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© 2001 American Society for Clinical Oncology Cyclophosphamide Plus Topotecan in Children With Recurrent or Refractory Solid Tumors: A Pediatric Oncology Group Phase II StudyByFrom the University of Arkansas for Medical Sciences, Little Rock, AR; the Pediatric Oncology Group Statistical Office, Gainesville, FL; Cardinal Glennon Children’s Hospital, and Washington University School of Medicine, St Louis, MO; Hackensack University Medical Center, Hackensack, NJ; and University of Montreal, Montreal, Canada. Address reprint requests to Robert L. Saylors III, MD, Children’s Oncology Group Offices, 440 E Huntington Dr, PO Box 60012, Arcadia, CA 91006-6012.
PURPOSE: To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors.
PATIENTS AND METHODS: A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was
RESULTS: A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewing’s sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades CONCLUSION: The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.
TOPOTECAN IS a water-soluble derivative of camptothecin, a product of the Camptotheca acuminata tree native to China.1,2 Topotecan is an inhibitor of topoisomerase I, an enzyme that introduces a break in one strand of DNA, allowing for controlled rotation of the cleaved strand and subsequent strand religation. This relaxes positively or negatively supercoiled DNA in front of an advancing replication fork, thus reducing torsional strain on the DNA. Topotecan, and other camptothecin derivatives, stabilize the topoisomerase I–covalent complex in which the enzyme is linked to DNA through a 3'-phosphotyrosyl bond. Collision of an advancing replication fork results in the generation of a double-strand DNA break or stalling of the replication fork, either of which may initiate apoptosis.1,3 This mechanism of action suggests that topotecan, and other camptothecin analogs, may exhibit enhanced cytotoxicity when combined with DNA damaging agents. We and other investigators have performed clinical studies delivering alkylating or platinating agents before the camptothecin analogs topotecan or irinotecan. All have reported a degree of hematopoietic toxicity in excess of that expected from either agent delivered alone, suggesting synergy within these combinations.4-7 The Pediatric Oncology Group previously performed a phase I study of cyclophosphamide in combination with topotecan, which established a recommended phase II dose of cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days, followed by filgrastim beginning on day 6.6 This trial used a relatively low cumulative dose of cyclophosphamide (1.25 g/m2), which infrequently results in grade 4 hematopoietic toxicity, and demonstrated that the dose of topotecan that could be delivered in combination with this dose of cyclophosphamide was only 37.5% of the recommended pediatric phase II topotecan dose, which we interpreted as indicative of synergistic augmentation of the hematopoietic cytotoxicity resulting from each drug. The promising activity seen in heavily pretreated patients with rhabdomyosarcoma, neuroblastoma, osteosarcoma, and Wilms tumor in this phase I study led to the present phase II investigation to determine the whether the increased hematopoietic cytotoxicity with the combination of cyclophosphamide and topotecan is also reflected in an increased response rate compared with the previous Pediatric Oncology Group study that administered topotecan alone on the same schedule.
Patient Selection and Evaluation After obtaining approval by the institutional review board and written informed consent from the responsible parent and/or guardian, 91 patients with histologically confirmed recurrent or refractory solid tumors were entered onto this phase II trial (Table 1). All patients were 21 years of age or younger, had a life expectancy of at least 6 weeks, modified Lansky score of  50, and adequate nutritional status as assessed by weight over the third percentile for age. Prior therapy with cyclophosphamide was permitted but prior therapy with topotecan was not. Patients were eligible if they had received  two prior chemotherapy regimens, except if the patients had been previously enrolled on a phase I or single-agent phase II study, in which case two prior chemotherapy regimens in addition to the phase I or single-agent phase II study were allowed. Absolute neutrophil count (ANC) greater than 1,500/µL and platelet count greater than 100,000/µL were required as evidence of bone marrow recovery from prior chemotherapy. Patients with inadequate peripheral blood counts as a result of bone marrow infiltration were also eligible. Other requirements included adequate hepatic function (bilirubin 1.5 mg/dL and AST twice normal) and normal renal function (serum creatinine < 1.5 mg/dL or creatinine clearance 60% of age-adjusted normal). Patients who were pregnant, breast-feeding, or less than 6 weeks from the administration of extensive radiation therapy or nitrosourea therapy were excluded. Patients previously treated with bone marrow transplantation, with or without total-body irradiation, were eligible provided that they met all other eligibility requirements, were free of graft-versus-host disease, and at least 6 months had elapsed since the bone marrow transplantation. Treatment courses were repeated every 21 days in the absence of irreversible toxicity or progressive disease.
Before the first treatment, all patients had a complete history and physical examination performed. All patients also had imaging studies using the most appropriate modality to document the size of measurable lesions. Laboratory studies obtained before study enrollment included complete blood cell count with differential; bone marrow aspirate and biopsy if the bone marrow was likely to be compromised; urinalysis; electrolytes including calcium, magnesium, and phosphorus; serum creatinine; ALT; lactate dehydrogenase; and bilirubin. Patients were monitored with weekly physical examinations, twice weekly complete blood cell counts until recovery from hematopoietic toxicity, and urinalysis daily during therapy. Renal (serum creatinine) and hepatic function (ALT, lactate dehydrogenase, and bilirubin), as well as electrolytes (including calcium, magnesium, and phosphorus), were monitored before each course of therapy. Response was determined by appropriate imaging studies before the second and third courses and then after every second course.
Drug Dosages and Administration The Division of Cancer Treatment, National Cancer Institute, supplied topotecan as a lyophilized powder in a vial containing 4 mg of the active drug without preservatives. After reconstitution with sterile water, the drug was further diluted in normal saline or 5% dextrose solution for intravenous administration. Cyclophosphamide and filgrastim were obtained from commercial suppliers by the treating institutions.
Response and Toxicity Criteria
Statistical Methods
A total of 91 patients, 83 of whom were fully assessable for response and toxicity, were enrolled onto the study (Table 1). Among the five ineligible patients, two patients had received more than two prior chemotherapy regimens, two patients were treated before registration, and one patient had an elevated initial creatinine. Among the three inassessable patients, two died (before their first evaluation) from effects of the tumor, and one patient did not have measurable disease at the time of enrollment.
The 83 assessable patients received a total of 307 treatment courses (median, two courses; range, one to 13 courses). The highest response rates (Table 2) were seen in rhabdomyosarcoma patients, where 10 of 15 patients achieved a PR, in neuroblastoma patients, where six of 13 patients achieved a PR, and in Ewing’s sarcoma patients, where six of 17 patients achieved an objective response (two CRs and four PRs). Using the three-stage sequential analysis, there is sufficient evidence to conclude that the objective response rate exceeds 10% for rhabdomyosarcoma patients (P
As listed in Table 3, 18 of the 25 responding patients were removed from the study and treated with additional chemotherapeutic regimens. Three of the patients with rhabdomyosarcoma achieving PR, both of the patients with Ewing’s sarcoma achieving CR and one achieving PR, five of the patients with neuroblastoma achieving PR, and the patient with Sertoli-Leydig cell tumor, were removed from the study after a median of five courses (range, two to 13 courses) for the administration of high-dose chemotherapy with stem-cell rescue. Five of the patients who received no further therapy after completing protocol treatment developed progressive disease 5, 6, 7, 10, and 21 months after their initial response. One patient with rhabdomyosarcoma underwent surgical excision of the site of recurrent disease after three courses of therapy, was subsequently treated with six additional courses of therapy, and remains free of disease 16+ months after the cessation of therapy. One patient with neuroblastoma, who achieved a PR after four courses of therapy, was taken off therapy after the sixth course because of the parents’ request and has persistently stable disease for 28+ months in the absence of any further therapy.
In the previous Pediatric Oncology Group studies of topotecan, alone and in combination with cyclophosphamide, long-term stabilization of disease was frequently seen in patients who failed to achieve CR or PR.6,9 In this study, a total of 17 patients pooled across all strata were reported to have stable disease. These patients received a median of three courses of therapy (range, one to 11 courses), suggesting that cyclophosphamide plus topotecan-containing regimens may be effective when combined with other drugs, particularly for osteosarcoma, in which five of the 18 assessable patients achieved stable disease. Because prior therapy with alkylating agents, including cyclophosphamide and ifosfamide, was permitted in this trial, we attempted to determine whether the response rate varied according to prior therapy with these agents. Eleven of the 15 patients with rhabdomyosarcoma had been treated with ifosfamide (median, eight courses; range, two to nine courses) and seven had been treated with cyclophosphamide (median, four courses; range, one to 12 courses), five of whom had been treated with both agents. The median duration of time between prior therapy with ifosfamide and/or cyclophosphamide and enrollment onto this trial was 9 months (range, 1 to 61 months), which was not different between responders (median, 10 months; range, 1 to 50 months) and nonresponders (median, 8 months; range, 1 to 61 months). Two of the 10 PRs were in the two patients who had not received prior ifosfamide or cyclophosphamide, and the remaining eight PRs were in the patients who had received ifosfamide alone (five patients), cyclophosphamide alone (two patients), or both agents (one patient). The five nonresponders had been treated with both agents (four patients) or ifosfamide (one patient). All patients with Ewing’s sarcoma had been treated with both ifosfamide (median, eight courses; range, two to 10 courses) and cyclophosphamide (median, eight courses; range, two to 12 courses). Four of the 13 neuroblastoma patients had been treated with ifosfamide (median, one course; range, one to two courses), 12 of the 13 had been treated with cyclophosphamide (median, three courses; range, one to 11 courses), and four had been treated with both agents. One of the six PRs was in a patient that had not received prior ifosfamide or cyclophosphamide, and the remaining five PRs were in the patients who had received cyclophosphamide alone (three patients) and both agents (two patients). Because patients who had received prior stem-cell transplantation were eligible for this trial, we analyzed the effect of this intensive prior therapy on outcome after treatment with topotecan and cyclophosphamide. There were a total of 10 patients who had received prior autologous bone marrow or peripheral-blood stem-cell transplantations (one with rhabdomyosarcoma, one with an undifferentiated sarcoma, one with Wilms tumor, two with Ewing’s sarcoma, and five with neuroblastoma). The median time to relapse after transplantation was 14 months (range, 5 to 32 months). There were one CR (Ewing’s sarcoma), three PRs (all neuroblastoma), one minor response (undifferentiated sarcoma), and one stable disease (rhabdomyosarcoma) in response to cyclophosphamide and topotecan among these patients, suggesting that there is no difference in the response rate in patients who had previously undergone stem-cell transplantation. The toxicity of the cyclophosphamide and topotecan therapy was generally limited to the hematopoietic system, as predicted by the phase I study. Fifty-three percent of courses (163 of 307 courses) were associated with grades 3 and 4 neutropenia. The median onset of severe neutropenia (ANC < 500/µL) was day 5 (range, 1 to 8 days) after completion of the 5-day chemotherapy administration schedule, and the duration of severe neutropenia was a median of 5 days (range, 2 to 15 days). Forty-four percent of courses (136 of 307 courses) were associated with grades 3 and 4 thrombocytopenia (platelet count < 50,000/µL). The median onset of grades 3 and 4 thrombocytopenia was day 7 (range, 1 to 14 days) after completion of the 5-day chemotherapy administration schedule and the duration of this degree of thrombocytopenia was a median of 7 days (range, 3 to 14 days). Because of variable reporting of the timing and number of platelet transfusions by the treating institutions, the duration of thrombocytopenia reported was calculated using data from only the 33 courses in which prophylactic or therapeutic platelet transfusions clearly were not administered by the treating physician. Twenty-seven percent of courses (84 of 307 courses) were associated with grades 3 and 4 anemia. Other reported toxicities of grades 3 or greater were nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). The prior phase I study indicated that hematuria was very uncommon when mesna was delivered with the cyclophosphamide, and when it did occur, it was in patients with a prior history of hematuria secondary to chemotherapy and/or irradiation. Therefore, mesna was not included in the present protocol, and, as before, the only two patients reporting hematuria had also reported hematuria after prior ifosfamide therapy. There were no toxic deaths in this study. Despite the intensely myelosuppresive nature of this therapy, infectious complications were infrequent. There were 34 reported episodes of grades 3 and 4 infection (including admissions for fever and neutropenia), of which five were episodes of bacteremia or fungemia requiring systemic antimicrobial therapy. There was also one episode of cutaneous herpes zoster infection and one episode of infectious cystitis, both of which were successfully treated. There were no deaths from infectious causes.
This phase II multi-institutional trial demonstrated that the combination of cyclophosphamide and topotecan is active in pediatric rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma. When compared with the data generated by the Pediatric Oncology Group using topotecan alone, a greater degree of antitumor activity was demonstrated when topotecan was combined with cyclophosphamide.9 In neuroblastoma, there were two responses (CR + PR) in 37 patients with neuroblastoma to topotecan alone, whereas the combination resulted in six responses in 13 patients with neuroblastoma. In rhabdomyosarcoma there were no responses to topotecan alone, whereas the combination resulted in 10 responses in 15 patients, which is similar to the response rate obtained in the upfront window setting in previously untreated patients with rhabdomyosarcoma.10 In Ewing’s sarcoma/peripheral neuroectodermal tumor, there were two responses in 29 patients to topotecan alone, whereas the combination resulted in six responses in 17 patients with Ewing’s sarcoma/peripheral neuroectodermal tumor. Moreover, the responses seem to be independent of prior exposure to cyclophosphamide and/or ifosfamide. These excellent results were achieved despite the fact that the dose of topotecan administered in this study yields a predicted area under the curve of 42 ng/mL·hr, based on pharmacokinetic data from our previous phase I study, which is below the predicted area under the curve necessary (52 to 88 ng/mL·hr) to induce CR or PR in the mouse neuroblastoma xenograft model.6,11,12 However, mouse xenograft studies confirm that topoisomerase I inhibitors possess enhanced activity when administered concurrently with alkylating agents, particularly when the alkylating agent is administered at the beginning of a continuous exposure of topotecan.13-15 Clinical studies using topoisomerase I inhibitors in combination with alkylating or platinating agents have demonstrated a degree of hematopoietic toxicity in excess of that expected from either agent delivered alone, indicating that there may be synergy within these combinations, at least with regard to hematopoietic toxicity.4-7 Our data suggest that the cyclophosphamide and topotecan combination may increase antitumor effect as well, at least for pediatric rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma. The study was designed to minimize the number of previous chemotherapeutic regimens received by the patients in an effort to avoid testing the drugs on patients likely to have drug-resistant tumors. However, the intensity with which patients with Ewing’s sarcoma and neuroblastoma are treated in contemporary cooperative group trials and the frequent use of myeloablative therapy coupled with autologous stem-cell transplantation led to a population that had received one or two highly intensive prior therapies. Despite this, an analysis of the data indicate that patients can respond to the topotecan and cyclophosphamide combination after greater than 1 year of intensive alkylating-agent therapy and/or ablative therapy with autologous stem-cell rescue. The data from the ongoing Pediatric Oncology Group up-front phase II window trials designed to elucidate the true response rate to cyclophosphamide and topotecan in previously untreated high-risk patients with neuroblastoma and Ewing’s sarcoma should, as did the Intergroup Rhabdomyosarcoma Study Group trial, confirm this trend toward high activity levels and may lead to the inclusion of the cyclophosphamide and topotecan combination in phase III trials for these diseases as well.10 Patients with osteosarcoma had occasional PRs that occurred at a level below the threshold needed to declare efficacy (two PRs in 18 assessable patients). Stabilization of recurrent and/or metastatic disease was seen frequently in patients with osteosarcoma (five with stable disease in 18 assessable patients) at a rate similar to that observed in the phase I study of this combination, in which one patient with PR and two with stable disease were observed in seven treated patients with osteosarcoma. Although encouraging, these data do not warrant the inclusion of topotecan and cyclophosphamide into currently available phase III osteosarcoma treatment protocols. These data do raise the interesting possibility of including additional agents into the cyclophosphamide and topotecan regimen, particularly agents with minimal hematopoietic toxicity, in an attempt to increase the response rate in patients with osteosarcoma. The topotecan and cyclophosphamide combination was generally well tolerated. The previous phase I study suggested that the only appreciable toxicity was likely to be hematopoietic. Indeed, grades 3 or 4 neutropenia was reported in 53% of the cases, grades 3 or 4 thrombocytopenia was reported in 44% of cases, and grades 3 or 4 anemia was reported in 27% of cases. Despite this degree of hematopoietic toxicity, only 11% of courses were complicated by grades 3 or 4 infection (including admission for fever and neutropenia). This may reflect the brief duration (median, 5 days; range, 2 to 15 days) of severe neutropenia. Nonhematopoietic toxicity was rare and did not recur in the same patient with subsequent treatment. The cyclophosphamide and topotecan combination was not highly emetogenic, with only two reported episodes of grade 3 emesis, and was in many cases delivered as an outpatient. In this study, as in the previous phase I trial, the skin rash that is frequently reported with high-dose topotecan administration was not reported. We conclude that the combination of topotecan and cyclophosphamide is active in pediatric rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma. Occasional responses were seen in osteosarcoma, and stabilization of this disease was frequent and occasionally long-lasting. The therapy is well tolerated and may be given as an outpatient. We recommend that the topotecan and cyclophosphamide combination be considered for inclusion into phase III trials in rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma. Consideration might also be given to the evaluation of cyclophosphamide (and other alkylating agents) in combination with other effective schedules of topotecan administration, such as the daily x 3, (daily x 5) x 2, and daily x 21 schedules that have been previously tested in pediatric malignancies.12,16-19
Supported in part by National Cancer Institute grant nos. CA 29691, CA 07431, CA 20549, CA 28476, CA 35587, CA 11233, CA 32053, CA 69428, CA 30969, CA 29139, CA 29293, CA 33603, CA 25408, CA 15089, CA 53128, and CA 05587.
1. Slichenmeyer WJ, Rowinsky EK, Donehower RC, et al: The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85: 271-291, 1993 2. Liu LF: DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem 38: 351-375, 1989 3. Sinha BK: Topoisomerase inhibitors: A review of their therapeutic potential in cancer. Drugs 49: 11-19, 1995[Medline] 4. Rowinsky EK, Kaufmann SH: Topotecan in combination chemotherapy. Semin Oncol 24: 11-26, 1997
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Murren JR, Anderson S, Fedele J, et al: Dose-escalation and pharmacodynamic study of topotecan in combination with cyclophosphamide in patients with refractory cancer. J Clin Oncol 15: 148-157, 1997 6. Saylors RL, Stewart C, Wall DA, et al: Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: A Pediatric Oncology Group study. J Clin Oncol 16: 945-952, 1998[Abstract] 7. Kushner BH, Kramer K, Meyers PA, et al: Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol 35: 468-474, 2000[Medline] 8. Kepner JL, Chang MN: Legalized peeking in tests about a binomial proportion. Gainesville, FL, University of Florida Department of Statistics Technical Report, 2000 9. Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Ped Hematol/Oncol 20: 315-318, 1998 10. Meyer WH, Breitfeld PP, Lyden ER, et al: The drug pair, topotecan/cyclophosphamide, is active in previously untreated rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. Proc Am Soc Clin Oncol 10: 582a, 2000 (abstr 2288) 11. Thompson J, Stewart C, Zamboni W, et al: Systemic exposure to topotecan related to antitumor response in human neuroblastoma xenografts. Proc Am Assoc Cancer Res 38: A2043, 1997 (abstr 2043)
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Zamboni WC, Stewart CF, Thompson J, et al: Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90: 505-511, 1998 13. Giovanella B, Potmesil M, Wall ME, et al: Treatment of human cancer xenografts with camptothecin analog in combination with cytoxan or X-irradiation. Proc Am Assoc Cancer Res 35: 454, 1994 (abstr 2711) 14. Coggins CA, Elion GB, Houghton PJ, et al: Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41: 485-490, 1998[Medline] 15. Castellino RC, Elion GB, Keir ST, et al: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts. Cancer Chemother Pharmacol 45: 345-349, 2000[Medline] 16. Santana V, Zamboni W, Gajjar A, et al: Pharmacokinetically-guided use of topotecan (TPT), given (daily x 5) x 2, in children with relapsed solid tumors. Proc Am Soc Clin Oncol 19: 511a, 1997 (abstr 1839)
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Blaney SM, Needle MN, Gillespie A, et al: Phase II trial of topotecan administered as a 72-hour continuous infusion in children with refractory solid tumors: A collaborative Pediatric Branch—National Cancer Institute, and Children’s Cancer Group Study. Clin Cancer Res 4: 357-360, 1998 18. Herben VM, ten Bokkel Huinik WW, Schot ME, et al: Continuous infusion of low-dose topotecan: Pharmacokinetics and pharmacodynamics during a phase II study in patients with small-cell lung cancer. Anticancer Drugs 9: 411-418, 1998[Medline]
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Frangoul H, Ames MM, Mosher RB, et al: Phase I study of topotecan administered as a 21 day continuous infusion in children with recurrent solid tumors: A report from the Children’s Cancer Group. Clin Cancer Res 5: 3956-3962, 1999 Submitted May 17, 2000; accepted April 19, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
