© Springer Science+Business Media New York 2015
Katrin Scheinemann and Eric Bouffet (eds.)Pediatric Neuro-oncology10.1007/978-1-4939-1541-5_2121. High-Dose Chemotherapy/Stem Cell Transplantation (HDSCT)
(1)
Department of Pediatrics, Alberta Children’s Hospital, Calgary, AB, Canada
(2)
Division of Pediatric Oncology, Department of Pediatrics, British Columbia’s Children’s Hospital, Vancouver, BC, Canada
Keywords
High-dose chemotherapyStem cell rescueThiotepaMelphalanRegimensIntroduction
Treatment of CNS tumors relies on the expertise of neurosurgeons to obtain as complete as possible a resection of the tumors to facilitate best outcomes. Radiation treatment (RT) despite its long-term effects on cognition and growth remains an additional modality. Increasing recognition of side effects from radiation has directed the development and enhancement of chemotherapy regimens for responsive tumors. The use of chemotherapy for a variety of brain tumors may permit delay of RT and decrease long-term side effects. Within specific entities, it may even allow omission of RT. As can be seen in previous chapters, the use of chemotherapy has had a significant impact on how brain tumors are treated today.
Sensitivity to chemotherapeutic agents and their demonstrated benefits has lead to consideration of higher doses of such agents with the use of stem cell support (HDCST) to maintain dose intensity in order to improve outcomes. This chapter discusses the use of HDSCT for brain tumors.
Chemotherapy Regimens
In the mid 1980s, Finlay’s [1] group advanced a series of regimens for the treatment of brain tumors. Finlay used thiotepa, a lipophilic agent that has excellent penetration into the CSF and achieves concentrations equivalent to that in plasma [2]. Myelosuppression, particularly with thrombocytopenia, is generally seen at lower doses, while mucositis, neurologic toxicities, and skin hyperpigmentation are seen at higher doses. Thiotepa in combination with other agents still forms the backbone of many successful regimens for brain tumors. Initial toxic mortality (TRM) with 900 mg/m2 of thiotepa and 1,500 mg/m2 of etoposide was unacceptable at 16 % [1]. Since that initial experience, better patient selection, an improved delivery, and dose adjustments of medications, e.g., use of Calvert correction to dose carboplatin [3], combination with other agents, e.g., busulfan, carmustine, etc., have decreased TRM [4, 5]. Treatment-related toxicity, however, remains an ongoing concern with older individuals. Response rates as high as 50 %, with a progression-free survival (PFS), have been seen in patients with high-grade astrocytoma. Similarly patients with recurrent medulloblastoma treated with thiotepa 300 mg/m2/day, carboplatin 500 mg/m2/day, and etoposide 250 mg/m2/day, each for 3 days, showed a 35 % (8 of 23 patients) PFS at a median of 35 months after stem cell rescue (range, 10–63 months). Thiotepa has been combined with other drugs such as busulfan [6, 7] and cyclophosphamide [8, 9] to obtain reasonable survival in recurrent brain tumors.
The children’s cancer group (CCG) study CCG99703 defined the maximum-tolerated dose (MTD) for thiotepa for the recently completed ACNS0333 study that treated infants with atypical teratoid rhabdoid tumors and the ACNS0334 study that is treating patients with medulloblastoma. The thiotepa MTD was defined at 10 mg/kg (300 mg/m2/day for children >36 months). Carboplatin was given based on the Calvert correction [3]. Three tandem transplants, given approximately 21–28 days apart, provide the dose intensity speculated to provide long-term survival benefit.
The pediatric oncology group (POG) as well as scientists at Duke University investigated the use of melphalan in HDCST regimens and published their early experience. TRM was high (4 of 19 children) in the POG experience [10]. This decreased when the accompanying cyclophosphamide was fractionated into multiple doses each day maintaining the same overall dose [11]. Melphalan has also been combined with busulfan and separately with carboplatin and etoposide. TRM was found to be lower in those experiences.
Very specifically for treatment of medulloblastoma, the scientists at St. Jude have advanced a new treatment approach that is discussed in the following section. Suffice to say that HDCST has a possible niche in treatment of high-risk tumors in order to improve overall survival (OS) and event-free survival (EFS) [12].
Hematopoietic Stem Cell Transplant for Medulloblastoma
Natural History
The epidemiology of medulloblastoma and primitive neuroectodermal tumors (PNET) is discussed in Chap. 12. Improved surgical resections using advanced magnetic resonance imaging guidance, advancements in chemotherapy, more effective radiation therapy techniques, and better supportive care have substantially improved outcomes of children with medulloblastoma and PNET in the recent past [13]. In addition to age, amount of residual tumor after definitive resection, and presence of metastatic disease, there is new evidence that identifies histologic subtypes and molecular mechanisms that substantially impact outcome [14]. Given the significant improvement in adjuvant modalities, the extent of surgery needs to be weighed against possible neurological damage from this modality. Radiation to the posterior fossa with a boost to the tumor bed is an essential part of treatment but causes significant long-term deficits in younger children. The addition of chemotherapy to radiation has the advantage of improved survival rates as well as allowing decreases or delays in radiation treatment [15]. The use of chemotherapy has permitted omission of radiation in a specific low-risk subgroup of patients [16, 17].
Although 80 % of children with localized MB are likely to be cured with recent therapy combinations albeit with deficits, the cure rates for disseminated disease patients, those having supratentorial PNETs, and those with recurrent disease remain poor [18].
Use of High-Dose Chemotherapy
The experience with high-dose chemotherapy with stem cell rescue is derived mostly from patients with recurrent or high-risk medulloblastoma. Patients with recurrent MB/PNET treated with conventional treatments have a cure rate of less than 5 % [18]. High-dose chemotherapy with stem cell rescue in such patients might be a viable option as shown by the early work of Finlay et al. [1].
The initial experience in patients with recurrent MB/PNET utilized various combinations that included agents such as thiotepa, busulfan, cyclophosphamide, platinum drugs, and etoposide to obtain event-free survivals of 20–50 %. All regimens were myeloablative in nature and regimen-related toxicity was substantial. Patients, who had failure at only their primary site, were more likely to be survivors over the long term compared with those who had metastatic disease [10].
Gajjar et al. have nicely reviewed the recent experience with HDCT in patients with recurrent disease. They report results on 231 patients with recurrent disease with 202 having received radiation prior to relapse. Heterogeneity within the treated groups makes interpretation of results difficult. Comparing patients who received HDCST with those who did not, there is a slight benefit seen in EFS. Those receiving radiation in their previous treatment regimen fared poorly compared to those who had not been radiated. Of 159 patients who received HDCST, 35 disease-free survivors were reported (22 %). Of these 159 HDCST recipients, 133 relapsed after having received RT in their previous treatment. Among the latter, disease-free survival was 17.3 % [18].
Strother et al. [19] used HDCST with peripheral blood stem cell support following craniospinal radiation in 53 patients with newly diagnosed medulloblastoma or sPNET. Chemotherapy consisted of cyclophosphamide (4,000 mg/m2), cisplatin (75 mg/m2), and vincristine for each cycle. High-risk patients received topotecan on a phase II window. The 2-year PFS for standard and high-risk patients were 93.6 % and 73.7 %, respectively. Longer-term data from the same study includes a total of 134 patients (86 average risk, 48 high risk) and was reported by Gajjar et al. [12]; there were no treatment-related deaths in the cohort. Five-year OS was 85 % (95 % CI 75–94) in patients with average-risk status and 70 % (95 % CI 54–84) in the high-risk group. The EFS for the average and high-risk groups were 83 % (CI 73–93) and 70 % (CI 55–85) (p = 0.046), respectively. Disease histology had an impact on outcomes with classic histology showing an EFS of 84 % (CI 74–95), and anaplastic tumors had an EFS of 57 % (CI 33–80) p = 0.04. In the authors’ own experience, the OS and EFS for average-risk patients receiving this treatment at his institution have remained at 100 % at 3 years.
Conclusions
The mainstay of treatment for MB/PNET is surgery with an attempt to obtain as complete as possible a resection followed by radiation and chemotherapy. Treatment of patients with high-risk disease and especially recurrent disease remains a challenge. The use of HDCST may add benefit in such cases. However, its use in frontline therapy of average-risk medulloblastoma, even with impressive results shown by Stother et al. and Gajjar et al., remains debatable and will be assessed in the follow-up study that will use the same regimen without stem cell rescue after chemotherapy cycles.
Hematopoietic Stem Cell Transplant for Ependymoma
Natural History
Ependymoma and its epidemiology are addressed in Chap. 8 of this textbook. The mainstays of therapy for ependymoma are surgery and radiation therapy, and the response of this tumor to chemotherapy is questionable. Overall survival rates have been disappointing with 5-year overall survival and progression-free survival of 50–64 % and 23–45 %, respectively [20]. The extent of surgical resection is a critical prognostic factor, yet practically, children with infratentorial ependymoma often have tumors that are difficult to resect due to their adherence to the brainstem and extension of tumor into the cerebellar pontine angle or down the cervical spine. The standard approach for the therapy of ependymoma is the use of RT to the tumor site. Recent advances in RT using conformal approaches are now considered standard treatment for children over the age of 12 months with 3-year progressive-free survival of approximately 70 % [21]. Short-term outcomes of cognitive function suggest that this treatment has acceptable results, but long-term results are still being evaluated.
Given the concerns of RT to very young children, numerous trials have investigated the role of chemotherapy for the treatment of ependymoma with mixed results [22]. A review by Bouffet et al. of all phase 2 studies in ependymoma showed disappointing results with only 11 % showing a response to single-agent chemotherapy with less than 5 % showing complete responses, with the best results seen with cisplatin [23]. However, the POG infant tumor trial had 48 children with ependymoma enrolled on it and nearly half of the 25 evaluable young children showed a partial or complete response to two courses of vincristine and cyclophosphamide, with a 5-year progression-free survival of 27 % [15, 18]. The use of HDCST in this tumor has thus been investigated.
Use of High-Dose Chemotherapy
A phase 2 study investigated autologous stem cell transplantation following conditioning with busulfan 150 mg/m2/day for 4 days followed by thiotepa 300 mg/m2/day for the next 3 days in 16 children with refractory or relapsed ependymoma. Half of the subjects had previously received RT and all had measureable disease. None of the subjects had a radiologic response of over 50 % and only three subjects were survivors with all three getting gross total resections and local radiation. There was significant toxicity of the skin and the gastrointestinal tract, and there was one treatment-related death [24].
The “Head Start” protocols were designed to use intensive chemotherapy and autologous stem cell transplantation to replace or delay radiation therapy. Children younger than 3 were eligible for the Head Start 1 and 2 protocols, and the protocols also allowed older children to enroll provided that they had incompletely resected disease (age 3–6 on Head Start 1 and age 3–10 on Head Start 2). Those with neuraxis dissemination were allowed to enter the arm of the study containing high-dose methotrexate on Head Start 2. Five cycles of induction therapy were given containing vincristine, cyclophosphamide, etoposide, and cisplatin. Those with disseminated disease enrolled on Head Start 2 also received high-dose methotrexate. Stem cells were collected after the first or second cycles of induction chemotherapy. There were 29 children under the age of 10 years of age who were enrolled on this study. The estimated 5-year EFS and OS were 12 % (±6 %) and 38 % (±10 %), respectively [25]. There was a TRM of 10.3 % on this protocol, mostly in the early phases of the study. Interestingly, four of the five children with metastatic disease are long-term survivors with the only death being one who died of toxicity. The radiation-free survival of those on this study was only 8 %, and of the 12 survivors, only 3 did not receive radiation. The authors concluded that HDCST using this protocol showed disappointing results [25].
The Head Start 3 protocol investigated those under the age of 10 with newly diagnosed ependymoma and 19 subjects were enrolled. Similar to the above trials, five cycles of induction therapy were delivered followed by a sixth cycle comprising HDCST. Children between 6 and 10 or those with residual disease would receive RT. This study found different outcomes between those with supratentorial tumors and those with infratentorial tumors. The 3-year EFS and 3-year OS were a remarkable 86 % (±13 %) and 100 %, respectively, for the supratentorial group. This was in contrast with those with infratentorial disease who had a PFS and OS of 27 % (±13 %) and 73 % (±13 %), respectively. All three subjects with residual disease with supratentorial tumors achieved a CR with chemotherapy, compared to only one of the six with infratentorial resi-dual disease. The study concluded that intensive induction and consolidation chemotherapy should be explored further in trials for supratentorial ependymoma [26].
The Australia and New Zealand collaborative group studied a heterogeneous group of children as part of their ANZCCSG BabyBrain99 study for infants with malignant brain tumors. Thirty-three children with malignant tumors under the age of 3 were enrolled in the study that followed primary resection with 4 cycles of induction chemotherapy. A second-look surgery could be offered at cycle 4 of treatment followed by consolidation therapy using carboplatin (AUC 12 mg/mL/min) over 4 days and melphalan 4.6 mg/kg on day 5 with autologous stem cell support. The children would then receive involved-field irradiation 6 weeks postrecovery. Twenty-two of the 33 children received all the courses including the stem cell transplant. There were six subjects with ependymoma included in the cohort, and they had the best outcomes of any of the tumor types with a 5-year EFS of 67 % [27].
A recent report from Korea investigated the feasibility and effectiveness of tandem HDCSTs in children under the age of 3 years. They enrolled five patients who were given 6 cycles of induction chemotherapy followed by tandem transplants [28]. RT was deferred in all children until after the age of 3 years, and all patients were alive at time of publication. The preparative regimen for the autologous transplant included carboplatin 500 mg/m2/day for 3 days, followed by 3 days of thiotepa 300 mg/m2/day and etoposide 250 mg/m2/day for the first transplant, followed by a second transplant with cyclophosphamide 1,500 mg/m2/day for 4 days and melphalan 60 mg/m2/day for 3 days. They allowed a 12-week interval between the two transplants in order to prevent toxic deaths. One of the five who had a supratentorial tumor was alive without recurrence at 62 months and did not receive any radiation. Three of the five subjects had measureable disease going into the first transplant, and two of these three went into a complete remission following the tandem transplants. Overall four of the five remained alive and disease free, although only the one with supratentorial lesion avoided radiation. The investigators concluded that tandem transplants is feasible in young patients with anaplastic ependymoma, was well tolerated, and requires further investigation in a larger trial [28].
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