Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors

Number: 0496

Policy

1. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with high-risk neuroblastoma (see below for definition of high-risk neuroblastoma) in any of the following situations when the member meets the transplanting institution's protocol selection criteria.  In the absence of a protocol, Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of high-risk neuroblastoma in members without concurrent disease that would seriously compromise the chance of obtaining a durable complete remission and any of the following selection criteria are met:  

   1. As primary treatment for persons in Stage II to Stage III neuroblastoma (see table in the background section below for staging of neuroblastoma) when associated with more than 10 copies of the n-myc oncogene; or  
   2. As primary treatment for persons in Stage IV neuroblastoma; or 
   3. As therapy for primary recurrent or refractory (see note below) disease when further treatment with a conventional-dose therapy is unlikely to attain a durable remission.

   Definition of High-Risk Neuroblastoma:

   High-risk neuroblastoma is defined as any one of the following categories:  

   1. Stage IV disease with either of the following:

      1. Infants less than 1 year of age with amplified n-myc gene status;
      2. Persons 1 year of age or older; or
   2. Stage IVS disease in infants less than 1 year of age with amplified n-myc gene status; or  
   3. Stage III disease with either of the following:
      
      
      1. Infants less than 1 year of age with amplified n-myc gene status; or
      2. Persons 1 year of age or older with amplified n-myc gene status and/or unfavorable histology; or   

   4. Stage IIA or IIB disease, in persons 1 year of age or older, with amplified n-myc gene status and unfavorable histology.

2. Aetna considers a repeat autologous hematopoietic cell transplantation medically necessary for persons with chemosensitive neuroblastoma who have relapsed after an autologous hematopoietic cell transplant. 

3. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for neuroblastoma because of insufficient evidence of its effectiveness.

4. Aetna considers tandem (also known as sequential) autologous transplantation medically necessary for the treatment of persons with high-risk neuroblastoma who meet the criteria for hematopoietic cell transplantation set forth above. 

5. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with relapsed or progressive chemotherapy sensitive Ewing's sarcoma family of tumors that is not widely metastatic.

6. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of members with Ewing's sarcoma family of tumors because of insufficient evidence of its safety and effectiveness.

7. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with primitive neuroectodermal tumors (PNET) including medulloblastoma and pineoblastoma.

8. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of members with PNET including medulloblastoma and pineoblastoma because of insufficient evidence of its safety and effectiveness.

9. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with ependymoma who are ineligible for radiotherapy.

10. Aetna considers an allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of members with ependymoma because of insufficient evidence of its safety and effectiveness.

11. Aetna considers autologous hematopoietic cell transplantation medically necessary for members with extraocular retinoblastoma.

12. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for members with retinoblastoma because of insufficient evidence of its safety and effectiveness.

13. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of persons with progressive or relapsed chemosensitive Wilm's tumor.

14. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of Wilms’ tumor because of insufficient evidence of its safety and effectiveness.

15. Aetna considers autologous hematopoietic stem cell transplantation experimental and investigational for the treatment of soft tissue sarcomas because of insufficient evidence of its safety and effectiveness.

16. Aetna considers adoptive cellular immunotherapy from haploidentical or matched donors experimental and investigational following hematopoietic stem cell transplantation for childhood solid tumors because the effectiveness of this approach has not been established. (See CPB 0641 - Adoptive Immunotherapy and Cellular Therapy)

Note: Primary refractory is defined as a tumor that does not achieve a complete remission after initial standard-dose chemotherapy. Relapse is defined as a tumor recurrence after a prior complete remission.

Background

Neuroblastoma

Neuroblastoma, the most common solid tumor of childhood (i.e. excluding leukemia), arises from primitive neural crest cells and thus can occur anywhere along the sympathetic chain.  The most common site of origin is within the abdomen arising in an adrenal gland or paraspinal ganglion.  Metastatic disease, involving most commonly liver, lymph nodes or bone marrow, is present in 50 to 66 % of children at the time of diagnosis.  The staging of neuroblastoma is shown in the table below:

International Staging System for Neuroblastoma

Stage I: 

Localized tumor with complete gross excision with or without microscopic residual disease; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically

Stage IIA:

Localized tumor with incomplete gross excision; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically

Stage IIB: 

Localized tumor with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumor.  Enlarged contralateral lymph nodes must be negative microscopically.

Stage III: 

Unresectable unilateral tumor infiltrating across 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 (unresectable) or by lymph node involvement

Stage IV: 

Any primary tumor with dissemination to distant lymph nodes, bone marrow, liver, skin and/or other organs (except as defined for Stage IVS)

Stage IVS: 

Localized primary tumor (as defined for stages I or II), with dissemination limited to skin, liver, and/or bone marrow (limited to infants less than 1 year of age)

Source: Castleberry et al, 1997.

Most patients with Stage I, II or IVS disease can be cured with surgical resection with or without additional chemotherapy or radiation therapy.  Stage II tumors can usually be resected, but microscopic or small amounts of gross residual disease may remain in the paraspinal regions.  Radiation therapy has been used both to reduce the frequency of local tumor recurrence and to eradicate microscopic or macroscopic distant metastases.  Patients with Stage II neuroblastoma with microscopic residual disease may benefit from local irradiation.  In patients with residual disease or positive lymph nodes, the addition of radiation therapy appears to improve the prognosis.  However, the majority of patients with Stage III and IV disease are not curable with the above approaches.  Unfortunately, 68 % of patients over 1 year of age present with either Stage III or IV disease.  Patients under the age of 1 have a relatively better prognosis; only 25 % present with disseminated disease with a larger proportion having either Stage I or IVS disease.

Neuroblastoma may be classified as low-, intermediate-, or high-risk based on the stage of the tumor and the number of copies of the oncogene n-myc.  According to accepted guidelines, high-dose chemotherapy (HDC) followed by autologous or allogeneic bone marrow transplant is a treatment option for patients with high-risk neuroblastoma (see Table below).

Table: Neuroblastoma Risk Stratification

INSS Stage	Age	MYCN status	Shimada histology	Ploidy	Risk
1	0 - 21 y	Any	Any	Any	Low
2A/2B	< 365	Any	Any	Any	Low
2A/2B	≥ 365 d - 21 y	Non-amplified	Any	-	Low
2A/2B	≥ 365 d - 21 y	Amplified	Fav	-	Low
2A/2B	≥ 365 d - 21 y	Amplified	Unfav.	-	High
3	< 365 d	Non-amplified	Any	Any	Intermediate
3	< 365 d	Amplified	Any	Any	High
3	> 365 d - 21 y	Non-amplified	Fav.	-	Intermediate
3	> 365 d - 21 y	Non-amplified	Unfav.	-	High
3	> 365 d - 21 y	Amplified	Any	-	High
4	< 365 d	Non-amplified	Any	Any	Intermediate
4	< 365 d	Amplified	Any	Any	High
4	≥ 365 d-21 y	ANY	Any	-	High
4S	< 365 d	Non-amplified	Fav.	DI>1	Low
4S	< 365 d	Non-amplified	Any	DI=1	Intermediate
4S	< 365 d	Non-amplified	Unfav.	Any	Intermediate
4S	< 365 d	Amplified	Any	Any	High

KEY: INSS Stage = International Staging System for Neuroblastoma; Fav. = favorable; Unfav. = unfavorable.

Source: Castleberry et al, 1997; Grupp, 2003.

Autologous bone marrow transplant (ABMT) refers to re-infusion of the patient's previously harvested bone marrow stem cells, which function to re-populate the bone marrow that has been ablated by prior HDC.  The critical stem cells can also be harvested from the peripheral blood via multiple pheresis procedures.  This latter procedure is also referred to as peripheral stem cell support.  Occasionally the collective term autologous stem cell support or transplant (ASCT) is used to refer to either autologous bone marrow or peripheral stem cell transplant.

Allogeneic bone marrow transplant refers to the use of functional hematopoietic stem cells from a healthy donor to restore bone marrow function following HDC.  For patients with marrow-based malignancies, the use of allogeneic stem cells offers the advantage of lack of tumor cell contamination.  Furthermore, allogeneic stem cells may be associated with a beneficial graft versus tumor effect.

Tandem or sequential transplant protocols utilize a cycle of HDC with ASCT followed in approximately 6 months, by a second cycle of HDC and/or total body irradiation (TBI), with another ASCT.  This is done in an attempt to obtain greater and extended response rates. 

High-dose chemotherapy for neuroblastoma typically consists of inpatient administration of a platinum compound and an epipodophyllotoxin (i.e. etoposide or teniposide) in variable combination with melphalan, cyclophosphamide or doxorubicin.  Total body irradiation is often added to the chemotherapy regimen.  Any regimen that includes TBI will require a prolonged hospital stay averaging about 30 days.  Patients receiving HDC with or without TBI are usually initially treated in a private room for about 1 week until the blood counts start to drop.  Then patients are typically transferred to a specialized laminar flow room for the duration of their hospital stay.

Average length of stay for patients undergoing HDC in conjunction with TBI is 30 days.  Discharge parameters are similar to above: fever-free for 48 hours, adequate blood counts (WBC greater than 500).  Patients may be discharged even if an adequate platelet count is transfusion dependent; platelet transfusions can be given on an outpatient basis.

Patients with neuroblastoma should generally be referred to a pediatric hematologist/oncologist for the entire course of their disease.

Studies on HDC/Bone Marrow Transplant for Neuroblastoma

Stram and associates (1995) compared the outcome of stage IV patients (n = 207) treated with the same initial induction regimen followed or not followed by HDC and autologous stem cell support.  These investigators found that the 4-year event-free survival (EFS) (i.e., either death due to any cause, progressive disease, or a second malignancy) was 40 % in the HDC group compared to 19 % in the conventionally treated group.  Subgroups that appeared to benefit most from HDC included those with a partial tumor response to induction therapy, and those whose tumors had amplification of the n-myc oncogene.

The Children's Cancer Study Group (Matthay et al, 1994, 1998, and 1999) conducted a randomized phase III trial in patients with high-risk neuroblastoma comparing intensive consolidation chemotherapy using cisplatin/etoposide/doxorubicin/ifosfamide versus myeloablative chemotherapy and autologous marrow support using carboplatin/etoposide/melphalan and fractionated TBI.  In this protocol, all patients initially received a 22-week course of induction chemotherapy with cisplatinum, etoposide, doxorubicin and cyclophosphamide plus surgical debulking of residual primary tumor followed by local irradiation of gross residual tumor, if necessary.  At week 8 during the induction chemotherapy, patients were randomized to receive either intensive consolidation or HDC-ABMT.  Those randomized to the transplant arm underwent bone marrow harvest at week 12.  Prior to HDC-ABMT, patients were additionally evaluated to determine candidacy.  Those with greater than 2 % neuroblastoma cells within the marrow and those with progressive disease while on chemotherapy were not considered candidates for a subsequent transplant.

The authors reported that the 3-year EFS was 34 % in the HDC-ABMT arm (n = 189) compared to 18 % in the control group (n = 190), a statistically significant difference.  Furthermore, they stated that amplification of the n-myc oncogene, elevated serum ferritin, and poor response to induction therapy identify an "ultra" high-risk group who should be selected early for novel therapies.

In the 1994 study, Matthay et al compared the toxicity, relapse rate, and progression-free survival of high-risk neuroblastoma patients receiving identical induction therapy and myeloablative chemotherapy plus TBI followed by allogeneic or autologous purged bone marrow transplantation.  The authors concluded that the overall outcome for patients with neuroblastoma given the same induction therapy followed by autologous purged marrow was similar to that with allogeneic marrow.  This was in accordance with the study of Evans et al (1994) that found survival for patients with high-risk neuroblastoma rescued with autologous bone marrow transplant was not statistically significantly different from the result obtained with allogeneic bone marrow transplant.

In a recent review, Dallorso and colleagues (2000) stated that autologous hematopoietic stem cell transplantation has been increasingly used in the treatment of several high-risk solid tumors of childhood in the last 2 decades; and that results from the Children's Cancer Group randomized trial confirmed the data from retrospective studies, which reported the superiority of autologous hematopoietic stem cell transplantation over standard chemotherapy for neuroblastoma.

In a phase II clinical trial for children with high-risk neuroblastoma (n = 55), Grupp et al (2000) reported that a program of induction chemotherapy followed by tandem HDC with stem cell rescue in rapid sequence is a feasible treatment strategy and may improve disease-free survival.  In a recent study, Marcus et al (2003) reported that the use of induction chemotherapy, aggressive multi-modality therapy for the primary tumor, followed by tandem myeloablative cycles with stem cell transplant in patients with stage 4 or high-risk stage 3 neuroblastoma (n = 52) has resulted in acceptable toxicity, a very low local recurrence risk, and an improvement in survival.

Takahashi et al (2008) noted that neuroblastoma is the most common extra-cranial solid tumor of childhood, and iodine-131-metaiodobenzylguanidine (MIBG) therapy is a new approach for grade IV neuroblastoma.  These researchers described the case history of a 3-year old girl with recurrent neuroblastoma who received MIBG therapy with reduced-intensity allogeneic stem cell transplantation (RIST) because of an extensive bone marrow involvement.  The post-transplant course was uneventful and complete chimerism was obtained.  Neither acute nor chronic graft-versus-host disease (GVHD) was observed.  The patient remained in remission for 3 months after RIST until the second relapse.  The authors stated that MIBG therapy combined with RIST warrants further investigation.

Allogeneic Stem Cell Transplant for Neuroblastoma

Hale et al (2013) noted that, although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1)  and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year overall survival (OS) were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in complete remission (CR) or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

Sung et al (2012) observed that no effective curative option is available for children with neuroblastoma (NB) who failed tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). The investigators evaluated the feasibility and efficacy of reduced-intensity allogeneic stem cell transplantation (RI alloSCT) in six children with NB who failed tandem HDCT/autoSCT. A cyclophosphamide/fludarabine regimen was used as a conditioning for HLA-matched SCT, and ATG was added for haploidentical SCT. Peripheral blood stem cells from four HLA-matched donors and two haploidentical donors were transplanted. Immune suppression was rapidly tapered if graft-versus-host disease (GVHD) was absent. Regimen-related short-term toxicity was manageable, and complete donor chimerism was achieved in the early period after transplant. Grade I/II acute GVHD developed or was induced in all patients. Tumor response, attributed to a graft-versus-tumor (GVT) effect, was observed in two of six patients after induction of acute GVHD. The other four patients with significant tumor burden prior to transplant had tumor progression despite presence of GVHD. However, it was difficult to effectively reduce the tumor burden prior to transplant through the use of conventional treatment modalities. Although regimen-related short-term toxicity was manageable in intensively pretreated patients with NB, GVT effect was not sufficiently strong to control tumor progression in patients who had a significant tumor burden at transplant. Therefore, new treatment modalities to effectively reduce tumor burden prior to transplant in concert with post-transplant adjuvant treatment to enhance the GVT effect are needed to improve the outcome after RI alloSCT.

Sung et al (2012) wrote that, although a graft-versus-tumor effect has not yet been convincingly demonstrated in the setting of relapsed NB, the strategy of employing RI alloSCT has provided hope that treatment-related mortality will be reduced and a therapeutic benefit will emerge. However, alloSCT for NB is still investigational and there remain many issues to be elucidated in many areas. At present, alloSCT is reserved for specific clinical trials testing the immunomodulatory effect against NB.

Ewing's Sarcoma Family of Tumors

Ewing's sarcoma, first described by James Ewing in 1921 as a diffuse endothelioma of bone, is the second most common primary bone tumor seen among young children and adolescents.  It is not a single condition, but a group of morphologically and clinically closely related disorders with similar molecular biology – expression of tumor-specific chimeric oncoproteins through balanced chromosomal translocations involving the EWS gene – often referred to as the Ewing's sarcoma family of tumors (ESFT).  This entails Askin tumor, Ewing's sarcoma of bone, extra-osseous Ewing's sarcoma, and peripheral neuroectodermal tumor (PNET).  These are aggressive neoplasms with almost 25 % of patients having clinically evident metastases at presentation.  Ewing's sarcoma has therefore been considered as a systemic disease necessitating local as well as systemic treatment.  Because most patients with clinically apparent localized disease at diagnosis may also have occult metastatic (i.e., systemic) disease, a multi-disciplinary approach (i.e., multi-drug chemotherapy, local disease control with surgery and/or radiation therapy) is indicated for all patients.  Despite marked improvements in survival during the past 40 years for patients with localized disease, lesser improvements have been seen in patients with metastatic or recurrent disease (Thacker et al, 2005; Maheshwari and Cheng, 2010).

Aggressive therapeutic approaches such as autologous stem cell transplantation have been shown to be beneficial in patients with advanced Ewing's sarcoma.  On the other hand, allogeneic stem cell transplantation does not appear to offer much improvement in these patients.  Capitini and colleagues (2009) noted that further clinical trials are needed to evaluate the role for allogeneic SCT for Ewing's sarcoma.

Burdach and colleagues (2000) compared outcome after autologous and allogeneic stem-cell transplantation (SCT) in patients with advanced Ewing's tumors.  These investigators analyzed the results of 36 patients who were treated with the myeloablative Hyper-ME protocol (hyper-fractionated total body irradiation, melphalan, etoposide +/- carboplatin).  Minimal follow-up for all patients was 5 years.  All subjects underwent remission induction chemotherapy and local treatment before myeloablative therapy.  Seventeen of 36 patients had multi-focal primary Ewing's tumor, 18 of 36 had early, multiple or multi-focal relapse, 1 of 36 patients had unifocal late relapse.  Twenty-six of 36 were treated with autologous and 10 of 36 with allogeneic hematopoietic stem cells.  These researchers analyzed the following risk factors, which could possibly influence the EFS: number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis.  Event-free survival for the 36 patients was 0.24 (0.21) +/- 0.07.  Eighteen of 36 patients suffered relapse or died of disease, 9 of 36 died of treatment related toxicity (DOC).  Nine of 36 patients are alive in CR.  Age greater than or equal to 17 years at initial diagnosis significantly deteriorated outcome (p < 0.005).  According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT.   Incidence of DOC was more than twice as high after allogeneic (40 %) compared to autologous (19 %) SCT, even though the difference did not reach significance (p = 0.08, Fisher's exact test).  The authors concluded that because of the rather short observation period, secondary malignant neoplasms may complicate the future clinical course of some of the patients who were viewed as event-free survivors.  Event-free survival in patients with advanced Ewing's tumors is not improved by allogeneic SCT due to a higher complication rate.

In a retrospective study, Laurence and colleagues (2005) analyzed 46 patients treated in the authors' institution between 1987 and 2000 for localized or primary metastatic Ewing's tumors by HDC followed by autologous stem cell rescue.  Median follow-up was 7.1 years.  Median age was 21 years (range of 15 to 46 years).  A total fo 22 % of patients had metastases at diagnosis.  The tumor site was axial in 56 % of patients.  Median tumor size was 9.5 cm.  The treatment regimen consisted of induction chemotherapy, local treatment, maintenance chemotherapy, and consolidation HDC based on alkylating agents.  No toxic death was observed in the intensive therapy phase.  Five-year OS and progression-free survival (PFS) were 63 +/- 7.7 % and 47 +/- 7.6 %, respectively.  Pejorative prognostic factors in this population were metastases at diagnosis (5-year OS: 34 % versus 71 %, p = 0.017) and poor pathologic response (5-year OS: 44 % versus 77 %, p = 0.03).  These findings showed a high long-term survival rate with HDC followed by autologous stem cell rescue in adults.

Fraser et al (2006) reported the findings of 36 patients with high-risk Ewing's sarcoma and other pediatric solid tumors who received ASCT.  Overall survival was 63 % (95 % confidence interval [CI]: 47 % to 79 %) at 1 year and 33 % (95 % CI: 16 % to 50 %) at 3 years.  Patients with a diagnosis of Ewing's sarcoma or desmoplastic small round cell tumor had significantly better survival than those with other diagnoses with estimated 3-year OS of 54 % (95 % CI: 29 %  to 79 %) for this group of patients (p = 0.03).  There were 2 transplant-related deaths; both attributable to hepatic veno-occlusive disease.  Median follow-up among survivors was 3.5 years (range of 0.6 years to 7.9 years).  The authors concluded that these data justify continued investigation of ASCT as a consolidation therapy in patients with metastatic or relapsed Ewing's sarcoma and desmoplastic small round cell tumor.

Gardner and associates (2008) identified risk factors associated with PFS in patients with Ewing's sarcoma undergoing ASCT.  A total of 116 patients underwent ASCT in 1989 to 2000 and reported to the Center for International Blood and Marrow Transplant Research.  Eighty patients (69 %) received ASCT as first-line therapy and 36 (31 %) for recurrent disease.  Risk factors affecting ASCT were analyzed with use of the Cox regression method.  Metastatic disease at diagnosis, recurrence prior to ASCT and performance score less than 90 were associated with higher rates of disease recurrence/progression.  Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49 % (95 % CI: 30 to 69) and 34 % (95 % CI: 22 to 47), respectively.  The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT following recurrence was 14 % (95 % CI: 3 to 30).  Progression-free survival rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients.  The authors concluded that ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.

In a retrospective study, Diaz et al (2010) analyzed the outcome and identified risk factors associated with PFS in 47 children with high-risk Ewing's sarcoma who underwent autologous peripheral blood stem cell (PBSC) transplantation.  The conditioning regimen used in all patients consisted of high dose of busulfan and melphalan.  Median age was 13 years (range of 4 to 21 years).  A total of 43 % of patients had metastases at diagnosis.  The probability of transplant-related mortality (TRM) was 6 % +/- 3 %.  Recurrence/progressive disease was observed in 17 patients.  The probability of recurrence/progression was 39 % +/- 7 %.  With a median follow-up of 92 months (range of 6 to 168 months), the PFS was 56 % +/- 4% for the whole group.  In multi-variate analysis, localized disease at diagnosis and obtaining CR by 3 months after transplantation were variables associated to better outcomes.  The probability of PFS was 78 % +/- 8 % and 27 % +/- 10 % for patients with localized and metastatic disease at diagnosis, respectively (p = 0.0001).  These findings showed a high long-term survival using high-dose of busulfan and melphalan as conditioning regimen in children with high-risk Ewing's tumors.  Patients with localized disease at diagnosis and those with good response to treatment before or after transplant would benefit most.

An UpToDate review on “Treatment of the Ewing sarcoma family of tumors” (Harmon and Gebhardt, 2016) states that “Allogeneic stem-cell transplantation offers no advantage over autologous transplantation and has a higher complication rate”.

Primitive Neuroectodermal Tumors and Ependymoma

Available evidence indicates that HDC in conjunction with autologous bone marrow/stem cell transplantation may improve survival rates in patients with high-risk/recurrent MB and sPNET despite treatment toxicity.  On the othe hand, there is insufficient evidence to support such a role for allogeneic bone marrow/sem cell transplantation.

Perez-Martínez et al (2005) presented the findings of 19 patients with high-risk and recurrent MB and supratentorial PNET (sPNET) (13 classified in the high-risk group and 6 with recurrent disease) who received HDC and autologous stem cell rescue (ASCR).  In the high-risk group, all patients underwent neurosurgical debulking.  Standard chemotherapy was prescribed in 10 patients.  Radiotherapy was given to 4 patients (all older than 4 years old).  In the recurrence disease group, 5 patients underwent surgery.  Radiotherapy was given to those who were not previously irradiated.  The HDC in 12 patients consisted of busulfan 4 mg/kg/day, orally over 4 days in 6-hourly divided doses and melphalan at a dose of 140 mg/m2/day by intravenous infusion over 5 mins on day-1.  Three patients additionally received thiotepa 250 mg/m2/day intravenously over 2 days, and 4 patients additionally received topotecan 2 mg/m2/day over 5 days by intravenous infusion over 30 mins.  The other 7 patients received busulfan and thiotepa at the same doses.  Patient's stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12 microg/kg twice-daily subcutaneously for 4 consecutive days.  Cryopreserved peripheral blood progenitor cells were re-infused 48 hrs after completion of chemotherapy.  With a median follow-up of 34 months (range of 5 to 93 months), 8 complete responses and 1 partial response were observed.  Three patients died of treatment-related toxicities (15 %).  The 2-year EFS was 37.67 +/- 14 % in all patients and 57 +/- 15 % for the high-risk group.

Sung et al (2007) examined the effects of single or tandem double HDC in the treatment of children with newly diagnosed high-risk or relapsed MB and sPNET in order to defer or avoid radiotherapy in young children.  A total of 37 HDC were given to 25 children with newly diagnosed high-risk or relapsed MB/sPNET.  Tandem double HDC was used for 12 of 15 patients initially intended to receive double HDC.  Three-year EFS (+/- SE) in 6 newly diagnosed high-risk (greater than 3 years old), 8 newly diagnosed (less than 3 years old), and 11 relapsed MB/sPNET was 83.3 +/- 15.2 %, 62.5 +/- 20.5 %, and 29.1 +/- 15.7 %, respectively.  Three-year EFS for patients in CR or PR and in less than PR at first HDC was 67.4 +/- 11.0 % and 16.7 +/- 15.2 %, respectively (p = 0.001).  Three-year EFS in patients initially intended to receive double HDC and single HDC was 66.0 +/- 12.4 % and 40.0 +/- 15.5 %, respectively.  For 19 patients in CR or PR at first HDC, 3-year EFS was 88.9 +/- 10.5 % in tandem double HDC group, and 44.4 +/- 16.% in single HDC group, respectively (p = 0.037).  Although 4 TRMs occurred during 25 first HDC, no TRM occurred during 12 second HDC.  In 4 of 8 young children, cranio-spinal radiotherapy was successfully withheld without subsequent relapse.  The authors concluded that HDC may improve the survival of children with newly diagnosed high-risk MB/sPNET, and, to some extent, the survival of those with relapsed MB/sPNET.  They stated that further study is needed to evaluate the effectiveness of tandem double HDC.

Kadota et al (2008) determined the response, toxicity, and survival for children with progressive or recurrent MB and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells.  Subjects were in second remission or had minimal residual disease at the time of study entry.  The conditioning regimen consisted of cyclophosphamide 6,000 mg/m(2) plus melphalan 180 mg/m(2).  A total of 29 evaluable pediatric patients were accrued.  The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded.  Best responses were: complete response = 6, continuous complete response = 13, partial response = 6, stable disease = 2, and progressive disease = 2.  There were 6 MB and 3 germinoma survivors with a median follow-up of 7.5 years (range of 2.8 to 10 years).  Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease.  The authors concluded that myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving complete response or continuous complete response status and 9/29 becoming long-term survivors.

Cheuk and colleagues (2008) reported the outcomes of pediatric brain tumors treated with autologous hematopoietic stem cell transplant (AHSCT) in a quaternary referral center in Hong Kong over 10 years (June 1996 to May 2006).  A total of 13 patients with MB (n = 9), cerebral PNET (n = 1), ependymoma (n = 1), germ cell tumor (n = 1) and cerebellar rhabdoid (n = 1) were transplanted because of tumor residual (n = 1) or recurrence (n = 12).  Uniform upfront treatment protocols were adopted according to specific tumor types.  Prior to AHSCT, 8 patients (61.5 %) achieved CR and 5 (38.5 %) were in PR.  Conditioning employed thiotepa 300 mg/m2, etoposide 250 mg/m2)and carboplatin 500 mg/m2 daily for 3 days.  Toxicity included mucositis and neutropenic fever in all patients, grade 4 hepatic toxicity in 4 patients (including hepatic veno-occlusive disease in 2 patients) and grade 4 renal toxicity in 1 patient.  The 5-year EFS was 53.9 %.  Five patients died of disease recurrence or progression 8 to 21 months after transplant with a median disease-free period of 8 months post-transplant.  One died of transplant-related complications in the early post-transplant period.  Seven survived for a median of 5.4 years (maximum follow-up of 9.8 years), with 6 having Lansky-Karnofsky performance score above 80.  All survivors had CR before transplant though 2 had leptomeningeal spread.  The authors concluded that AHSCT can achieve long-term survival in children with recurrent brain tumor.  However, those with macroscopic residual tumor before transplant can not be salvaged.

Fangusaro et al (2008) reported the findings of intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed sPNET.  A total of 43 children with sPNET were prospectively treated on 2 serial studies (HS I and II).  After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with 5 cycles of intensified induction chemotherapy (ICHT) (vincristine, cisplatin, cyclophosphamide, and etoposide).  Patients on HS II with disseminated disease received high-dose methotrexate during ICHT.  If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR.  Five-year EFS and OS were 39 % (95 % CI: 24 % to 53 %) and 49 % (95 % CI: 33 % to 62 %), respectively.  Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs.  Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors.  A total of 64 % of survivors (12 of 20) were alive without exposure to radiation therapy.  The authors concluded that ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients.

Butturini et al (2009) examined the outcome of children with recurrent MB and sPNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue.  A total of 33 children were referred for myeloablative chemotherapy: 14 of those children were never transplanted because of pre-transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant.  Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles.  The 3-year post-transplant EFS rate in unirradiated versus previously irradiated children was 83 % +/- 15 % versus 20 % +/- 12 %, respectively (p = 0.04).  One child who had never been exposed to radiotherapy died of toxicity; the other children received post-transplant radiotherapy and remained disease free.  Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of less than 1 year between initial radiotherapy and myeloablative chemotherapy predicted a greater risk of toxic death (p = 0.02), whereas a history of meningeal metastases at diagnosis and a poor response to the initial rescue therapy predicted a greater risk of post-transplant recurrence (p = 0.03 and p = 0.08, respectively).  The authors concluded that myeloablative doses of thiotepa-based chemotherapy and radiotherapy were able to cure most children who had radiotherapy-naive, chemo-responsive recurrences.  Children who developed recurrences after cranio-spinal radiotherapy had poorer outcomes; however, cure was possible in those who had good prognostic features at presentation, chemo-responsive recurrences, and a long interval between initial radiotherapy and myeloablative chemotherapy.

Dunkel et al (2010) examined the effects of high-dose carboplatin, thiotepa, and etoposide with ASCR for patients with previously irradiated recurrent MB.  A total of 25 patients, aged 7.6 to 44.7 years (median of 13.8 years) at ASCR, were treated.  Three (12 %) died of treatment-related toxicities within 30 days of ASCR, due to multi-organ system failure (n = 2) and aspergillus infection with veno-occlusive disease (n = 1).  Tumor recurred in 16 at a median of 8.5 months (range of 2.3 to 58.5 months).  Six were event-free survivors at a median of 151.2 months post-ASCR (range of 127.2 to 201.6 months).  The Kaplan-Meier estimate of median OS is 26.8 months (95 % CI: 11.9 months to 51.1 months) and of EFS and OS are both 24 % (95 % CI: 9.8 % to 41.7 %) at 10 years post-ASCR.  M-0 (versus M-1+) recurrence prior to protocol, lack of tissue confirmation of relapse, and initial therapy of radiation therapy (RT) alone (versus RT + chemotherapy) were not significantly associated with better EFS (p = 0.33, 0.34, and 0.27, respectively).  Trends toward better EFS were noted in patients (n = 5) who received additional RT as part of their retrieval therapy (p = 0.07) and whose recurrent disease was demonstrated to be sensitive to re-induction chemotherapy (p = 0.09).  This retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent MB.  The use of additional RT may be associated with better outcome.

Ependymomas are rare primary central nervous system (CNS) tumors in adults.  It is also the third most common brain tumor in children with OS ranging from 24 % to 75 % at 5 years.  They occur most commonly in the spinal cord, where histopathological evaluation is critical to differentiate the grade I myxopapillary ependymoma from the grade II ependymoma or grade III anaplastic ependymoma.  Brain ependymomas are either grade II or III.  Treatment for all grades and types includes maximum surgical resection.  For myxopapillary ependymoma, complete removal while maintaining capsule integrity may be curative.  Some grade II ependymomas may be observed carefully after imaging confirms complete resection, but grade III tumors require adjuvant radiation treatment.  Current standard treatments includes radiation therapy and surgical resection.  Chemotherapy has a role in infants to avoid/delay radiation therapy and can be helpful to improve resectability (Zacharoulis and Moreno, 2009; Gilbert et al, 2010).

However, the National Comprehensive Cancer Network's (NCCN) clinical practice guidelines in oncology on "central nervous system cancers" (2010) states that "the role of chemotherapy in the treatment of ependymomas is poorly defined.  Although many drugs have been tried, ependymomas do not appear particularly responsive to chemotherapy.  In children or adults with newlt diagnosed ependymomas, no studies have demonstrated a survival advantage with chemotherapy plus irradiation, when compared with irradiation alone".  Furthermore, the NCCN guideline does not mention the use of autologous or allogeneic bone marrow/stem cell transplantation as a therapeutic option for patients with ependymoms.  Also, in an UpToDate review on ependymoma, Kieran (2010) noted that HDC with stem cell rescue has not shown benefits in children with recurrent disease.  Bone marrow/stem cell transplant was not mentioned as a management tool of patients with ependymoma.

In a phase II clinical trial, Grill et al (1996) presented the findings of 16 children with refractory or relapsed ependymoma who received HDC followed by autologous ABMT.  The conditioning regimen consisted of busulfan 150 mg/m2/day for 4 days and thiotepa 300 mg/m2/day for the 3 following days.  All patients had previously been treated by surgery and conventional chemotherapy; 8 of them had also received irradiation at doses ranging from 45 to 55 Gy at the tumor site.  At the time of transplantation, 9 patients were in first relapse, 5 in second relapse and 2 in third relapse or more; all had measurable disease; 15 patients were evaluable for response.  No radiological response greater than 50 % was observed.  Stable disease and progressive disease were documented in 10 and 5 cases, respectively.  The duration of response to this treatment, which lasted for a median time of 7 months (range of 5 to 8 months), was only evaluable in 5 patients who did not receive further treatment after ABMT.  There were 3 disease-free survivors at 15, 25 and 27 months; all of whom were treated with second complete surgical resection and local radiotherapy (55 Gy).  Toxicity was severe, mainly digestive and cutaneous, and 1 toxicity-related death occurred.  The authors stated that unlike MB, ependymomas do not appear to be sensitive to this combination therapy.

Mason et al (1998) determined the toxicity, radiographical response rate and outcome following intensive chemotherapy with ThioTEPA, etoposide, carboplatinum and autologous bone marrow rescue (ABMR) for young children with recurrent CNS ependymoma.  ThioTEPA 300 mg/m2/day (total 900 mg/m2) and etoposide 250 to 500 mg/m2/day (total 750 to 1,500 mg/m2) were administered for 3 consecutive days with or without the addition of carboplatinum 500 mg/m2/day (total 1500 mg/m2) for an additional 3 consecutive days, and autologous bone marrow was re-infused 72 hrs following chemotherapy.  Eligibility criteria required adequate renal, hepatic and pulmonary function, and no tumor infiltration of bone marrow.  A total of 15 children with recurrent intra-cranial ependymoma, aged 5 months to 12 years (median of 22 months) were treated.  Five patients died of treatment related toxicities within 62 days of marrow re-infusion.  Eight have expired from progressive disease a median of 6 months post-ABMR, and 1 has died from unrelated causes.  One child remains alive 25 months post-ABMR, following further disease recurrence.  No partial or complete responses were observed.  This regimen of high-dose ThioTEPA and etoposide with or without additional carboplatinum with ABMR is not an effective strategy for treating children with recurrent ependymoma.

Wolff and Finlay (2004) noted that early attempts to use HDC technology to improve the effect of nitrosourea on high-grade gliomas resulted in minimal benefit as well as in severe toxicity.  Since then, other drugs have been applied in conjunction with either autologous bone marrow or peripheral blood stem cells, including thiotepa, etoposide, melphalan, cyclophosphamide, and busulfan.  The data suggested benefit in recurrent PNET, in newly diagnosed young children with PNET and possibly in young children with newly diagnosed ependymoma, as a strategy not only to improve tumor-free survival but also to avoid exposure to cranio-spinal irradiation.  In other tumors such as recurrent ependymoma and newly diagnosed or recurrent brain stem glioma, HDC remains ineffective.  New protocols under evaluation include new agents, multiple cycles of HDC and allogeneic transplantation as immunotherapeutic approach.

Raghuram et al (2012) performed a systematic review of the literature regarding outcome of patients with relapsed sPNET treated with HDC and HDC with hematopoietic stem cell rescue (HSCR) was performed to examine the potential predictive factors that would justify its use in this subset of patients.  A total of 46 patients were identified fulfilling the inclusion criteria.  Of those, 15 patients were infants and 15 were pineoblastomas.  With a median follow-up of 40 months (range of 3 to 123 months) 15 patients were reported alive.  Thirteen patients out of the 15 survivors did not receive cranio-spinal irradiation (CSRT).  The 12-month OS of the cohort was 44.2 ± 7.5 months.  Twelve-month OS for children less than 36 months was 66.7 ± 12.2 months while for older children it was 27.8 ± 10.6 (p = 0.003).  Twelve-month OS was 20.0 ± 10.3 for those patients with pineoblastoma versus 54.6 ± 9.0 for those with non-pineal sPNETs (p < 0.001).  Cox regression analysis revealed pineal location as the only independent adverse prognostic factor.  The authors concluded that HDC with HSCR might lead to survival primarily in younger children with relapsed sPNET even in the absence of concomitant use of radiotherapy, whereas the outcome in older children and/or in pineal location is extremely poor with this modality.

Retinoblastoma

Retinoblastoma is a rare, pediatric intra-ocular malignancy.  Extra-ocular retinoblastoma is rarely recorded in high income countries, but is very common in countries of low and middle income (Dimaras et al, 2012).  Leukocoria (white, shiny, jello-like eye) and strabismus secondary to retinoblastoma are usually first recognized by relatives. 

McDaid and colleagues (2005) evaluated the clinical effectiveness of treatments for childhood retinoblastoma.  Electronic databases were searched from inception to April 2004.  Studies of participants diagnosed with childhood retinoblastoma, any interventions and all clinical outcomes were eligible for inclusion.  Randomized and non-randomized controlled trials and cohort studies with clear comparisons between treatment groups were included.  Methodological quality was assessed.  A narrative synthesis was conducted.  Where possible, studies assessing common interventions were grouped together, with prospective and retrospective studies grouped separately.  Emphasis was placed on prospective studies.  A total fo 31 individual studies, from 42 publications, were included in the review.  Apart from 1 non-randomized controlled trial, only comparative studies of observational design were available for any of the treatments.  Four of the included studies were prospective and the remaining 27 were retrospective.  Most of the studies were of radiotherapy or chemotherapy, with few studies available on enucleation or focal treatments such as brachytherapy, photocoagulation, cryotherapy and thermotherapy.  The methodological quality was generally poor, with a high-risk of bias in all included studies.  The main problems were in relation to how treatment was allocated and lack of consideration of potentially confounding factors, such as initial disease severity, in the study design and data analysis.  The evidence base for effectiveness of treatments for childhood retinoblastoma is extremely limited.  Owing to the considerable limitations of the evidence identified, it was not possible to make meaningful and robust conclusions about the relative effectiveness of different treatment approaches for childhood retinoblastoma.  The authors concluded that the evidence base for the effectiveness of treatments for childhood retinoblastoma is not sufficiently robust to provide clear guidance for clinical practice.  Ideally, good-quality randomized controlled trials (RCTs) assessing the effectiveness of different treatment options for childhood retinoblastoma are required.  Research is required on all the treatments currently used for this condition.  Where RCTs are not feasible, for ethical or practical reasons, only high-quality, prospective, non-randomized studies should be given consideration, owing to the generally higher risk of bias in retrospective studies.  To reduce the risk of confounding due to allocation by clinical indication, studies should compare patients with similar disease severity rather than compare patients of mixed disease severities.  Standardized outcomes should be agreed for use in studies assessing the effectiveness of treatment.  These outcomes should encompass potential important adverse effects of treatment such as loss of visual acuity and cosmetic outcome, as well as beneficial effects.

Dunkel et al (2010) described a series of 8 patients treated with intensive chemotherapy, defined as the intention to include HDC with autologous hematopoietic stem cell rescue (ASCR).  Induction chemotherapy included cyclophosphamide (CY) and/or carboplatin with a topoisomerase inhibitor.  High-dose chemotherapy regimens were carboplatin and thiotepa with or without etoposide (n = 3) or carboplatin, etoposide, and cyclophosphamide (n = 2).  Seven patients had leptomeningeal disease and 1 patient had only direct extension to the central nervous system (CNS) via the optic nerve.  Three patients had stage 4b disease at the time of original diagnosis of the intra-ocular retinoblastoma; 5 had later onset at a median of 12 months (range of 3 to 69 months).  One patient died of toxicity (septicemia and multi-organ system failure) during induction and 2 had disease progression prior to HDC.  Five patients received HDC at a median of 6 months (range of 4 to 6) post-diagnosis of stage 4b disease.  Two patients survived event-free at 40 and 101 months; 1 was irradiated following recovery from the HDC.  The authors concluded that intensive multi-modality therapy may be beneficial for some patients with stage 4b retinoblastoma.  Moreover, they stated that longer follow-up will determine whether it has been curative.

Tsuruta et al (2011) trilateral retinoblastoma (TRb) is an intra-cranial neurogenic tumor associated with unilateral or bilateral retinoblastoma and has very poor prognosis.  Patients typically die from leptomeningeal tumor dissemination.  These researchers reported the case of a 3-year old girl who had been diagnosed with TRb and had a disseminated relapse after a tumorectomy, cerebrospinal irradiation, and conventional chemotherapy.  The disseminated tumor disappeared after the first autologous peripheral blood stem cell transplantation (PBSCT) with high-dose melphalan and thiotepa.  During the second complete remission, a second autologous PBSCT with high-dose busulfan and melphalan was performed.  Seven months after the first PBSCT, the second relapse occurred, and these investigators subsequently performed an allogeneic PBSCT with myeloablative chemotherapy consisting of melphalan, thiotepa, and cyclophosphamide.  The patient showed clinical improvement after the allogeneic PBSCT.  The authors concluded that although HDC have a curative effect for some patients with TRb, the prognoses of disseminated tumors are still poor.  They stated that further examination of the HDC is necessary for the time, the conditioning drugs, and the hematopoietic stem cell sources.

Palma et al (2012) reported 11 consecutive children with metastatic retinoblastoma (6 unilateral) treated in 3 South-American countries with HDC followed by ASCR.  One patient had metastatic retinoblastoma at diagnosis and the remaining ones had a metastatic relapse.  Metastatic sites included bone marrow (BM) = 6, bone = 4, orbit = 5 and CNS = 4.  All patients received induction with conventional chemotherapy achieving CR at a median of 5.7 months from the diagnosis of metastasis.  Conditioning regimens included carboplatin and etoposide with thiotepa in 6 or with CY in 4 or melphalan in 1 patient.  All patients engrafted after G-CSF-mobilized peripheral blood ASCR and no toxic deaths occurred.  Two children received post-ASCR CNS radiotherapy.  Seven children have disease-free survival (median follow-up of 39 months).  Central nervous system relapse, isolated (n = 3) or with systemic relapse (n = 1), occurring at a median of 7 months after ASCT was the most common event.  In the same period, 5 children with metastatic retinoblastoma did not qualify for HDC-ASCR and died.  The authors concluded that HDC-ASCR is a feasible and effective treatment for children with metastatic retinoblastoma in middle-income countries.  They noted that these findings provided preliminary data for the feasibility and safety for the replication of results obtained in higher-resource settings in middle-income countries.

Kasow et al (2012) reported 58 consecutive children with high-risk malignancies who were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study.  A total of 12 participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2)/day, with subsequent doses targeted to total systemic exposure of 100 +/- 20 ng h/ml and CY 750 mg/m(2)/day.  Seven participants received dose level 2.  CY dose escalation to 1 g/m(2)/day was considered excessively toxic; 1 died from irreversible veno-occlusive disease and 2 experienced reversible hepatotoxicity.  These adverse events halted further dose escalation.  A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose.  Diagnoses included neuroblastoma (n = 26), sarcoma (n = 9), lymphoma (n = 8), brain tumors (n = 5), Wilms (n = 2) and retinoblastoma (n = 1).  Twenty participants (39.3 %) were in CR1 at enrollment; median age was 5.1 years.  Most common non-hematological grade III to IV toxicity was gastrointestinal (n = 37).  Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively.  Twenty-six (51 %) participants remain alive at a median of 6.4 years after AHCT.  The authors concluded that CY 3.75 g/m(2), and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies.

Furthermore, an UpToDate review on "Overview of retinoblastoma" (Kaufman and Teed, 2012) states that "experimental protocols using transpupillary thermotherapy are currently being employed for small recurrent tumors, as are regimens employing high-dose chemotherapy with hematopoietic stem cell rescue for patients with extraocular disease.  Intravitreal chemotherapy has been successful in salvaging eyes with recurrent vitreous seeding and may ultimately play a role in primary therapy.  Intra-arterial chemotherapy has been beneficial in chemoreduction.  With advances in the field of genetics, gene and epigenetic modulation may become feasible treatments for retinoblastoma in the future".

In summary, there is currently insufficient evidence to support the use of autologous or allogeneic bone marrow or stem cell transplant for the treatment of retinoblastoma.

Wilms Tumor

Ha et al (2013) reviewed the event-free (EFS) and overall survival (OS) from publications describing outcome for children with relapsed Wilms' tumor receiving myeloablative high-dose chemotherapy. Comparisons are made between those receiving myeloablative high dose chemotherapy with autologous stem-cell rescue (HDT) and those not (NoHDT). Relevant information was extracted from individual patient or summary data and 3-year EFS and OS rates established. These rates were combined in a weighted manner to derive hazard ratios (HRs). Nineteen publications were identified (5 HDT, 6 NoHDT, 8 both). Pooling  all studies suggested an advantage to HDT with a hazard ratio (HR) for EFS of 0.87 (95% CI 0.67-1.12) and 0.94 (0.71-1.24) for OS. A stratified analysis confined to studies that provided individual patient data on both HDT and NoHDT gave HRs of 0.83 (0.56-1.24) and 0.92 (0.59-1.41). Further, analyses of risk groups, defined by treatment and/or histology prior to first relapse, suggested a HR for EFS of 0.90 (95% CI 0.62-1.31) for those of high and 0.50 (CI 0.31-0.82) for the very high risk patients. The investigators concluded that the evidence suggests a benefit from myeloablative high dose chemotherapy, although there are many caveats since the information is not from randomized trials, a great deal of uncertainty concerning the role of HDT in patients following relapse after treatment for their Wilms' tumour. The investigators stated that, for each risk group, they propose a randomized trial comparing a standard with a more intensive therapy with specific choice of  regimen tailored to the risk group (and co-operative groups) concerned.

Lee and colleagues (2011) stated that despite increasing evidence that tandem high-dose chemotherapy (HDCT) and autologous stem cell transplantation (autoSCT) might improve the survival of patients with high-risk solid tumors, patients with Wilms’ tumor may be at high risk of acute and chronic renal impairment during and after tandem HDCT/autoSCT because they usually have a single kidney.  These researchers investigated the feasibility of tandem HDCT/autoSCT in patients with Wilms’ tumor, focusing on renal function.  A total of 6 patients with relapsed/progressed Wilms’ tumor were assigned to undergo tandem HDCT/autoSCT.  One patient developed transient acute renal failure during the first HDCT/autoSCT.  All other patients underwent the second HDCT/autoSCT as scheduled.  Acute renal dysfunction during the second HDCT/autoSCT was transient and manageable.  Indicators of glomerular function such as creatinine clearance, serum creatinine, and albumin excretion were in the normal range at 3 years after tandem HDCT/autoSCT.  Sub-clinical tubular dysfunctions, such as increased excretion of β-N-acetylglucosaminidase and β2-microglobulin, were identified at 1 and 3 years after tandem HDCT/autoSCT; however, no patient required treatment for these conditions.  The authors concluded that these results were helpful to consider tandem HDCT/autoSCT as a treatment option in patients with Wilms’ tumor.  Moreover, they stated that longer duration of follow-up and close monitoring of tubular function are required if tandem HDCT/autoSCT is indicated in patients with Wilms’ tumor.

Furthermore, an UpToDate review on “Treatment and prognosis of Wilms tumor” (Chintagumpala and Muscal, 2013) states that “High-dose chemotherapy with stem cell rescue has been suggested as an option in patients with recurrent tumor, especially in those with adverse prognostic indicators.  However, the efficacy of this approach remains unknown .... High-dose chemotherapy with stem-cell rescue has been suggested as an option in patients with recurrent tumor, especially in those with adverse prognostic indicators. However, the efficacy of this approach remains unknown”.

Autologous Hematopoietic Stem Cell Transplantation for Soft Tissue Sarcomas

Peinemann and colleagues (2017) noted that soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors.  Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma.  In people with advanced local or metastatic disease, AHSCT applied HDCT is a planned rescue therapy for HDCT-related severe hematologic toxicity.  The rationale for this Cochrane review update was to determine whether any RCTs have been conducted and to clarify whether HDCT followed by AHSCT has a survival advantage.  These investigators evaluated the safety and efficacy of HDCT followed by AHSCT for all stages of NRSTS in children and adults.  For this update, these investigators revised the search strategy to improve the precision and reduce the number of irrelevant hits.  They searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), PubMed from 2012 to September 6, 2016, and Embase from 2012 to September 26, 2016.  They also searched online trial registries and congress proceedings from 2012 to September 26, 2016.  Terms representing STS and autologous HSCT were required in the title or abstract.  These researchers restricted the study design to RCTs.  They included studies if at least 80 % of participants had a diagnosis listed in any version of the World Health Organization (WHO) classification and classified as malignant.  The search included children and adults with no age limits.  These investigators used standard methodologic procedures expected by Cochrane.  The primary outcomes were OS and TRM.  The authors identified 1,549 records; 85 items from electronic databases, 45 from study registries, and 1,419 from congress proceedings.  The revised search strategy did not identify any additional RCTs.  In the previous version of the review, these researchers identified 1 RCT comparing HDCT followed by AHSCT versus standard-dose chemotherapy (SDCT).  The trial randomized 87 participants who were considerably heterogeneous with respect to 19 different tumor entities.  The data from 83 participants were available for analysis.  In the single included trial, OS at 3 years was 32.7 % in the HDCT-arm versus 49.4 % in the SDCT-arm and there was no difference between the treatment groups (HR 1.26, 95 % CI: 0.70 to 2.29, p = 0.44; 1 study, 83 participants; high quality evidence).  In a subgroup of participants who had a complete response before HDCT, OS was higher in both treatment groups and OS at 3 years was 42.8 % in the HDCT-arm versus 83.9 % in the SDCT-arm and favored the SDCT group (HR 2.92, 95 % CI: 1.1 to 7.6, p = 0.028; 1 study, 39 participants).  In the single included trial, the authors reported 1 treatment-related leukemia death 2 years after HDCT.  They also evaluated severe adverse events (SAEs) WHO grade 3 to 4 in 22 participants in the HDCT-arm and in 51 participants in the SDCT-arm.  The authors reported 11 events concerning digestive-, infection-, pain-, or asthenia-related toxicity in the HDCT-arm and 1 event in the SDCT-arm (moderate quality evidence).  The development of secondary neoplasia was not addressed.  These investigators judged the study to have an overall unclear risk of bias as 3 of 7 items had unclear and 4 items had low-risk of bias.  For GRADE, these investigators judged 3 items as high-quality and 3 items were not reported.  The authors concluded that the limited data of 1 single RCT with an unclear risk of bias and moderate-to-high quality evidence showed no survival advantage for HDCT.  If this treatment was offered it should only be given after careful consideration on an individual person basis and possibly only as part of a well-designed RCT.

UpToDate reviews on “Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and chest wall” (DeLaney et al, 2018) and “Treatment protocols for soft tissue and bone sarcoma” (Brenner et al, 2018) do not mention stem cell transplantation as a therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcomas” (Version 2.2018) does not mention stem cell transplantation as a therapeutic option.

Solid Organ Transplantation Following Hematopoietic Stem Cell Transplantation in Childhood

Faraci and colleagues (2019) reported data obtained from a retrospective multi-center pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT).  Information on solid organ transplantation (SOT) performed in pediatric recipients of either auto- or allo-HSCT between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6 %).  Overall, these investigators evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations.  The indication for SOT was organ failure related to intractable GVHD in 16 children (36.3 %), acute or chronic HSCT-related toxicity in 18 (40.9 %), and organ dysfunction related to the underlying disease in 10 (22.8 %).  The median follow-up was 10.9 years (95 % CI: 1.7 to 29.5).  The OS rate at 1 and 5 years after SOT was 85.7 % and 80.4 %, respectively: it was 74 % and 63.2 % after LTx, 83.2 % after HTx, and 100 % equally after LuTx and KTx.  The authors concluded that the findings of this multi-center survey confirmed that SOT represented a promising option in children with severe organ failure occurring following HSCT.  These researchers stated that additional studies are needed to further establish the effectiveness of SOT following HSCT and to better understand the mechanism underlying this encouraging success.

Adoptive Cellular Immunotherapy for Refractory Childhood Solid Tumors

Merker and colleagues (2019) noted that prognosis of refractory childhood cancers despite multi-modal treatment strategies remains poor.  These investigators reported a single-center experience encountered in 18 patients with refractory solid tumors treated with adoptive cellular immunotherapy (ACI) from haploidentical or matched donors following HSCT.  While 7 patients were in PR and 6 in CR, 5 patients suffered from relapsed diseases at the time of ACI.  1.5-year probabilities of OS and PFS were 19.5 % and 16.1 % for all patients.  Patients in CR showed estimated 1.5-year OS and PFS of 50.1 % and 42.7 %, respectively.  CR was induced or rather sustained in 10 children, with 2 still being alive 9.6 and 9.3 years after ACI.  Naïve, central and effector memory T-cells correlated with responses.  However, the majority of patients relapsed.  Cumulative incidence of relapse was 79.8 % at 1.5 years.  Acute GVHD (aGVHD) occurred in 9 of 18 patients (50 %) with aGVHD grade I to II observed in 6 (33 %) and aGVHD grade III observed in 3 (17 %) patients, manageable in all cases.  The authors concluded that the findings of this study indicated that donor-derived ACI at its current state offered palliation but no clear curative benefit for refractory childhood tumors/cancers and warrants further improvement.

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

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic [not covered for neuroblastoma]
38206	autologous
38230	Bone marrow harvesting for transplantation [not covered for neuroblastoma]
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor [not covered for neuroblastoma]
38241	autologous transplantation
38242	Allogeneic lymphocyte infusions
86813	HLA typing; A, B or C multiple antigens
86817	DR/DQ, multiple antigens
86821	lymphocyte culture, mixed (MCL)
Other CPT codes related to the CPB:
38204 - 38215	Bone Marrow or Stem Cell Services/Procedures
96401 - 96425	Chemotherapy (high dose)
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
HCPCS codes not covered for indications listed in the CPB:
M0075	Cellular therapy
S2107	Adoptive immunotherapy i.e. development of specific anti-tumor reactivity (e.g. tumor-infiltrating lymphocyte therapy) per course of treatment
Other HCPCS codes related to the CPB:
J9000 - J9999	Chemotherapy drugs code range
Q0083 - Q0085	Chemotherapy administration
ICD-10 codes covered if selection criteria are met:
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage [relapsed or progressive Ewing's sarcoma family of tumors covered for autologous bone marrow or stem cell transplant - not covered for allogeneic]
C64.1 - C64.9	Malignant neoplasm of kidney, except pelvis [Wilms' tumor]
C69.20 - C69.22	Malignant neoplasm of retina
C71.0 - C71.9	Malignant neoplasm of brain [neuroblastoma - covered for autologous & allogeneic bone marrow or stem cell transplant] [medulloblastoma covered for autologous only - not covered for allogeneic]
C72.0 - C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system [neuroblastoma - covered for autologous & allogeneic bone marrow or stem cell transplant] [medulloblastoma covered for autologous only - not covered for allogeneic] [autologous or allogeneic not covered for ependymoma]
C74.00 - C74.92	Malignant neoplasm of adrenal gland [neuroblastoma] [ autologous only]
C75.3	Malignant neoplasm of pineal gland
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue [soft tissue sarcomas]

The above policy is based on the following references: