Transplant Section - Autologous Hematopoietic Stem Cell Transplant

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

DESCRIPTION

When cancer patients receive high doses of chemotherapy, healthy bone marrow is destroyed in addition to cancer cells. Destruction of bone marrow cells is considered a lethal side effect of high-dose chemotherapy, so hematopoietic stem cells are infused or transplanted in order to restore bone marrow function. This process is known as stem cell transplantation (SCT).

In general, hematologic SCT may be performed when the patient’s disease is in complete remission as a consolidation therapy (i.e. to strengthen the remission), after initial chemotherapy treatment (called induction chemotherapy), or as a salvage therapy after relapse, or as an initial treatment in those not responding to standard chemotherapies.

Stem cells may be obtained from the patient’s own bone marrow (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, umbilical cord blood, or from the placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease.

Immunologic compatibility between infused stem cells and the patient (recipient) is not an issue in autologous SCT since the cells are the patient’s own. Autologous SCT is typically performed when the patient’s disease is in complete remission as a consolidation therapy.

Safety

• Patients who undergo autologous SCT are susceptible to chemotherapy-related toxicities such as liver and kidney failure, pulmonary failure, or opportunistic infection. 
  
• For marrow-based malignancies, such as multiple myeloma or chronic lymphocytic leukemia, reinfusion of autologous stem cells always carries the risk of reinfusion of the malignant stem cells.
  
• The risk of leukemic relapse has been reported to be higher for those receiving autologous stem cell transplants than for those receiving allogeneic stem cell transplants in the treatment of some marrow-based malignancies.

Note: For information and criteria specific to allogeneic SCT or tandem transplantation, refer to separate Regence Medical Policies:

POLICY/CRITERIA

Autologous stem cell transplant may be considered medically necessary for the diagnoses specified in the table below. Autologous stem cell transplant is considered investigational for all other indications, including but not limited to those identified as investigational in the table. A link to the position summary for each indication is provided. For those indications which do not meet the medically necessary criteria, consider applying Regence Medical Policy, Medicine 74, Research Urgent Treatments.

Note:  Collection and storage of cord blood from a neonate is considered not medically necessary when collected in advance for some unspecified future use (e.g. as an autologous stem-cell transplant in the original donor). 

POSITION SUMMARY

Effectiveness:

Acute Lymphoblastic Leukemia (ALL)                                Return to Table

Medically Necessary Indications

The evidence is sufficient to suggest that autologous stem cell transplant (SCT) may be effective for the treatment of ALL for the following indications:

• In both children and adults in first complete remission (CR1) when at high risk for relapse; and
• In children, for second or greater remission (CR≥2) or refractory relapse (partial remission or refractory to chemotherapy).

Childhood ALL

• In childhood ALL, conventional chemotherapy is associated with complete remission rates of about 95%, with long-term durable remissions of 60%.  Prognosis after a first relapse is related to the length of the original remission.  For example, leukemia-free survival is 40-50% for children whose first remission was longer than three years, compared to only 10-15% for those with early relapse.  Therefore, for patients in a first complete remission, stem-cell transplantation is considered necessary only in those at high risk of relapse. (12)
• Three reports describing the results of randomized controlled trials reported that overall outcomes after autologous SCT were generally equivalent to overall outcomes after conventional-dose chemotherapy in children being treated for high-risk ALL in CR1 or for relapsed ALL.  While SCT administered in CR1 was associated with fewer relapses than conventional-dose chemotherapy, it was also associated with more frequent deaths in remission (i.e., from treatment-related toxicity) (131-133)
• A more recently published randomized trial (PETHEMA ALL-93) reported no significant differences in disease-free survival or overall survival rates at median follow-up of 78 months in 106 children with very high-risk ALL in CR1 who received allogeneic or autologous SCT versus standard chemotherapy with maintenance treatment. (134) Similar results were observed using either intention-to-treat or per-protocol analyses.
• These results and reviews of other studies (135, 136) suggest that while overall and event-free survival are not different after SCT compared to conventional-dose chemotherapy, SCT remains an important therapeutic option in the management of childhood ALL, especially for patients considered at high risk of relapse. This conclusion is further supported by an evidence-based systematic review of the literature sponsored by the American Society for Blood and Marrow Transplantation (ASBMT). (137)
• The National Comprehensive Cancer Network (NCCN) clinical practice guidelines do not specifically address acute lymphoblastic leukemia.  However, since ALL is very similar to lymphoblastic lymphoma which originates in the lymph nodes as opposed to the blood or bone marrow, treatment strategies have generally been consistent for the two diseases. The NCCN guidelines for non-Hodgkin’s lymphoma indicate that autologous SCT is appropriate for treatment of poor risk lymphoblastic lymphoma patients. (76)

Adult ALL

• For adult patients, the decision between autologous SCT and conventional chemotherapy may reflect a choice between intensive therapy of short duration and longer but less-intensive treatment. This conclusion was based largely on four controlled trials that reported on 148 patients with adult ALL treated with autologous SCT and 151 patients managed with conventional-dose regimens for adult ALL in CR1. Two of these trials randomized patients to receive either high-dose chemotherapy followed by autologous SCT (n=109) or conventional-dose treatment (n=111). The largest trial by Fiere and colleagues found no significant differences between the two randomized cohorts in rates of relapse, median durations of survival and remission, or rates of overall and disease-free survival at three years after treatment. The rates of treatment-related mortality also did not differ significantly between the two randomized arms. Data from  a second randomized trial by Bernasconi and colleagues agree with this trial. (130)
• As a result of an evidence-based systematic review, the ASBMT recommends hematopoietic SCT for adults with high-risk disease in CR1, but not for standard-risk patients. (138) The ASBMT also recommends SCT for patients in CR2, although data are not available to directly compare outcomes with alternatives. 
• As noted for childhood ALL, the NCCN clinical practice guidelines do not specifically address acute lymphoblastic leukemia. However, since ALL is very similar to lymphoblastic lymphoma, treatment strategies have generally been consistent for the two diseases. The NCCN guidelines for non-Hodgkin’s lymphoma indicate that autologous SCT is appropriate for treatment of poor risk patients. (76)

Investigational Indications

Available evidence does not demonstrate that autologous stem cell transplant (SCT) is effective for the treatment of adult ALL in second or greater remission or refractory relapse (refractory to induction chemotherapy).

• Evidence for use of autologous SCT for the treatment of adult ALL in second or greater remission is limited to uncontrolled studies with no direct comparison groups. Very few of these studies reported outcomes other than the rates of relapse following treatment, and none reported all of the outcomes of interest (e.g., disease-free survival or overall survival). No studies provided adequate prognostic information on the patients studied. (12, 130)
• Evidence for use of autologous SCT for the treatment of adults with refractory ALL is also limited to uncontrolled studies with no direct comparison groups. Two clinical series with data on only 50 patients provided insufficient information on the distribution of patients treated with autologous SCT to permit comparison with the six reports that were found on conventional-dose salvage regimens (n=278). (12, 130)
• There are no evidence-based clinical practice guidelines that recommend autologous SCT as a treatment of  ALL in second or greater remission or refractory relapse.

Acute Myelogenous Leukemia (AML)                                Return to Table

Medically Necessary Indications

Autologous stem cell transplant (SCT), except as a first line treatment, may be effective for the treatment of AML.

• 50% to 70% of patients are expected to relapse after attaining first complete remission from AML, and conventional chemotherapy is generally not curative once relapse occurs. (63) Autologous SCT is associated with a prolonged disease-free survival in 30–40% of patients in first relapse or second complete remission. (5)
• The overall survival after autologous SCT is similar to that reported after allogeneic SCT from human leukocyte antigen-matched donors. The decreased treatment-related mortality of autologous transplant is counterbalanced by the increased relapse rate due to the lack of a beneficial graft-versus-leukemia effect. (5)
• One randomized trial of 120 patients with de novo AML compared allogeneic SCT, high-dose cytarabine, and autologous SCT as post-remission treatment. (64) The authors reported comparable survival outcomes, although the proportion of three-year failure-free survivors was larger in the allogeneic recipient group.
• The American Society for Blood and Marrow Transplantation (ASBMT) published a systematic review of peer-reviewed evidence on the role of cytotoxic therapy with SCT in pediatric patients with AML. (65) The findings of the ASBMT expert panel support use of autologous SCT in the treatment of AML stating, “Autologous SCT and chemotherapy in the first complete remission are equivalent in outcomes. The lack of data on quality of life, secondary malignancies, and other late effects of treatment prevent a recommendation of one treatment over another.”
• The ASBMT also published a systematic review on the role of cytotoxic therapy with SCT in adult patients with AML. (66). While the panel found no significant advantage of autologous SCT over chemotherapy, they report most of the data reflect outmoded treatment strategies and studies using modern technologies may affect outcomes. This panel also recommends autologous SCT for patients in second complete remission when no donor is available for an allogeneic transplantation.  
• The National Comprehensive Cancer Network clinical practice guidelines for acute myeloid leukemia indicate autologous SCT is appropriate for consolidation therapy in patients with good-risk or intermediate-risk cytogenetics or in patients with relapse after a long remission. (67)

Amyloidosis                                                                            Return to Table

Amyloidosis is a group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. (214)

Historically, this disease has had a poor prognosis, with a median survival from diagnosis of about 12 months, although outcomes have improved with the advent of combination chemotherapy with alkylating agents and autologous SCT. Emerging approaches include the use of immunomodulating drugs such as thalidomide or lenalidomide, and the proteasome inhibitor bortezomib. Regardless of the approach chosen, treatment of amyloidosis is aimed at rapidly reducing the production of amyloidogenic monoclonal light chain proteins by suppressing the underlying plasma cell imbalance, with supportive care to decrease symptoms and maintaining organ function. (8)

Medically Necessary Indications

Available evidence suggests that autologous stem cell transplant (SCT) may be effective in the treatment of amyloidosis which is rarely cured by conventional chemotherapy.

• Initial early results of autologous SCT in uncontrolled patient series reported clinical response rates nearly twice those reported for conventional chemotherapy, with two-year survival ranging from 56% to 68%. (83-86) However, procedure-related mortality rates of 15% to 43% were high, usually in cases that involved more than two organ systems or had symptomatic cardiac involvement. (84, 87, 88)
• A subsequent retrospective study analyzed outcomes of conventional therapy for primary amyloidosis in patients who would have been eligible for autologous SCT. (86) Survival of conventionally managed patients (n=229) at 24 months was 61%, which was similar to two-year survival reported for patients who received autologous SCT.
• Additional matched-pair analyses and retrospective series continued to provide evidence for  comparable or greater overall survival and improvement in symptoms of amyloidosis for those given autologous SCT. (89-93)
• One more recently published randomized multi-center trial involving eight centers reported the hematologic response rate did not differ between patients with amyloidosis who received conventional chemotherapy and those treated with myeloablative melphalan followed by autologous SCT. (94) According to intention-to-treat analysis, the complete and partial response rates were 24% and 28% respectively in the melphalan-dexamethasone recipients versus 22% and 14% in the autologous SCT group (p=0.11).
  
  Median survival for patients assigned to conventional chemotherapy was 56.9 months versus 22.2 months in the autologous SCT group (p=0.04). Analysis of patients who survived for at least six months and who received their assigned treatment showed no significant difference in survival rates in patients assigned to conventional chemotherapy compared to autologous SCT, with neither group reaching median survival after 80 months (p=0.38).
  
  This data suggests autologous SCT may be no more efficacious than conventional chemotherapy in prolonging survival among patients with amyloidosis. However, the results are limited by the size of the study, a lack of assessor blinding or allocation concealment, and a large attrition post-randomization. Given the poor cure rate for amyloidosis with conventional chemotherapy and the body of evidence from earlier, although nonrandomized trials which suggest a survival benefit, results from ongoing trials will be important in providing additional information.
• The current National Comprehensive Cancer Network clinical practice guidelines for multiple myeloma, which include guidelines for amyloidosis, recommend autologous SCT as primary therapy for systemic amyloidosis, although they caution that the optimal therapy is not established and that such treatment would best be performed in a clinical trial. (95)

Astrocytoma and Gliomas                                                    Return to Table

Investigational Indications

Available evidence has not established that autologous stem cell transplant (SCT) is effective as a treatment for malignant astrocytomas or gliomas, including glioblastoma multiforme and oligodendroglioma.

• There are no published randomized controlled trials comparing autologous SCT with conventional chemotherapy or radiotherapy, so it is not known if autologous SCT improves disease-free survival, stabilizes disease progression or improves overall survival. (38)
• Data published to date are from uncontrolled clinical series which report substantial morbidity and mortality without improved survival or control of disease progression. (38-44) Treatment related mortality for high dose chemotherapy with autologous SCT was 5% while mortality associated with conventional chemotherapy or radiotherapy is less than 1%. (38)
• Data from randomized trials comparing autologous SCT with conventional treatments are needed in order to control for bias and independent treatment effect. 
• The 2008 National Comprehensive Cancer Network Guidelines on Central Nervous System Tumors do not list high-dose chemotherapy with autologous SCT as a treatment option for patients with astrocytomas or gliomas. (45)

See separate position statements for primitive neuroectodermal tumors (PNETS) of the central nervous system.

Autoimmune Diseases                                                           Return to Table

Investigational Indications

Available evidence has not yet established that autologous stem cell transplant (SCT) is effective for the treatment of any autoimmune disease including, but not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis/scleroderma.

• Available evidence is from case reports, uncontrolled case series and retrospective analyses of registry data. (29-31, 33) Case series describe a variety of outcomes in patients with a diagnosis of one of five different autoimmune diseases (systemic sclerosis; systemic lupus erythematosus; multiple sclerosis; rheumatoid arthritis; aplastic anemia). There is much overlap between patient data reported from the U.S.-based and European-based registries and data reported from specific clinical centers. 
  
  Data from these studies are unreliable as there are no controls for potential bias and no comparisons to standard treatment for individual autoimmune diseases.
• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment determined from registry data that approximately 10% of patients died from the procedure. (30) The likelihood of deaths depended on the disease — the largest percentage of deaths was observed in patients with juvenile idiopathic arthritis and scleroderma (14-16%), and the smallest occurred in those with rheumatoid arthritis (2%). A treatment-related mortality of 4% (2/50) was reported in a more recent case series of patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. (31)
• There is agreement in the literature, including several editorials, that the role of autologous SCT is not yet established for any autoimmune disease. (29-37) Given the general complexity of the autoimmune diseases, the fluctuating nature of their clinical manifestations, and the wide variations in disease activity among patients with the same disease and in any one patient at various points in time, prospective, randomized controlled trials are needed to evaluate autologous SCT in an adequate number of patients for each disease indication. In addition, these trials should apply standardized patient selection criteria, disease severity stratification, treatment protocols, and clinical outcomes measurements.
• There are no evidence-based clinical practice guidelines that recommend autologous SCT as a treatment of any autoimmune disease.

Breast Cancer                                                                        Return to Table

Investigational Indications

Available evidence does not demonstrate that autologous stem cell transplant (SCT) for the treatment of breast cancer results in improved health outcomes when compared to conventional chemotherapy.

• A 1998 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment concluded there was not sufficient evidence to determine the relative effectiveness of high dose chemotherapy with autologous SCT compared to conventional dose chemotherapy. (117) The TEC assessment focused on autologous SCT as adjuvant therapy for high-risk primary (i.e., stage II/III) breast cancer. The analysis included two small randomized trials and twelve uncontrolled case series. Data was not sufficient due to  the lack of larger controlled studies, small sample sizes, inadequate follow-up, and potential selection bias.
• Evidence from four randomized trials did not support the conclusion that high-dose chemotherapy with autologous SCT improved outcomes when compared with conventional-dose adjuvant therapy in high-risk non-metastatic breast cancer. (118-121). An editorial accompanying one report noted that of ten adjuvant therapy trials comparing high-dose to conventional-dose regimens (pooled n=4,521), none reported a statistically significant benefit in overall survival for the high-dose chemotherapy with autologous SCT arm, and only one reported improved disease-free survival. However, eight trials lacked adequate statistical power, likely from two factors: slow accrual leading to early closure and overly optimistic expectations on the magnitude of benefit.(215)
• A Cochrane systematic review and meta-analysis pooled data from six randomized controlled trials comparing HDC with autologous SCT (n=438) to conventional dose chemotherapy (n=412) in the treatment of metastatic breast cancer. (122) The relative risk for treatment-related mortality was significantly higher in the arm randomized to HDC with autologous SCT (15 vs. 2 deaths; RR=4.07; 95% CI: 1.39, 11.88). Treatment-related morbidity also was more severe among those randomized to HDC with autologous SCT. Overall survival did not differ significantly between groups at one, three, or five years after treatment. Statistically significant differences in event-free survival at one year and five years favored the HDC with autologous SCT arms. Only one of the six included trials followed all patients for at least five years. Reviewers concluded that, in the interim, patients with metastatic breast cancer should not receive HDC with autologous SCT outside of a clinical trial, since available data showed greater treatment-related mortality and toxicity without improved overall survival.
• A second Cochrane systematic review and meta-analysis included data from 13 randomized controlled trials comparing high-dose chemotherapy with autologous SCT (n=2,535) to conventional dose chemotherapy (n=2,529) in patients with high-risk (poor prognosis) early breast cancer. (123) Treatment-related mortality was significantly greater among those randomized to high-dose chemotherapy with autologous SCT (65 vs. 4 deaths; RR=8.58; 95% CI: 4.13, 17.80). Treatment-related morbidity also was more common and more severe in the SCT arms. There were no significant differences between arms in overall survival rates at any time after treatment. Event-free survival was significantly greater in the SCT group at three years (RR=1.12; 95% CI: 1.06, 1.19) and four years (RR=1.30; 95% CI: 1.16, 1.45) after treatment. However, the two groups did not differ significantly with respect to event-free survival at five and six years after treatment. There was also no statistically significant difference between groups in the incidence of secondary malignancies at five to seven years of follow-up. Quality of life scores were significantly worse in the SCT arms than in controls soon after treatment, but differences were no longer statistically significant by one year. Reviewers concluded available data were insufficient to support routine use of high-dose chemotherapy with autologous SCT for patients with poor-prognosis early breast cancer.
• At a median follow-up of 12 years, researchers continue to demonstrate no recurrence-free survival or overall survival advantage for patients with high-risk primary breast cancer treated with high-dose chemotherapy with autologous SCT after standard dose chemotherapy. (124) Coombes and colleagues reported no benefit from replacing three cycles of conventional chemotherapy with a high-dose regimen and stem-cell rescue given as adjuvant therapy. (125) Three randomized controlled trials published in 2008 continue to show no statistically significant difference in overall survival for high-dose chemotherapy with autologous SCT when compared to conventional chemotherapy for the treatment of metastatic breast cancer. (126-128)
• The National Comprehensive Cancer Network practice guidelines for breast cancer do not address the use of autologous stem cell transplant for the treatment of breast cancer. (129)

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)                                                                                       Return to Table

Treatment regimens used for CLL are generally the same as those used for SLL, and outcomes of treatment are comparable for the two diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of six to ten years, while the median survival of high-risk CLL or SLL may be only two years. Although typically responsive to initial chemotherapy (or chemo-immunotherapy), CLL and SLL are rarely cured, and nearly all patients ultimately die of their disease.

See separate position statements for other non-Hodgkin lymphomas.

Investigational Indications

It is uncertain if autologous stem cell transplant (SCT) is effective for the treatment of CLL or SLL.

• Available evidence is from uncontrolled case series and registry data. Data from these studies are unreliable as there are no controls for potential bias and no comparisons to currently recommended treatments.
• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded that in the absence of randomized trials, existing data were insufficient to permit scientific conclusions regarding the use of autologous SCT for the treatment of either CLL or SLL. (68) Data were limited by inter-study heterogeneity in patient baseline characteristics, procedural differences, small sample size, and short follow-up.
• More recent review articles discuss uncertainties with respect to the intensity of pretransplant conditioning, the optimal timing of transplantation in the disease course, the baseline patient characteristics that best predict likelihood of clinical benefit from transplant, and the long-term risks of adverse outcomes. (69-74) The conclusions reached in these reviews suggest that while autologous SCT may prolong survival in selected patients with CLL or SLL, it has not yet been shown to be curative.
• In 2007, a systematic review of autologous SCT for CLL or SLL that included nine prospective studies, none of which were randomized, further highlighted the difficulties of inter-study comparisons of the evidence on this treatment. (75) The authors of the review concluded that in the absence of randomized controlled studies, it is uncertain whether autologous SCT is superior to conventional chemotherapy (or current chemo-immunotherapy) either as first-line consolidation treatment or as a salvage therapy in CLL or SLL patients, regardless of disease risk.
  
  While autologous SCT may achieve significant clinical response rates (74%–100%) with relatively low treatment-related mortality (0–9%), molecular remissions are typically short lived, with subsequent relapse. Secondary myelodysplasia and myelodysplastic syndrome that may progress to frank acute myelogenous leukemia has been reported in 5%–12% of patients in some studies, which suggests caution in considering this approach, especially given the indolent nature of CLL or SLL.
• The most recent National Comprehensive Cancer Network clinical practice guidelines do not include autologous SCT as a treatment option for CLL and SLL.(76)

Chronic Myelogenous Leukemia (CML)                              Return to Table

Investigational Indications

Available evidence does not demonstrate that autologous stem cell transplant (SCT) is effective for the treatment of CML compared to either imatinib mesylate (Gleevec®) or allogeneic SCT.

• Available evidence is from uncontrolled case series in patient populations with varied characteristics, using a variety of techniques to enrich the population of normal stem cells among the harvested cells. (17-24) Data from these studies is unreliable as there are no controls for potential bias and no comparisons to currently recommended treatments, e.g., Gleevec or allogeneic SCT.
• Patients included in the published studies were treated before Gleevec became available. Since this drug has been shown to induce remissions, even among patients in accelerated phase and blast crisis, early studies of autotransplants for CML are not relevant to current clinical practice. (25-28)
• There are no evidence-based clinical practice guidelines that recommend autologous SCT as a treatment of CML.

Epithelial Ovarian Cancer                                                     Return to Table

Epithelial ovarian cancer accounts for 4% of all cancers in women and must be distinguished from the much less common germ cell tumor of the ovary. (55) In this policy the term ovarian cancer will refer exclusively to epithelial ovarian cancer. For germ cell tumors of the ovary, see separate position statements under germ cell tumors.

All stages of ovarian cancer are first treated with cytoreductive surgery, including removal of the ovaries, fallopian tubes, and a total abdominal hysterectomy followed by combination chemotherapy.(61) The use of platinum and taxanes has improved progression-free survival and overall survival rates in advanced disease.(62) However, most of these women develop recurrences and die of their disease as chemotherapy drug resistance leads to uncontrolled cancer growth. (61) High-dose chemotherapy has been investigated as a way to overcome drug resistance.

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with autologous stem cell transplantation (SCT) is effective for the treatment of epithelial ovarian cancer.

• Data published prior to 2007 consists of prospective and retrospective analyses of case series and registry data which allows only indirect comparisons of high-dose chemotherapy with autologous SCT to conventional dose chemotherapy. (46-59) These comparisons are unreliable as data from the uncontrolled studies were flawed by age and selection bias and by differences in performance status and other baseline characteristics of patients included in the two sets of studies. Response duration and survival data were unavailable for comparison.
• Two phase III randomized trials of high-dose chemotherapy with autologous SCT reported no improvement in overall survival or progression-free survival when compared with standard dose chemotherapy. Conclusions from these trials are uncertain because the studies were of small size, data were combined from two different protocols, or the studies were not adequately powered to prove equivalence between high-dose chemotherapy with autologous SCT and conventional chemotherapy. (60, 61)
• The National Comprehensive Cancer Network clinical practice guidelines for ovarian cancer indicate that high-dose chemotherapy with autologous SCT is considered investigational. (62)

Ewing’s Sarcoma Family Tumors                       Return to Table

Current therapy for Ewing’s sarcoma favors induction chemotherapy, with local control consisting of surgery and/or radiation (dependent on tumor size and location), followed by adjuvant chemotherapy. Multi-agent chemotherapy, surgery, and radiation therapy have improved the progression-free survival in patients with localized disease to 60%–70%. (195)

The presence of metastatic disease is the most unfavorable prognostic feature for Ewing’s sarcoma, and the outcome for patients presenting with metastatic disease is poor, with 20%–30% progression-free survival. Thirty to forty percent of patients experience disease recurrence, and patients with recurrent disease have a five-year event-free survival and overall survival rate of less than 10%. (198) 

See separate position statements for central nervous system primitive neuroectodermal tumors (PNETS).

Medically Necessary Indications

Evidence suggests that high-dose chemotherapy with autologous SCT may be effective to consolidate remissions of Ewing’s sarcoma or as a salvage therapy for those with residual, recurrent, or refractory disease.

• High-dose chemotherapy with stem cell transplantation has been shown to be effective in patients with relapsed or progressive Ewing’s sarcoma in several small studies, even though it is associated with severe toxicity. (7, 195-197)  Due to the poor prognosis of recurrent disease, this treatment may be considered an option.
• A more recently published trial showed conflicting results from previous studies;  however, this study was also small and nonrandomized. (199) The authors noted that some previous studies included heterogeneous patient populations which could account for the different outcomes. They concluded that future trials of high dose chemotherapy with SCT must be conducted prospectively, with identification of a group at high risk for failure, and all patients entering the study at the same point in therapy.
• A large Phase III trial (EURO-EWING 99) is underway, and will likely serve to guide future treatment options for Ewing sarcoma family tumors. (200)
• The National Comprehensive Cancer Network clinical practice guidelines for the treatment of Ewing sarcoma family tumors indicate the role of high dose chemotherapy and stem cell transplant for high-risk ESFT patients is yet to be determined in randomized controlled trials and patients with recurrent or metastatic ESFTs should be considered for investigational approaches.(196) 

Investigational Indications

There is insufficient data to determine whether high-dose chemotherapy with autologous stem cell transplant (SCT) is effective as an initial treatment for Ewing’s sarcoma.

• No trials have been identified which directly compare high-dose chemotherapy with autologous SCT to multi-agent chemotherapy as initial treatment of Ewing sarcoma family tumors. Without such comparisons, it is not possible to determine if autologous SCT is as effective as or better than current standard treatment.
• The National Comprehensive Cancer Network clinical practice guidelines for bone cancer indicate primary treatment for all patients with Ewing’s sarcoma should include the following: 1) multi-agent chemotherapy along with appropriate growth factor support for 12-14 weeks; 2) local control therapy such as excision, with or without preoperative radiation therapy; and 3) adjuvant chemotherapy, including a combination of at least three standard dose chemotherapeutic agents. These guidelines indicate the role of high dose chemotherapy and stem cell transplant for high-risk ESFT patients is yet to be determined in randomized controlled trials and patients with recurrent and metastatic ESFTs should be considered for investigational approaches.(196)

Genetic Diseases and Acquired Anemias                             Return to Table

Medically Necessary Indications

High-dose chemotherapy with allogeneic stem cell transplant (SCT) is considered effective for the treatment of selected patients with the following disorders (10):

Aplastic anemia, severe or very severe, including congenital (e.g. Fanconi’s anemia, Diamond-Blackfan syndrome, Familial hemophagocytic lymphohistiocytosis (HLH)) or acquired (secondary to drug or toxin exposure). Appropriate patients include those with platelets less than 20 x 109/L, granulocytes less than 0.5 x 109/L, and reticulocytes less than 1% (corrected for hematocrit) and who have failed antithymocyte globulin therapy;

Anemia, sickle cell, for children or young adults with either a history of prior stroke or at increased risk of stroke or end-organ damage, and with an HLA-identical, related donor. Factors associated with a high risk of stroke or end-organ damage include: recurrent chest syndrome, recurrent vaso-occlusive crises, red blood cell alloimmunization on chronic transfusion therapy;

Homozygous beta-thalassemia (thalassemia major);

Infantile malignant osteopetrosis (Albers-Schönberg disease or marble bone disease);

Kostmann’s syndrome;

Leukocyte adhesion deficiencies;

Mucolipidoses (Gaucher’s disease, metachromatic leukodystrophy, globoid cell leukodystrophy, adrenoleukodystrophy) for patients who have failed conventional therapy, including diet and enzyme replacement and who are neurologically intact;

Mucopolysaccharidoses (Hunter’s, Hurler’s, Sanfilippo, Maroteaux-Lamy variants) in patients who are neurologically intact;

Severe combined immunodeficiencies;

Wiskott-Aldrich syndrome;

X-linked lymphoproliferative syndrome.

Four BlueCross BlueShield Association Technology Evaluation Center (TEC) assessments concluded that the evidence was sufficient to determine high-dose chemotherapy and allogeneic SCT is effective for certain genetically inherited diseases and acquired anemias. (94-97). Each TEC assessment determined there was an improvement in overall health outcomes for the above mentioned indications, especially for conditions where no alternative treatment is available.

Germ Cell Tumors (GCT)                                                      Return to Table

Germ-cell tumors (GCT) are composed primarily of testicular neoplasms (seminomas or nonseminomatous GCT) but also include ovarian and extragonadal GCTs (e.g., retroperitoneal or mediastinal tumors). Germ cell tumors of the ovary should be distinguished from the more common epithelial ovarian tumors which are addressed separately in this policy.

Therapy for GCT is generally dictated by stage, risk subgroup, and cell type. For example, primary therapy for early stage seminomas may rely on radiation therapy alone while more advanced stages of seminoma and non-seminomatous tumors ( stage ≥ IB) are given primary chemotherapy. Patients with stage IA non-seminomatous tumors may be managed initially by surgery, followed by adjuvant chemotherapy. First-line chemotherapy for good- and intermediate-risk patients with higher-stage disease is usually three or four cycles of a chemotherapeutic regimen followed by surgery to remove residual masses. Second-line therapy often consists of combined chemotherapy with agents not used for first-line treatment. The probability of long-term continuous complete remission diminishes with each successive relapse. (10) To determine the safety and efficacy of high-dose chemotherapy with autologous SCT, comparisons to these conventional treatments must be made.

Medically Necessary Indications

Evidence for high-dose chemotherapy with autologous SCT suggests it is an effective treatment for germ cell tumors that do not achieve a complete remission (i.e. partial response*) after initial therapy, for second remissions, or for relapsed/refractory germ cell tumors after a second complete response.

*The term “partial response” is defined as at least a 50% reduction in tumor burden while complete response is 100% reduction in tumor burden.

• Survival curves based on the outcome of high-dose chemotherapy with autologous SCT for 108 patients with poor prognosis germ cell tumors who failed standard dose chemotherapy revealed a 30% probability of survival at 15 months. In contrast, patients in this category who failed the best available standard dose chemotherapy decline rapidly and survival rates at 15 months are zero. Thus, high-dose chemotherapy with autologous SCT improves net health outcomes for patients who have failed standard courses of chemotherapy. (107)
• The 2008 National Comprehensive Cancer Network guidelines on testicular cancer recommend high-dose chemotherapy with autologous SCT if the patient experiences an incomplete response or relapses after salvage chemotherapy. (109)

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with autologous stem cell transplant (SCT) is effective as initial treatment of germ cell tumors or as an initial treatment of a first relapse (i.e., in lieu of a course of conventional chemotherapy after relapse from a first complete response).

• A 1991 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment concluded data were insufficient to permit conclusions about the outcomes of high-dose chemotherapy and autologous SCT as a component of initial therapy in patients with poor-risk tumors, or after a first relapse following initial standard-dose chemotherapy. (107)
• Subsequent review articles present uncertain evidence with respect to improved health outcomes of autologous SCT as a first-line treatment. In one review, only two of six pooled studies reported survival outcomes. It was unclear whether long-term survival was better for autologous SCT than for conventional-dose therapy in comparable patients. (108)
• In this same review, pooled results from five small studies using autologous SCT to treat germ tumors at first relapse reported the rate of continuous complete response was 56% with an estimated duration of 29 months. (108) Treatment-related mortality was 5%. In contrast, conventional-dose chemotherapy achieves five-year disease-free survival of 30% and treatment-related mortality of 2% or less. Since high dose chemotherapy with autologous SCT carries a higher risk of initial treatment-related mortality, it is important to compare the long-term survival after conventional therapy with long-term survival after HDC.
• Reported outcomes from randomized trials published after the TEC assessment demonstrated no statistically significant differences between conventional chemotherapy and high-dose chemotherapy with autologous SCT. (104, 105)
  
  In one trial of 219 previously untreated patients with poor-prognosis germ cell tumors, patients received either four cycles of standard chemotherapy or two cycles of standard chemotherapy followed by two cycles of  high dose chemotherapy with autologous SCT. (104) The one-year durable complete response rate was 48% after standard chemotherapy alone and 52% after standard chemotherapy and high dose chemotherapy with SCT (p=0.53). There was no statistically significant difference between the two treatment arms.
  
  A second randomized trial of 280 patients who had relapsed after a complete or partial remission reported no significant differences between treatment arms in three-year event-free survival and overall survival. (105) However, this study began before international consensus established the current risk group definitions. (106) Thus, the authors likely included some patients now considered to have good prognosis at relapse. Furthermore, the study did not compare the two groups in terms of thresholds that presently determine risk levels. Finally, 28% of those randomized to the high dose chemotherapy arm did not receive high dose chemotherapy because of progression, toxicity, or withdrawal of consent.(10)
• There are no published evidence-based clinical practice guidelines that recommend autologous SCT as initial treatment of germ cell tumors or as an initial treatment of a first relapse.

Hodgkin’s Lymphoma (HL)                                                   Return to Table

Up to 80% of newly diagnosed patients with Hodgkin’s lymphoma are curable using a combination chemotherapy and/or radiation.  Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. (139)

Medically Necessary Indications

Data suggests that high-dose chemotherapy with autologous stem cell transplantation (SCT) is effective for primary refractory* or relapsed Hodgkin’s lymphoma.

*Primary refractory Hodgkin’s lymphoma is defined as disease regression of less than 50% after four to six cycles of anthracycline-containing chemotherapy, disease progression during induction therapy, or progression within 90 days after the completion of first-line treatment. (141)

• A 1987 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment that focused on high-dose chemotherapy with autologous SCT concluded that for patients with relapsed disease, the evidence is sufficient to suggest that autologous SCT may achieve durable, complete remission and thereby improve long-term survival of Hodgkin’s disease.(142)
• The British National Lymphoma Investigation randomized trial showed progression-free survival benefit with autologous SCT over conventional chemotherapy in relapsed or refractory Hodgkin’s lymphoma patients. Forty patients with relapsed or refractory disease were given chemotherapy without transplant or high-dose chemotherapy with autologous SCT. (144) Event-free survival was significantly better at three years in the transplant group (53% versus 10%). (143, 144)
• In 2007, these findings were confirmed in a larger trial. (145) Patients relapsing after initial chemotherapy were randomized to chemotherapy without transplant or to autologous SCT. In the final analysis of 144 patients, freedom from treatment failure at three years was 55% in the transplanted group versus 34% in the nontransplanted group. This benefit was maintained in subgroup analysis, regardless of early or late relapse, and the results were confirmed in follow-up data at seven years. (146)
• The 2008 National Comprehensive Cancer Network guidelines recommend autologous SCT as the best option for patients with Hodgkin’s lymphoma that is incurable after primary treatment. (139)

Investigational Indications

The available evidence is not sufficient to determine whether high-dose chemotherapy with autologous stem cell transplant (SCT) is effective either as an initial therapy for Hodgkin’s lymphoma or for consolidation of a first complete remission.

• There are minimal data comparing outcomes of high dose chemotherapy with autologous SCT to conventional therapies as an initial treatment for Hodgkin’s lymphoma. One randomized trial was published in which patients with advanced Hodgkin’s lymphoma received front-line therapy with high dose chemotherapy and autologous SCT or conventional chemotherapy. (140) No benefit in outcomes was reported for autologous SCT.
• The 2008 National Comprehensive Cancer Network guidelines recommend chemotherapy and/or radiation as both first and second-line therapies for Hodgkin’s lymphoma. (139)  The guidelines recommend autologous SCT as the best option for patients with Hodgkin’s lymphoma that is incurable after primary treatment.

Multiple Myeloma (MM)                                                        Return to Table

MM is a systemic malignancy of relatively well-differentiated plasma cells. Management of myeloma is generally related to tumor mass.  Patients with a high tumor mass undergo systemic cytotoxic chemotherapy.  However, multiple myeloma rarely is cured with standard-dose chemotherapy. (16)

Patients with responsive myeloma are defined as those who achieve a complete or partial (at least 50% tumor reduction) response to high-dose chemotherapy.  Patients with resistant or refractory multiple myeloma are defined as those who achieve <50% reduction in tumor burden after high-dose chemotherapy. (202)  Multiple myeloma in a refractory relapse differs from primary progressive disease which is newly diagnosed myeloma that does not enter a partial or complete remission after initial conventional induction therapy.

Medically Necessary Indications

With the exception of refractory relapse, the evidence suggests high-dose chemotherapy with autologous stem cell transplant (SCT) may be an effective treatment for patients with MM including: newly diagnosed, primary refractory, and responsive MM patients who relapse after a durable complete or partial remission following an initial autologous SCT.

Newly diagnosed or responsive MM

• Available data support the conclusion that autologous SCT is at least as effective and may be more effective than conventional-dose chemotherapy for improving the health outcomes of patients with newly diagnosed or responsive MM.  Randomized controlled trials have shown event-free and overall survival after myeloablative therapy with autologous SCT was clearly better than after conventional chemotherapy. (202, 205, 206) Evidence-based reviews and meta-analyses confirm these findings. (203, 205, 207)
• In contrast, three later randomized controlled trials reported that autologous SCT was not associated with a significant difference in overall survival compared to conventional chemotherapy, which differs from the positive results noted above. (208-210) The reasons for the discrepant results compared to the positive findings of other randomized trials are uncertain, but may be related to conditioning regimen or patient age. For example, conditioning with total body irradiation and a smaller dose of melphalan used in some of these later trials was shown to be less effective. (211)
• A meta-analysis of randomized controlled trials compared chemotherapy versus myeloablative chemotherapy with single autologous SCT. (212)  The nine trials that met the selection criteria (n=2,411) included two of the studies mentioned above that did not detect a survival benefit from myeloablative chemotherapy. (208, 209)  The authors concluded that myeloablative therapy with autologous SCT increased the likelihood of progression-free survival but not overall survival; the odds ratio for treatment-related mortality was 3.01 (95% CI: 1.64-5.50) in the autologous SCT group. However, the effects of myeloablative chemotherapy and autologous SCT may have been diluted by the fact that up to 55% of patients in the standard chemotherapy group received myeloablative chemotherapy with autologous SCT as salvage therapy when the multiple myeloma progressed. This could account for the lack of a significant difference in overall survival between the two groups in the study.
• The National Comprehensive Cancer Network guidelines for multiple myeloma indicate a category one recommendation (strong evidence) to proceed directly to autologous SCT after induction chemotherapy. (201)

Primary refractory disease

• Two evidence-based reviews and one randomized controlled trial on newly diagnosed patients with primary refractory myeloma (i.e. newly diagnosed and not responsive to conventional induction chemotherapy) showed that autologous SCT induces durable remissions and extends the duration of overall survival and disease-free survival in a substantial proportion of patients with primary refractory disease. (202, 203, 205, 207)

Second autologous SCT for responsive MM relapsed after a prior autologous SCT

• The American Society for Blood and Marrow Transplantation (ASBMT) evidence-based systematic review reported that some responsive myeloma patients who relapsed after a first autotransplant achieved durable complete or partial remissions after a second autotransplant as salvage therapy. (203)
• Retrospective studies report durable complete or partial responses and extended survival for patients with responsive MM treated with a second autologous SCT after a prior autologous SCT, particularly when a long disease- or progression-free interval followed the first transplant. (16)  Although retrospective studies are unreliable, it is unlikely that prospective trials will ever be conducted to rigorously compare outcomes on the effectiveness of a second autologous SCT in responsive MM after a prior failed autologous SCT. (16)

Investigational Indications

Data are insufficient to determine whether autologous stem cell transplant (SCT) is effective for the treatment of multiple myeloma in a refractory relapse.

• There are no randomized controlled trials comparing autologous SCT for the treatment of MM in refractory relapse to standard treatment. Most of the data consists of uncontrolled case series of patients, and outcomes were poor.  Treatment-related toxicity was frequent and severe in heavily pretreated patients. (202)
• Both a 2003 evidence-based systematic review and the clinical guidelines of the American Society for Blood and Marrow Transplantation emphasize the lack of data from randomized controlled trials. (203, 204)  The review and  current guideline conclude that autologous SCT is preferred as de novo rather than salvage therapy, since this minimizes risks of myelodysplasia and other toxicities that occur from extended treatment with alkylating agents.
• The National Comprehensive Cancer Network guidelines for multiple myeloma discuss use of conventional chemotherapy as a salvage treatment for refractory multiple myeloma and recommend autologous SCT as salvage only in the context of a clinical trial. (201)

Neuroblastoma (peripheral)                                                    Return to Table

Neuroblastoma is the most common extracranial solid tumor of childhood. (147) These tumors originate where sympathetic nervous system tissue is present, within the adrenal medulla or paraspinal sympathetic ganglia. They are remarkable for their broad spectrum of clinical behavior, with some undergoing spontaneous regression, others differentiating into benign tumors, and still others progressing rapidly and resulting in patient death. (7)

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and high) that determine treatment plans. (148) Risk variables include age at diagnosis, clinical stage of disease as defined by the International Neuroblastoma Staging System (INSS), tumor histology, and certain molecular characteristics, including the presence of the myelocytomatosis viral related (MYCN) oncogene.

High-risk neuroblastoma is characterized by an age older than one year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings. (148) It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis (149), even in the setting of other coexisting favorable factors.

Conventional chemotherapy rarely results in long-term survival in the 60% of children with high-risk tumors. Therefore, research on high dose chemotherapy has focused on those with high-risk neuroblastoma.

See separate position statements for central nervous system primitive neuroectodermal tumors (PNETs).

Medically Necessary Indications

The evidence suggests high-dose chemotherapy with autologous stem cell transplant (SCT), except as a treatment of low- to intermediate-risk patients, may be effective for the treatment of neuroblastoma.

• In general, most patients with low-stage disease have excellent outcomes with minimal therapy, and with INSS stage 1 disease, most patients can be treated by surgery alone. (147) Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery. (147)
• In contrast, for high-risk patients, myeloablative consolidation with autologous SCT has been shown to improve event-free survival in three randomized studies.. (150-152)
• One study showed improved five-year overall survival in a high-risk group of patients with stage four disease and older than one year of age compared with the control group. (152)
• Additionally, most children older than one year with advanced-stage disease die due to progressive disease, despite intensive multimodality therapy and relapse remains common. (147)
• There are no published evidence-based clinical practice guidelines that address the use of high-dose chemotherapy with autologous SCT for the treatment of neuroblastoma.

Non-Hodgkin’s Lymphoma (NHL)                                         Return to Table

Non-Hodgkin’s lymphomas (NHL) are hematologic (blood, bone marrow, or lymph node) cancers arising from lymphocytes arrested at various stages of maturation. In general, NHL can be divided into two prognostic groups, indolent and aggressive.

Indolent NHL has a relatively good prognosis with a median survival of ten years; however, it is not curable in advanced clinical stages. (154) Follicular lymphoma is the most common indolent NHL (70%–80% of cases), and often the terms indolent lymphoma and follicular lymphoma are used synonymously. Also included in the indolent NHLs are small lymphocytic lymphoma/chronic lymphocytic leukemia*, lymphoplasmacytoid lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphoma. (14)

* See separate position statements for small lymphocytic lymphoma and chronic lymphocytic leukemia.

Aggressive NHL has a shorter natural history; however, 30%–60% of these patients can be cured with intensive combination chemotherapy regimens. (154) Aggressive lymphomas include diffuse large B-cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, and Burkitt’s lymphoma.

Medically Necessary Indications

Evidence suggests that high-dose chemotherapy with autologous stem cell transplant (SCT) may be effective for the treatment of NHL, except as initial treatment.

In 2004, Lenz and colleagues reported on the results of a trial of 307 patients with advanced stage lymphoma in first remission, including follicular lymphoma, mantle cell lymphoma, or lymphoplasmacytoid lymphoma. (162) Patients were randomized to receive either consolidative therapy with autologous SCT or interferon therapy. The five-year progression-free survival rate was considerably higher in the autologous transplant arm (64.7%) compared to the interferon arm (33.3%). The median follow-up of patients was too short to allow any comparison of overall survival.

One randomized trial of 89 patients with relapsed, non-transformed follicular lymphoma with partial or complete response after standard induction chemotherapy reported results of patients randomized to one of three arms: conventional chemotherapy, high-dose chemotherapy and unpurged autologous SCT, or high-dose chemotherapy with purged (immunologically treated to remove residual disease) autologous stem-cell support. (163) Overall survival at four years for the chemotherapy versus unpurged versus purged arms was 46%, 71%, and 77%, respectively. Two-year progression-free survival was 26%, 58%, and 55%, respectively. No statistically significant difference was found between the two autologous SCT arms. Although several studies have consistently shown improved disease-free survival with autologous SCT for relapsed follicular lymphoma, this study was the first to show a difference in overall survival benefit. (164)

Several randomized trials compared outcomes of autologous SCT used to consolidate a first complete remission in patients with intermediate or aggressive NHL with outcomes of an alternative strategy that delayed transplants until relapse. (165-168) The preponderance of evidence showed that consolidating first complete responses with SCT did not improve overall survival for the full population of enrolled patients. (171) However, a subgroup analysis at eight years’ median follow-up reported superior overall survival (64% vs. 49%, p=0.04) and disease-free survival (55% vs. 39%; p=0.02) for patients at elevated risk of relapse who were consolidated with an autologous SCT. (163, 169)

A large, multi group, prospective, randomized Phase III comparison of consolidation strategies is ongoing to confirm results of the above subgroup analysis in a larger population with diffuse large B-cell lymphoma at high- and high-intermediate risk of relapse. Nevertheless, many clinicians view the above subgroup analysis as sufficient evidence to support use of autologous SCT to consolidate a first complete response when the risk of relapse is high. (170)

The 2008 National Comprehensive Cancer Network guidelines recommend autologous SCT as the treatment of choice for relapsed or refractory NHL. In addition, the guidelines support the use of autologous SCT as a consolidation treatment after induction chemotherapy or as second-line/salvage therapy for various NHLs. (76)

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with autologous SCT is effective as initial therapy for NHL.

• Six randomized trials including both indolent and aggressive NHL subtypes compared high-dose chemotherapy with autologous SCT to conventional dose chemotherapy as a first-line treatment for NHL. There was no improvement in overall survival in the SCT group. (155-160)
• One evidence-based systematic review and meta-analysis reported while complete response rates were significantly higher in the SCT group in thirteen studies with 2,018 patients, high-dose chemotherapy with SCT did not have an effect on overall survival when compared to conventional chemotherapy, (p=0.004). (161)
• There are no evidence-based clinical practice guidelines that recommend autologous SCT as initial therapy for NHL. (76)

Other Solid Tumors of Childhood                                          Return to Table

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy and autologous stem cell transplant (SCT) is effective to treat rhabdomyosarcoma, Wilms’ tumor with favorable histology, osteosarcoma, or retinoblastoma.

Rhabdomyosarcoma (RMS)

Most children with RMS present with localized disease, and with conventional multimodal chemotherapy therapy, the cure rate in this group is 70%–80%. (179) However, approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the five-year survival is 20%–30% for this “high-risk” group. (179, 180)

• Data on the use of high-dose chemotherapy with autologous SCT for the treatment of rhabdomyosarcoma are relatively scarce, due in part to the rarity of this condition; therefore data are limited to nonrandomized studies.
• One review summarized published data on the role of high-dose chemotherapy with SCT in the treatment of metastatic or recurrent rhabdomyosarcoma in 398 patients from 22 studies. (181) Based on all of the data analyzing event-free survival and overall survival, the authors concluded that there was no significant advantage to undergoing this treatment.
• One prospective nonrandomized study of 52 patients with metastatic RMS, compared patients in complete remission after induction chemotherapy. Those who received high-dose chemotherapy and SCT were compared to 44 patients who received conventional chemotherapy. (182) No significant differences existed between the two study groups in baseline characteristics. The difference in three-year event-free survival and overall survival was not statistically significant. Although there was some delay to relapse in the high-dose chemotherapy /SCT group, there was no clear survival benefit from using high-dose chemotherapy and SCT compared to conventional chemotherapy.
• The National Comprehensive Cancer Network clinical practice guidelines are silent on the use of autologous stem cell transplant for rhabdomyosarcoma. (194)

Wilms’ Tumor with favorable histology*

Wilms tumor is the most common primary malignant renal tumor of childhood and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Tumor histology is a strong and independent prognostic factor with Wilms’ tumors generally divided into two categories: favorable histology and unfavorable (or anaplastic) histology. (78) Wilms’ tumor with favorable histology is highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%. (77)

Available evidence does not demonstrate that high-dose chemotherapy with autologous SCT is effective for the treatment of Wilms’ tumor with favorable histology.

• There are no randomized trials comparing high-dose chemotherapy with autologous SCT to conventional treatments for Wilms’ tumors with favorable histology. Published studies concentrate on treatment of high-risk disease, i.e., tumors with unfavorable (or anaplastic) histology.
• There are no evidence-based clinical practice guidelines that recommend high-dose chemotherapy with autologous SCT as a treatment of Wilms’ tumors with favorable histology.

* See Wilms’ tumor- recurrent, high-risk for the position summary on Wilms tumor with unfavorable histology.

Osteosarcoma

Most treatment protocols for osteosarcoma use neoadjuvant chemotherapy, surgical resection of the tumor (and/or metastases), followed by adjuvant chemotherapy. Patients with localized disease have a much better prognosis than those with metastatic disease, and the prognosis for those with metastatic disease is determined, in part, by the number and surgical resectability of the metastases. With current multimodality chemotherapy, approximately 75% of all patients are cured (185) Overall event-free survival for patients with metastatic disease at diagnosis is about 20%–30%. (183)

• Rare small case series and case reports examining the use of high-dose chemotherapy with autologous SCT in osteosarcoma report no clear benefit in event-free survival or overall survival. (184)
• The National Comprehensive Cancer Network clinical practice guidelines do not recommend high-dose chemotherapy with autologous SCT as a treatment option for osteosarcoma. (185)

Retinoblastoma

Retinoblastoma is usually confined to the eye, and with current therapies (e.g. radiation, chemotherapy and surgery), has at least a 90% cure rate. However, once disease has spread beyond the eye, survival rates drop significantly; five-year disease-free survival is reported to be less than 10% in those with extraocular disease. (186)

• Most studies of high-dose chemotherapy with SCT for high-risk retinoblastoma have been very small series or case reports from which firm conclusions concerning health outcomes cannot be reached. (187-192) However, the results have been promising in terms of prolonging disease-free survival in these patients, particularly those without central nervous system involvement. Given the 90% cure rate for currently available treatments and the treatment-related morbidity associated with high-dose chemotherapy and autologous stem cell transplant, results from ongoing phase III trials are needed to further evaluate the overall health benefit of this therapy for the treatment of retinoblastoma.
• A single-arm, Phase III trial is underway to estimate the proportion of children with extraocular retinoblastoma who achieve long-term event-free survival after high-dose chemotherapy with SCT compared to historical controls. The estimated date of completion of the trial is July 2009. (193)
• There are no evidence based clinical practice guidelines that recommend high-dose chemotherapy with autologous SCT as a treatment of Retinoblastoma.

Ependymoma                                                                           Return to Table

Ependymoma is a neuroepithelial tumor that arises from the ependymal lining cell of the ventricles of the brain and is therefore usually contiguous with the ventricular system. (96) Ependymomas are distinct from ependymoblastomas (a primitive neuroepithelial cell tumor) due to their more mature histologic differentiation. For this reason, ependymomas are not formally considered primitive neuroectodermal tumors (PNETs).

Initial treatment of ependymoma consists of maximal surgical resection followed by radiotherapy. Chemotherapy usually does not play a role in the initial treatment of ependymoma. However, disease relapse is common, typically occurring at the site of origin. Treatment of recurrence is problematic as further surgical resection or radiation therapy is usually not possible. (9) Given the poor response to conventional-dose chemotherapy, high dose chemotherapy with autologous stem cell transplant (SCT) has been investigated as a possible salvage therapy.

Investigational Indications

Available evidence is not sufficient to determine if high-dose chemotherapy with autologous SCT is effective as a salvage therapy to treat ependymoma.

• There are no published randomized, controlled trials reporting outcomes of high dose chemotherapy with autologous SCT for patients with ependymoma.
• Literature published to date consists primarily of small case series with variable outcomes. (97, 98)  For example, Mason and colleagues reported on a case series of 15 patients with recurrent ependymoma. (97)  Similarly, Grill and colleagues reported a disappointing experience in 16 children.(98)
• The National Comprehensive Cancer Network guidelines on central nervous system cancers do not address high dose chemotherapy with autologous SCT as a treatment option for ependymoma. (45)

Primitive Neuroectodermal Tumors (PNETs), including Medulloblastoma                                                                                                Return to Table

Primitive neuroepithelial tumors (PNETs) arise from neuroepithelial cells and include medulloblastoma, neuroblastoma arising in the central nervous system (CNS), ependymoblastoma, or pinealoblastoma. All show similar histology and are distinguished by their site of origin, biologic behavior, and different genetic alterations. (99) Many studies include PNETs in general and do not make a distinction between the site of origin. The most common central nervous system PNET is medulloblastoma, and thus, most studies focus on this diagnosis. (9)

Initial therapy of central nervous system PNETs focuses on neurosurgical resection, plus radiation therapy with or without adjuvant conventional-dose chemotherapy. Sixty percent of children survive five years or more with this approach. In patients with residual tumor or recurrent disease, further surgery or radiation therapy usually is not an option, and conventional chemotherapy rarely is successful. Additionally, the use of radiotherapy in children may be limited by its adverse neurodevelopmental effects. Studies of high-dose chemotherapy with autologous stem cell transplant for central nervous system PNETs have focused primarily on residual or recurrent disease. (9)

Other central nervous system tumors include astrocytoma, oligodendroglioma, and glioblastoma multiforme. However, these tumors arise from glial cells and not neuroepithelial cells. See separate position statements concerning other central nervous system tumors.

Due to their neuroepithelial origin, peripheral neuroblastoma and Ewing’s sarcoma may be considered PNETs. See separate policy statements concerning neuroblastoma (peripheral) and Ewing sarcoma. 

Medically Necessary Indications

Given the poor response of conventional chemotherapy in patients with recurrent or residual disease and the potential adverse neurodevelopmental effects of repeated radiotherapy for children, available evidence suggests an overall survival benefit for high-dose chemotherapy and autologous SCT when used as a salvage therapy for recurrent or residual PNETs including medulloblastoma.

• While no randomized, controlled trials are available that compare high-dose chemotherapy with autologous SCT with standard therapies for PNETs, several case series indicate a benefit of this therapy in overall survival. (100-103)
• In a larger case series (n=134) following maximum tumor resection, all patients received risk-adapted radiotherapy followed by four cycles of high-dose chemotherapy with autologous SCT. (100) After resection, patients were classified as having average-risk or high-risk disease. Five-year overall survival was 85% among the average-risk cases (95% CI: 75–94) and 70% in the high-risk patients (95% CI 54-84). Five-year event-free survival was 83% (95% CI: 73–93) and 70% (95% CI: 55–85) for average- and high-risk patients, respectively. No treatment-related deaths were reported.
• A case series of 53 patients with newly diagnosed medulloblastoma or supratentorial PNETs and high-risk or average-risk disease, reported results on use of high-dose chemotherapy and autologous SCT after initial surgery and radiotherapy. Patients with high-risk disease also received topotecan between surgery and radiotherapy. Early actuarial analysis of outcomes yielded estimates of 94% progression-free survival at two years for average-risk patients and 74% for high-risk patients. (101)
• Bertuzzi and colleagues published results of a study in which fourteen patients with poor prognosis PNETs were treated with high dose chemotherapy followed by autologous SCT. (102) The overall response rate for the PNET patients was 86% (72% CR, 14% PR). Their overall two-year survival was 50%.
• In a small case series of 23 patients with recurrent medulloblastoma treated with high-dose chemotherapy and autologous SCT, seven patients were event-free survivors at a median of 54 months, with overall survival estimated at 46% at 36 months. (103) In contrast, the median survival after recurrent medulloblastoma treated with conventional therapy may be as low as five months. The authors acknowledged the potential for effects of patient selection bias on their results, since not all patients eligible for the protocol were enrolled.
• Other central nervous system PNETs (pinealblastoma, ependymoblastoma, and central neuroblastoma) are uncommon. There were few data regarding high-dose therapy for these rare tumors, although it was thought that the results with medulloblastoma may be extrapolated to other PNETs. (9)
• The National Comprehensive Cancer Network (NCCN) Guidelines on central nervous system cancers do not address the treatment of Medulloblastoma or other similar PNET tumors.(45)

Solid Tumors in Adults                                                          Return to Table

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with autologous stem cell transplant (SCT) is effective as a treatment of solid tumors in adults, including but not limited to the following:

• Bile duct cancer
• Cervical cancer
• Colon cancer
• Esophageal cancer
• Fallopian tube cancer
• Gall bladder cancer
• Lung cancer, any histology
• Malignant melanoma
• Nasopharyngeal cancer
• Neuroendocrine tumors
• Osteosarcoma, adult
• Pancreatic cancer
• Paranasal sinus cancer
• Prostate cancer
• Rectal cancer
• Renal cell cancer
• Soft tissue sarcomas
• Stomach cancer
• Thymus cancer
• Thyroid cancer
• Unknown primary origin cancer
• Uterine cancer

Data on the use of autologous SCT for the treatment of solid tumors in adults consists mainly of anecdotal reports and small case series; the number of randomized trials is limited. (15, 172-174)

• A 1995 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment focused on the malignancies listed above determined the evidence did not permit conclusions concerning the effect of high-dose chemotherapy with autologous SCT on patient survival. (172) While 125 articles were identified that reported on the results of high-dose chemotherapy in a variety of solid tumors, only 17 included survival data from groups of patients with the same cancer. Data from these studies are unreliable either due to small sample size or lack of controls which would permit direct comparisons with currently recommended treatments.
• In a phase III trial published after the TEC assessment, 318 patients with small cell lung cancer were randomly assigned to standard chemotherapy or high-dose chemotherapy with SCT. (175) There was no statistically significant difference in overall survival between the two groups.
• More recent uncontrolled pilot studies and reviews on high-dose chemotherapy with hematopoietic SCT for patients with a variety of solid tumors provide inadequate evidence of improved outcomes. (59, 176-178) Data from these small studies are unreliable as there are no controls for potential bias and no direct comparisons to currently recommended treatments.
• There are no evidence-based clinical practice guidelines that recommend high-dose chemotherapy with autologous SCT for the treatment of the solid tumors listed above.

Waldenstrom’s Macroglobulinemia (WM)                             Return to table

Investigational Indications

Available evidence does not demonstrate that autologous stem cell transplant (SCT) is effective for the treatment of Waldenström’s Macroglobulinemia.

• A 2002 International Workshop summarized clinical experience from small feasibility studies (combined n=49) that reported response rates but lacked data on survival and other long-term outcomes. (110) A total of 9 (18%) achieved complete remissions and 39 (80%) achieved partial remissions, but data on the durability of these responses were unavailable. 
• A retrospective analysis of registry data conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) reported three-year overall survival rates of 70% (95% CI: 40–93%) for WM patients treated with autologous SCT (n=10). (114) Although the CIBMTR results appear favorable, it should be noted that patients in this report were heavily pretreated, highly heterogeneous in terms of disease characteristics and risk factors, and received a variety of conditioning regimens, including myeloablative and reduced intensity conditioning.
• Taken together, data are insufficient to form conclusions about the potential clinical efficacy of SCT for Waldenström’s Macroglobulinemia. Subsequent additional review articles are in general agreement with this position. (115, 116)
• The current National Comprehensive Cancer Network clinical practice guidelines state SCT (type not specified) is recommended as salvage therapy for Waldenström’s Macroglobulinemia only in a clinical trial setting. (95) Other consensus statements have been published suggesting autologous SCT may have a role in treating selected patients with Waldenström’s Macroglobulinemia; however, evidence is not cited to support these statements. (111-113)

Wilms’ tumors (recurrent, high-risk with unfavorable histology*)                                                                                                              Return to Table

Wilms’ tumor is highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%. (77) Tumor histology is a strong and independent prognostic factor with tumors generally divided into two categories: favorable histology and unfavorable (or anaplastic) histology. Anaplasia may be focal or diffuse; tumors with diffuse anaplasia have a poorer prognosis. (78) Other adverse prognostic features include stage IV disease, tumors with any histologic findings recurring in the abdomen after radiation therapy, recurrence within six months of nephrectomy or recurrence after initial three-drug therapy. (79, 80) Fifty percent of patients with anaplastic tumors have tumor progression or relapse, and the outcome for patients with relapse is poor. (77)

*See also Wilm’s tumor favorable histology position statement.

Medically Necessary Indication

The available evidence concerning the use of high-dose chemotherapy with autologous stem cell transplant (SCT) suggests there may be a beneficial effect on survival in patients with recurrent, high-risk disease.

• Studies of high-dose chemotherapy with autologous SCT for high-risk Wilms’ tumor are limited to very small case series or case reports; however, improved survival rates over historical controls have been reported. (77, 81, 82)
• Approximately 500 cases of Wilms’ tumor are diagnosed in the United States annually. (80) Given the rarity of this tumor, randomized trials or larger case series in patients with recurrent disease are unlikely. Encouraging results from the data published to date suggest a benefit in patients with poor prognoses.
• There are no evidence-based clinical practice guidelines that address high-dose chemotherapy with autologous SCT as a treatment of Wilms’ tumors with unfavorable histology.

References

Cross References

Allogeneic Hematopoietic Stem Cell Transplant, Regence Medical Policy, Transplant, Policy No. 43

Tandem Hematopoietic Stem Cell Transplant, Regence Medical Policy, Transplant, Policy No. 44

Gleevec®, imatinib mesylate, Regence Medication Policy, Policy No. dru043

Transplant Section Table of Contents