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MP 8.01.34 High-dose Chemotherapy with Hematopoietic Stem-cell Support for Solid Tumors of Childhood
Medical Policy

Section
Therapy

Original Policy Date
 4/30/00

Last Review Status/Date
Reviewed with literature search/5:2008

Issue

5:2008

 

 Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

High-dose Chemotherapy

High-dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. The most significant adverse effect of HDC is bone marrow ablation. Thus, HDC is usually followed by infusion of hematopoietic stem cells to repopulate the bone marrow (termed stem-cell support or SCS). Potential donors and sources of stem cells include autologous (in which the stem cells are harvested from the patient’s bone marrow or peripheral blood prior to myeloablative therapy), or allogeneic (in which the stem cells are harvested from a donor, with as close a match possible between the donor and recipient to minimize potential graft versus host disease). In addition, blood harvested from the umbilical cord and placenta shortly after delivery of neonates contains stem and progenitor cells. Cord blood is discussed in greater detail in policy No. 7.01.50.

Solid Tumors of Childhood

Solid tumors of childhood are defined as those not arising from myeloid or lymphoid cells. Some of the most common solid tumors of childhood are neuroblastoma, Ewing’s sarcoma/Ewing’s Sarcoma Family of Tumors, Wilms’ tumor, rhabdomyosarcoma, osteosarcoma and retinoblastoma.
The prognosis for pediatric solid tumors has improved over the last 2 decades, mostly due to the application of multiagent chemotherapy and improvements in local control therapy (including aggressive surgery and advancements in radiation therapy). (1) However, patients with metastatic, refractory or recurrent disease continue to have poor prognoses and these “high-risk” patients are candidates for more aggressive therapy, including HDC with SCS, in an effort to improve event free survival (EFS) and overall survival (OS).
Phase III studies with HDC and SCS have clearly shown improvement in outcomes for patients with high-risk neuroblastoma, and HDC and autologous stem cell transplant as consolidation therapy has become the preferred treatment in these patients. (1,2)
This type of therapy has also been used to treat the other childhood solid tumors addressed in this policy. Some studies have shown benefit while others have not, and conclusions have been drawn mainly from small, nonrandomized and retrospective trials or case reports. This is due, in part, to the relative rarity of these pediatric cancers. Prospective clinical trials are necessary to identify specific high-risk groups, with randomization to compare HDC with SCS to standard therapy. (1)
Notes: Other solid tumors of childhood include germ cell tumors which are considered separately in policy No. 8.01.35. For solid tumors arising in the central nervous system derived from primitive neuroepithelial cells (i.e., central PNET) see policy No. 8.01.28 and from glial cells (i.e., astrocytoma, oligodendroglioma, or glioblastoma multiforme) see policy No. 8.01.31.
Brief descriptions of the solid tumors of childhood that are addressed in this policy are as follows.

Peripheral Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood (3), with two-thirds of the cases presenting in children younger than 5 years of age. (4) 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.
Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate and high) (5) that determine treatment plans. Risk variables include age at diagnosis, clinical stage of disease, tumor histology, and certain molecular characteristics, including the presence of the MYCN oncogene. Tumor histology is categorized as favorable or unfavorable, according to the degree of tumor differentiation, proportion of tumor stromal component and index of cellular proliferation. (6) It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis (7), even in the setting of other coexisting favorable factors. Loss of heterozygosity (LOH) at chromosome arms 1p and 11q occurs frequently in neuroblastoma. (8) 1p LOH is associated with MYCN amplification, but 11q is usually found in tumors without this abnormality. (8) Some recent studies have shown that 1p LOH and unbalanced 11q LOH are strongly associated with outcome in patients with neuroblastoma (8), and both are independently predictive of worse progression-free survival in patients with low and intermediate risk disease. Although the use of these LOH markers in assigning treatment in patients is evolving, they may prove useful to stratify treatment.
Clinical stage of disease is based upon the International Neuroblastoma Staging System (INSS) as follows:
Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor.
Stage 2A: Localized tumor with incomplete gross excision; lymph nodes negative for tumor.
Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor.
Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or by lymph node involvement.
Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.
Stage 4S: Localized primary tumor as defined for stage 1, 2A or 2B, with dissemination limited to skin, liver, and/or bone marrow (marrow involvement less than 10%), limited to children younger than 1 year of age.
The low-risk group includes patients less than one year of age with stage 1, 2, or 4S with favorable histopathology and no MYCN oncogene amplification. (5) High-risk neuroblastoma is characterized by an age older than 1 year, disseminated disease, MYCN oncogene amplification and unfavorable histopathologic findings. (5)
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. (3) Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery. (3) In contrast, most children older than 1 year with advanced-stage disease die due to progressive disease, despite intensive multimodality therapy (3), and relapse remains common. Treatment of recurrent disease is determined by the risk group at the time of diagnosis, and the extent of disease and age of the patient at recurrence. 

Ewing’s Sarcoma and the Ewing Family of Tumors

Ewing’s sarcoma family of tumors (ESFT) encompasses a group of tumors which have in common some degree of neuroglial differentiation and a characteristic underlying molecular pathogenesis (chromosomal translocation). The translocation usually involves chromosome 22 and results in fusion of the EWS gene with one of the members of the ETS family of transcription factors, either FLI1 (90–95%) or ERG (5–10%). These fusion products function as oncogenic aberrant transcription factors. Detection of these fusions is considered to be specific for the ESFT, and helps further validate the diagnosis. Included in ESFT are “classic” Ewing’s sarcoma of bone, extraosseous Ewing’s, peripheral primitive neuroectodermal tumor (pPNET) and Askin tumors (chest wall).
ESFT are most commonly diagnosed in adolescence, and can be found in bone (most commonly) or soft tissue, however, the spectrum of ESFT has also been described in various organ systems. Ewing’s is the second most common primary malignant bone tumor. The most common primary sites are the pelvic bones, the long bones of the lower extremities and the bones of the chest wall.
Current therapy for Ewing’s sarcoma favors induction chemotherapy, with local control consisting of surgery and/or radiation (dependent upon tumor size and location), followed by adjuvant chemotherapy. Multiagent chemotherapy, surgery and radiation therapy have improved the progression-free survival (PFS) in patients with localized disease to 60–70%. (9) The presence of metastatic disease is the most unfavorable prognostic feature, and the outcome for patients presenting with metastatic disease is poor, with 20–30% PFS. Other adverse prognostic factors that may categorize a patient as having “high-risk” Ewing’s are tumor location (e.g. patients with pelvic primaries have worse outcomes), larger tumor size and older age of the patient. However, “high-risk” Ewing’s has not always been consistently defined in the literature. Thirty to forty percent of patients with ESFT experience disease recurrence, and patients with recurrent disease have a 5-year EFS and OS rate of less than 10%. (10)

Wilms’ Tumor

Wilms’ tumor, the most common primary malignant renal tumor of childhood, is highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%. (14) Tumor histology is a strong and independent prognostic factor with tumors generally divided into two categories: favorable histology and unfavorable (or anaplastic) histology. Anaplastic histology is defined as microscopic areas within the tumor with nuclear atypia and abnormal mitotic figures. (15) Anaplasia may be focal or diffuse, with tumors having diffuse anaplasia having a poorer prognosis. (15) Ten to 15% of patients with favorable histology tumors and 50% of patients with anaplastic tumors have tumor progression or relapse (14), and the outcome for patients with relapse is poor. Other adverse prognostic features include stage IV disease (16), tumors with any histology that recur in the abdomen after radiation therapy, recurrence within 6 months of nephrectomy or recurrence after initial three-drug therapy. (17)

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, shows skeletal muscle differentiation. The most common primary sites are the head and neck (e.g., parameningeal, orbital, pharyngeal), genitourinary tract and extremities. (11) Most children with RMS present with localized disease, and with conventional multimodal therapy, the cure rate in this group is 70–80%. (12) However, approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the 5-year survival is 20–30% for this “high-risk” group. (12, 13)

Osteosarcoma

Osteosarcoma is a primary malignant bone tumor that is characterized by formation of bone or osteoid by the tumor cells. Osteosarcoma occurs predominantly in the appendicular skeleton of adolescents. In children and adolescents, more than 50% of these tumors arise from bones around the knee. Most treatment protocols for osteosarcoma use neoadjuvant chemotherapy, surgical resection of the tumor (and/or metastases), followed by adjuvant chemotherapy. Prognostic factors include site and size of the primary tumor, presence of metastases at the time of diagnosis, resection adequacy and tumor response to preoperative chemotherapy (measured as percent of tumor necrosis in the resection specimen). 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. Overall EFS for patients with metastatic disease at diagnosis is about 20–30%. (18)

Retinoblastoma

Retinoblastoma is the most common primary tumor of the eye in children. It may occur as a heritable tumor (40%) or nonheritable (60%). (19) Cases may be unilateral or bilateral, with bilateral tumor almost always occurring in the heritable type. The type of treatment depends on the extent of disease. Retinoblastoma is usually confined to the eye, and with current therapy has at least a 90% cure rate. (19) However, once disease has spread beyond the eye, survival rates drop significantly; 5-year disease-free survival is reported to be less than 10% in those with extraocular disease. (19) Extraocular disease may be localized to the soft tissues surrounding the eye, or to the optic nerve, extending beyond the margin of resection. Further extension may result in involvement of the brain and meninges, with subsequent seeding of the cerebrospinal fluid, as well as distant metastases to the lungs, bone, and bone marrow.

Policy

High-dose chemotherapy and autologous hematopoietic stem-cell support may be considered medically necessary for initial treatment of high-risk neuroblastoma and to treat recurrent or refractory neuroblastoma.
High-dose chemotherapy and hematopoietic stem-cell support is considered investigational as initial treatment of low- or intermediate-risk neuroblastoma.
Multiple cycle high-dose chemotherapy and hematopoietic stem-cell support (i.e., tandem or multiple transplants) is considered investigational for treatment of neuroblastoma.
Salvage allogeneic transplant for neuroblastoma or other pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.
High-dose chemotherapy and hematopoietic stem-cell support may be considered medically necessary to consolidate remission of high-risk Ewing’s sarcoma, or as salvage therapy for those with residual, recurrent, or refractory disease.
High-dose chemotherapy and hematopoietic stem-cell support is considered investigational as initial treatment or to consolidate remission of low- or intermediate-risk Ewing’s sarcoma.
High-dose chemotherapy for other solid tumors of childhood is considered investigational, including, but not limited to the following:

  • Rhabdomyosarcoma
  • Wilms’ tumor
  • Osteosarcoma
  • Retinoblastoma

Policy Guidelines

Hematopoietic stem-cell support refers to any source of stem cells, i.e., autologous, allogeneic, syngeneic, or umbilical cord blood.
Relapse is defined as tumor recurrence after a prior complete response.
Primary refractory disease is defined as a tumor that does not achieve a complete remission after initial standard-dose chemotherapy.
In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic stem-cell support services to the hematology section (CPT 38204-38242). Not all codes are applicable for each HDC/stem-cell support procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describes services associated with cryopreservation, storage, and thawing of cells (38208-38215).
CPT 38208 and 38209 describe thawing and washing of cryopreserved cells
CPT 38210-38214 describe certain cell types being depleted
CPT 38215 describes plasma cell concentration
The policy statement regarding multiple cycle high-dose chemotherapy and hematopoietic stem-cell support (i.e., tandem or multiple transplants) only mentions neuroblastoma as that is the only indication in this policy where studies regarding multiple-cycle therapy have been published.

Benefit Application

BlueCard/National Account Issues

The following considerations may supersede this policy:

  • State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).
  • Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.
  • Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.

Rationale

Data regarding high-dose chemotherapy (HDC) and stem-cell support (SCS) for selected pediatric solid tumors are summarized in the following sections, with the most current data as of April 2008 and, if applicable, a brief discussion of active clinical trials.
Peripheral Neuroblastoma
The policy regarding neuroblastoma was originally based on 2 TEC Evaluations from 1987 and 1988 (20,21).
In the 1990s, some studies attributed an improvement in the treatment of high-risk neuroblastoma to the use of myeloablative doses of chemotherapy with autologous SCS. (22) However, none of these studies involved a randomized comparison and selection bias may have influenced results. (22) Since then, three well designed, randomized trials have been conducted, and have supported these findings, as summarized below.
In a study published in 1999, Matthay and colleagues (22) randomly assigned 129 children with high-risk neuroblastoma to a combination of myeloablative chemotherapy, total-body irradiation and transplantation of autologous bone marrow and compared their outcomes to those of 150 children randomly assigned to intensive nonmyeloablative chemotherapy. The 3-year EFS rate among patients assigned to transplantation was 43 +/- 6% versus 27 +/- 5% among those assigned to continuation chemotherapy ('p=0.027). However, overall survival in the two groups was not significantly different, with 3-year estimates of 43 or 44% for those assigned to transplant or those to continued chemotherapy, respectively ('p=0.87).
In a study published in 2005, Berthold and colleagues randomly assigned 295 patients with high-risk neuroblastoma to myeloablative therapy (melphalan, etoposide and carboplatin) with autologous SCS or to oral maintenance chemotherapy with cyclophosphamide. (23) The primary endpoint was EFS with secondary endpoints of OS and treatment-related deaths. Intention-to-treat analysis showed that the patients who received the myeloablative therapy had an increased 3-year EFS compared with the oral maintenance group ('47% [95% CI: 38–55] vs. 31% ['95% CI: 23–39]), but did not have significantly increased 3-year overall survival (62% ['95% CI: 54–70] vs. 53% ['95% CI: 45–62] p=0.0875). Two patients died from therapy-related complications during induction, no patients who received oral maintenance therapy died from treatment-related toxic effects, and 5 patients who received the myeloablative therapy died from acute complications related to the therapy.
In a study published in 2005, Pritchard and colleagues (24) reported the results of a randomized, multicenter study that involved 167 children with stage 3 or 4 neuroblastoma who were treated with standard induction chemotherapy and then underwent surgical resection of their tumor. Sixty-nine percent of the patients ('n=90) who achieved complete or good partial response to the induction chemotherapy were eligible for randomization to HDC (melphalan) with autologous SCS or no further treatment (NFT). Seventy-two percent (n=65) of the eligible children were randomized, with 21 surviving at the time of the analysis (median follow-up 14.3 years). A significant difference in the 5-year EFS and OS was seen in children older than 1 year of age with stage 4 disease ('n=48 children with stage 4; 5-year EFS 33% vs. 17% in the melphalan vs. NFT group p= 0.01).

Since myeloablative consolidation for treatment of high-risk neuroblastoma has been shown to improve EFS in these randomized studies (only Pritchard showed improved OS in the group with stage 4 disease and older than 1 year of age), it is considered by some investigators to be the preferred treatment in these patients. (25)
Studies are now looking at the possible improvement in EFS and OS with the use of tandem HDC/SCS.
Future studies for high-risk neuroblastoma include a phase III randomized study of single versus tandem myeloablative consolidation therapy followed by peripheral blood SCS.
http://www.cancer.gov/clinicaltrials/COG-ANBL0532
Ewing’s Sarcoma and the Ewing Family of Tumors
During the 1980s and 90s, several small series, case reports and a report from the European Bone Marrow Transplant Registry suggested that consolidation with HDC and SCS could improve the outcome for patients with high risk ESFT. (26) The original policy position on Ewing’s was based upon these studies/reports.
These aforementioned studies were characterized by small numbers of patients, and comparison of the studies was difficult for several reasons: within each report, patients often received a variety of chemotherapeutic regimens, many of the studies did not share the same patient eligibility criteria (and in some the definition of “high risk” included patients with criteria that did not result in inferior prognosis), and some studies used for stem-cell reconstitution autologous peripheral blood stem cells, some autologous bone marrow, and others allogeneic bone marrow.
Subsequently, in 2001, Meyers et al. (26) reported a prospective study with HDC and autologous stem-cell reconstitution in patients with Ewing’s sarcoma metastatic to bone and/or bone marrow, which showed conflicting results compared to the previous studies. Thirty two eligible patients were enrolled and given standard induction chemotherapy consisting of 5 cycles of cyclophosphamide-doxorubicin-vincristine, alternating with ifosfamide-etoposide. Twenty-three patients proceeded to the HDC consolidation phase with melphalan, etoposide, total body irradiation (TBI) and SCS; (of the 9 patients who did not proceed, 2 were secondary to toxicity and 4 to progressive disease). Three patients died during the high-dose phase. Two-year event-free survival (EFS) for all eligible patients was 20% and 24% for the 29 patients who received the high-dose consolidation therapy. The study concluded that consolidation with HDC, TBI and autologous stem-cell support failed to improve the probability of EFS for this cohort of patients when compared with a similar group of patients treated with conventional therapy. The authors note that their findings differ from some previous studies, and state that some previous studies suffered from heterogeneous patient populations. The authors conclude that future trials of HDC and SCS 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.
EURO-EWING 99: A Phase III, randomized, controlled, multicenter (international) study for patients with Ewing’s sarcoma is in progress. Approximately 1,200 patients are expected to enroll. The primary objective is to compare the event-free and overall survival of patients with tumors of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide, and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery. The study includes both patients with localized disease and those with metastases, includes three arms for low, intermediate and high risk patients, and is the first randomized approach of HDC with SCS in high risk Ewing’s patients. The anticipated end date for this study is March 2010. (EURO-E.W.I.N.G. Study Committee. EURO-E.W.I.N.G. 99 Study Manual—EUROpean Ewing Tumor Initiative of National Groups Ewing Tumor Studies 1999 [available at http://euro-ewing.uni-muenster.de/ewing99.html])
Rhabdomyosarcoma
HDC with SCS has been evaluated in a limited number of patients with “high-risk” RMS (stage 4 or relapsed) in whom complete remission is achieved after standard induction therapy. Data are relatively scarce, due in part to the rarity of the condition. Weigel and colleagues (27) reviewed and summarized published data on the role of HDC with SCS in the treatment of metastatic or recurrent rhabdomyosarcoma, which involved a total of 389 patients from 22 studies. Based upon all of the data analyzing EFS and OS, they concluded that there was no significant advantage to undergoing this type of treatment.
Carli and colleagues (28) conducted a prospective nonrandomized study of 52 patients with metastatic RMS, who were in complete remission after induction therapy and subsequently received HDC (“megatherapy”) and SCS and compared them to 44 patients who were in remission after induction therapy who subsequently received conventional chemotherapy. No significant differences existed between the 2 study groups (i.e., no differences in clinical characteristics, induction chemotherapy received, sites of primary tumor, histologic subtype, age, or presence/extent of metastases). Three-year EFS and OS were 29.7% and 40%, respectively, for the HDC/SCS group and 19.2% and 27.7%, respectively, for the group that received standard consolidation chemotherapy. The difference was not statistically significant (p=0.3 and 0.2 for EFS and OS, respectively). The median time after chemotherapy to relapse was 168 days for the HDC group, and 104 days for the standard chemotherapy group (p=0.05). Therefore, although there was some delay to relapse, there was no clear survival benefit from using HDC and SCS compared to conventional chemotherapy.
COG-ARST0431 is an ongoing Children’s Oncology Group (COG) clinical trial for patients with metastatic RMS, regardless of age and histology. The trial will evaluate high-dose combination chemotherapy and radiation therapy. In reviewing the trial outline, it appears that the chemotherapy doses are nonmyeloablative as SCS is not included, and G-CSF will be administered (http://www.cancer.gov/search/viewclinicaltrials.aspx?version=healthprofessional&cdrid=489215). No current Phase III trials with myeloablative regimens and SCS for rhabdomyosarcoma were identified in reviewing the National Cancer Institute (NCI) clinical trial database.
Wilms’ Tumor
Most studies of HDC and SCS for high-risk Wilm’s tumor have been very small series or case reports (14, 29, 30), however, improved survival rates over historical controls have been reported. A Phase II study in progress is evaluating the survival rates of patients with relapsed or recurrent Wilm’s tumor assigned to one of three treatment regimens which may or may not include HDC and autologous SCS (http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=68913&version=patient&protocolsearchid=4447343). Expected enrollment is 75 with an anticipated completion date November 2008.
Osteosarcoma
Rare small series and case reports are available examining the use of HDC and SCS in osteosarcoma, without a clear benefit in overall outcome. (31)
Review of the NCI clinical trial database did not return any current trials examining HDC and SCS in patients with high-risk osteosarcoma. (18)

Retinoblastoma
Most studies of HDC and SCS for high-risk retinoblastoma have been very small series or case reports (32-37), however, the results have been promising in terms of prolonging disease-free survival in these patients, particularly those without CNS involvement.
A single-arm, Phase III trial is underway to estimate the proportion of children with extraocular retinoblastoma who achieve long-term EFS after HDC and SCS compared to historical controls. The estimated date of completion of the trial is July 2009 (http://www.cancer.gov/clinicaltrials/COG-ARET0321#EntryCriteria_CDR0000573987).
Summary
In summary, to date, the use of HDC with SCS has become the preferred treatment for children with “high-risk” neuroblastoma, after randomized studies have shown improved EFS and OS. For ESFT, one of the more recently published studies (26) showed conflicting results from previous studies which have supported the current policy. However, this study was small and nonrandomized. A large Phase III trial (EURO-EWING 99) is underway, which will likely serve to guide future treatment options for ESFT. Prospective clinical trials, with randomization (when possible) are needed to compare outcomes for the other solid pediatric tumors addressed in this policy treated with HDC with SCS versus standard chemotherapy.

 

References:

 

  1. Hale GA. Autologous hematopoietic stem cell transplantation for pediatric solid tumors. Expert Rev Anticancer Ther 2005; 5(5), 835-46.
  2. Fish JD, Grupp SA. Stem cell transplantation for neuroblastoma. Bone Marrow Transplant 2008; 41:159-65.
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  4. Physician Data Query (PDQ®). Neuroblastoma treatment: health professional version. National Cancer Institute; last updated 11/27/2007. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/healthprofessional. Last accessed April 2008.

  5. Yalcyn B, van Dalen EC, Caron HN et al. High dose chemotherapy and autologous stem cell rescue for children with high risk neuroblastoma (protocol). The Cochrane Library 2008, Issue 1:1-6.

  6. Shimada H, Ambros IM, Dehner LP et al. Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 1999; 86:349-63.

  7. Tang XX, Zhao H, Kung B et al. The MYCN enigma: significance of MYCN expression in neuroblastoma. Cancer Res 2006; 66(5):2826-33.

  8. Attiyeh EF, London WB, Mosse YP et al. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005; 353(21):2243-53.

  9. Barker LM, Pendergrass TW, Sanders JE et al. Survival after recurrence of Ewing’s sarcoma family of tumors. J Clin Oncol 2005; 23:4354-62.

  10. Physician Data Query (PDQ®). Ewing family of tumors treatment: health professional version. National Cancer Institute; last updated 03/26/2008. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/ewings/healthprofessional. Last accessed April 2008.

  11. Physician Data Query (PDQ®). Childhood rhabdomyosarcoma treatment: health professional version. National Cancer Institute; last updated 03/26/2008. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/childrhabdomyosarcoma/healthprofessional. Last accessed April 2008.

  12. Admiraal R, Van der Paardt M, Kobes J et al. High dose chemotherapy for children with stage IV rhabdomyosarcoma (protocol). Cochrane Database of Systematic Reviews 2007, Issue 3.

  13. Koscielniak E, Klingebiel TH, Peters C et al. Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group. Bone Marrow Transplant 1997; 19 (3): 227-31.

  14. Campbell AD, Cohn SL, Reynolds M et al. Treatment of Relapsed Wilms’ Tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: the experience at Children’s Memorial Hospital. J Clin Oncol 2004; 22:2885-90.

  15. Faria P, Beckwith JB, Mishra K et al. Focal versus diffuse anaplasia in Wilms tumor- new definitions with prognostic significance: a report from the National Wilms Tumor Study Group. Am J Surg Pathol 1996 Aug; 20(8):909-20.

  16. Arya M, Shergill IS, Gommersall L et al. Current trends in the management of Wilms’ tumour. BJU International 2006; 97(5):899-900.

  17. Physician Data Query (PDQ®). Wilm’s tumor and other childhood kidney tumors treatment: health professional version. National Cancer Institute; last updated 11/27/2007. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/wilms/healthprofessional. Last accessed April 2008.

  18. Physician Data Query (PDQ®). Osteosarcoma/Malignant fibrous histiocytoma of bone treatment: health professional version. National Cancer Institute; last updated 04/02/2008. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/osteosarcoma/healthprofessional. Last accessed April 2008.

  19. Physician Data Query (PDQ®). Retinoblastoma treatment: health professional version. National Cancer Institute; last updated 01/03/2008. Available online at http://www.cancer.gov/cancertopics/pdq/treatment/retinoblastoma/healthprofessional. Last accessed April 2008.

  20. 1987 TEC Evaluations; p. 51

  21. 1988 TEC Evaluations; p. 398

  22. Matthay KK, Villablanca JG, Seeger RC et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999; 341:1165-73.

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  25. Pearson AD, Pinkerton CR, Lewis IJ et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol 2008; 9:247-56.

  26. Meyers PA. High-dose therapy with autologous stem cell rescue for pediatric sarcomas. Curr Opin Oncol 2004; 16:120-5.

  27. Weigel BJ, Breitfeld PP, Hawkins D et al. Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 2001; 23(5):272-6.

  28. Carli M, Colombatti R, Oberlin O et al. High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma. J Clin Oncol 1999; 17(9):2796-803.

  29. Kremens B, Gruhn B, Klingebiel T et al. High-dose chemotherapy with autologous stem rescue in children with nephroblastoma. Bone Marrow Transplant 2002; 30:893-98.

  30. Spreafico F, Bisogno G, Collini P et al. Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology. Pediatr Blood Cancer 2008 Feb 21 [Epub ahead of print].

  31. Fagioli F, Aglietta M, Tienghi A et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 2002 ; 20(8):2150-6.

  32. Dunkel IJ, Aledo A, Kernan NA et al. Successful treatment of metastatic retinoblastoma. Cancer 2000; 89(10):2117-21.

  33. Jubran RF, Erdreich-Epstein A, Butturini A et al.: Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol 2004; 26(1):31-4.

  34. Kremens B, Wieland R, Reinhard H et al. High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 2003; 31:281-4.

  35. Matsubara H, Makimoto A, Higa T et al. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 2005; 35(8):763-6.

  36. Namouni F, Doz F, Tanguy ML et al. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer 1997; 33(14):2368-75.

  37. Rodriguez-Galindo C, Wilson MW, Haik BG et al. Treatment of metastatic retinoblastoma. Ophthalmology 2003; 110(6):1237-40.

 

Codes

Number

Description
38204 Management of recipient hematopoietic cell donor search and cell acquisition 
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic 
38206 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous 
38208 Thawing of previously frozen harvest 
38209 Washing of harvest 
38210 Specific cell depletion with harvest, T cell depletion 
38211 Tumor cell depletion 
38212 Red blood cell removal 
38213 Platelet depletion 
38214 Plasma (volume) depletion 
38215 Cell concentration in plasma, mononuclear, or buffy coat layer 
38220 Bone marrow; aspiration only 
38221 Bone marrow; biopsy, needle or trocar 
CPT  38230  Bone marrow harvesting for transplantation 
  38240  Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic 
  38241  Same as 38240 but autologous 
  86812, 86813, 86816, 86817, 86821, 86822  Histocompatibility studies code range
 
(e.g., for allogeneic transplant) 
ICD-9 Procedure  41.00 Bone marrow transplant, not otherwise specified 
41.01  Autologous bone marrow transplant 
  41.02  Allogeneic bone marrow transplant with purging 
  41.03  Allogeneic bone marrow transplant without purging 
  41.04  Autologous hematopoietic stem-cell transplant 
  41.05  Allogeneic hematopoietic stem-cell transplant 
41.07 Autologous hematopoietic stem cell transplant with purging 
41.08 Allogeneic hematopoietic stem cell transplant with purging 
41.09 Autologous bone marrow transplant with purging 
  41.91  Aspiration of bone marrow from donor for transplant 
  99.79  Other therapeutic apheresis (includes harvest of stem cells) 
ICD-9 Diagnosis  170.0–170.9  Malignant neoplasm of bone and articular cartilage (i.e., osteosarcoma and Ewing’s sarcoma) code range 
  171.0–171.9  Malignant neoplasm of connective and other soft tissue (i.e., rhabdomyosarcoma) code range 
  189.0  Malignant neoplasm of kidney (i.e., Wilms’ tumor) 
  190.5  Retinoblastoma 
  194.0  Malignant neoplasm of adrenal gland (i.e., neuroblastoma) 
HCPCS  G0265  Cryopreservation, freezing and storage of cells for therapeutic use, each cell line 
  G0266  Thawing and expansion of frozen cells for therapeutic use, each cell line 
  G0267  Bone marrow or peripheral stem-cell harvest, modification or treatment to eliminate cell type(s) (e.g., T cells, metastatic carcinoma) 
  Q0083, Q0084, Q0085  Chemotherapy administration code range 
  J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9040, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9395, J9600, J9999 Chemotherapy drugs code range 
  S2140  Cord blood harvesting for transplantation, allogeneic 
  S2142  Cord blood-derived stem-cell transplantation, allogeneic 
  S2150  Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services) 
Type of Service  Therapy 
Place of Service  Inpatient/Outpatient 

Index

Ewing’s Sarcoma, High-dose Chemotherapy
High-dose chemotherapy, solid tumors of childhood
Neuroblastoma, High-dose Chemotherapy
Osteosarcoma, High-dose Chemotherapy
Retinoblastoma, High-dose Chemotherapy
Wilms’ Tumor, High-dose Chemotherapy

Policy History

Date Action Reason
04/30/00 Add to Therapy section New policy; policy based on original master policy on high-dose chemotherapy; however, policy statement is unchanged
12/18/02 Replace policy Update CPT codes only
04/29/03 Replace policy Policy updated; policy statement unchanged
07/15/04 Replace policy Policy updated with literature review for the period of 2003 through May 2004; policy statement unchanged
09/27/05 Replace policy Policy updated with literature review for the period of May 2004 through May 2005; reference number 34 added and reference number 35 updated. Policy statement unchanged
04/17/07 Replace policy Policy updated with literature review; policy statement added to indicate that multiple cycle high-dose chemotherapy and hematopoietic stem-cell support (i.e., tandem or multiple transplants) is considered investigational for treatment of neuroblastoma. All other policy statements unchanged. Reference numbers 35 and 36 added and reference number 37 updated.
05/08/08 Replace policy  Policy extensively consolidated and rewritten; updated with literature search. References also extensively revised; no changes to policy statements 

 

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