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Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group

From the Vanderbilt Cancer Center, Nashville, and Saint Jude’s Children’s Research Hospital, Memphis, TN; Children’s Cancer Group, Arcadia, University of California San Francisco, San Francisco, and Children’s Hospital of Orange County, Orange, CA; Children’s National Medical Center, Washington, DC; Primary Children’s Hospital, Salt Lake City, UT; University of Texas, M.D. Anderson Cancer Center, Houston, TX; University of Minnesota Medical Center, Minneapolis, and United Hospital, St Paul, MN; Saint Peter’s University Hospital and University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ; Children’s Hospital of Pittsburgh, Pittsburgh, PA; Trinity Lutheran Hospital, Kansas City, MO; Boulder Community Hospital, Boulder CO; and Babies Hospital, Lincoln Hospital, Columbia University, New York, NY.

Address reprint requests to Mark T. Jennings, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: mark.jennings@ mcmail.vanderbilt.edu; cc: smason{at}childrensoncologygroup.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: This Children’s Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT).

PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy.

RESULTS: Ten percent ± 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% ± 9% of patients improved. The neuroradiographic response rate for regimen B was 19% ± 8% for chemotherapy and 23% ± 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% ± 5% (estimate ± SE) at 1 year and 6% ± 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P < .05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course.

CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
HISTORICALLY, "standard therapy" for diffuse pontine gliomas (DPG) constituted a radiotherapeutic prescription of 45 to 55 Gy, delivered in single daily fractions of 1.8 to 2.0 Gy. Unfortunately, the median time to disease progression (TDP) has been only 5 to 7 months, with an expected overall survival (OS) of 9 to 13 months.^1,2 Pilot and collaborative group studies in the treatment of pediatric patients with DPG have used hyperfractionated external-beam radiotherapy (HFEBRT) successively at doses of 64.8, 66, 70.2, 72, and 78 Gy. Response rates, which usually included patients with stable disease (SD) (0% to 24% change in tumor area), have been reported to be in the range of 62% to 77%. However, these HFEBRT trials have not significantly altered the TDP or provided durable responses.^1,2

Although HFEBRT has been disappointing, it is worth investigating for the following reasons. First, the intention of HFEBRT is to exploit the different dose relationships exhibited between nonproliferating normal tissues and malignant tumor cells, whereby increasing the dose fractionation allows for greater repair of the sublethal radiation damage sustained by neurons and endothelia within the CNS, in comparison to that of the rapidly dividing tumor cells. Theoretically, delivery of the same dose by hyperfractionation affords a comparable control rate while ameliorating the late morbidity of the therapy. Conversely, one can increase the dosage intensity to the tumor beyond the conventional 54- to 60-Gy range without risking additional toxicity.³ Second, radiation therapy (and chemotherapy) is enhanced by good tissue perfusion and oxygenation, so that smaller dose fractions may allow hypoxic cells within the core of the neoplasm to reoxygenate.^4-7 Third, despite the poor response and survival rates among DPG patients in previous HFEBRT studies, "The radiographic response rate suggests that this therapy might be useful if coupled with other forms of treatment."¹ The tumor’s reaction to multifractionated radiotherapy may be altered by chemotherapy in terms of its repair of sublethal damage, reoxygenation, repopulation, and reassortment into different phases of the cell cycle. There is experimental precedent for this.⁸

Absent alternative means of cytoreduction, chemotherapy has been attempted for control of brainstem gliomas (BSG). Single-agent trials have given way to high-dose, multiagent combinations.² The challenge of this approach is to combine potentially synergistic agents acting within different phases of the cell cycle but with tolerable toxicities. Platinators and topoisomerase inhibitors are thought to have more than an additive interaction in a number of tumor types, including gliomas.^9-13 A trial of cisplatin and etoposide in newly diagnosed adult patients with malignant gliomas demonstrated a 55% overall response rate, with 26% SD incidence among glioblastoma patients, when treated before and after radiotherapy. The TDP was delayed as long as 38.5 weeks among the glioblastoma patients and to 73 weeks among anaplastic astrocytoma patients.⁹ The "baby Pediatric Oncology Group" protocol design consisted of alternating 28-day cycles of AAB-AAB, in which regimen A consisted of cyclophosphamide and vincristine and regimen B was cisplatin and etoposide.¹⁴ This combination has yielded very encouraging results among infants with malignant gliomas and DPG. The 2-year progression-free survival (PFS) and OS rates were 54% and 65%, respectively, in children with malignant gliomas, which exceeded those achieved in older children treated with postoperative radiotherapy alone (PFS 20%; OS 40%), irradiation with lomustine-vincristine-prednisone or the "eight-in-one" combination chemotherapy with radiation therapy.^14-16 Similarly, the 28% 2-year PFS and 42% 2-year survival rates observed among patients with DPG were superior to results obtained with HFEBRT.^14,17

We report the results of the Children’s Cancer Group (CCG) group-wide phase II trial CCG-9941 of induction chemotherapy followed by HFEBRT among children with BSG. Because there were several possible alkylator-platinator-topoisomerase inhibitor combinations worthy of testing, and to avoid bias, it was elected to randomize patients between two regimens of chemotherapeutic agents (carboplatin, etoposide, and vincristine v cisplatin, etoposide, cyclophosphamide, and vincristine), which were anticipated to differ in relative intensity. This study has three specific aims, as follows: first, to determine response rates for induction with two arms by objective neuroradiologic criteria among children with BSG before HFEBRT; second, to determine the toxicity of these drug regimens independently and with subsequent HFEBRT administration; and third, to determine whether HFEBRT served as a "consolidation" treatment to prolong survival if a cytoreductive response was achieved after induction. Two implicit questions posed were whether achieving a preradiation response was necessary for an improvement in postradiation survival, and did a difference in dose-intensity affect either response or survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Eligibility
Children with DPG, as diagnosed by clinical and magnetic resonance imaging examination, biopsy-proven malignant gliomas of the brainstem, or both, were the primary subjects for this protocol. Patients with focal, enhancing tumors of the mesencephalon, optic tectum, cervicomedullary junction, or predominantly exophytic tumors were accepted only with pathologic confirmation of a malignant glioma. Eligibility criteria required that patients be newly diagnosed, previously untreated, have an indwelling catheter, and be between 3 and 25 years of age. Normal hematologic, renal, and hepatic function was necessary for inclusion. Exclusion criteria included a more than 4-week delay after initial diagnosis, infectious meningitis, postoperative complications likely to delay initiation of chemotherapy, and the diagnosis of neurofibromatosis unless there was pathologic confirmation of a malignant glioma. The older patients, parents, or legal guardians were required to sign an informed consent meeting the requirements of participating institutional review boards, the United States Food and Drug Administration, and the National Cancer Institute.

Pathology
Pathologic specimens from patients undergoing neurosurgical biopsy or resection were centrally reviewed and graded by World Health Organization¹⁸ and Daumas-Duport¹⁹ diagnostic criteria.

Treatment
The CCG-9941 phase II trial randomized patients between two arms for three cycles of induction chemotherapy to be administered every 21 days. Regimen A consisted of the intravenous administration of carboplatin (600 mg/m²/d on days 1 to 2), etoposide (167 mg/m²/d on days 1 to 3), and vincristine (1.5 mg/m²/d administered on days 1, 8, and 15). Regimen B comprised the intravenous administration of cisplatin (100 mg/m² on day 1), cyclophosphamide (1,500 mg/m²/d on days 2 to 3), etoposide (167 mg/m²/d on days 1 to 3), and vincristine (1.5 mg/m²/d administered on days 1, 8, and 15) (Fig 1). Patients in both arms received granulocyte colony-stimulating factor. Responses were neuroradiographically assessed after three courses of induction chemotherapy. The patients then advanced to HFEBRT, after which they were reevaluated radiologically. The HFEBRT prescription was for 72 Gy divided into 72 twice-daily fractions of 1 Gy administered on weekdays. Toxicity was judged by standard CCG criteria and analyzed separately for each chemotherapy arm and course as well as during HFEBRT. Patients were to be followed for life, regardless of whether they completed the prescribed treatment protocol.

View larger version (17K): [in this window] [in a new window]   Fig 1. Schema of dosages and schedules of chemotherapy administration for regimens A and B. CBDCA, carboplatin; VP16, etoposide; VCR, vincristine; cDDP, cisplatin; CPM, cyclophosphamide.

Statistical Methods
The primary end points for statistical survival analysis were event-free survival (EFS), defined as the minimum time from study entry to disease progression, the occurrence of a second malignant neoplasm or death from any cause, and OS, which was the duration of survival from time of study entry to death from any cause. Nonparametric estimates of EFS probabilities were obtained by the product-limit estimate, with SEs computed by the Greenwood formula. Comparison of EFS and OS between treatments was based on the log-rank test.²⁰ Comparison of frequency counts was based on the ² test, and comparison of continuous measurement data was based on analysis of variance.²¹

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Between May 27, 1994, and April 17, 1997, 65 patients were registered onto CCG-9941. Two patients were declared ineligible because they did not meet entry criteria.

Demographic Characteristics
Thirty-two patients were randomized to regimen A and 31 to regimen B. The male:female ratio was 1.17:1. The patients’ ages ranged from 3 to 15 or more years (median, 6 years). The distribution of sex and age was similar in the two treatment groups. Forty-three patients were classified as white, eight Hispanic, seven African-American, and three "other"; for two, race was unknown. There was a somewhat higher percentage of nonwhite patients treated with regimen B (P < .10, ² test). The pathologic diagnoses established among the regimen A patients included anaplastic astrocytoma (four patients, of whom two were Daumas-Duport grade 3 and two were grade 4), anaplastic oligodendroglioma (one patient with Daumas-Duport grade 4), and glioblastoma multiforme (one child with Daumas-Duport grade 4). Among the regimen B patients, there was one anaplastic astrocytoma (Daumas-Duport grade 4) and two glioblastomas (Daumas-Duport grade 4) diagnosed. Central neuroradiographic review established the mean pretreatment tumor volume among 19 regimen A patients to be 61.89 cm³ (standard deviation, 31.3; range, 6.1 to 106.6 cm³). Among 18 regimen B patients, the initial mean tumor volume was 86.98 cm³ (standard deviation, 42.7; range, 26.2 to 182.3 cm³).

Therapies Administered
Biopsy, surgical resection, or both were performed on six patients in regimen A and three in regimen B. Only two of these were subtotal resections (50% to 90% resection); there was one partial resection (< 50%).

Among patients receiving regimen A chemotherapy, the 32 patients were treated with all or part of the first course, 26 received the second course, and 21 (66%) completed the third course of induction chemotherapy. Five patients were withdrawn during or after the initial cycle of treatment, four of these for PD. Another five were withdrawn after the second course, four of these for PD. One patient was withdrawn after the third course for terminal care. Twenty-four group A patients were treated with radiotherapy; however, four did not complete the 72-Gy prescription on a hyperfractionated schedule. The relative number of patients requiring corticosteroid support varied between 67% and 81% over the three induction courses; 67% were treated with corticosteroids during all or part of HFEBRT.

Among the 31 regimen B patients, 30 were treated with all or part of the first course, 26 received the second course, and 25 (81%) finished the three intended courses of induction chemotherapy. One patient neurologically deteriorated on the night of randomization and was never treated. Four patients were withdrawn after the first treatment: one as a result of PD and two for toxicity and one was lost to follow-up. One patient was withdrawn after the second cycle because of PD. Twenty-five children were treated with radiotherapy; however, two of these received considerably less than the prescribed dose of 72 Gy. The relative number of patients requiring corticosteroid support varied between 68% and 77% over the three induction courses; 80% were treated with corticosteroids during all or part of HFEBRT.

Response Rate
Among the 32 patients treated with regimen A, three (10% ± 5%) of 30 assessable patients exhibited response (PR or MR) to induction chemotherapy, although only two (6.7% ± 5%) of 30 satisfied the criterion for PR. Twenty-six patients were assessable for response to combined induction and radiotherapy; seven (27% ± 9%) of 26 patients demonstrated response, including four (15% ± 7%) of 26 PR. Among the 31 patients treated with regimen B induction chemotherapy, PR or MR was evident in five (19% ± 8%) of 26 assessable patients, with PR in one (4% ± 4%) of 26. After induction chemotherapy and HFEBRT, a PR+MR rate of five (23% ± 9%) of 22 and a PR rate of three (14% ± 7%) of 22 was observed. Neither the difference in postinduction response rate nor the difference in the combination induction/HFEBRT response rate was statistically significant between the two regimens. These results are listed in Table 1.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves demonstrating EFS from study entry for regimens A and B.

View larger version (14K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curves demonstrating OS from study entry for regimens A and B.

View larger version (17K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curves demonstrating survival from last induction chemotherapy by response to induction. PR, partial response; MR, minor response; SD, stable disease; PD, progressive disease; WD, withdrawn.

Grade 3 or 4 elevations in liver transaminases were noted transiently in one and two patients, respectively, during the second and third courses of regimen A, as well as in two children during the first cycle of regimen B. Central neurotoxicity consisted of encephalopathy, somnolence, seizures, auditory hallucinations, or worsening neurologic deficits, which were not clearly attributable to tumor progression. Four patients experienced grade 3 or 4 central neurotoxicity during the first (two patients) and second courses (one child) of regimen A, with an additional patient developing it during HFEBRT. The relative incidence of severe central neurotoxicity was similar with regimen B, but noted after the second (one patient) or third (one patient) induction courses or during HFEBRT (two patients). Grade 3 or 4 peripheral neurotoxicity was noted in two patients in each study arm. There were five episodes of pancreatic toxicity, principally hyperglycemia, noted among the regimen B patients; a single patient was affected during each of the induction courses and two during HFEBRT administration.

Cause of Death
In regimen A, the primary or major contributing cause of death was locally progressive disease among 91% of those who died, one of whom died in the setting of concomitant sepsis. Another died as a result of multiorgan toxicity resulting from treatment of her second malignancy, an acute lymphoblastic leukemia. The remaining child was lost to follow-up after progressing during the induction phase. In regimen B, 94% of deaths occurred in the setting of progressive disease. There were two patients in regimen B who deteriorated soon after diagnosis and were withdrawn. One patient apparently experienced tonsillar herniation, and the second developed varicella encephalitis during the first course of therapy. The exact cause of death was not further established for these two patients. There were five patients (15.6%) in regimen A and seven (22.6%) in regimen B whose course was complicated by intraventricular or leptomeningeal dissemination.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The Norton-Simon hypothesis predicts that a tumor’s rate of regression is a direct function of the intensity of therapy, as well as the growth rate of the neoplasm before the initiation of treatment.²² We hypothesized that pretreatment with intensive chemotherapy and growth factor support might achieve sufficient cytoreduction to enhance the theoretically predicted improvement in control of residual disease with HFEBRT. The desired results would be an improvement in the response rate, delay in the TDP beyond the anticipated fifth to seventh month, and improved OS.² Chemotherapeutic agents, which have previously seemed effective among malignant gliomas elsewhere in the CNS, did not achieve similar response results in this patient population. Our overall findings are similar to those of other larger trials of multiagent chemotherapy,^14,23-30 whether administered before or after radiotherapy, in the treatment of BSG (Table 2). As illustrated in Figs 2 and 3, the current study of 63 patients found no appreciable difference in EFS and OS, respectively, despite the relatively greater intensity of chemotherapy in regimen B. We have detailed the toxicity data for both regimens so that it may be of use in the design of future studies. Hyperfractionated radiotherapy could not be demonstrated to consolidate the response to induction chemotherapy among those patients achieving a PR or MR.

This study has been unable to substantiate the first theoretic prediction that chemo- or radiotherapeutic dosage intensification would improve response rates among patients with BSG. The second hypothesis, that volume predicts resistance to therapy and hence survival, also does not seem to apply among gliomas intrinsic to the brainstem. Although a response to induction chemotherapy was associated with significantly longer survival, the neoadjuvant chemotherapy in this protocol did not meaningfully improve either response rate, EFS, or OS for the group as a whole relative to previous series of BSG patients treated with radiotherapy with or without chemotherapy.² Hence, we conclude that preradiation chemotherapy at these dosage levels is toxic, and in most cases ineffective, in the treatment of BSG.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The appendix listing participating investigators is available online at www.jco.org.

	ACKNOWLEDGMENTS

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted April 24, 2001; accepted May 3, 2002.

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