Prior Authorization Review Panel MCO Policy Submission

Transcription

1 Prior Authorization Review Panel MCO Policy Submission A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review. Plan: Aetna Better Health Submission Date: 8/1/2018 Policy Number: 0496 Effective Date: Revision Date: 5/10/2018 Policy Name: Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors Type of Submission Check all that apply: New Policy Revised Policy* Annual Review No Revisions *All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below: CPB 496 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors This CPB has been revised to state that autologous hematopoietic stem cell transplantation is considered experimental and investigational for the treatment of soft tissue sarcomas. Name of Authorized Individual (Please type or print): Signature of Authorized Individual: Dr. Bernard Lewin, M.D. Revised 05/10/18

2 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 1 of /14/2018 ( Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors Number: 0496 Policy I. 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 Policy History Last Review 05/10/2018 Effective: 02/01/2002 Next Review: 05/09/2019 Review History Definitions Additional Information

3 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 2 of 66 seriously compromise the chance of obtaining Clinical Policy a durable complete remission and any of the Bulletin Notes following selection criteria are met: A. 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 B. As primary treatment for persons in Stage IV neuroblastoma; or C. 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: A. 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 B. Stage IVS disease in infants less than 1 year of age with amplified n-myc gene status; or C. Stage III disease with either of the following:

4 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 3 of 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 D. Stage IIA or IIB disease, in persons 1 year of age or older, with amplified n-myc gene status and unfavorable histology. II. Aetna considers a repeat autologous hematopoietic cell transplantation medically necessary for persons with chemosensitive neuroblastoma who have relapsed after an autologous hematopoietic cell transplant. III. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for neuroblastoma because of insufficient evidence of its effectiveness. IV. 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. V. 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. VI. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of members

5 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 4 of 66 with Ewing's sarcoma family of tumors because of insufficient evidence of its safety and effectiveness. VII. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with primitive neuroectodermal tumors (PNET) including medulloblastoma and pineoblastoma. VIII. 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. IX. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of members with ependymoma who are ineligible for radiotherapy. X. 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. XI. Aetna considers autologous hematopoietic cell transplantation medically necessary for members with extraocular retinoblastoma. XII. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for members with retinoblastoma because of insufficient evidence of its safety and effectiveness.

6 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 5 of 66 XIII. Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of persons with progressive or relapsed chemosensitive Wilm's tumor. XIV. Aetna considers allogeneic hematopoietic cell transplantation experimental and investigational for the treatment of Wilms tumor because of insufficient evidence of its safety and effectiveness. XV. 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. 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

7 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 6 of 66 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

8 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 7 of 66 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, 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.

9 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 8 of 66 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 Age MYCN Shimada Ploidy Risk Stage status histology y 2A/2B < 365 Any Any Any Low Any Any Any Low Nonamplified Any - Low 365 d 21 y Amplified Fav - Low 365 d 21 y 365 d Amplified Unfav. - High 21 y 3 < Nonamplified 365 d Any Any Intermediate

10 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Clini... Page 9 of 66 INSS Age MYCN Shimada Ploidy Risk Stage status histology < 365 d > 365 d 21 y > 365 d 21 y > 365 d 21 y Amplified Any Any High Non amplified Non Fav. - Intermediate Unfav. - High amplified Amplified Any - High 4 < 365 d Non- amplified Any Any Intermediate < 365 Amplified Any Any High d ANY Any - High 365 d-21 y 4S < Non- 365 amplified d < Non- 365 amplified d Fav. DI>1 Low Any DI=1 Intermediate

11 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 10 of 66 INSS Stage Age MYCN status Shimada histology Ploidy Risk < Non- Unfav. Any Intermediate 365 amplified d < 365 d Amplified Any Any High KEY: INSS Stage = International Staging System for Neuroblastoma; Fav. = favorable; Unfav. = unfavorable. Source: Castleberry et al, 1997; Grupp, 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.

12 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 11 of 66 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. The length of stay for patients receiving chemotherapy alone is related to resolution of complications such as: (i) resolution of fever (i.e., fever-free for 48 hours while off all antibiotics); (ii) adequate blood counts (i.e., WBC greater than 500); (iii) resolution of other morbidity such as mucositis and diarrhea. The patient must also be able to maintain adequate oral intake. Hospital stays typically range from 2 to 4 weeks. Patients may be discharged even if an adequate platelet count is transfusion dependent; platelet transfusions can be given on an outpatient basis. Lengths of stay may be shorter if the transplant institution is equipped with a day hospital and nearby lodging. The patient may

13 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 12 of 66 then be discharged to return to the day hospital on an outpatient basis. 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. StudiesonHDC/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 highrisk neuroblastoma comparing intensive

14 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 13 of 66 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

15 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 14 of 66 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 highrisk 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 highrisk 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 diseasefree 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

16 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 15 of 66 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 reducedintensity 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 graftversus-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 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

17 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 16 of 66 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 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 highdose 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 HLAmatched 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

18 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 17 of 66 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 posttransplant adjuvant treatment to enhance the GVT effect are needed to improve the outcome after RI allosct. Sung, et al. (2012) wrote that, although a graftversus-tumor effect has not yet been convincingly demonstrated in the setting of relapsed NB, the strategy of employing RI allosct has provided hope that treatmentrelated 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:

19 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 18 of 66 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., multidrug 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.

20 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 19 of 66 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 stemcell 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) +/ 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 complete remission (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 / after

21 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 20 of 66 autologous and / 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. Eventfree 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.

22 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 21 of 66 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. Engelhardt et al (2007) reported the findings of HDC and ASCT in 35 consecutive adult patients with poor-risk Ewing's sarcoma or rhabdomyosarcoma (n = 11) and soft tissue sarcomas (STS) (n = 24) undergoing ASCT. At a median follow-up of months after ASCT, 11 patients were alive, with 9 in sustained CR and each one in partial remission (PR) and stable disease. Median OS from ASCT was 17.1 months. Response to pre-treatment, Karnofsky index greater than 80 %, R (0) resection and firstline ASCT were associated with long-term OS (p < 0.05). The authors concluded that these data indicate that (i) patients achieving a CR or PR following induction, with preserved performance status and R (0) resection may benefit from ASCT, and (ii) that this can be an useful

23 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 22 of 66 therapeutic modality in a subset of patients, in some achieving remarkable responses. 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 firstline 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. Drabko et al (2008) presented results of megachemotherapy and ASCT in children with Ewing's sarcoma in 4 Polish pediatric transplantation centers. Between 1995 and 2007, ASCT was performed in 54 patients (25

24 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 23 of 66 girls and 29 boys) with Ewing's sarcoma. A total of 26 patients were in CR before megachemotherapy, 23 were in partial remission, 3 patients had progression of the disease and the status of 2 patients was unknown. A total of 41 children received busulfan 16 mg/kg and melphalan 140 mg/m(2), 8 children carboplatin 1,500 mg/m(2), VP mg/kg, melfalan 160 mg/m(2) and 5 children other megachemotherapy protocols. Probability of survival of patients after transplantation, in CR is 0.79 with median 35 months of observation time. For patients after transplantation in PR probability of survival was 0.25 with median observation time of 14 months. Patients in progressive disease died 1,3 and 7 months after transplantation; 32 children are alive and 22 patients died, 21 of them due to disease progression. The authors concluded that (i) megachemotherapy and ASCT is a safe in patients with high-risk Ewing's sarcoma in CR, (ii) proportion of patients with sustained remission after transplantation in greater as compared to the published data related to high-risk group without megachemotherapy, and (iii) according to the authors' data megachemotherapy did not improve outcome in patients with PR of the disease. 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

25 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 24 of 66 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 = ). 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: Medulloblastoma (MB), a primitive neuroectodermal tumor (PNET) that arises in the posterior fossa, is the most common malignant brain tumor among children. It mainly arises in the cerebellum and fourth ventricle. Most cases of MB are sporadic. Most often intra-cranial

26 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 25 of 66 hypertension reveals the disease typically with headache and vomiting. Brain and spinal MRI can establish the diagnosis of posterior fossa tumor and define the extent of the disease. Cerebral spinal fluid study completes the staging. Histological examination of the tumor confirms the diagnosis of MB. Patients are classified into 2 risk groups: (i) standard-risk MB, defined by non-metastatic disease treated by total or subtotal tumor resection; and (ii) highrisk patients who have disseminated disease and/or residual disease. Tumor molecular genetic findings allow the use of emerging prognostic factors and may ultimately contribute to the development of targeted therapy. Current treatment in the oldest children combines surgical resection followed by radiotherapy and chemotherapy. The aim of recent studies was to increase survival and decrease sequelae by reducing cranio-spinal irradiation in older children with standard risk MB. Treatment in younger patients is as much as possible restricted to surgery and chemotherapy. However, long-term sequelae after treatment for MB remain frequent and the detection and treatment of those sequelae is an essential part of the follow-up of the patients (Yazigi-Rivard et al, 2008). 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.

27 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 26 of 66 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 highrisk 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 reinfused 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 treatmentrelated toxicities (15 %). The 2-year EFS was /- 14 % in all patients and 57 +/- 15 % for the high-risk group.

28 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 27 of 66 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 / %, / 20.5 %, and / %, respectively. Threeyear EFS for patients in CR or PR and in less than PR at first HDC was / % and / 15.2 %, respectively (p = 0.001). Three-year EFS in patients initially intended to receive double HDC and single HDC was / % and / %, respectively. For 19 patients in CR or PR at first HDC, 3-year EFS was / 10.5 % in tandem double HDC group, and /- 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

29 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 28 of 66 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

30 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 29 of 66 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

31 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 30 of 66 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

32 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 31 of 66 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, chemoresponsive recurrences, and a long interval between initial radiotherapy and myeloablative chemotherapy. Dunkel et al (2010) examined the effects of highdose 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 multiorgan 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 eventfree survivors at a median of months post- ASCR (range of to months). The

33 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 32 of 66 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

34 Hematopoietic Cell Transplantation for Selected Childhood Solid Tumors - Medical Cl... Page 33 of 66 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