Clinical Policy Bulletin: Hematopoietic Stem Cell Transplant for Solid Tumors in Adults
Aetna considers autologous or allogeneic hematopoietic stem cell transplant (ablative and non-myeloablative) for the treatment of any of the following solid tumors in adults experimental and investigational because its effectiveness for these indications has not been established:
Solid tumors (also known as solid neoplasms) in adults represent a heterogeneous group of malignancies that encompass various body systems. While some solid tumors are very chemo-radiosensitive (e.g., Ewing’s sarcoma and gonadal tumors); as a whole they are not curable by chemotherapy. The use of hematopoietic stem cell transplant (HSCT) has been investigated for the treatment of selected solid tumors. This approach arose from studies that allogeneic HSCT has been successfully employed for patients with aplastic anemia and hemoglobinopathies. Storb et al (2003) stated that the allogeneic graft-versus-tumor (GVT) effects observed in patients who received HSCT for hematological malignancies have stimulated trials of allogeneic HSCT in patients with refractory metastatic solid tumors. The graft-versus-leukemia (GVL) effect is an important component of the therapeutic effect of allogeneic HSCT. Data from experimental animal models as well as from preliminary clinical trials suggested that a GVT effect, analogous to the GVL effect, may be generated against solid tumors such as breast cancer, renal cell cancer, and other malignancies. The use of non-myeloablative, immunosuppressive conditioning regimens, also known as reduced-intensity conditioning (RIC) regimens, offers the opportunity to achieve full-donor engraftment with reduced transplant-related complications and mortality, thus, enabling also patients of advanced age and with co-morbidities to receive allografting. Bregni and colleagues (2004) stated that advanced renal cell cancer has emerged from pilot studies as a disease susceptible to the GVT effect; and future studies will show if tumor responses observed after allografting will translate into a clinically meaningful survival advantage. Other tumors in which tumor responses have been demonstrated include breast cancer, colorectal cancer, ovarian cancer, soft-tissue sarcoma, and others. In contrast, advanced melanoma may not be amenable to GVT effect.
Non-myeloablative HSCT provides a safer approach to explore the effectiveness of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including breast cancer, ovarian cancer, renal cell carcinoma, and others (Espinoza-Delgado and Childs, 2004). Busca et al (2006) evaluated the feasibility and effectiveness of RIC regimen to achieve complete donor chimerism following allogeneic HSCT in patients with metastatic solid tumors. Seven patients with renal cell carcinoma, 3 with colorectal carcinoma, and 1 with soft tissue sarcoma received allogeneic HSCT after fludarabine (90 mg/m2) and total body irradiation (200 cGy). At day 30, median donor chimerism was 94 %. Regression of tumor metastases was observed in 1 patient with renal cell carcinoma. Eight patients (73 %) died from progressive disease (median progression-free survival of 3.7 months) and 1 (9 %) from treatment-related complications; 2 patients were alive 152 and 862 days after transplantation, respectively. The authors concluded that these preliminary results suggested that allogeneic HSCT with RIC regimen for metastatic solid tumors is feasible, although it may lead to durable responses in only a minority of patients.
Demirer et al (2008) noted that allogeneic transplantation of hematopoietic cells from an HLA-compatible donor has been used to treat hematological malignancies. Allogeneic transplantation not only replaces the marrow affected by the disease, but exerts an immune GVT effect mediated by donor lymphocytes. The development of RIC before allogeneic transplantation has allowed this therapy to be used in elderly and disabled patients. An allogeneic GVT effect is observed in a proportion of patients with breast, colorectal, ovarian, pancreatic, and renal cancer treated with allogeneic transplantation. In general, the tumor response is associated with the development of acute and chronic graft-versus-host disease (aGVHD and cGVHD). The authors stated that further improvements will depend on the identification of the antigen targets of GVT, and on reduction of the toxicity of the procedure.
In a multi-center clinical trial, Aglietta and co-workers (2009) examined RIC regimens for allogeneic HSCT in patients with metastatic colorectal cancer (mCRC). A total of 39 participants with progressing mCRC were treated with different RIC regimens. At the time of transplant, disease status was partial response (PR) in 2 (5 %) patients, stable disease (SD) in 6 (15 %), and progressive disease (PD) in 31 (80 %). All patients engrafted (median donor T cell chimerism of 90 % at day +60). Transplant-related morbidities were limited. Grades II to IV aGVHD occurred in 14 patients (35 %) and cGVHD in 9 (23 %) patients. Transplant-related mortality occurred in 4 patients (10 %). The best tumor responses were 1 complete response (CR) (2 %), 7 PR (18 %), and 10 SD (26 %), giving an overall disease control in 18 of 39 patients (46 %). The authors concluded that allogeneic HSCT after RIC regimen is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. They stated that investigation of an allogeneic cell-based therapy in less advanced patients is warranted.
A recent review on allogeneic and autologous transplantation for hematological diseases, immune disorders, and solid tumors by the European Group for Blood and Marrow Transplantation (Ljungman et al, 2010) stated that allogeneic HSCT is considered (i) a clinical option (can be performed after careful assessment of risks and benefits) for renal cancer relapsed/resistant to cytokine therapy, (ii) a developmental therapy (further trials are needed) for breast and ovarian cancer, and (iii) a developmental therapy that is not recommended for other solid tumors with the possible exception of colorectal cancer. The authors stated that currently allogeneic HSCT should only be considered in the context of prospective clinical trials.
Autologous HSCT pursuing an immune GVT effect has also been evaluated for patients with advanced and refractory solid malignancies. Neito et al (2004) noted that over the past 20 years, HDC with autologous HSCT has been explored for a variety of solid tumors in adults, especially breast cancer, ovarian cancer, and non-seminomatous germ-cell tumors. The findings of prospective phase II studies seemed superior in many cases to the outcome expected with standard-dose chemotherapy. The authors stated that the value of HDC for adult solid tumors remains, in most instances, a controversial issue; and is currently under the scrutiny of randomized phase III trial evaluation. Pedrazzoli et al (2006) stated that since the early 1980s HDC with autologous HSCT was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast cancer, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this regard, the Centers for Medicare and Medicaid Services (2006) noted that there are insufficient data to establish definite conclusions regarding the effectiveness of autologous HSCT for solid tumors (other than neuroblastoma).
Available clinical practice guidelines have not recommended HSCT for the treatment of solid tumors in adults. The Dutch Urological Tumors National Working Group (2006) did not mention autologous or allogeneic HSCT as a therapeutic option for patients with renal cell carcinoma. The Dutch Thyroid Carcinoma Working Group (2007) did not discuss autologous or allogeneic HSCT as a therapeutic option for patients with thyroid carcinoma. Furthermore, the Cancer Care Ontario Program in Evidence-based Care's clinical guideline on stem cell transplantation in adults (Imrie et al, 2009) stated that (i) HDC with autologous HSCT has no proven efficacy in advanced epithelial ovarian cancer, germ-cell tumors, primary breast cancer, or small-cell lung cancer, and (ii) there is also no benefit for HDC with autologous bone marrow transplantation in patients with breast cancer compared with standard-dose chemotherapy alone.
The National Cancer Institute's Physician Data Query on treatment for cervical cancer (2010), colon cancer (2010), endometrial cancer (2010), esophageal cancer (2010), extra-hepatic bile duct (2010), gallbladder cancer (2010), gastric cancer (2010), melanoma (2010), nasopharygeal cancer (2010), non-small cell lung cancer (2010), pancreatic cancer (2010), paranasal sinus and nasal cavity cancer (2008), prostate cancer (2010), rectal cancer (2010), small cell lung cancer (2010), soft tissue sarcoma treatment (2010), thymoma and thymic carcinoma (2010), thyroid cancer (2010), and uterine cancer (2008) do not mention autologous or allogeneic HSCT as a therapeutic option.
Kasper et al (2010) noted that prognosis of patients with metastatic soft tissue sarcoma (STS) remains poor. Whether high-dose chemotherapy (HDCT) with stem cell support improves the long-term outcome for these patients is debatable. These investigators presented a prospective, single-institutional, phase II study that enrolled 34 STS patients with advanced and/or metastatic disease. After 4 courses of chemotherapy consisting of doxorubicin and ifosfamide, responding patients in at least partial response (PR) were treated with HDCT (n = 9); all other patients continued chemotherapy for 2 more cycles. After standard chemotherapy, PR (n = 10), stable disease (SD, n = 6) and progressive disease (PD, n = 14) were attained for the evaluable patients. A total of 29 patients died and 5 are alive with the disease. Median progression free survival (PFS) was 11.6 months (range of 8 to 15) for patients treated with HDCT (n = 9) versus 5.6 months (range of 0 to 19) for patients treated with standard chemotherapy. Median overall survival (OS) was 23.7 months (range of 12 to 34) versus 10.8 months (range of 0 to 39), respectively. The subgroup of patients treated with HDCT gained significant survival benefit. Nevertheless, HDCT as a possible consolidation strategy remains highly investigational.
In a Cochrane review, Peinemann and colleagues (2011) evaluated the effectiveness and safety of HDCT followed by autologous HSCT for all stages of STS in children and adults. These investigators searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted. Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with non-rhabdomyosarcoma STS (NRSTS) and autologous HSCT had to constitute at least 80 % of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis. Study data were recorded by 2 review authors independently. For studies with no comparator group, the authors synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were OS and treatment-related mortality (TRM). These researchers included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 subjects that received HSCT and 69 subjects that received standard care. Only 1 study reported comparative data. In the 1 comparative study, OS at 2 years after HSCT was estimated as statistically significantly higher (62.3 %) compared with subjects that received standard care (23.2 %). In a single-arm study, the OS 2 years after HSCT was reported as 20 %. In a pooled analysis of the individual data of 54 subjects, OS at 2 years was estimated as 49 % (95 % confidence interval: 34 % to 64 %). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias. The authors concluded that due to a lack of comparative studies, it is unclear whether subjects with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes not covered for indications listed in the CPB:
Other CPT codes related to the CPB:
HCPCS codes not covered for indications listed in the CPB:
Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation and related complications; including: pheresis and cell preparations/storage marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical diagnostic; emergency, and rehabilitative services, and the number of days of pre- and post-transplant care in the global definition
ICD-9 codes not covered for indications listed in the CPB:
147.0 - 147.9
Malignant neoplasm of nasopharynx
150.0 - 150.9
Malignant neoplasm of esophagus
151.0 - 151.9
Malignant neoplasm of stomach
153.0 - 153.9
Malignant neoplasm of colon
154.0 - 154.8
Malignant neoplasm of rectum, rectosigmoid junction, and anus
Malignant neoplasm of intrahepatic bile duct
156.0 - 156.9
Malignant neoplasm of gall bladder and extrahepatic bile duct
157.0 - 157.9
Malignant neoplasm of pancreas
160.2 - 160.9
Malignant neoplasm of accessory sinuses (paranasal)
162.0 - 162.9
Malignant neoplasm trachea, bronchus, and lung
Malignant neoplasm of thymus
171.0 - 171.9
Malignant neoplasm of connective and other soft tissue
172.0 - 172.9
Malignant neoplasm of skin
174.0 - 174.9
Malignant neoplasm of female breast
175.0 - 175.9
Malignant neoplasm of male breast
Kaposi's sarcoma, soft tissue
180.0 - 180.9
Malignant neoplasm of cervix uteri
182.0 - 182.8
Malignant neoplasm of body of uterus
Malignant neoplasm of fallopian tube
Malignant neoplasm of prostate
189.0 - 189.9
Malignant neoplasm of kidney and other and unspecified urinary organs
Malignant neoplasm of thyroid gland
230.0 - 234.9
Carcinoma in situ
The above policy is based on the following references:
Swedish Council on Technology Assessment in Health Care (SBU). Stem cell transplantation for metastasized kidney cancer - early assessment briefs (Alert). Stockholm, Sweden: Swedish Council on Technology Assessment in Health Care (SBU); 2001.
Storb RF, Lucarelli G, McSweeney PA, Childs RW. Hematopoietic cell transplantation for benign hematologic disorders and solid tumors. Hematology Am Soc Hematol Educ Program. Hematology. 2003;372-397.
Bregni M, Bernardi M, Ciceri F, Peccatori J. Allogeneic stem cell transplantation for the treatment of advanced solid tumors. Springer Semin Immunopathol. 2004;26(1-2):95-108.
Espinoza-Delgado I, Childs RW. Nonmyeloablative transplantation for solid tumors: A new frontier for allogeneic immunotherapy. Expert Rev Anticancer Ther. 2004;4(5):865-875.
Nieto Y, Jones RB, Shpall EJ. Stem-cell transplantation for the treatment of advanced solid tumors. Springer Semin Immunopathol. 2004;26(1-2):31-56.
Busca A, Novarino A, de Fabritiis P, et al. Nonmyeloablative allogeneic blood stem cell transplantation in patients with metastatic solid tumors. Hematology. 2006;11(3):171-177.
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. 2006;17(10):1479-1488.
Aglietta M, Barkholt L, Schianca FC, et al; EBMT Solid Tumor Working Party. Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adoptive cell therapy approach. The European group for blood and marrow transplantation experience. Biol Blood Marrow Transplant. 2009;15(3):326-335.
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. 2009;65(2):214-218.
Ljungman P, Bregni M, Brune M, et al; European Group for Blood and Marrow Transplantation. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe 2009. Bone Marrow Transplant. 2010;45(2):219-234.
IQWiG. Autologous stem cell transplantation for breast cancer. Cologne, Germany: Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG); 2009.
IQWiG. Autologous stem cell transplantation for soft tissue sarcoma. Cologne, Germany: Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG); 2009.
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. 2010;45(7):1234-1238.
Peinemann F, Smith LA, Kromp M, et al. Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas. Cochrane Database Syst Rev. 2011;(2):CD008216.
Peinemann F, Kroger N, Bartel C, et al. High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma -- a systematic review. PLoS One. 2011;6(2):e17127.
Thiel U, Wawer A, Wolf P, et al; Solid Tumor Working Party (STWP) and the Pediatric DiseaseWorking Party (PDWP) of the European Group for Blood and Marrow Transplantation (EBMT); Asia Pacific Blood and Marrow Transplantation (APBMT); Pediatric Registry for Stem Cell Transplantations (PRST); MetaEICESS Study Group. No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol. 2011;22(7):1614-1621.
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