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F e a s i b i l i t y o f F o u r C o n s e c u t i v e H i g h - D o s e C h e m o t h e r a p y
C y c l e s W i t h S t e m - C e l l R e s c u e f o r P a t i e n t s W i t h N e w l y
D i a g n o s e d M e d u l l o b l a s t o m a o r S u p r a t e n t o r i a l P r i m i t i v e
N e u r o e c t o d e r m a l T u m o r A f t e r C r a n i o s p i n a l R a d i o t h e r a p y :
R e s u l t s o f a C o l l a b o r a t i v e S t u d y
Douglas Strother, David Ashley, Stewart J. Kellie, Akta Patel, Dana Jones-Wallace, Stephen Thompson, Richard Heideman, Ely Benaim, Robert Krance, Laura Bowman, and Amar Gajjar Purpose: This study was designed to determine the
Results: Fifty of the 53 patients commenced high-dose
feasibility and safety of delivering four consecutive cycles
chemotherapy, and 49 patients completed all four cycles.
of high-dose cyclophosphamide, cisplatin, and vincris-
The median length of chemotherapy cycles one through
tine, each followed by stem-cell rescue, every 4 weeks,
four was 28, 27, 29, and 28 days, respectively. Engraft-
after completion of risk-adapted craniospinal irradiation
ment occurred at a median of 14 to 15 days after infusion
to children with newly diagnosed medulloblastoma or
of stem cells or autologous bone marrow. The intended
supratentorial primitive neuroectodermal tumor (PNET).
dose-intensity of cyclophosphamide was 1,000 mg/m2/
Patients and Methods: Fifty-three patients, 19 with
wk; the median delivered dose-intensity was 1,014,
high-risk disease and 34 with average-risk disease,
1,023, 974, and 991 mg/m2/wk for cycles 1 through 4,
were enrolled onto this study. After surgical resection,
respectively; associated median relative dose-intensity
high-risk patients were treated with topotecan in a
was 101%, 102%, 97%, and 99%. No deaths were attrib-
6-week phase II window followed by craniospinal ra-
utable to the toxic effects of high-dose chemotherapy.
diation therapy and four cycles of high-dose cyclophos-
Early outcome analysis indicates a 2-year progression-
phamide (4,000 mg/m2 per cycle), with cisplatin (75
free survival of 93.6% ؎ 4.7% for the average-risk pa-
mg/m2 per cycle), and vincristine (two 1.5-mg/m2
tients. For the high-risk patients, the 2-year progression-
doses per cycle). Support with peripheral blood stem
free survival is 73.7% ؎ 10.5% from the start of therapy
cells or bone marrow and with granulocyte colony-
and 84.2% ؎ 8.6% from the start of radiation therapy.
stimulating factor was administered after each cycle of
Conclusion: Administering four consecutive cycles of
high-dose chemotherapy. Treatment of average-risk
high-dose chemotherapy with stem-cell support after sur-
patients consisted of surgical resection and craniospinal
gical resection and craniospinal irradiation is feasible in
irradiation, followed by the same chemotherapy given
newly diagnosed patients with medulloblastoma/supra-
to patients with high-risk disease. The expected dura-
tentorial PNET with aggressive supportive care. The early
tion of the chemotherapy was 16 weeks, with a cumu-
outcome results of this approach are very encouraging.
lative cyclophosphamide dose of 16,000 mg/m2 and a
J Clin Oncol 19:2696-2704. 2001 by American
planned dose-intensity of 1,000 mg/m2/wk.
Society of Clinical Oncology.
HIGH-DOSECHEMOTHERAPYwithbonemarrowor nancies,includingrelapsedtumorsoftheCNS.15-20Inchildren stem-cell rescue has been used as an adjuvant to with brain tumors, high-dose chemotherapy has been used primary therapy or as salvage therapy to treat adult1-9 and most often in patients with high-grade glioma before irradia- pediatric10-14 patients with various primary or relapsed malig- tion21 or at the time of disease progression22-24 or to avoidradiotherapy for infants and very young children.25,26 Treatment for patients with newly diagnosed medullo- blastoma or primitive neuroectodermal tumor (PNET) in- From the Department of Pediatrics, Baylor College of Medicine, cludes surgical resection followed by craniospinal radio- Houston, TX; Departments of Hematology-Oncology and Biostatistics therapy. Adjuvant chemotherapy has been shown to and Epidemiology, Division of Neurology, St Jude Children’s ResearchHospital, and Department of Pediatrics, College of Medicine, Univer- increase the cure rate for patients with high-risk or average- sity of Tennessee, Memphis, TN; and Department of Hematology risk disease and is now a standard part of contemporary Oncology, Royal Children’s Hospital, Melbourne, the Oncology Unit,The Children’s Hospital at Westmead, and The University of Sydney, Amongst the agents effective in these embryonal CNS Submitted November 30, 2000; accepted February 20, 2001. tumors, cyclophosphamide has proven activity against re- Supported in part by Cancer Center (CORE) grant no. CA 21765 and grant no. P01 CA 23009 from the National Cancer Institute and by lapsed medulloblastoma and PNET at conventional doses in the American Lebanese Syrian Associated Charities. chemotherapy-naive patients or at high doses in heavily Address reprint requests to Amar Gajjar, MD, Department of Hema- tology-Oncology, Rm 6024, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; email: amar.gajjar@ Cyclophosphamide has a steep dose-response curve30,31 supporting the assumption that increasing the administered 2001 by American Society of Clinical Oncology.
0732-183X/01/00-2696
dose should increase tumor-cell kill.32,33 Prolonged myelo- Journal of Clinical Oncology, Vol 19, No 10 (May 15), 2001: pp 2696-2704 HIGH-DOSE CHEMOTHERAPY FOR MEDULLOBLASTOMA suppression has limited the opportunities to escalate dosage Table 1. Patient Characteristics
of cyclophosphamide. However, with recent advances in hematopoietic stem-cell apheresis and rescue with periph- eral blood stem cells or autologous marrow and the avail- ability of hematopoietic cytokines to enhance marrow recovery, high doses of cyclophosphamide are now toler- ated with myelosuppression of minimal duration. Thus, the dose-intensity can be optimized, as repeated dosing is now possible in shorter periods of time.34,35 Multiple cycles of high-dose chemotherapy with stem- cell rescue have been used to treat a number of malignant tumors including lung cancer in adults and brain tumors in children.36-39 However, no study has demonstrated the feasibility of sequential delivery of multiple courses of high-dose chemotherapy to patients with newly diagnosedmedulloblastoma/supratentorial PNET immediately afterextensive irradiation of the craniospinal axis, which in-cludes approximately 40% of the total marrow space.
cytologic examination of lumbar CSF at least 10 days after surgicalresection of the tumor; (2) absence of bony metastasis as confirmed by In this report, we document the feasibility of using bone scan; (3) gross total resection or Յ 1.5 cm2 residual disease as high-dose cyclophosphamide combined with cisplatin and confirmed by documentation in the operative note and by gadolinium- vincristine with stem-cell rescue and hematopoietic cyto- enhanced postoperative MRI of the head no more than 48 hours after kine support and provide early outcome data in children surgery. Patients with brainstem invasion documented in the operative with newly diagnosed medulloblastoma or supratentorial note but with no visible tumor on MRI were considered to haveaverage-risk disease.
PNET after surgical resection and craniospinal irradiation.
High-risk disease was defined as (1) presence of metastatic disease documented by gadolinium-enhanced MRI of the head and spine or bythe presence of malignant cells in the lumbar spinal fluid, confirmed by cytologic examination obtained at least 10 days after surgery; and (2)presence of more than 1.5 cm2 residual disease as confirmed by Between October 1996 and June 1999, 53 patients with previously postoperative gadolinium-enhanced MRI. Patients with metastatic dis- untreated medulloblastoma or supratentorial PNET were treated at one ease outside the neuraxis were not eligible for protocol treatment.
of the participating institutions (Baylor College of Medicine, Houston,TX, n ϭ 8; Royal Children’s Hospital, Melbourne, Australia, n ϭ 9; The Children’s Hospital at Westmead, Sydney, Australia, n ϭ 4; and StJude Children’s Research Hospital, Memphis, TN, n ϭ 32). The All patients underwent an attempt at maximal surgical resection of clinical characteristics of these patients at the time of diagnosis are the tumor. Patients with high-risk disease were treated with a 6-week phase II window of topotecan therapy. After completing the window Patients aged Ն 3 and Յ 21 years old at the time of diagnosis and therapy, the patients underwent repeat imaging studies to assess the who had not previously received chemotherapy or irradiation were response of the tumor to topotecan. High-risk patients next received eligible for enrollment onto the protocol. Prior corticosteroid therapy craniospinal irradiation (36 Gy, M0-1; 39.6 Gy, M2-3) and three- was allowed. Patients had to begin treatment within 28 days of dimensional conformal boost to the tumor bed (total dose, 55.8 Gy) definitive surgery. Additional eligibility criteria included normal renal and, where appropriate, local sites of metastasis (total dose, 50.4 Gy).
function (serum creatinine Յ 1.2 mg/dL or technetium clearance Ն 70 The median duration of radiation therapy was 1.5 months. After a mL/min · m2]), normal liver function (AST Յ 1.5 times normal and 6-week rest period, patients began four cycles of high-dose chemother- bilirubin Յ 1.5 mg/dL), normal bone marrow function (hemoglobin Ն apy, each followed by stem-cell or bone marrow rescue (Table 2).
10 g/dL, WBC count Ն 3,000/␮L, absolute neutrophil count [ANC] After surgical resection, patients with average-risk disease began Ն1,500/␮L, and platelets Ն 100,000/mm3) and an the Eastern Coop- craniospinal irradiation (23.4 Gy), followed by three-dimensional erative Oncology Group (ECOG) performance score of 0 to 3, except conformal boost to the posterior fossa (cumulative dose, 36 Gy) and the in cases of posterior fossa syndrome. The institutional review board of tumor bed (total, 55.8 Gy). The median duration of irradiation was 1.4 each participating institution approved the protocol, and informed months. After a 6-week rest period, they received the same schedule of consent for treatment was obtained from patients, parents, or legal high-dose chemotherapy as those with high-risk disease (Table 2).
Twenty-four hours after the completion of each cycle of chemother- Disease was staged as high risk or average risk using postsurgical apy, all patients received peripheral blood stem cells (PBSCs), bone tumor volume and a modification of the Chang staging system.40 marrow, or both. All patients received daily support with granulocyte Average-risk disease was defined as (1) absence of metastatic disease colony-stimulating factor (G-CSF) until the ANC was Ն 2,000/␮L for as confirmed by gadolinium-enhanced magnetic resonance imaging 2 consecutive days. The planned duration of each cycle was 28 days; (MRI) of the head and spine and by the absence of tumor cells in the the next cycle of chemotherapy was to begin once the hemoglobin Table 2. Treatment Plan for Each Cycle of Chemotherapy
spectrum antibiotics. In addition, any patient with a Ͼ 10% weight lossfrom the time of starting therapy received nutritional support using total parenteral nutrition (TPN), nasogastric feeding tube, or both.
Cisplatin 75 mg/m2 IV; vincristine 1.5 mg/m2 (max 2 Cyclophosphamide (2 g/m2) IV; mesna by continuous During protocol therapy, the disease status of all patients and the types of toxicity they experienced were monitored with appropriate Cyclophosphamide (2 g/m2) IV; mesna by continuous laboratory assessments and imaging studies. Version 2 of NationalCancer Institute Common Toxicity Criteria was used to grade toxicity.
After completion of therapy, all patients were observed on a regularbasis to monitor physical and disease status as well as their neuroen- G-CSF 5 ␮g/kg/d SC/IV till ANC Ͼ 2,000/␮L for 2 docrine and neuropsychologic function.
Abbreviations: IV, intravenously; SC, subcutaneously.
Though not the primary end point of the study, delivered dose- intensity of cyclophosphamide was defined as the total amount of drug concentration was Ն 8 g/dL, the platelet count was Ն 75,000/␮L, and given in milligrams per square meter over the number of weeks cyclophosphamide was administered. Relative dose-intensity was theratio of the delivered dose-intensity to the expected dose-intensity (1,000 mg/m2/wk). Descriptive statistics were used to report the effects In most cases, PBSCs were harvested and cryopreserved after of variables of interest on the feasibility of delivering high-dose mobilization with G-CSF before radiation therapy (for patients with average-risk disease) or after topotecan administration (for patients For both the average-risk and high-risk groups, progression-free with high-risk disease). Patients in whom mobilization could not be survival (PFS) was measured from the date of enrollment onto the accomplished before starting craniospinal irradiation underwent a bone study to the date of progression, death, or last contact. In addition, PFS marrow harvest before starting chemotherapy. Of the 49 patients who was measured from the date of radiation therapy, after the topotecan received all four cycles of chemotherapy, PBSCs were harvested from window, to the date of progression, death, or last contact in the 28 patients, bone marrow was harvested from 11, and both PBSCs and high-risk subset. The method of Kaplan and Meier41 was used to bone marrow were harvested from 10 (Table 3).
estimate PFS distributions. Standard errors of the Kaplan-Meier esti-mates were calculated by the method of Peto et al.42 After placement of double-lumen Hickman line, patients were admitted to the hospital for each course of high-dose chemotherapy.
Feasibility of Chemotherapy Delivery Mesna and continuous hydration were given with cyclophosphamide toprevent hemorrhagic cystitis. All patients received trimethoprim-sulfa- Of the 53 patients with newly diagnosed medulloblas- methoxazole as prophylaxis against Pneumocystis carinii pneumonia.
toma or PNET who were enrolled during the study period, If patients could not tolerate trimethoprim-sulfamethoxazole, they were 50 received high-dose chemotherapy per protocol. Two of treated with either dapsone or aerosolized pentamidine according to thepreference of the investigator. Transfusions of platelets were adminis- the three patients who did not receive such therapy had tered as necessary to maintain a platelet count greater than 30,000/ experienced disease progression after completion of radia- mm3, and transfusions of irradiated packed RBCs were administered to tion therapy, and were treated with alternative therapy; the maintain a hematocrit concentration of greater than 20% to 25%. If third case did not meet the ECOG criteria for high-dose patients experienced fever (body temperature of Ն 38°C) and had an chemotherapy. Of the 50 patients who received high-dose ANC Ͻ 500/␮L, they were hospitalized and treated with broad- chemotherapy, 49 completed all four cycles (Fig 1). Theplanned time to completion of high-dose chemotherapy was Table 3. Stem-Cell Harvest
16 weeks, and the median time to completion was 16.9 weeks in the 49 patients (range, 15.4 to 23.3 weeks). The planned duration of each cycle of high-dose chemotherapy was 28 days, and the median duration of chemotherapy cycles 1, 2, 3, and 4 were 28, 27, 29, and 28 days, respectively (range for all cycles, 24 to 60 days) (Table 4).
The intended dose-intensity of cyclophosphamide was 1,000 mg/m2/wk. The median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m2/wk for cycles 1 through 4, respectively; associated median relative dose-intensity 2.9 ϫ 106 -2.67 ϫ 107 0.92 ϫ 108-1.88 ϫ 109 was 101%, 102%, 97%, and 99% (Table 5).
HIGH-DOSE CHEMOTHERAPY FOR MEDULLOBLASTOMA high-dose cyclophosphamide during the final cycle. Onechild experienced grade 3 fever without infection on the dayshe was to receive the second daily dose of cyclophospha-mide during the third cycle; this finding prevented thedelivery of that dose. For another patient, the second cycleof cyclophosphamide was modified downward by 50%because of prolonged fever and neutropenia during the firstcycle of chemotherapy. He tolerated the second course welland received the regular dose of cyclophosphamide for theremaining two cycles. Finally, one patient did not receivethe second dose of cyclophosphamide during one cyclebecause of an abnormal ECG reading that was later found tohave been because of a technical problem. The patientreceived subsequent courses of cyclophosphamide at theappropriate doses and on schedule. In five patients, thecyclophosphamide dose was determined on the basis of thebody-surface area at the time of the first round of chemo-therapy. No adjustments were made for weight loss duringchemotherapy. This resulted in five patients receiving a totalof 10 cycles of chemotherapy with doses of cyclophospha- Fig 1. Progression of patients through chemotherapy regimen.
mide ranging from 5% to 21% higher than the planned dose(median, 8%).
Seven patients required reduction of cyclophosphamide Renal function tests and audiography were performed dosage throughout the course of treatment. Because of before every cycle of chemotherapy to determine the dose delayed hematopoietic recovery during the third cycle, one and toxicity of cisplatin. The results of these tests led to patient did not receive high-dose cyclophosphamide during modifications of the cisplatin dosage for 15 patients by the the final cycle. Two patients experienced reduced pulmo- fourth cycle of chemotherapy. In nine patients, the cisplatin nary function after the first and third cycles: one received a dose was reduced by 50% because of grade 3 ototoxicity.
half dose of cyclophosphamide for the second cycle but was One patient was legally blind; hence, cisplatin was elec- able to resume planned chemotherapy for the remainder of tively discontinued after two cycles of high-dose chemo- the cycles, and the other received a 25% reduction during therapy to ensure preservation of hearing. In four patients, the fourth cycle. Pulmonary function returned to normal the dose of cisplatin was reduced because of renal toxicity, after completion of therapy for both these patients. For including temporary renal failure in one patient, who did not another patient, the cyclophosphamide dose was reduced by get reduced dose of cisplatin because of pre-existing renal 25% for both days of the final cycle because of absence of toxicity. In all four patients, renal toxicity resolved after stem cells for rescue. Because of delayed hematopoietic completion of therapy. In one patient, the cisplatin dose was recovery during the third cycle, one patient did not receive Table 4. Length of Cycle and of WBC Recovery Time With G-CSF Support
Table 5. Delivered Dose-Intensity of Cyclophosphamide
Vincristine doses were modified for 15 patients primarily tics between patients who received stem cells and those who because of absence of deep tendon reflexes, neuropathic pain, and foot and wrist drop. One patient did not receive Of the 49 patients who completed all four courses of the final daily dose of vincristine because of low blood chemotherapy, four did not receive bone marrow or stem- counts. Neurologic toxicity resolved within a year of com- cell rescue after the final cycle of therapy. One did not receive any cyclophosphamide and thus did not requirestem-cell support. Three of the four did not have sufficient Characteristics of Hematopoietic Toxicity and cells for rescue. One of these three patients received a reduced dose of cyclophosphamide, whereas the other two All patients had neutropenia after each cycle of high-dose were given the full dose and required 31 and 33 days, chemotherapy; however, only 55% of the cycles resulted in respectively, for recovery of platelet count.
hospital admission for fever and neutropenia. The percent-age of patients requiring hospitalization was 62%, 45%,61%, and 55%, for cycles 1 through 4, indicating that there Table 6. Hematologic Toxicity
was no cumulative risk for fever and neutropenia. The median length of stay per cycle ranged from 5 to 7 days Low platelet counts required transfusion of platelets in 92% of the cycles; most patients required no more than two transfusions per cycle during the first three cycles. How- ever, 57% of the patients required three or more transfusions No. of patients hospitalized for neutropenia during the last cycle. Transfusions of RBCs were required during 88% of the cycles; three fourths of these patients required no more than two transfusions per cycle for each of The number of PBSCs infused per cycle ranged from 1.0 ϫ 106 to 23.8 ϫ 106 cells/kg for the 131 cycles, and the number of bone marrow cells delivered ranged from 0.54 ϫ 108 to 20 ϫ 108 cells/kg for 75 cycles. With the use of G-CSF and PBSC or bone marrow support, the resulting median engraftment time (until the ANC exceeded 2,000/␮L for 2 consecutive days) ranged from 14 to 15 days per cycle, although the time to engraftment was slightly longer during the final two courses for patients who re- ceived bone marrow (Table 8). However, there was no clinically significant difference in engraftment characteris- HIGH-DOSE CHEMOTHERAPY FOR MEDULLOBLASTOMA Table 7. Transfusion Data
complications noted before death 4 months after chemother- apy because of rapid onset of metastatic disease.
Nausea and vomiting were treated with antiemetics; however, five patients required hospitalization. Abdominal pain and gastritis necessitated at least one hospitalization.
Seizures and mucositis required one admission each.
Supplementation and nutritional support were necessary for 22 patients. Eighteen patients received TPN for main- tenance of adequate weight and protein intake duringhigh-dose chemotherapy. Three patients received nutritionalsupport through a nasogastric tube. One patient received TPN for one cycle but received nasogastric feeding for Most of the toxicity that occurred during high-dose subsequent cycles. The median duration of TPN was 111 chemotherapy was anticipated. However, one patient re- quired intervention with digoxin and furosemide because of grade 3 cardiotoxicity (reduced ejection fraction) and hypo-tension after the first course of high-dose chemotherapy.
Of the 53 patients enrolled onto the study, five patients The patient was subsequently treated off-study with a have died because of progressive disease. Of the 48 patients different chemotherapy regimen and is currently free of alive at last follow-up, the median time at risk is 2.5 years disease. There were no instances of hepatic veno-occlusive (minimum, 1.3 years; maximum, 4.2 years). The 2-year PFS disease or hemorrhagic cystitis recorded.
for the 36 average-risk patients is 93.6% Ϯ 4.7%. Of the 19high-risk patients, four had progressive disease while on the topotecan window. The 2-year PFS from the start of therapy Among the patients who were admitted to the hospital is 73.7% Ϯ 10.5%. All high-risk patients went on to receive during chemotherapy for fever and neutropenia or suspected radiation therapy. The 2-year PFS from the start of radiation sepsis, the etiology was definitely ascertained in only seven patients. Infectious agents included herpes zoster infection (two patients), central line sepsis (two patients), pneumonia(one patient), varicella (one patient), and disseminated The current study demonstrates that an intensive chemo- therapy regimen is feasible and safe after surgical resectionand craniospinal irradiation in the front-line treatment of pediatric patients with medulloblastoma and supratentorial One patient who experienced renal failure during the PNET. Using PBSC or autologous bone marrow rescue and second cycle of therapy also experienced transient elevation cytokine support, we were able to deliver high doses of of hepatic transaminase activity (grade IV toxicity) during chemotherapy within the planned short 28-day interval.
that cycle; changes resolved before the next course of Adequate blood cell counts were required before each new chemotherapy. The patient had no residual hepatic or renal cycle of chemotherapy was begun, requiring rapid hemato-poietic recovery if the next course of chemotherapy was tobe delivered on schedule. Four cycles of cyclophosphamide Table 8. Time to Marrow Recovery for Patients Rescued With PBSC
delivered over a median of 16.9 weeks resulted in an Versus BM
average median dose-intensity of 1,000.55 mg/m2/wk. Each cycle of high-dose chemotherapy was delivered according to the planned 28-day schedule for approximately two thirds Our study is the first to test delivery of multicyclic, dose-intensive chemotherapy over a relatively short period Patients rescued only with bone marrow† of time as front-line management of pediatric medulloblas- toma or supratentorial PNET immediately after postopera-tive craniospinal irradiation. The now standard CDDP/ *Dose range of 1.0 ϫ 106 to 23.8 ϫ 106 CD34ϩ cells/kg.
†Dose range of 0.54 ϫ 108 to 20.0 ϫ 108 cells/kg.
CCNU/vincristine regimen published by Packer et al43 uses Table 9. Comparison of Cyclophosphamide Dose-Intensity
pulmonary complications, using echocardiograms and pul- monary function tests. When renal function was compro- mised or ototoxicity occurred, the dose of cisplatin was reduced. Ototoxicity was the most common nonhematologic toxicity in this patient population and is a well-documented toxicity related to the cumulative effects of cisplatin and radiotherapy.45,46 In addition, neurosensory and neuromotorfunction were closely monitored to detect toxicity that mightrequire an adjustment in the dose of vincristine. Except for the eight cycles of chemotherapy planned over a 48-week hearing deficits, toxicities associated with vincristine and period after completion of radiation therapy. A contempo- cisplatin resolved shortly after completion of therapy.
rary national protocol incorporating cyclophosphamide in- Even though the outcome results of our study are prelim- stead of CCNU includes multiple cycles of standard-dose inary, they compare very favorably with those in the cyclophosphamide. The Pediatric Oncology Group (POG) published literature. For average-risk patients treated with 9031 protocol delivered the same cumulative dose as our similarly reduced-dose radiation therapy and conventional study (16,000 mg/m2) but at half the dose-intensity (500 chemotherapy, a recently completed study documented a mg/m2/wk).44 Other protocols do not approach the cumula- 3-year PFS at 86% Ϯ 4%.43 The POG 9031 study was tive dose or the dose-intensity of this study (Table 9). This designed for high-risk patients. The study compared the study delivers cyclophosphamide not only at high doses but 2-year event-free survival of children with newly diagnosed also within a short period of time; thus, in theory this high-risk medulloblastoma randomized to receive chemo- treatment regimen optimizes the efficacy of this agent.
therapy before irradiation versus chemotherapy after radia- Because of their toxicity profiles, most high-dose chemo- tion for patients with metastatic disease at presentation. The therapy regimens used to treat pediatric CNS tumors have 2-year event-free survival was 61% Ϯ 6.8% in the former been associated with mortality rates ranging from 2% to group versus 74% Ϯ 6.5% in the latter.44 16%; to date, we note no toxic deaths in the current trial.
High-dose chemotherapy with stem-cell rescue is used to Furthermore, veno-occlusive disease, a common hepatic treat various CNS and other pediatric malignancies that are toxicity seen in 4% to 15% of patients with similar high- associated with a relatively poor prognosis. Multiple short dose chemotherapy regimens for pediatric brain tumors, cycles of tandem high-dose chemotherapy optimizes dose- was not seen in this patient population.15-17,25 intensity. This strategy of dose optimization has shown The dose-limiting toxicity of cyclophosphamide is my- promise in treating patients with high-risk neuroblastoma, elosuppression; however, the hematologic toxicity is signif- soft tissue sarcoma, and non-Hodgkin’s lymphoma.5,9,11 icantly attenuated with cytokine support and stem-cell Rapid delivery is possible because of autologous stem-cell and/or bone marrow rescue. Two thirds of our patients or bone marrow rescue, which overcomes the myelosup- required one to two transfusions of packed RBCs and pression caused by the treatment regimen. We have platelets between cycles. Fifty percent required three or demonstrated that this high-dose, multicyclic therapy is more platelet transfusions in the later cycles. In addition, feasible and safe in the postirradiation setting; further although approximately half of the patients were hospital- follow-up is needed before definitive conclusions can be ized for fever and neutropenia during each cycle, the length made regarding outcome in comparison with conven- of stay for most was 1 week or less. The planned dose- intensity for the study was well tolerated, especially in viewof the temporal proximity to craniospinal irradiation; the high dose-intensity was achieved because of the ameliorated We thank Dr Larry Kun for helpful discussions during preparation of myelosuppression associated with hematopoietic rescue.
the manuscript; Flo Witte, MA, and Patsy Burnside, respectively, for Previous studies have shown that cyclophosphamide editorial assistance and typing the manuscript; Jennifer Havens, Jen- doses delivered in this study carry a slight risk of hemor- nifer Taylor, Richard Rochester, Lisa Beattie, Amy St. Claire, KenBurnette, Natalie Pitts, Nancy Kline, Sonya Burchett, Shannon Correll, rhagic pericarditis, a toxicity that we did not encounter in and Pat Alcoser for providing excellent patient care and research our study.31 Nonhematologic toxicity has been uncommon assistance; and Jana Freeman, Lyra Pearson, and Jennifer Houlihan for to date; patients were monitored closely for cardiac and 1. Legros M, Dauplat J, Fleury J, et al: High-dose chemotherapy 2. Antman KH, Rowlings PA, Vaughan WP, et al: High-dose with hematopoietic rescue in patients with stage III to IV ovarian chemotherapy with autologous hematopoietic stem-cell support for cancer: Long term results. J Clin Oncol 15:1302-1308, 1997 breast cancer in North America. J Clin Oncol 15:1870-1879, 1997 HIGH-DOSE CHEMOTHERAPY FOR MEDULLOBLASTOMA 3. Ayash LJ, Eilas A, Ibrahim J, et al: High-dose multimodality 18. Gururangan S, Dunkel IJ, Goldman S, et al: Myeloablative therapy with autologous stem-cell support for stage IIIB breast carci- chemotherapy with autologous bone marrow rescue in young children with recurrent malignant brain tumors. J Clin Oncol 16:2486-2493, 4. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional- dose chemotherapy compared with high-dose chemotherapy plus au- 19. Mahoney DH, Strother D, Camitta B, et al: High-dose melpha- tologous hematopoietic stem-cell transplantation for metastatic breast lan and cyclophosphamide with autologous bone marrow rescue for cancer: Philadelphia Bone Marrow Transplant Group. N Engl J Med recurrent/progressive malignant brain tumors in children: A pilot Pediatric Oncology Group study. J Clin Oncol 14:382-388, 1996 5. Stoppa AM, Bouabdallah C, Chabannon C, et al: Intensive 20. Johnson DB, Thompson JM, Corwin JA, et al: Prolongation of sequential chemotherapy with repeated blood stem-cell support for survival for high-grade malignant gliomas with adjuvant high-dose untreated poor-prognosis non-Hodgkin’s lymphoma. J Clin Oncol BCNU and autologous bone marrow transplantation. J Clin Oncol 6. Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VA- 21. Heideman RL, Douglass EC, Krance RA, et al: High-dose COP-B plus autologous bone marrow transplantation for advanced chemotherapy and autologous bone marrow rescue followed by inter- diffuse non-Hodgkin’s lymphoma: Results of a prospective randomized stitial and external-beam radiotherapy in newly diagnosed pediatric trial by the Non-Hodgkin’s Lymphoma Cooperative Study Group.
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9. Bokemeyer C, Franzke A, Hartman JT, et al: A phase I/II study of sequential, dose-escalated, high dose ifosfamide plus doxorubicin 25. Dupuis-Girod S, Hartman O, Benhamou E, et al: Will high dose with peripheral blood stem cell support for the treatment of patients chemotherapy followed by autologous bone marrow transplantation with advanced soft tissue sarcomas. Cancer 80:1221-1227, 1997 supplant cranio-spinal irradiation in young children treated for medul- 10. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, 26. Mason WP, Grovas A, Halpern S, et al: Intensive chemotherapy autologous bone marrow transplantation, and 13-cis-retinoic acid: and bone marrow rescue for young children with newly diagnosed Children’s Cancer Group. N Engl J Med 341:1165-1173, 1999 malignant brain tumors. J Clin Oncol 16:210-221, 1998 11. Grupp SA, Stern JW, Bunin N, et al: Tandem high-dose therapy 27. 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