chemotherapy. Investigators concluded there is no clear benefit from high-dose chemotherapy with autologous HCT compared with standard-dose chemotherapy. The American Society for Blood and Marrow Transplantation (now referred to as the American Society for Transplantation and Cellular Therapy) updated the guidelines related to indications for autologous and allogeneic HCT in 2020 (Kanate, 2020). The tumors for which the Society has provided recommendations are listed below. 2020 Recommendations for Use of Autologous and Allogeneic Hematopoietic Cell Transplantation High-risk Ewing sarcoma treated with Allogeneic HCT is considered Developmental High-risk Ewing sarcoma treated with Autologous HCT is considered Standard of care (clinical evidence available) Metastatic Renal Cancer treated with Allogeneic HCT is considered DevelopmentalMetastatic Renal Cancer treated with Autologous HCT is Not generally recommended 2023 Update Annual policy review completed with a literature search using the MEDLINE database through February 2023. No new literature was identified that would prompt a change in the coverage statement. 2024 Update Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. In general, the 5-year survival rate for soft-tissue sarcomas is over 65%. The prognosis of patients with unresectable or metastatic soft tissue sarcomas is poor, with a 5-year survival estimate of 17 % (ASCO, 2023). A variety of single-agent and combination regimens are used for treatment, with targeted therapies available for some subtypes (NCCN, 2023). Based on initial observations that patients who achieved complete remission (CR) had longer survival, several phase 1 and 2 trials using autologous HCT were conducted in the 1990s to improve outcomes (Pedrazzoli, 2006). These trials were composed of sample size ranging from 2 to 55, 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 the 5-year OS rate was 32% (Pedrazzoli, 2006). One study of 21 patients with soft tissue sarcoma showed a PFS and OS benefit only in patients with no evidence of disease prior to HCT (Kasper, 2007). In another phase 2 study, 21 (38%) of 55 patients responded to doxorubicin-based induction chemotherapy but estimated 5-year OS did not differ statistically between those who did (14%) and did not (3%) receive an autologous HCT (p=.08) (Schlemmer, 2006). Few studies not included in the Cochrane review have described outcomes after HCT 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 (Kasper, 2010). After 4 courses of chemotherapy, 9 patients with at least a partial response underwent high-dose chemotherapy and autologous HCT. All other patients continued chemotherapy for 2 more cycles. Median PFS for patients treated with HCT was 11.6 months (range, 8 to 15 months) and 5.6 months for patients treated with standard chemotherapy (p=.047); median OS for the 2 groups was 23.7 months (range, 12 to 34 months) and 10.8 months (range, 0 to 39 months; p=.027), respectively. A 2020 registry study retrospectively evaluated the effectiveness of autologous HCT in the treatment of soft tissue sarcoma using data from the European Society for Blood and Marrow Transplantation database between 1996 and 2016 (N=338) (Heilig, 2020). The PFS and OS were 8.3 and 19.8 months, respectively. The PFS and OS at 5 years were 13% and 25%, respectively. Predictors of favorable benefit with HCT were younger age, better remission status before transplantation, and melphalan-based preparative regimens. The authors concluded that autologous HCT should not be performed on patients with soft tissue sarcoma in routine clinical practice without further investigation. A phase 3 trial randomized 318 patients with SCLC to standard chemotherapy or to HCT (Lorigan, 2005). No statistically significant difference in response rates was seen between the 2 groups (response rate, 80% in standard arm group vs. 88% in the HCT group; difference, 8%; 95% CI, -1% to 17%; p=.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 HCT arm (95% CI, 13.1 to 15.4 months; p=.76). One randomized study and several single-arm studies of HCT and autologous HCT for SCLC are summarized in a 2007 review article (Crivellari, 2007). Overall, most of the data from these studies, including the randomized study, showed no increase in OS with autologous HCT. Outcomes of a phase 2 trial were reported of 21 patients with pretreated metastatic nasopharyngeal cancer (Toh, 2011). Median patient age was 48 years (range, 34 to 57 years), and patients had received a median of 2 previous chemotherapy regimens (range, 1 to 8 regimens). All patients had extensive metastases. Patients underwent a nonmyeloablative allo-HCT 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 to 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 HCT.

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