Introduction

Myeloablative or high-dose chemotherapy with autologous hematopoietic progenitor cell rescue (HDC/AuHCR) was first evaluated in the treatment of brain tumors in the late 1970s. Historically, brain tumors have been treated by surgical resection and radiation therapy. However, the deleterious long-term consequences of radiation therapy in very young children,¹ and the success of adjuvant chemotherapy in increasing the cure rates of certain brain tumors,² led to the introduction of myeloablative chemotherapy to initially delay and later avoid the use of radiotherapy in infants and toddlers. This strategy had been previously investigated for patients with recurrent disease and in older patients with newly diagnosed tumors with a dismal prognosis with conventional therapy.³ For brain tumors, as with other cancers, the rationale underlying myeloablative chemotherapy was the steep dose–response curve of the cytotoxic alkylating agents used in the myeloablative regimens, and therefore their potential to overcome drug resistance. Specific to brain tumors, however, was the concept that increasing chemotherapy doses might overcome the blood–brain barrier thereby improving penetrance of the tumor by cytocidal drugs.

The typical design of myeloablative chemotherapy regimens in brain tumors has incorporated a single cycle of myeloablative chemotherapy followed by AuHCR administered to patients with minimal tumor burden (achieved by a combination of surgery, chemotherapy or irradiation). With the replacement of bone marrow by peripheral blood as the source of hematopoietic progenitor cells, and consequent larger yields of such cells, multiple cycles of high dose, myeloablative chemotherapy, each followed by hematopoietic progenitor cell rescue (tandem transplants) have become increasingly employed, both for recurrent patients as well as for young children newly diagnosed with malignant brain tumors (as in the recently completed Children's Cancer Group trial CCG 99703).

In this article, we will review the status of these approaches in the treatment of malignant brain tumors of differing histologies.

Medulloblastoma and other PNETs

Medulloblastomas and other primitive neuroectodermal tumors (PNETs) are chemosensitive tumors arising typically in the pediatric age group. Conventional chemotherapy and reduced dose craniospinal irradiation administered after surgical gross total resection of localized disease has increased the 5-year event-free survival (EFS) from 50 to 80%² and has become the standard therapy for children over 3 or 4 years of age (depending upon the country of treatment). The use of HDC/AuHCR has been evaluated in three patient settings: young children (usually less than 6 years of age), older patients with newly diagnosed high-risk tumors (metastatic medulloblastoma, pineoblastoma, malignant glioma) and patients with recurrent tumors.

Chronologically, the first patient population for whom HDC was attempted was those patients who had failed radiotherapy, with or without maintenance chemotherapy.^{4, 5, 6} This strategy has produced responses in about a third of patients, but long-term survival remains low.^{6, 7, 8} In contrast, results of HDC have been very encouraging in young children with PNET or medulloblastoma recurring after chemotherapy only, using focal⁹ or reduced dose craniospinal irradiation following HDC.¹⁰ Since then, HDC/AuHCR has been extensively used in an attempt to avoid cranial irradiation in newly diagnosed young children with malignant brain tumors.^{10, 11, 12}

Neurocognitive dysfunction has been documented in children who receive brain irradiation.^{1, 13, 14, 15} The severity is related to age as well as dose. Although difficult to define exact age groups, it is generally recognized that children under 3 years of age are at highest risk of such sequelae, with patients in the 3–6 years of age range having moderately severe sequelae especially when tumors are located in supratentorial area. One of the unresolved questions is until what age radiotherapy must be avoided and alternative strategies recommended. More data are needed on neurocognitive sequelae in modern times to answer this difficult question.

Mason et al.¹² evaluated HDC/AuHCR in children less than 6 years of age with newly diagnosed malignant brain tumors ('Head Start' I protocol), 27 of whom were children with medulloblastoma or other PNET. Patients received five cycles of induction chemotherapy with vincristine, etoposide, cisplatin and cyclophosphamide, 3 weeks apart, followed by consolidation chemotherapy with a single myeloablative cycle of thiotepa, carboplatin and etoposide. A total of 2-year overall survival (OS) was around 60%, while EFS from diagnosis and consolidation was reported to be 40 and 50%, respectively. The addition of high-dose intravenous methotrexate in the induction regimen for patients with newly diagnosed high-risk or disseminated medulloblastoma (Head Start II) was reported by Chi et al.,¹¹ to produce survival matching that for the localized medulloblastoma children not receiving methotrexate (Figure 1). The 3-year EFS and OS were 49 and 60%, respectively. The outcome of supratentorial PNETs with Head Start I and II combined has been similar, with a 5-year EFS of 39% and OS of 49%.¹⁶

Figure 1.

Event-free (EFS) and overall survival (OS) for disseminated medulloblastoma from Head Start II.

Full figure and legend (61K)

Brain stem PNETs had been universally fatal in prior publications.^{17, 18} A recent study by Fangusaro et al.¹⁹ reported the best long-term survival with two out of six patients surviving treatment with intensive induction chemotherapy and consolidation with myeloablative chemotherapy (Head Start I or II) and radiation therapy.

The major factor predictive of favorable outcome with myeloablative chemotherapy for PNET/medulloblastoma transplanted before progression is the achievement of minimal tumor burden status before transplant, either by complete surgical resection or by pretransplant conventional therapy. Despite the variation in the definition of minimal residual disease, it generally includes disappearance or minimal residuals at primary tumor (that is, <1.5 cm), no positive CSF cytology and minimal radiological signs of metastatic disease.

Advances in hematopoietic progenitor stem cell apheresis and rescue with peripheral blood progenitor cells or bone marrow (BM), and the availability of hematopoietic cytokines, have provided an opportunity to intensify doses of chemotherapeutic agents with a steep dose–response curve, such as cyclophosphamide (CY) and thiotepa. With hematopoietic progenitor cell rescue, patients are able to tolerate repeat doses in shorter intervals, even after craniospinal irradiation. Outcome after sequential submyeloablative doses of chemotherapy has also been encouraging in newly diagnosed patients >3 years of age with medulloblastomas or supratentorial PNETs after completion of risk adapted craniospinal irradiation with four consecutive cycles of high-dose CY (4 gm/m²), cisplatin and vincristine.^{20, 21} Gajjar et al.^{20, 21} reported a 5-year EFS of 83% for the average risk patients and 70% for the high-risk patients. For children less than 3 years of age with malignant brain tumors, CCG 99703 was conducted as pilot study to evaluate the feasibility and toxicity of administering repetitive doses of HDC followed by peripheral blood hematopoietic progenitor cell rescue. Following best surgery and staging, patients were treated with three cycles of CY, etoposide, vincristine and cisplatin (induction) and three cycles of carboplatin and escalating doses of thiotepa (consolidation). The preliminary results for M0 MB patients, the 6-month EFS was 100% in totally resected patients and 78% in the subtotally resected group. The 3-year OS for M0 MB patients was 76% with a 67% EFS in this group. Toxicity profile has been favorable.²²

There is also experience with two consecutive myeloablative chemotherapies (tandem transplants) as means to dose intensify for patients with recurrent malignant brain tumors. Preliminary outcome is promising in phase I settings.^{23, 24, 25} Single active agents such as carboplatin, CY and melphalan have been used separately in a tandem fashion. The response rates in recurrent PNETs have been reported to be between 60 and 80% with long-term survival in very few patients. As of the present time, there are no data comparing single-cycle myeloablative chemotherapy regimens with tandem myeloablative or submyeloblative regimens in prospective randomized trials.

In conclusion, HDC/AuHCR has shown some promises in medulloblastomas and PNETs (Table 1).

Table 1 - Therapy utilizing high-dose chemotherapy for newly diagnosed medulloblastoma and PNET.

Full table

AT/RT of the brain

Atypical teratoid/rhabdoid tumor (AT/RT) is a relatively rare pediatric brain tumor. Prognosis with conventional therapy utilizing surgery, irradiation and standard-dose chemotherapy remains poor. The rarity of these tumors has precluded large prospective studies, but some data suggest a better outcome in older patients, perhaps because they are able to tolerate radiotherapy. Myeloablative chemotherapy has been attempted with variable results, especially in young patients. Cure even in the absence of radiotherapy has been documented in some reports.^{26, 27, 28}

Malignant gliomas

Malignant gliomas are much less common in the pediatric age group than in adults; therapy is based on aggressive surgical resection whenever feasible, followed by local field irradiation and adjuvant chemotherapy. The prognosis of these tumors is extremely poor. The role of standard-dose chemotherapy in the treatment of pediatric malignant gliomas has been well documented in randomized trials.^{29, 30} Nevertheless, long-term survival for children with anaplastic astrocytoma and glioblastoma multiforme remains poor, with fewer than 25% surviving disease free beyond 3 years from diagnosis.

Although myeloablative doses of single-agent carmustine were not found to be effective in children³¹ and results of some initial reports using thiotepa and CY were modest at best,^{32, 33} there are data suggesting a beneficial role of myeloablative thiotepa and etoposide in the therapy of recurrent malignant glioma.³⁴ In addition, the phase II Children Cancer Group Study CCG 9922, which used myeloablative thiotepa, BCNU and etoposide followed by focal irradiation, despite being closed prematurely due to pulmonary toxicities, resulted in a 2-year progression-free survival of 46% in patients with centrally reviewed, radically resected glioblastoma multiforme.³⁵ Recently Massimino et al.³⁶ published their experience treating malignant gliomas at diagnosis with induction chemotherapy followed by consolidation with high-dose thiotepa that showed a progression-free survival of 46% and an OS of 43% at 4 years. The addition of temozolomide to conditioning regimens may prove to be beneficial: a phase I dose escalation study of temozolomide given with thiotepa and carboplatin resulted in 30% long-term survival in small cohort of 12 patients (Table 2).³⁷ Analysis of factors affecting outcome after myeloablative chemotherapy in malignant glioma indicates that the amount of residual tumor burden on entering myeloablative chemotherapy is the most powerful predictor of outcome.

Table 2 - High-dose chemotherapy for malignant gliomas.

Full table

Myeloablative chemotherapy has also been attempted in children with diffuse pontine gliomas,^{17, 19} but has not been shown to increase either survival or duration of survival.

Ependymoma

Ependymomas are another group of childhood brain tumors whose poor prognosis has prompted the evaluation of myeloablative chemotherapy both at recurrence and in newly diagnosed young children. Conventional therapy employs aggressive surgery followed by focal irradiation. However, ependymomas may recur after many years, and recurrences are usually resistant to both irradiation and chemotherapy. Unfortunately, myeloablative chemotherapy has not been shown to improve survival either after recurrence^{38, 39} or in young children with newly diagnosed disease.⁴⁰

Central nervous system germ-cell tumors

Primary central nervous system germ-cell tumors carry a very good prognosis and are sensitive to both chemotherapy and radiation therapy. The conventional approaches to these tumors at initial diagnosis result in cure of over 85–95% of patients with pure germinoma and 65% of patients with mixed malignant germ-cell tumors of the brain. Recurrent disease has a dismal prognosis with conventional chemotherapy. Myeloablative chemotherapy is effective in patients with recurrent germinoma (>80% cure rate) but is less effective in recurrent mixed malignant germ-cell tumors, in whom fewer than 50% are long-term survivors.^{41, 42}

Acute and long-term toxicities

The almost universal complications after HDC are pancytopenia and mucositis. The duration and severity of pancytopenia is a consequence of several variables related to the hematopoietic stem cells reinfused (or persisting) after HDC and the ability of the stroma to sustain hematopoieisis. They include the amount of chemotherapy and irradiation (that is, craniospinal radiotherapy) the patients had received before stem cell collection and autotransplantation, the conditioning regimen itself and characteristics of the hematopoietic stem cells infused. Since the introduction of hematopoietic growth factors, myeloid recovery is accelerated and neutropenia usually lasts 2 weeks or less. In contrast, thrombocytopenia may last several months, especially in heavily pretreated patients.⁴³

Mucositis is often severe, requiring narcotic analgesics and intravenous alimentation. This is especially the case after thiotepa-containing regimens and in patients with prior spinal irradiation. Patients receiving thiotepa may also develop generalized skin erythema and desquamation, secondary to the excretion of thiotepa in sweat. Acute neurological dysfunction, including hallucinations, coma, seizures, headaches, ataxia-tremor-dysarthria syndrome, anorexia and nausea syndrome are reported in about 50% of patients in the first 3 months after transplant. These symptoms are possibly associated with iatrogenic metabolic dysfunction or with direct neurotoxicity of chemotherapy. They are usually reversible.⁴⁴

Other common and possibly severe toxicities relate to microvasculature damage: capillary leaking and vaso-occlusive disease may develop. Nephrotoxicity is possible especially after platinum-containing regimens. Acute pulmonary toxicity is described in persons treated with busulfan, BCNU and less commonly thiotepa. These complications are usually transient, but especially if associated with infection secondary to neutropenia, they may lead to multiorgan system failure and death. As discussed above, toxic death rates were as high as 35% in early studies. In more recent studies, the toxic mortality rate has declined to below 10%. Again, life-threatening toxicities may be more frequent in heavily pretreated patients.

There are relatively few data on the long-term toxicity of HDC for brain tumors. Furthermore it is difficult to differentiate the consequences of HDC from those of the other components of therapy or from the brain tumors themselves. However, hearing loss has been reported in about half of children who received carboplatin-containing conditioning regimens.⁴⁵ Neurological and intellectual functions in children who received HDC but not radiotherapy during their first years of life were either in the low average or only moderately impaired.⁴⁶

Second cancers are reported in persons treated with HDC/AuHCR for cancers other than brain tumors. For example, the risk of a second cancer developing in persons who received HDC for Hodgkin's disease or breast cancer is about 10–20% after 15 years.⁴⁷ Whether this will be true also for survivors of HDC/AuHCR for brain tumors is unknown. Similarly, reproductive and endocrine impairments have been reported in patients treated with HDC for other cancers, as well as in children with brain tumors treated with conventional dose chemotherapy and irradiation. The extent of these complications after HDC in brain tumor remains unknown.

Conclusions

The published data indicate a role for HDC/AuHCR in the management of specific subsets of patients with PNET and medulloblastoma either at diagnosis or after a relapse, if the patient was not previously treated with radiotherapy; in patients with recurrent CNS germ-cell tumors and a possible role in patients with recurrent malignant gliomas (provided the tumors can be reduced to a minimal tumor burden prior to myeloablative chemotherapy).

There are still many unanswered questions. First, it is unclear whether myeloablative chemotherapy is superior to conventional treatment. The process of patient selection applied to determine which patients are eligible to undergo myeloablative chemotherapy can bias the comparison between the two strategies, and no randomized studies have been conducted to date. Myeloablative chemotherapy has an inherent higher short-term morbidity and mortality. On the other hand, long-term toxicities do not appear qualitatively or quantitatively more severe after myeloablative chemotherapy than following conventional chemotherapy strategies. In particular, HDC/AuHCR permits avoidance or at least delay and dose reduction of irradiation in young children, with resultant minimization of the unacceptably severe sequelae of irradiation to the brain in the young child. A major challenge is to determine when radiotherapy is necessary post HDC/AuHCR. Whether to use post transplant radiotherapy in all children vs only to those with unfavorable features, or just reserve radiotherapy after relapses is still not well defined. However, it is encouraging that retrieval for standard-risk medulloblastoma at relapse is high. Most children who relapse post HD/AuHCR are however, still in an age group in whom deleterious neurocognitive effect would be expected. Despite the lack of precise data, it seems highly appropriate to employ myeloablative chemotherapy for young patients (even if impossible to precisely define this age) with chemoresponsive tumors in the early phases of therapy or those who relapse after chemotherapy only. Good controlled studies are needed to define patients who would need radiotherapy after HDC/AuHCR. Unless older and/or heavily pretreated patients relapse at a distant time beyond their initial treatment, or relapse only in local sites, and are thus deemed appropriate to receive further irradiation in addition to the myeloablative chemotherapy, such patients, as well as those with bulky disease unresponsive to chemotherapy, should not be subjected to likely ineffective myeloablative chemotherapy, but should receive more novel approaches, including escalation of new drugs or tandems, in the context of clinical studies.

It is still unknown whether the use of tandem transplants for patients with bulky residual tumor or for heavily pretreated patients will improve outcome compared with single-cycle myeloablative chemotherapy regimens.

In conclusion, the use of myeloablative chemotherapy has dramatically changed our approach to the treatment of young children with newly diagnosed medulloblastoma, PNET and possibly other malignant brain tumors of early childhood, as well as the retrieval of select patients with recurrent malignant brain tumors. In most cases involving recurrent brain tumors, however, this treatment modality has been able to achieve only transient responses. This could be exploited in strategies using myeloablative chemotherapy to obtain maximum tumor debulking, followed by other types of therapies, such as immunotherapy or antiangiogenic therapies that may be effective in eradicating minimal residual disease.

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