- Email: [email protected]
High-dose chemotherapy with autologous stem cell rescue for brain tumors
Critical Reviews in Oncology/Hematology 41 (2002) 197– 204 www.elsevier.com/locate/critrevonc
High-dose chemotherapy with autologous stem cell rescue for brain tumors Ira J. Dunkel a,*, Jonathan L. Finlay b a
Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Box 185, 1275 York A6enue, New York, NY 10021, USA b New York Uni6ersity Medical Center, 317 East 34th Street, New York, NY 10016, USA Accepted 19 October 2000
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. High-dose chemotherapy regimens 2.1. Thiotepa-based regimens . . 2.2. Melphalan-based regimens . 2.3. Source of stem cells . . . . .
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3. Results . . . . . . . . . . . . . . . . . . . . . 3.1. High-grade astrocytomas . . . . . . . 3.2. Ependymomas . . . . . . . . . . . . . 3.3. Brain stem tumors . . . . . . . . . . . 3.4. Medulloblastomas . . . . . . . . . . . 3.5. Supratentorial PNET’s . . . . . . . . 3.6. Infants with malignant brain tumors
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4. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The use of high-dose chemotherapy with stem cell rescue for malignant brain tumors is reviewed. Promising results have been reported in patients with medulloblastomas, supratentorial PNET’s and high-grade astrocytomas. Results thus far have been disappointing for ependymomas and brain stem gliomas. The role of this treatment strategy for other chemotherapy-sensitive tumors such as oligodendrogliomas and central nervous system germ cell tumors has yet to be determined. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: High-grade astrocytoma; Ependymoma; Oligodendroglioma; Brain stem tumor; Medulloblastoma; PNET (primitive neuroectodermal tumor); Germ cell tumor; Hematopoietic stem cell transplantation; Chemotherapy
* Corresponding author. Tel.: + 1-212-6392153; fax: + 1-212-7173239. E-mail address: [email protected] (I.J. Dunkel). 1040-8428/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 5 6 - 1
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1. Introduction Historically, brain tumors were treated with neurosurgical resection and radiation therapy. The addition of chemotherapy has been proven to be beneficial for many tumor types, but most adults and many children continue to have a poor prognosis. These factors logically led to the exploration of the use of high-dose chemotherapy with stem cell rescue, with the hematopoietic stem cell support intended to be a means of increasing chemotherapy dose intensity. In this article, we will review the current status of this approach for brain tumors.
2. High-dose chemotherapy regimens
2.1. Thiotepa-based regimens Thiotepa is an extremely lipophilic drug that achieves a 1:1 plasma to cerebrospinal fluid ratio after intravenous administration [1]. Studies in dogs demonstrated excellent penetration into normal and tumor-bearing brain tissue [2]. While a pediatric phase II trial found hematopoietic dose-limiting toxicity at 65 mg/m2 [3], use of hematopoietic stem cells allows dose escalation to 900 mg/m2. These properties have led several pediatric neuro-oncology groups to include it within highdose chemotherapy regimens for malignant brain tumors. Our group has investigated several high-dose thiotepa-based regimens since 1986 (see Tables 1 and 2). The initial regimen included thiotepa (900 mg/m2) and etoposide (1500 mg/m2) each divided into three daily doses. A 16% toxic mortality rate was encountered in 45 patients aged 8 months to 36 years treated on CCG-9883 [4]. Subsequently the etoposide dose was
decreased (750 mg/m2) and carmustine (600 mg/m2 divided over 3–4 days) was added to the regimen, but that was found to be even more toxic in 11 patients aged 5–18 years [5]. More recently, carboplatin (1500 mg/m2 divided over 3 days, or area under the curve (AUC) = 7 per day via Calvert formula [6,7] for 3 days) followed by thiotepa and etoposide has been explored [8]. Tumor location and histology do not appear to be predictive of toxicity. Experience and better patient selection have decreased the risk of a treatment-related death, but this is still certainly an important issue, particularly for patients over 30 years of age [9]. Investigators at Columbia University modestly decreased the doses of carmustine (450 mg/m2) and thiotepa (500 – 700 mg/m2), and increased the dose of etoposide (1200 – 1500 mg/m2) and noted only one treatment-related death in 18 adult patients aged 19–47 treated [10]. French investigators led by Chantal Kalifa have investigated a regimen that includes busulfan and thiotepa (Table 3). Busulfan has been dosed at 600 mg/m2 divided into 16 oral doses over 4 days. Originally, thiotepa was dosed at 1050 mg/m2 divided into three daily doses [11]. Severe neurotoxicity (drowsiness, hallucinations, coma) was seen in the cohort of 20 patients aged 8 months to 16 years, and more recently the dose of thiotepa has been decreased to 900 mg/m2 [12]. Thiotepa has also been used in combination with cyclophosphamide. Investigators at St Jude treated 11 children aged 4–16 years with thiotepa (900 mg/m2) and cyclophosphamide (6000 mg/m2), both divided daily over 3 days [13]. Two patients developed interstitial pneumonitis (fatal in one case). No severe hepatic or neurologic toxicities were encountered. Kedar reported a series of nine patients aged 3–14 years treated with cyclophosphamide (3000 –3900 mg/m2 divided into four daily doses) and thiotepa (750 –900 mg/m2 divided
Table 1
Agent
Day 5
Day 4
Day 3
Thiotepa (300 mg/m2) Etoposide (250–500 mg/m2) Stem cell rescue
X X
X X
X X
Day 2
Day 1
Day 0
X
Table 2
Agent
Day 8
Day 7
Day 6
Carboplatin (500 mg/m2 or AUC= 7) Thiotepa (300 mg/m2) Etoposide (250 mg/m2) Stem cell rescue
X
X
X
Day 5
Day 4
Day 3
X X
X X
X X
Day 2
Day 1
Day 0
X
I.J. Dunkel, J.L. Finlay / Critical Re6iews in Oncology/Hematology 41 (2002) 197–204
199
Table 3
Agent
Day 8
Day 7
Day 6
Day 5
Busulfan (150 mg/m2) Thiotepa (300 mg/m2) Stem cell rescue
X
X
X
X
Day 4
Day 3
Day 2
X
X
X
Day 1
Day 0
X
Table 4
Agent
Day 8
Day 7
Day 6
Day 5
Cyclophosphamide (1500 mg/m2) Melphalan (60 mg/m2) Stem cell rescue
X
X
X
X
into three daily doses) [14]. Two patients suffered treatment-associated toxic deaths.
Day 4
Day 3
Day 2
X
X
X
Day 1
Day 0
X
lected via apheresis. A minimum of 2–5× 106 CD34/kg is usually infused.
2.2. Melphalan-based regimens 3. Results Pediatric Oncology Group investigators explored a regimen that included cyclophosphamide (3000–6000 mg/m2 divided into four daily doses) and melphalan (180 mg/m2 divided into three daily doses) in 19 children aged 2– 21 years with recurrent or progressive malignant brain tumors [15]. Four of the 19 died of treatment-related complications. Investigators at Duke University also used those agents (Table 4) [16]. In their study, however, the dose of cyclophosphamide was fixed (6000 mg/m2 divided into four daily doses) and the dose of melphalan escalated (75– 180 mg/m2 divided into three daily doses). Their report also included a small number of patients treated with busulfan (600 mg/m2 divided into 16 oral doses over four days) and melphalan (140–180 mg/m2 as a single dose), or carboplatin (2100 mg/m2 divided into three daily doses) and etoposide (1500 mg/m2 divided into three daily doses). In the total group of 49 patients aged 8 months to 27 years, there was only one death related to toxicity, from pulmonary aspergillosis. 2.3. Source of stem cells Hematopoietic stem cells may be collected from either the bone marrow or peripheral blood. Initially, bone marrow was used, but more recently peripheral blood has been the preferred source due to more rapid engraftment and ease of collection. Few stem cells circulate in the normal peripheral blood, but at recovery from a previously administered cycle of chemotherapy or after priming with the G-CSF, increased numbers circulate and sufficient numbers can be col-
3.1. High-grade astrocytomas High-grade astrocytomas are malignant astrocytic neoplasms that most commonly occur in the cerebral hemispheres of adults, but which may be encountered throughout the central nervous system of both children and adults. The prognosis for patients with a newly diagnosed anaplastic astrocytoma or glioblastoma multiforme remains poor despite treatment with surgery, radiation therapy, and conventional chemotherapy [17,18]. This poor outcome prompted many trials in the 1980’s of high-dose single agent carmustine in adults [19–27]. The largest experience was reported by Biron [28]. Ninety-eight patients (89 newly diagnosed, nine relapsed) were treated with carmustine (800 mg/m2 as a single dose) and then received radiation therapy (4500 cGy) beginning on approximately day 45 post-autologous BMT. The toxic mortality rate was 6.1% and overall survival was only 10% at 36 months, with a median survival of 11 months. Overall, these experiences indicated that, despite some encouraging response data, the median survival for both recurrent and newly diagnosed patients did not appear to have been improved. Substantial pulmonary, hepatic and neurologic toxicity (including irreversible dementia and encephalopathy) were encountered, particularly at doses \1200 mg/m2. Heideman et al. treated 11 children with newly diagnosed malignant astrocytomas and two children with
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recurrent high-grade astrocytomas with thiotepa and cyclophosphamide [13]. Surgery for six of the patients, including five newly diagnosed, was limited to a biopsy. Response was evaluated on day 30, and on day 60 those patients with stable disease or better received radiation therapy. One complete response and three partial responses were noted. Median progression-free survival was 9 months, and one patient was progression-free at 30 months. Two others, progression-free at 23 and 24 months, died of pneumonia and shunt failure. Kedar included three patients with newly diagnosed high-grade astrocytomas in his series of patients treated with cyclophosphamide and thiotepa [14]. Subsequently they also received hyperfractionated radiation therapy (7560 cGy). One of the three survived disease-free at 22 months. The Pediatric Oncology Group investigators included three patients with high-grade astrocytomas in their report of cyclophosphamide and melphalan, and all died within 7 months, one from treatment-related complications and two from progressive disease [15]. The Duke investigators noted that of the six patients with glioblastoma multiforme in their report, one was an event-free survivor (duration not specified) [16]. Finlay reported that among the first ten patients (aged 8 months to 19 years) with recurrent malignant astrocytomas (nine with glioblastoma multiforme) treated (five received thiotepa and etoposide and five carmustine, thiotepa and etoposide) four radiographic complete responses were documented [29]. Those promising results stimulated the Children’s Cancer Group to further investigate the thiotepa and etoposide regimen, and they noted five of 18 patients with recurrent high-grade astrocytomas to be event-free survivors at 39–59 months [4]. Investigators from Lyon subsequently treated 22 patients aged 4– 20 years with highgrade gliomas with the thiotepa and etoposide regimen [30]. They noted a 29% response rate, but only three patients were disease-free survivors at 54– 65 months. The Children’s Cancer Group, based on their encouraging results from the trial for patients with recurrent disease, ran a pilot phase II study (CCG-9922) of the carmustine-thiotepa-etoposide regimen, followed by involved field radiation therapy, for children with newly diagnosed glioblastoma multiforme [5]. The study needed to be closed prematurely because five of 11 patients developed nonfatal grade III or IV pulmonary or neurological toxicities. However, three patients achieved a complete response, and the 2-year progression-free survival was an impressive 46% (9 14%). In summary, high-dose carmustine for adult patients with high-grade astrocytomas was not better than conventional therapy. High-dose multi-agent regimens have demonstrated promise in children, but have had significant toxicity, and deserve further investigation.
3.2. Ependymomas Ependymomas may arise throughout the central nervous system, but usually are contiguous with the ventricular system. In children they are usually intracranial and are highly lethal. A Children’s Cancer Group trial treated 42 patients with posterior fossa ependymomas with craniospinal radiation therapy, and half were randomized to receive chemotherapy [31]. No difference was appreciated between the two arms, and the 10 year overall survival for the entire group was only 39%. Patients with recurrent ependymomas have a very guarded prognosis. Goldwein reported a 29% 2-year survival following conventional salvage therapies, but noted that only seven of 52 patients had not yet suffered a subsequent recurrence [32]. High-dose chemotherapy with stem cell rescue has not been proven to be beneficial thus far. Grill et al. reported the French results with high dose busulfan and thiotepa in 16 children aged 1–17 years with recurrent or refractory ependymoma [33]. None of the 15 evaluable patients responded. Three patients were diseasefree survivors at a relatively short follow-up period of 15–27 months. All three had had complete resections of residual tumor and involved-field radiation therapy, so the contribution of the high-dose chemotherapy could not be determined. Our group treated 15 children aged 5 months to 12 years with recurrent ependymomas with the thiotepa and etoposide or carboplatin, thiotepa and etoposide regimens [34]. Five died of treatment-related toxicities. The single survivor at the time of the report subsequently died of progressive tumor.
3.3. Brain stem tumors Diffuse pontine tumors are highly lethal malignancies. Radiation therapy, the standard therapy for this disease, results in only 10% of patients achieving 3-year survival [35]. Conventional dose chemotherapy has not been proven to be effective. Unfortunately, these diffuse pontine tumors remain highly lethal despite the use of high-dose chemotherapy. Kalifa reported that all four children with recurrent brain stem tumors treated with busulfan and thiotepa died of their disease within 4 to 8 months [11]. Kedar included six patients with newly diagnosed brain stem tumors in his series of patients treated with cyclophosphamide and thiotepa, and subsequent hyperfractionated radiation therapy [14]. Only one of the six survived disease-free, at 24 months from diagnosis. Our group, in conjunction with the Children’s Cancer Group, treated 16 children aged 3–14 years with diffuse pontine brain stem tumors with high-dose chemotherapy [36]. Ten had recurrent or refractory disease. Six such patients received thiotepa and
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etoposide, two received carmustine, thiotepa, and etoposide, and two received carboplatin, thiotepa, and etoposide. Six newly diagnosed patients received the carmustine, thiotepa, and etoposide regimen and then 6 weeks later were treated with hyperfractionated radiation therapy (7200– 7800 cGy). Median survival was only 4.7 months for the patients with resistant or recurrent disease, and only 11.4 months for the newly diagnosed patients, and there were no long-term eventfree survivors. French investigators treated 24 children B18 years of age with newly diagnosed diffuse pontine brain stem tumors with external beam radiation therapy followed by high-dose busulfan and thiotepa [37]. Eleven others who had enrolled on study did not receive the highdose chemotherapy, due to early progression in nine and parental refusal in two. Median survival was 10 months for the entire study group, and only 10 months for the patients who received high-dose chemotherapy. There were no long-term survivors.
3.4. Medulloblastomas Medulloblastomas are cerebellar neuroectodermal tumors that most commonly occur in children. Trials performed by the Children’s Cancer Group and by the International Society of Paediatric Oncology/ German Society of Paediatric Oncology noted that 60% of children with medulloblastoma achieve 5-year eventfree survival with the standard treatment modalities of neurosurgical resection, radiation therapy and conventional chemotherapy [38,39]. However, for patients whose medulloblastomas recur or are refractory to initial therapy, the prognosis is dismal. Reports from Stanford University Medical Center and the Children’s Hospital of Philadelphia noted no long-term survivors following recurrence [40,41]. The French group has reported 20 young children with recurrent medulloblastoma who had originally been treated with chemotherapy only. At recurrence they were treated with busulfan and thiotepa, followed by radiation therapy [12]. Thirteen had a primary site relapse only and received radiation therapy (5000–5500 cGy) to the posterior fossa only, without craniospinal
irradiation. Ten of these patients were free of disease at a median of 37 months. Of the seven with metastatic disease at recurrence, only one was free of disease, at 13 months. Overall, the 20 patients were estimated to have a very encouraging 31-month event-free survival of 50%. The Pediatric Oncology Group series included eight children with recurrent or progressive medulloblastoma who were treated with cyclophosphamide and melphalan [15]. Four responses were noted and 2 patients were surviving at 24 and 25 months. The Duke investigators included 18 patients with recurrent medulloblastoma in their series [16]. Fifteen received cyclophosphamide and melphalan, two received carboplatin and etoposide, and one received busulfan and melphalan. Six of the patients had primary site recurrences only, and four of these were free of disease at 27–49 months. Three of these four were older than 25 years of age, and no failures were noted in any patient older than 24 years of age. In contrast, none of the 12 with metastatic disease at recurrence was an event-free survivor. Our group, in conjunction with the Children’s Cancer Group, treated 23 patients aged 2– 44 years (median 13 years) with recurrent medulloblastoma [8] with the carboplatin, thiotepa, and etoposide regimen. In addition to the high-dose chemotherapy, 21 patients received other treatments: neurosurgical resection in seven, conventional chemotherapy in 17, and external beam irradiation in 11 cases. Three patients died of treatment-related toxicities, due to multiorgan system failure in two, and Aspergillus infection with veno-occlusive disease in one. Estimates of event-free and overall survival were 34% (9 10%) and 46% (9 11%), respectively, at 36 months. Unpublished data suggest that the addition of radiation therapy to the high-dose chemotherapy retrieval regimen is associated with improved survival. In summary, high-dose chemotherapy with stem cell rescue is a promising strategy for patients with recurrent medulloblastoma (Table 5). Patients treated after failure at the primary site only appear to fare better than those with metastatic disease.
Table 5 High-dose chemotherapy: results for recurrent medulloblastoma Regimen
c Patients
Outcome
Ref.
Busulfan–Thiotepa Cyclophosphamide–Melphalan Cyclophosphamide–Melphalan Carboplatin–Thiotepa–Etoposide
20 8 15 23
50% EFS (31 mo) 2 OS (24–25 mo) 3 EFS (27–47 mo) 34% EFS (36 mo)
[12] [15] [16] [8]
EFS, event-free survival; OS, overall survival; mo, months.
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3.5. Supratentorial PNET’s PNET’s that are histologically similar to medulloblastomas may arise in other locations within the central nervous system. A Children’s Cancer Group trial demonstrated that children with newly diagnosed supratentorial PNET have a 45% estimated 3 year progression-free survival with neurosurgical resection, radiation therapy and chemotherapy at standard doses [42]. Once these tumors recur, however, they are almost invariably lethal. The Pediatric Oncology Group investigators included only one patient with a supratentorial PNET in their series. Only a minor response was noted, and the patient survived 8 months [15]. The Duke group included five patients with recurrent supratentorial PNET in their series [16]. Neither of the two patients with pineoblastoma were event-free survivors, but two of the three patients with PNET of other supratentorial locations were event-free survivors at 33 and 34 months. Our group reported 16 patients with recurrent supratentorial PNET with high-dose chemotherapy [43]. Four received the thiotepa and etoposide regimen and twelve the carboplatin, thiotepa, and etoposide regimen. Twelve patients died of progressive disease or complications of therapy, and four patients were alive with no evidence of disease at a mean follow-up period of 2.7 years. Three of the four survivors received local field radiation therapy after recovery from the highdose chemotherapy. In summary, very little data have been reported regarding the use of high-dose chemotherapy for supratentorial PNET. However, based on the encouraging results reported for recurrent medulloblastoma, this is a tumor type for which high-dose chemotherapy deserves further investigation.
3.6. Infants with malignant brain tumors Infants with malignant brain tumors are a special group of patients with a poor prognosis. The neuropsychological consequences of radiation therapy administered to young children are considered to be intolerable by most parents and pediatric neuro-oncologists, and, therefore, these patients are treated with neurosurgical resection and chemotherapy in an attempt to delay or avoid radiation therapy. The Pediatric Oncology Group reported an estimated 2-year progression-free survival of 37% for children less than 3-years-old with malignant brain tumors with this strategy [44]. For those with malignant astrocytoma, ependymoma, medulloblastoma, brain stem tumor and supratentorial PNET, respectively, the results were 54, 42, 34, 28, and 19%. Using a different chemotherapy regimen, the Children’s Cancer Group reported 55, 26, 22, and 0% 3 year
estimated progression-free survival for infants less than 18-months-old with non-pineal supratentorial PNET, ependymoma, medulloblastoma, and pineal PNET, respectively [45]. Our group has treated children less than 6 years of age with newly diagnosed malignant brain tumors with a protocol that included high-dose chemotherapy. Patients received five cycles of vincristine, cisplatin, cyclophosphamide, and etoposide. Stem cells were harvested early, usually at recovery from the first cycle. If, after five cycles, disease progression had not occurred, the patients proceeded to high-dose carboplatin, thiotepa, and etoposide regimen with stem cell rescue. If they had no evidence of disease prior to high-dose chemotherapy, they did not receive any radiation therapy. If there was evidence of unresectable residual disease, then 6 weeks after stem cell rescue they began involved field radiation therapy. In the first 62 children treated, the 3 year overall and event-free survival estimates were 40 and 25%, respectively [46]. Patients with high-grade astrocytomas and brain stem tumors have fared poorly, while those with medulloblastoma, PNET, and ependymoma have achieved greater than 30% 2-year event-free survival estimates. This short duration treatment appeared to have efficacy comparable to longer duration conventional chemotherapy regimens used by the cooperative groups. The Children’s Cancer Group is currently evaluating the use of a similar approach in a limited institution cooperative group setting. Our group has also used high-dose thiotepa-based chemotherapy for 20 young children (median 2.9 years) whose disease had recurred after treatment with chemotherapy, but no radiation therapy, on an infant protocol [47]. Ten were event-free survivors with a median follow-up of 37.9 months, for a Kaplan-Meier estimate of 3-year event-free survival of 47% (914%). Seven of the event-free survivors also received radiation therapy, versus five of the ten who suffered an event. 4. Future directions High-dose chemotherapy for brain tumors appears to be most established in the treatment of patients with recurrent medulloblastoma. Even for that indication, however, there is great need for the development of both more effective and less toxic regimens, and we would strongly recommend that appropriate patients continue to be treated on well-designed clinical research protocols. High-dose chemotherapy may be beneficial for central nervous system tumors such as oligodendrogliomas and germ cell tumors that are frequently sensitive to chemotherapy at conventional doses [48,49]. Little has been published in the peer-reviewed literature to date [50], but trials are on going [51].
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We and others, such as investigators from the Children’s Cancer Group, have begun to explore the feasibility and efficacy of multiple cycles of high-dose chemotherapy (‘tandem transplants’) for selected patients with brain tumors. Results are not yet available in the published literature. Finally, it is important to remember that the efficacy of high-dose chemotherapy with stem cell rescue will always depend on the specific agents used. While results to date have been disappointing for tumors such as brain stem gliomas and ependymomas, future trials with different chemotherapy combinations may prove to be effective.
[9]
[10]
[11]
[12]
[13]
Reviewers Dr Pierre-Yves Dietrich, Me´ dicin Adjoint, PD, Department of Medicine, Oncology Division, University Hospital of Geneva, Rue Micheli-du-Crest 24, CH-1211 Geneva 14, Switzerland. Dr James H. Garvin, New York Presbyterian Hospital, Pediatric Oncology Department, 180 Fort Washington Avenue, HP5, New York, NY 10032, USA. Dr Chantal Kalifa, Institut Gustave Roussy, Rue Camille Desmoulins 34-53, F-94805 Villejuif, France. Eric Bouffet, MD, Consultant Paediatric Oncologist, Children’s Department, Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
[14]
[15]
[16]
[17]
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[26] Wolff SN, Phillips GL, Herzig GP. High-dose carmustine with autologous bone marrow transplantation for the adjuvant treatment of high-grade gliomas of the central nervous system. Cancer Treat Rep 1987;71:183 –5. [27] Mbidde EK, Selby PJ, Perren TJ, et al. High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma. Br J Cancer 1988;58:779 – 82. [28] Biron P, Vial C, Chauvin F, et al. Strategy including surgery, high dose BCNU followed by ABMT and radiotherapy in supratentorial high grade astrocytomas: a report of 98 patients. In: Dicke KA, Armitage JO, Dicke-Evinger MJ, editors. Autologous bone marrow transplantation: Proceedings of the Fifth International Symposium. Omaha, The University of Nebraska Medical Center, 1991. p. 637 – 45. [29] Finlay JL, August C, Packer R, et al. High-dose multi-agent chemotherapy followed by bone marrow ‘rescue’ for malignant astrocytomas of childhood and adolescence. J Neurooncol 1990;9:239 – 48. [30] Bouffet E, Mottolese C, Jouvet A, et al. Etoposide and thiotepa followed by ABMT (autologous bone marrow transplantation) in children and young adults with high-grade gliomas. Eur J Cancer 1997;33:91 – 5. [31] Evans AE, Anderson JR, Lefkowitz-Boudreaux IB, et al. Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with or without adjuvant CCNU, vincristine, and prednisone: a Childrens Cancer Group study. Med Pediatr Oncol 1996;27:8 –14. [32] Goldwein JW, Glauser TA, Packer RJ, et al. Recurrent intracranial ependymomas in children: survival, patterns of failure, and prognostic factors. Cancer 1990;66:557 – 63. [33] Grill I, Kalifa C, Doz F, et al. A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma: a phase II study. Pediatr Neurosurg 1996;25:7 –12. [34] Mason WP, Goldman S, Yates AJ, Boyett J, Li H, Finlay JL. Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma — a report of the Children’s Cancer Group. J Neurooncol 1998;37:135 – 43. [35] Packer RJ, Boyett JM, Zimmerman RA, et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy: a Childrens Cancer Group phase I/II trial. Cancer 1994;74:1827 – 34. [36] Dunkel IJ, Garvin JH, Goldman S, et al. High dose chemotherapy with autologous bone marrow rescue for children with diffuse pontine brain stem tumors. J Neurooncol 1998;37:67 –73. [37] Bouffet E, Raquin M, Doz F, et al. Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 2000;88:685 – 92. [38] Evans AE, Jenkin RDT, Sposto R, et al. The treatment of medulloblastoma: results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine and prednisone. J Neurosurg 1990;72:572 – 82. [39] Bailey CC, Gnekow A, Wellek S, et al. Prospective randomized trial of chemotherapy given before radiotherapy in childhood medulloblastoma: International Society of Paediatric Oncology and the German Society of Paediatric Oncology: SIOP II. Med Pediatr Oncol 1995;25:166 –78. [40] Belza MG, Donaldson SS, Steinberg GK, et al. Medulloblastoma: freedom from relapse longer than 8 years — a therapeutic cure?
J Neurosurg 1991;75:575 – 82. [41] Torres CF, Rebsamen S, Silber JH, et al. Surveillance scanning of children with medulloblastoma. N Engl J Med 1994;330:892 – 5. [42] Cohen BH, Zeltzer PM, Boyett JM, et al. Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol 1995;13:1687 – 96. [43] Dunkel IJ, Johnson JH, Gardner SL, Finlay JL. High-dose chemotherapy with autologous stem cell rescue for medulloblastoma and supratentorial PNET. In Dicke KA, Keating A, eds. Autologous marrow and blood transplantation: proceedings of the eighth international symposium in Arlington, TX, Charlottesville, VA, Carden Jennings, 1997. p. 381 – 6. [44] Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than 3 years of age with malignant brain tumors. N Engl J Med 1993;328:1725 – 31. [45] Geyer JR, Zeltzer PM, Boyett JM, et al. Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group. J Clin Oncol 1994;12:1607 – 15. [46] Mason WP, Grovas A, Halpern S, et al. Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 1998;16:210 – 21. [47] Gururangan S, Dunkel IJ, Goldman S, et al. Myeloablative chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors. J Clin Oncol 1998;16:2486 – 93. [48] Cairncross G, Macdonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 1994;12:2013 –21. [49] Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation-a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. J Clin Oncol 1996;14:2908 – 15. [50] Saarinen UM, Pihko H, Makipernaa A. High-dose thiotepa with autologous bone marrow rescue in recurrent malignant oligodendroglioma: a case report. J Neurooncol 1990;9:57 – 61. [51] Cairncross G, Swinnen L, Stiff P, et al. High-dose thiotepa with hematopoietic reconstitution (deferring radiation) for newly diagnosed aggressive oligodendroglioma. Proc Ann Meet Am Soc Clin Oncol 1997;16:388a.
Biographies Ira Dunkel received his M.D. from Duke University in 1985 and is currently an Assistant Attending Pediatrician at the Memorial Sloan-Kettering Cancer Center. Jonathan Finlay received his M.B., Ch.B. from the University of Birmingham in the United Kingdom in 1973. He is currently a Professor of Pediatrics and Chief of the Pediatric Oncology and Neuro-oncology Programs at the New York University School of Medicine, as well as Director of the Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders, New York University Medical Center.
High-dose chemotherapy with autologous stem cell rescue for brain tumors Ira J. Dunkel a,*, Jonathan L. Finlay b a
Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Box 185, 1275 York A6enue, New York, NY 10021, USA b New York Uni6ersity Medical Center, 317 East 34th Street, New York, NY 10016, USA Accepted 19 October 2000
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. High-dose chemotherapy regimens 2.1. Thiotepa-based regimens . . 2.2. Melphalan-based regimens . 2.3. Source of stem cells . . . . .
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3. Results . . . . . . . . . . . . . . . . . . . . . 3.1. High-grade astrocytomas . . . . . . . 3.2. Ependymomas . . . . . . . . . . . . . 3.3. Brain stem tumors . . . . . . . . . . . 3.4. Medulloblastomas . . . . . . . . . . . 3.5. Supratentorial PNET’s . . . . . . . . 3.6. Infants with malignant brain tumors
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4. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The use of high-dose chemotherapy with stem cell rescue for malignant brain tumors is reviewed. Promising results have been reported in patients with medulloblastomas, supratentorial PNET’s and high-grade astrocytomas. Results thus far have been disappointing for ependymomas and brain stem gliomas. The role of this treatment strategy for other chemotherapy-sensitive tumors such as oligodendrogliomas and central nervous system germ cell tumors has yet to be determined. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: High-grade astrocytoma; Ependymoma; Oligodendroglioma; Brain stem tumor; Medulloblastoma; PNET (primitive neuroectodermal tumor); Germ cell tumor; Hematopoietic stem cell transplantation; Chemotherapy
* Corresponding author. Tel.: + 1-212-6392153; fax: + 1-212-7173239. E-mail address: [email protected] (I.J. Dunkel). 1040-8428/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 1 5 6 - 1
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1. Introduction Historically, brain tumors were treated with neurosurgical resection and radiation therapy. The addition of chemotherapy has been proven to be beneficial for many tumor types, but most adults and many children continue to have a poor prognosis. These factors logically led to the exploration of the use of high-dose chemotherapy with stem cell rescue, with the hematopoietic stem cell support intended to be a means of increasing chemotherapy dose intensity. In this article, we will review the current status of this approach for brain tumors.
2. High-dose chemotherapy regimens
2.1. Thiotepa-based regimens Thiotepa is an extremely lipophilic drug that achieves a 1:1 plasma to cerebrospinal fluid ratio after intravenous administration [1]. Studies in dogs demonstrated excellent penetration into normal and tumor-bearing brain tissue [2]. While a pediatric phase II trial found hematopoietic dose-limiting toxicity at 65 mg/m2 [3], use of hematopoietic stem cells allows dose escalation to 900 mg/m2. These properties have led several pediatric neuro-oncology groups to include it within highdose chemotherapy regimens for malignant brain tumors. Our group has investigated several high-dose thiotepa-based regimens since 1986 (see Tables 1 and 2). The initial regimen included thiotepa (900 mg/m2) and etoposide (1500 mg/m2) each divided into three daily doses. A 16% toxic mortality rate was encountered in 45 patients aged 8 months to 36 years treated on CCG-9883 [4]. Subsequently the etoposide dose was
decreased (750 mg/m2) and carmustine (600 mg/m2 divided over 3–4 days) was added to the regimen, but that was found to be even more toxic in 11 patients aged 5–18 years [5]. More recently, carboplatin (1500 mg/m2 divided over 3 days, or area under the curve (AUC) = 7 per day via Calvert formula [6,7] for 3 days) followed by thiotepa and etoposide has been explored [8]. Tumor location and histology do not appear to be predictive of toxicity. Experience and better patient selection have decreased the risk of a treatment-related death, but this is still certainly an important issue, particularly for patients over 30 years of age [9]. Investigators at Columbia University modestly decreased the doses of carmustine (450 mg/m2) and thiotepa (500 – 700 mg/m2), and increased the dose of etoposide (1200 – 1500 mg/m2) and noted only one treatment-related death in 18 adult patients aged 19–47 treated [10]. French investigators led by Chantal Kalifa have investigated a regimen that includes busulfan and thiotepa (Table 3). Busulfan has been dosed at 600 mg/m2 divided into 16 oral doses over 4 days. Originally, thiotepa was dosed at 1050 mg/m2 divided into three daily doses [11]. Severe neurotoxicity (drowsiness, hallucinations, coma) was seen in the cohort of 20 patients aged 8 months to 16 years, and more recently the dose of thiotepa has been decreased to 900 mg/m2 [12]. Thiotepa has also been used in combination with cyclophosphamide. Investigators at St Jude treated 11 children aged 4–16 years with thiotepa (900 mg/m2) and cyclophosphamide (6000 mg/m2), both divided daily over 3 days [13]. Two patients developed interstitial pneumonitis (fatal in one case). No severe hepatic or neurologic toxicities were encountered. Kedar reported a series of nine patients aged 3–14 years treated with cyclophosphamide (3000 –3900 mg/m2 divided into four daily doses) and thiotepa (750 –900 mg/m2 divided
Table 1
Agent
Day 5
Day 4
Day 3
Thiotepa (300 mg/m2) Etoposide (250–500 mg/m2) Stem cell rescue
X X
X X
X X
Day 2
Day 1
Day 0
X
Table 2
Agent
Day 8
Day 7
Day 6
Carboplatin (500 mg/m2 or AUC= 7) Thiotepa (300 mg/m2) Etoposide (250 mg/m2) Stem cell rescue
X
X
X
Day 5
Day 4
Day 3
X X
X X
X X
Day 2
Day 1
Day 0
X
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Table 3
Agent
Day 8
Day 7
Day 6
Day 5
Busulfan (150 mg/m2) Thiotepa (300 mg/m2) Stem cell rescue
X
X
X
X
Day 4
Day 3
Day 2
X
X
X
Day 1
Day 0
X
Table 4
Agent
Day 8
Day 7
Day 6
Day 5
Cyclophosphamide (1500 mg/m2) Melphalan (60 mg/m2) Stem cell rescue
X
X
X
X
into three daily doses) [14]. Two patients suffered treatment-associated toxic deaths.
Day 4
Day 3
Day 2
X
X
X
Day 1
Day 0
X
lected via apheresis. A minimum of 2–5× 106 CD34/kg is usually infused.
2.2. Melphalan-based regimens 3. Results Pediatric Oncology Group investigators explored a regimen that included cyclophosphamide (3000–6000 mg/m2 divided into four daily doses) and melphalan (180 mg/m2 divided into three daily doses) in 19 children aged 2– 21 years with recurrent or progressive malignant brain tumors [15]. Four of the 19 died of treatment-related complications. Investigators at Duke University also used those agents (Table 4) [16]. In their study, however, the dose of cyclophosphamide was fixed (6000 mg/m2 divided into four daily doses) and the dose of melphalan escalated (75– 180 mg/m2 divided into three daily doses). Their report also included a small number of patients treated with busulfan (600 mg/m2 divided into 16 oral doses over four days) and melphalan (140–180 mg/m2 as a single dose), or carboplatin (2100 mg/m2 divided into three daily doses) and etoposide (1500 mg/m2 divided into three daily doses). In the total group of 49 patients aged 8 months to 27 years, there was only one death related to toxicity, from pulmonary aspergillosis. 2.3. Source of stem cells Hematopoietic stem cells may be collected from either the bone marrow or peripheral blood. Initially, bone marrow was used, but more recently peripheral blood has been the preferred source due to more rapid engraftment and ease of collection. Few stem cells circulate in the normal peripheral blood, but at recovery from a previously administered cycle of chemotherapy or after priming with the G-CSF, increased numbers circulate and sufficient numbers can be col-
3.1. High-grade astrocytomas High-grade astrocytomas are malignant astrocytic neoplasms that most commonly occur in the cerebral hemispheres of adults, but which may be encountered throughout the central nervous system of both children and adults. The prognosis for patients with a newly diagnosed anaplastic astrocytoma or glioblastoma multiforme remains poor despite treatment with surgery, radiation therapy, and conventional chemotherapy [17,18]. This poor outcome prompted many trials in the 1980’s of high-dose single agent carmustine in adults [19–27]. The largest experience was reported by Biron [28]. Ninety-eight patients (89 newly diagnosed, nine relapsed) were treated with carmustine (800 mg/m2 as a single dose) and then received radiation therapy (4500 cGy) beginning on approximately day 45 post-autologous BMT. The toxic mortality rate was 6.1% and overall survival was only 10% at 36 months, with a median survival of 11 months. Overall, these experiences indicated that, despite some encouraging response data, the median survival for both recurrent and newly diagnosed patients did not appear to have been improved. Substantial pulmonary, hepatic and neurologic toxicity (including irreversible dementia and encephalopathy) were encountered, particularly at doses \1200 mg/m2. Heideman et al. treated 11 children with newly diagnosed malignant astrocytomas and two children with
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recurrent high-grade astrocytomas with thiotepa and cyclophosphamide [13]. Surgery for six of the patients, including five newly diagnosed, was limited to a biopsy. Response was evaluated on day 30, and on day 60 those patients with stable disease or better received radiation therapy. One complete response and three partial responses were noted. Median progression-free survival was 9 months, and one patient was progression-free at 30 months. Two others, progression-free at 23 and 24 months, died of pneumonia and shunt failure. Kedar included three patients with newly diagnosed high-grade astrocytomas in his series of patients treated with cyclophosphamide and thiotepa [14]. Subsequently they also received hyperfractionated radiation therapy (7560 cGy). One of the three survived disease-free at 22 months. The Pediatric Oncology Group investigators included three patients with high-grade astrocytomas in their report of cyclophosphamide and melphalan, and all died within 7 months, one from treatment-related complications and two from progressive disease [15]. The Duke investigators noted that of the six patients with glioblastoma multiforme in their report, one was an event-free survivor (duration not specified) [16]. Finlay reported that among the first ten patients (aged 8 months to 19 years) with recurrent malignant astrocytomas (nine with glioblastoma multiforme) treated (five received thiotepa and etoposide and five carmustine, thiotepa and etoposide) four radiographic complete responses were documented [29]. Those promising results stimulated the Children’s Cancer Group to further investigate the thiotepa and etoposide regimen, and they noted five of 18 patients with recurrent high-grade astrocytomas to be event-free survivors at 39–59 months [4]. Investigators from Lyon subsequently treated 22 patients aged 4– 20 years with highgrade gliomas with the thiotepa and etoposide regimen [30]. They noted a 29% response rate, but only three patients were disease-free survivors at 54– 65 months. The Children’s Cancer Group, based on their encouraging results from the trial for patients with recurrent disease, ran a pilot phase II study (CCG-9922) of the carmustine-thiotepa-etoposide regimen, followed by involved field radiation therapy, for children with newly diagnosed glioblastoma multiforme [5]. The study needed to be closed prematurely because five of 11 patients developed nonfatal grade III or IV pulmonary or neurological toxicities. However, three patients achieved a complete response, and the 2-year progression-free survival was an impressive 46% (9 14%). In summary, high-dose carmustine for adult patients with high-grade astrocytomas was not better than conventional therapy. High-dose multi-agent regimens have demonstrated promise in children, but have had significant toxicity, and deserve further investigation.
3.2. Ependymomas Ependymomas may arise throughout the central nervous system, but usually are contiguous with the ventricular system. In children they are usually intracranial and are highly lethal. A Children’s Cancer Group trial treated 42 patients with posterior fossa ependymomas with craniospinal radiation therapy, and half were randomized to receive chemotherapy [31]. No difference was appreciated between the two arms, and the 10 year overall survival for the entire group was only 39%. Patients with recurrent ependymomas have a very guarded prognosis. Goldwein reported a 29% 2-year survival following conventional salvage therapies, but noted that only seven of 52 patients had not yet suffered a subsequent recurrence [32]. High-dose chemotherapy with stem cell rescue has not been proven to be beneficial thus far. Grill et al. reported the French results with high dose busulfan and thiotepa in 16 children aged 1–17 years with recurrent or refractory ependymoma [33]. None of the 15 evaluable patients responded. Three patients were diseasefree survivors at a relatively short follow-up period of 15–27 months. All three had had complete resections of residual tumor and involved-field radiation therapy, so the contribution of the high-dose chemotherapy could not be determined. Our group treated 15 children aged 5 months to 12 years with recurrent ependymomas with the thiotepa and etoposide or carboplatin, thiotepa and etoposide regimens [34]. Five died of treatment-related toxicities. The single survivor at the time of the report subsequently died of progressive tumor.
3.3. Brain stem tumors Diffuse pontine tumors are highly lethal malignancies. Radiation therapy, the standard therapy for this disease, results in only 10% of patients achieving 3-year survival [35]. Conventional dose chemotherapy has not been proven to be effective. Unfortunately, these diffuse pontine tumors remain highly lethal despite the use of high-dose chemotherapy. Kalifa reported that all four children with recurrent brain stem tumors treated with busulfan and thiotepa died of their disease within 4 to 8 months [11]. Kedar included six patients with newly diagnosed brain stem tumors in his series of patients treated with cyclophosphamide and thiotepa, and subsequent hyperfractionated radiation therapy [14]. Only one of the six survived disease-free, at 24 months from diagnosis. Our group, in conjunction with the Children’s Cancer Group, treated 16 children aged 3–14 years with diffuse pontine brain stem tumors with high-dose chemotherapy [36]. Ten had recurrent or refractory disease. Six such patients received thiotepa and
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etoposide, two received carmustine, thiotepa, and etoposide, and two received carboplatin, thiotepa, and etoposide. Six newly diagnosed patients received the carmustine, thiotepa, and etoposide regimen and then 6 weeks later were treated with hyperfractionated radiation therapy (7200– 7800 cGy). Median survival was only 4.7 months for the patients with resistant or recurrent disease, and only 11.4 months for the newly diagnosed patients, and there were no long-term eventfree survivors. French investigators treated 24 children B18 years of age with newly diagnosed diffuse pontine brain stem tumors with external beam radiation therapy followed by high-dose busulfan and thiotepa [37]. Eleven others who had enrolled on study did not receive the highdose chemotherapy, due to early progression in nine and parental refusal in two. Median survival was 10 months for the entire study group, and only 10 months for the patients who received high-dose chemotherapy. There were no long-term survivors.
3.4. Medulloblastomas Medulloblastomas are cerebellar neuroectodermal tumors that most commonly occur in children. Trials performed by the Children’s Cancer Group and by the International Society of Paediatric Oncology/ German Society of Paediatric Oncology noted that 60% of children with medulloblastoma achieve 5-year eventfree survival with the standard treatment modalities of neurosurgical resection, radiation therapy and conventional chemotherapy [38,39]. However, for patients whose medulloblastomas recur or are refractory to initial therapy, the prognosis is dismal. Reports from Stanford University Medical Center and the Children’s Hospital of Philadelphia noted no long-term survivors following recurrence [40,41]. The French group has reported 20 young children with recurrent medulloblastoma who had originally been treated with chemotherapy only. At recurrence they were treated with busulfan and thiotepa, followed by radiation therapy [12]. Thirteen had a primary site relapse only and received radiation therapy (5000–5500 cGy) to the posterior fossa only, without craniospinal
irradiation. Ten of these patients were free of disease at a median of 37 months. Of the seven with metastatic disease at recurrence, only one was free of disease, at 13 months. Overall, the 20 patients were estimated to have a very encouraging 31-month event-free survival of 50%. The Pediatric Oncology Group series included eight children with recurrent or progressive medulloblastoma who were treated with cyclophosphamide and melphalan [15]. Four responses were noted and 2 patients were surviving at 24 and 25 months. The Duke investigators included 18 patients with recurrent medulloblastoma in their series [16]. Fifteen received cyclophosphamide and melphalan, two received carboplatin and etoposide, and one received busulfan and melphalan. Six of the patients had primary site recurrences only, and four of these were free of disease at 27–49 months. Three of these four were older than 25 years of age, and no failures were noted in any patient older than 24 years of age. In contrast, none of the 12 with metastatic disease at recurrence was an event-free survivor. Our group, in conjunction with the Children’s Cancer Group, treated 23 patients aged 2– 44 years (median 13 years) with recurrent medulloblastoma [8] with the carboplatin, thiotepa, and etoposide regimen. In addition to the high-dose chemotherapy, 21 patients received other treatments: neurosurgical resection in seven, conventional chemotherapy in 17, and external beam irradiation in 11 cases. Three patients died of treatment-related toxicities, due to multiorgan system failure in two, and Aspergillus infection with veno-occlusive disease in one. Estimates of event-free and overall survival were 34% (9 10%) and 46% (9 11%), respectively, at 36 months. Unpublished data suggest that the addition of radiation therapy to the high-dose chemotherapy retrieval regimen is associated with improved survival. In summary, high-dose chemotherapy with stem cell rescue is a promising strategy for patients with recurrent medulloblastoma (Table 5). Patients treated after failure at the primary site only appear to fare better than those with metastatic disease.
Table 5 High-dose chemotherapy: results for recurrent medulloblastoma Regimen
c Patients
Outcome
Ref.
Busulfan–Thiotepa Cyclophosphamide–Melphalan Cyclophosphamide–Melphalan Carboplatin–Thiotepa–Etoposide
20 8 15 23
50% EFS (31 mo) 2 OS (24–25 mo) 3 EFS (27–47 mo) 34% EFS (36 mo)
[12] [15] [16] [8]
EFS, event-free survival; OS, overall survival; mo, months.
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3.5. Supratentorial PNET’s PNET’s that are histologically similar to medulloblastomas may arise in other locations within the central nervous system. A Children’s Cancer Group trial demonstrated that children with newly diagnosed supratentorial PNET have a 45% estimated 3 year progression-free survival with neurosurgical resection, radiation therapy and chemotherapy at standard doses [42]. Once these tumors recur, however, they are almost invariably lethal. The Pediatric Oncology Group investigators included only one patient with a supratentorial PNET in their series. Only a minor response was noted, and the patient survived 8 months [15]. The Duke group included five patients with recurrent supratentorial PNET in their series [16]. Neither of the two patients with pineoblastoma were event-free survivors, but two of the three patients with PNET of other supratentorial locations were event-free survivors at 33 and 34 months. Our group reported 16 patients with recurrent supratentorial PNET with high-dose chemotherapy [43]. Four received the thiotepa and etoposide regimen and twelve the carboplatin, thiotepa, and etoposide regimen. Twelve patients died of progressive disease or complications of therapy, and four patients were alive with no evidence of disease at a mean follow-up period of 2.7 years. Three of the four survivors received local field radiation therapy after recovery from the highdose chemotherapy. In summary, very little data have been reported regarding the use of high-dose chemotherapy for supratentorial PNET. However, based on the encouraging results reported for recurrent medulloblastoma, this is a tumor type for which high-dose chemotherapy deserves further investigation.
3.6. Infants with malignant brain tumors Infants with malignant brain tumors are a special group of patients with a poor prognosis. The neuropsychological consequences of radiation therapy administered to young children are considered to be intolerable by most parents and pediatric neuro-oncologists, and, therefore, these patients are treated with neurosurgical resection and chemotherapy in an attempt to delay or avoid radiation therapy. The Pediatric Oncology Group reported an estimated 2-year progression-free survival of 37% for children less than 3-years-old with malignant brain tumors with this strategy [44]. For those with malignant astrocytoma, ependymoma, medulloblastoma, brain stem tumor and supratentorial PNET, respectively, the results were 54, 42, 34, 28, and 19%. Using a different chemotherapy regimen, the Children’s Cancer Group reported 55, 26, 22, and 0% 3 year
estimated progression-free survival for infants less than 18-months-old with non-pineal supratentorial PNET, ependymoma, medulloblastoma, and pineal PNET, respectively [45]. Our group has treated children less than 6 years of age with newly diagnosed malignant brain tumors with a protocol that included high-dose chemotherapy. Patients received five cycles of vincristine, cisplatin, cyclophosphamide, and etoposide. Stem cells were harvested early, usually at recovery from the first cycle. If, after five cycles, disease progression had not occurred, the patients proceeded to high-dose carboplatin, thiotepa, and etoposide regimen with stem cell rescue. If they had no evidence of disease prior to high-dose chemotherapy, they did not receive any radiation therapy. If there was evidence of unresectable residual disease, then 6 weeks after stem cell rescue they began involved field radiation therapy. In the first 62 children treated, the 3 year overall and event-free survival estimates were 40 and 25%, respectively [46]. Patients with high-grade astrocytomas and brain stem tumors have fared poorly, while those with medulloblastoma, PNET, and ependymoma have achieved greater than 30% 2-year event-free survival estimates. This short duration treatment appeared to have efficacy comparable to longer duration conventional chemotherapy regimens used by the cooperative groups. The Children’s Cancer Group is currently evaluating the use of a similar approach in a limited institution cooperative group setting. Our group has also used high-dose thiotepa-based chemotherapy for 20 young children (median 2.9 years) whose disease had recurred after treatment with chemotherapy, but no radiation therapy, on an infant protocol [47]. Ten were event-free survivors with a median follow-up of 37.9 months, for a Kaplan-Meier estimate of 3-year event-free survival of 47% (914%). Seven of the event-free survivors also received radiation therapy, versus five of the ten who suffered an event. 4. Future directions High-dose chemotherapy for brain tumors appears to be most established in the treatment of patients with recurrent medulloblastoma. Even for that indication, however, there is great need for the development of both more effective and less toxic regimens, and we would strongly recommend that appropriate patients continue to be treated on well-designed clinical research protocols. High-dose chemotherapy may be beneficial for central nervous system tumors such as oligodendrogliomas and germ cell tumors that are frequently sensitive to chemotherapy at conventional doses [48,49]. Little has been published in the peer-reviewed literature to date [50], but trials are on going [51].
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We and others, such as investigators from the Children’s Cancer Group, have begun to explore the feasibility and efficacy of multiple cycles of high-dose chemotherapy (‘tandem transplants’) for selected patients with brain tumors. Results are not yet available in the published literature. Finally, it is important to remember that the efficacy of high-dose chemotherapy with stem cell rescue will always depend on the specific agents used. While results to date have been disappointing for tumors such as brain stem gliomas and ependymomas, future trials with different chemotherapy combinations may prove to be effective.
[9]
[10]
[11]
[12]
[13]
Reviewers Dr Pierre-Yves Dietrich, Me´ dicin Adjoint, PD, Department of Medicine, Oncology Division, University Hospital of Geneva, Rue Micheli-du-Crest 24, CH-1211 Geneva 14, Switzerland. Dr James H. Garvin, New York Presbyterian Hospital, Pediatric Oncology Department, 180 Fort Washington Avenue, HP5, New York, NY 10032, USA. Dr Chantal Kalifa, Institut Gustave Roussy, Rue Camille Desmoulins 34-53, F-94805 Villejuif, France. Eric Bouffet, MD, Consultant Paediatric Oncologist, Children’s Department, Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
[14]
[15]
[16]
[17]
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Biographies Ira Dunkel received his M.D. from Duke University in 1985 and is currently an Assistant Attending Pediatrician at the Memorial Sloan-Kettering Cancer Center. Jonathan Finlay received his M.B., Ch.B. from the University of Birmingham in the United Kingdom in 1973. He is currently a Professor of Pediatrics and Chief of the Pediatric Oncology and Neuro-oncology Programs at the New York University School of Medicine, as well as Director of the Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders, New York University Medical Center.