Hematopoietic Cell Transplantation for Solid Tumors in Adults

Number: 0811

Policy

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:

• Bile duct (cholangiocarcinoma)
• Breast
• Central nervous system tumors (e.g., astrocytoma, choroid plexus tumors, ependymoma, gliomas, oligodendroglioma; not an all-inclusive list)Footnotes*
• Cervix
• Colon
• Esophagus
• Fallopian tube
• Gallbladder
• Kidney
• Liver
• Lung
• Melanoma
• Nasopharynx
• Neuroendocrine tumors
• Pancreas
• Paranasal sinus
• Prostate
• Rectum
• Soft tissue sarcomasFootnotes^*
• Stomach
• Thymus 
• Thyroid
• Tumors of unknown primary origin
• Uterus.

Footnotes* Aetna considers autologous hematopoietic stem cell transplant medically necessary in young adults with primitive neuroectodermal tumors, medulloblastoma, and Ewing sarcoma family of tumors when criteria are met in CPB 0496 - Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors.

Background

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.

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, high-dose chemotherapy (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).

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.

There is insufficient evidence regarding the safety and effectiveness of autologous/allogeneic HSCT for the treatment of central nervous system (CNS) tumors (e.g., astrocytoma, choroid plexus tumors, ependymoma, germ cell tumors, gliomas, medulloblastoma, oligodendroglioma, and primitive neuroectodermal tumors).

Baek and colleagues (2013) evaluated the feasibility and effectiveness of myeloablative HDC and autologous SCT (autoSCT) in patients with relapsed or progressed CNS-germ cell tumors (CNS-GCTs).  A total of 11 patients with non-germinomatous GCTs (NGGCTs) and 9 patients with germinomas were enrolled.  Patients received between 2 and 8 cycles of conventional chemotherapy prior to HDCT/autoSCT with or without radiotherapy (RT).  Overall, 16 patients proceeded to the first HDCT/autoSCT, and 9 proceeded to the second HDCT/autoSCT.  CTE (carboplatin-thiotepa-etoposide) and cyclophosphamide-melphalan (CM) regimens were used for the first and second HDCT, respectively.  Toxicities during HDCT/autoSCT were acceptable, and there were no treatment-related deaths.  Twelve patients experienced relapse or progression; however, 4patients with germinomas remain alive after subsequent RT.  Therefore, a total of 12 patients (4 NGGCTs and 8 germinomas) remained alive with a median follow-up of 47 months (range of 22 to 90) after relapse or progression.  The probability of 3-year OS was 59.1 ± 11.2 % (36.4 ± 14.5 % for NGGCTs versus 88.9 ± 10.5 % for germinomas, p = 0.028).  Radiotherapy, particularly craniospinal RT, was associated with a better tumor response prior to HDCT/autoSCT and a better final outcome.  The authors concluded that HDCT/autoSCT was feasible, and survival rates were encouraging.  Moreover, they stated that further study with a larger cohort of patients is needed to ascertain the role of HDCT/autoSCT in the treatment of relapsed or progressed CNS-GCTs.

Samuel et al (2013) noted that choroid plexus carcinomas (CPCs) are rare epithelial CNS tumors.  Choroid plexus carcinomas occur mainly in infants and young children, comprising approximately 1 to 4 % of all pediatric brain neoplasms.  There is very limited information available regarding tumor biology and CPC treatment due to its rarity.  There have been various case reports and meta-analyses of reported cases with CPC.  Surgical resection is often challenging but remains a well-established treatment option.  Chemotherapy is often reserved for recurrent or refractory cases, but the goal of treatment is usually palliative.  These investigators presented a case of recurrent, adult CPC with disseminated lepto-meningeal involvement treated with salvage chemotherapy including high-dose ifosfamide, carboplatin, and etoposide; once a remission was achieved, this response was consolidated with a syngeneic stem cell (bone marrow) transplant after a preparative regimen of HDC with carboplatin, etoposide, and thiotepa.  Although the patient tolerated the transplant well and remained disease-free for 12 months, she subsequently succumbed to relapsed disease 18 months post-transplant.  The authors believed that this was the first report of using syngeneic stem cell transplant in CPC to consolidate a remission achieved by salvage chemotherapy.

Kostaras and Easaw (2013) stated that medulloblastoma accounts for almost 1/3 of pediatric CNS cancers, but is very rare in the adult population.  As a result, adult patients with medulloblastoma are often treated according to therapies developed for children with similarly staged disease at diagnosis, based on the assumption that adult and pediatric tumors have similar properties.  These researchers summarized the evidence and made recommendations for the management of recurrent disease in adult patients with medulloblastoma.  These investigators conducted a systematic literature search to find publications addressing treatment of recurrent medulloblastoma in adults.  Current treatment strategies for adult patients with relapsed medulloblastoma are based on the results of retrospective case series and published consensus recommendations, and include maximal safe re-resection where possible, combined with chemotherapy and/or re-irradiation.  They described the results of 13 publications involving 66 adult patients treated with HDC plus SCT for recurrent medulloblastoma.  The authors concluded that HDC with SCT may be a treatment option for a small proportion of adult patients who are unlikely to benefit from conventional chemotherapy and who are fit and have their disease recurrence contained within the CNS.  Moreover, they stated that potential cases in which SCT is being considered should be discussed at a multi-disciplinary tumor board that includes involvement by hematologic oncologists and transplant specialists.

An UpToDate review on "Overview of the management of central nervous system tumors in children" (Lau and Teo, 2013) does not mention the use of stem cell transplant as a therapeutic option.  Furthermore, the National Comprehensive Cancer Network’s clinical practice guideline on "Central nervous system cancers" (Version 2.2013) states that although evidence of its advantage over conventional treatment is lacking, the panel included HDC-autoSCT as a category 2B option for progressive or recurrent primary CNS lymphomas.  Moreover, there is no recommendation regarding HDC-SCT for other types of CNS tumors.

Uehara et al (2015) stated that an increasing number of children with advanced malignancies have recently received HDC with HSCT, followed by surgery. These investigators reviewed their experience with surgery after HDC and autologous (auto) or allogeneic (allo) HSCT to elucidate the problems associated with this treatment and establish the optimum surgical management strategy. They retrospectively reviewed the cases of 24 children with advanced malignancy treated with HDC and HSCT before tumor resection at the authors’ institution. The tumors included 18 neuroblastomas, 5 soft tissue sarcomas, 2 hepatoblastomas, and 1 Wilms tumor. The source of hematopoietic stem cells was auto-HSCT in 19 patients and allo-HSCT in 5 patients. To be able to undergo surgery, it was necessary that the patient's general condition, including hemostasis, should be fairly good and that the results of hematological examinations should include a white blood cell (WBC) count of greater than 1,000/µL, hemoglobin level of greater than 10 g/dL and platelet count of greater than 5 × 10(4)/µL. The mean duration before WBC recovery after HSCT was 14.5 ± 1.4 days after auto-HSCT and 23.8 ± 1.2 days after allo-HSCT, respectively (p < 0.01). The mean duration before platelet recovery after HSCT was 46.5 ± 5.2 days for auto-HSCT and 48.6 ± 5.5 days for allo-HSCT (not significant). The mean interval between allo-HSCT and surgery was significantly longer (92.8 ± 6.2 days) than that between auto-HSCT and surgery (57.0 ± 3.9 days) (p<0.01), likely because of the use of steroids and immunosuppressants after HSCT. The tumors were completely resected in all cases without severe complications. All the patients treated with allo-HSCT had an acute graft versus host (aGVH) reaction at 2 to 3 weeks after HSCT, and specifically required the administration of steroids and immunosuppressants to prevent aGVH. The post-operative complications included paralytic ileus in 2 cases and a tacrolimus-associated encephalopathy in 1 case involving allo-HSCT. In 50 % of the patients, the WBC count was not elevated after surgery, whereas the post-operative serum C-reactive protein (CRP) level was elevated in all cases. The authors concluded that these findings indicated that surgical treatment can be safely performed even after HDC with HSCT if attention is paid to myelosuppression and the adverse effects of both chemotherapeutic agents and immunosuppressants.

Jahnukainen et al (2015) noted that high-dose therapy (HDTx) with autologous stem cell rescue has been widely applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan, whereas high-dose (HD) thiotepa is less commonly used. These investigators reported retrospectively their single-institution experience from 1986 to 2012 of single and tandem HDTx with special emphasis on HD-thiotepa as the backbone of HD regimen in Ewing family tumors, including all 24 patients in the Helsinki University Hospital referral area in population-based fashion (Ewing sarcoma, n = 9; Askin tumor, n = 9; and peripheral neuro-ectodermal tumor, n = 6). The 10-year OS for the entire cohort was 0.73 ± 0.01; 13 out of the 24 underwent HDTx (10 single, 3 tandem). The HDTx regimen consisted of HD-thiotepa (900 mg/m), VP16, and carboplatin. Additional HD-melphalan and total body irradiation (TBI) were used in the tandem regimens. There was no toxic mortality; the 5-year event-free survival (EFS) was 0.73 ± 0.16 for high-risk cases transplanted in 1CR. In the relapse group, 1 out of the 3 survived. Radiotherapy to axial sites was given safely in combination with HD-thiotepa in all 3 patients. Thiotepa-based HDTx approach resulted in an encouraging outcome without toxic mortality for high-risk patients. The authors concluded that HD-thiotepa merits further studies in larger controlled series.

An UpToDate review on "Overview of treatment approaches for hepatocellular carcinoma" (Abdalla and Stuart, 2016) does not mention hematopoietic stem cell transplant as a therapeutic option.  Also, National comprehensive Cancer network’s clinical practice guideline on "Hepatobiliary cancers" (Version 2.2016) does not mention hematopoietic stem cell transplant as a therapeutic option.

National comprehensive Cancer network’s clinical practice guideline on "Neuroendocrine tumors" (Version 2.2016) does not mention hematopoietic stem cell transplant as a therapeutic option.

National comprehensive Cancer network’s clinical practice guideline on "Occult primary (Cancer of unknown primary [CUP])" (Version 2.2016) does not mention hematopoietic stem cell transplant as a therapeutic option.

National comprehensive Cancer network’s clinical practice guideline on "Ovarian cancer (Including fallopian tube cancer and primary peritoneal cancer)" (Version 1.2016) does not mention hematopoietic stem cell transplant as a therapeutic option for fallopian tube cancer.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes not covered for indications listed in the CPB:
38204	Management of recipient hematopoietic progenitor cell donor search and cell acquistion
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic
38206	autologous
38207-38215	Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
38230	Bone marrow harvesting for transplantation; allogenic
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
38242	Allogeneic lymphocyte infusions
Other CPT codes related to the CPB:
86813	HLA typing; A, B or C multiple
86817	DR/DQ, multiple antigens
86821	lymphocyte culture, mixed (MCL)
HCPCS codes not covered for indications listed in the CPB:
S2142	Cord blood-derived stem cell transplantation; allogeneic
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation and related complications; including: pheresis and cell 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-10 codes covered if selection criteria are met (not all-inclusive):
C41.0 - C41.9	Malignant neoplasm of bone and articular cartilage of other and unspecified sites [Ewing sarcoma]
C70.0 - C70.9	Malignant neoplasm of meninges
C71.0 - C71.9	Malignant neoplasm of brain [medulloblastoma]
C72.0 - C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C11.0 - C11.9	Malignant neoplasm of nasopharynx
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal
C22.0	Liver cell carcinoma
C22.1	Intrahepatic bile duct carcinoma
C23 - C24.9	Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas
C31.0 - C31.9	Malignant neoplasm of accessory sinuses (paranasal)
C33 - C34.92	Malignant neoplasm trachea, bronchus, and lung
C37	Malignant neoplasm of thymus
C43.0 - C43.9	Malignant melanoma of skin
C46.1	Kaposi's sarcoma of soft tissue
C47.0 - C47.9, C49.0 - C49.9	Malignant neoplasm of peripheral nerves, autonomic nervous system, connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of female and male breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C61	Malignant neoplasm of prostate
C64.1 - C66.9 C68.0 - C68.9	Malignant neoplasm of kidney and other and unspecified urinary organs
C73	Malignant neoplasm of thyroid gland
C7A.1 - C7A.8	Malignant poorly differentiated neuroendocrine tumors
C80.0 - C80.1	Malignant neoplasm without specification of site
D00.00 - D09.9	Carcinoma in situ

The above policy is based on the following references: