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© 2001 American Society for Clinical Oncology Up-Front Window Trial of Topotecan in Previously Untreated Children and Adolescents With Metastatic Rhabdomyosarcoma: An Intergroup Rhabdomyosarcoma StudyFrom the Intergroup Rhabdomyosarcoma Study Group representing the Children’s Cancer Group, the Pediatric Oncology Group, and the Intergroup Rhabdomyosarcoma Statistical Office, Arcadia, CA. Address reprint requests to Intergroup Rhabdomyosarcoma Study Group Operations Office, Children’s Oncology Group, 440 E Huntington Dr, No 300, PO Box 60012, Arcadia, CA 91066-6012; email jleeson{at}nccf.org
PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m2 of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m2, dactinomycin 1.5 mg/m2, and cyclophosphamide 2.2 g/m2 (VAC) and vincristine 1.5 mg/m2, topotecan 0.75 mg/m2 daily x 5, and cyclophosphamide 250 mg/m2 daily x 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.
RHABDOMYOSARCOMA (RMS) is the most common soft tissue sarcoma in children and adolescents (approximately 350 cases each year in the United States).1 With the use of contemporary multiagent chemotherapy, radiotherapy, and surgery, more than 70% of children with local or regional RMS can be cured.2,3 Unfortunately, outlook remains poor for patients who have metastatic disease at diagnosis, despite the addition of new agents and intensification of therapy with known active agents.2 The rapid identification and testing of promising new therapies is urgently needed to improve the outcomes of children with disseminated disease. To identify potentially active agents, the Intergroup Rhabdomyosarcoma Study Group (IRSG) used an up-front window approach to treatment, giving new agent(s) before conventional chemotherapy to assess the activity of the investigational drug(s). The aim is to assess the antitumor activity of the new agent before the onset of multidrug resistance. This approach has successfully identified active agents such as melphalan, which failed to show activity in traditional phase II trials.4,5 The antitumor activity of camptothecins has been recognized for more than 30 years.6 However, their severe toxicity profile (myelosuppression, gastrointestinal toxicity, and hemorrhagic cystitis) precluded their further development until recently. The unique mechanism of action of these agents—inhibition of the enzyme DNA topoisomerase I—has now aroused renewed interest. Topoisomerase I inhibitors cause lethal DNA damage during replication.6,7 Two camptothecin derivatives, topotecan and irinotecan, have proved to be effective compounds for treating human cancer. Topotecan is an active molecule that is eliminated largely by the kidneys. Significant objective responses have been obtained in preclinical studies of colon carcinoma, ovarian carcinoma, human soft tissue sarcomas, RMS, neuroblastoma, osteosarcoma, and brain tumors.7,8 Moreover, studies in xenograft models of human tumors have shown that the antitumor activity is highly dependent on dose and schedule.6 Responses are most frequent when topotecan is given daily at low doses for protracted periods of time. The dose-limiting toxicity is bone marrow suppression, especially neutropenia and thrombocytopenia. However, bone marrow recovery is relatively rapid (10 to 14 days). Mild nausea without vomiting is observed in some patients. No cumulative toxicity was observed in phase I studies in which most patients were heavily pretreated. Given the promising results observed in these models and the unique mechanism of action, the IRSG developed an up-front window trial to evaluate the efficacy and toxicity of topotecan in children with metastatic RMS and undifferentiated sarcoma and to assess whether it could be safely used with conventional multiagent, multimodal therapy.
Patients Patients were eligible for study entry if they were younger than 21 years of age and had newly diagnosed, histologically proven metastatic RMS or undifferentiated sarcoma. Patients with parameningeal tumors with extracranial extension who required irradiation at day 0 and pregnant and/or lactating females were not eligible. Protocol treatment was required to begin within 42 days of the definitive surgical procedure (eg, biopsy); patients must have had measurable residual disease and have received no prior chemotherapy (except corticosteroids) or radiation therapy. Patients were required to have normal organ function (creatinine < 1.2 mg/mL; bilirubin < 1.5 mg/dL; absolute neutrophil count [ANC] > 1,500/µL; platelets > 150,000/µL) unless infiltrated by tumor. All patients and/or parent/guardians signed informed consent after institutional review board approval.
Treatment Plan
Radiotherapy (RT) for local disease control started at week 15 of therapy. Dactinomycin was not given during RT. Patients received conventional or fractionated RT to all sites of known disease (except bone marrow) at the time of diagnosis. The volume encompassed the extent of disease before the initiation of chemotherapy plus a 2-cm margin (if possible). Gross disease received 50.4 Gy and microscopic residual disease received 41.4 Gy, both doses given in 1.8-Gy daily fractions. Radiotherapy was stopped in the event of uncontrolled infection and an ANC of less than 750/µL and/or platelet count of less than 75,000/µL. Radical surgery was not recommended unless total removal could be performed without significant loss of function, disfigurement, and delay in initiating systemic treatment. If there was proven residual disease 3 to 6 months after radiation therapy and if there was no residual unresectable disease elsewhere, then aggressive resection was encouraged. In those patients with single pulmonary metastatic disease at diagnosis, biopsy proof of tumor was recommended.
Toxicity and response were documented at the end of each phase of therapy. Any unexpected toxicity
Definition of Response
Statistical Considerations
From October 1994 through November 1, 1996, 50 patients were registered on study. Two were found to be ineligible (one was misdiagnosed and one was found to not have metastatic disease). The characteristics of the 48 eligible patients are depicted in Table 1. The median age at diagnosis was 10 years (range, 0 to 19). Almost one half of the patients had alveolar RMS and 83% had tumors of more than 5 cm in diameter. Major sites of metastatic disease at diagnosis included: lung (n = 21), bone (n = 21), regional nodes (n = 21), distant nodes (n = 18), bone marrow (n = 12), pleural effusion (n = 11), ascites (n = 8), and liver (n = 2). More than 80% of these patients had two or more metastatic sites at the time of diagnosis.
Response and Toxicity to Topotecan Window Therapy The overall response to topotecan was 46% (95% CI, 31% to 61%). The rates of CR and PR were 4% (95% CI, 0.5% to 14%) and 42% (95% CI, 28% to 57%), respectively. Six patients (12%) did not respond to therapy, and 14 (29%) had progressive disease while receiving window therapy. Responses to topotecan differed by histologic subtype: 65% (95% CI, 43% to 84%) of patients with alveolar RMS responded to topotecan, whereas only 28% (95% CI, 8% to 58%) of children with embryonal RMS had responses (Table 2, P = .08). Response to topotecan did not seem to be dependent on the dose used (P = .61).
Seven patients received topotecan at a starting dose of 2.0 mg/m2 without G-CSF support. Four of these experienced grade 4 neutropenia and one developed coagulase-negative staphylococcal bacteremia. One patient died 26 days after the first dose of topotecan from adult respiratory distress syndrome. This episode could not be attributed with certainty to the administration of topotecan. One patient at this dose level received an increased dose of topotecan 2.4 mg/m2 during the second course of window therapy; no significant toxicities were observed. Sixteen patients received 28 courses of topotecan at an initial dose of 2.0 mg/m2 with G-CSF. Three received 2.4 mg/m2 during their second topotecan cycle. Grade 3 or 4 neutropenia occurred in 11 patients; grade 3 or 4 thrombocytopenia in three, and grade 3 or 4 anemia in seven. Other relevant toxicities encountered at this dose level included bacteremia (n = 2; coagulase-negative staphylococci and corynebacterium), rash (n = 1), hypokalemia (n = 1), hypophosphatemia (n = 1), and urinary tract infection (n = 1). Twenty-five patients received 45 courses of topotecan at a dose level of 2.4 mg/m2 with G-CSF support. Two of these inadvertently received an increased dose of topotecan (2.9 and 3.0 mg/m2) during the second cycle. Grade 3/4 neutropenia was documented in 18 patients. Other grade 3/4 toxicities included anemia (n = 7), fever and neutropenia (n = 6), and thrombocytopenia (n = 4). Rash (n = 3) and bacteremia (n = 1) were also observed. One patient died 14 days after the first dose of topotecan from rapidly progressive disease. Another died 14 days after the second dose of topotecan from tracheobronchitis and interstitial pneumonitis, having had an objective response after the first dose of topotecan. Twenty-one patients had tumor involvement of bone marrow, pleural fluid, or ascitic fluid at the time of diagnosis. The incidence of hematologic toxicity (specifically grade 4 neutropenia) was not significantly different for patients with or without evidence of bone marrow or pleural/ascitic fluid involvement with tumor. The response rates were higher than in other patients but this could be explained on the basis of a higher number of patients with alveolar RMS in the group without a positive bone marrow or effusion.
Response and Toxicity to Continuation Therapy
Outcome
Estimates of FFS and survival were significantly related to the number of metastatic sites present at the time of diagnosis. For patients with one or two metastatic sites at diagnosis, 2-year FFS was 33% (95% CI, 13% to 53%) and 2-year survival was 62% (95% CI, 41% to 83%). For patients with three or more metastatic sites, 2-year FFS was 16% (95% CI, 2% to 30%) and 2-year survival was 32% (95% CI, 13% to 50%).
This trial has clearly identified topotecan as a new active agent in pediatric RMS. Nearly one half of all patients with previously untreated metastatic disease responded with a PR or CR to this agent, and toxicity was tolerable and manageable, consisting primarily of myelosuppression when used alone and in combination with conventional therapy. For several years, the IRSG has used an up-front window approach to test promising new agents identified in the preclinical xenograft model.5 This method of drug evaluation may optimize assessment of the activity of new agents in patients whose tumors have not become drug-resistant because of extensive pretreatment. This approach has been used to identify several potential active agents for treating RMS and other malignancies, such as small-cell lung cancer and osteosarcoma. Its advantages and potential applications are demonstrated by the high level of activity of topotecan produced in our trial, as compared with the complete absence of tumor responses observed when 22 previously treated children with RMS received a similar topotecan regimen in a classic phase II trial.12 When used in combination with the xenograft tumor model, which often provides useful information about the potential efficacy of new agents, this approach allows identification of new active agents and permits generation of data regarding their safety when used with conventional therapy. Such information is essential before incorporation of new agents into randomized phase III trials in which the new agent’s potential impact on survival can then be evaluated. In mice-bearing childhood solid tumor xenografts, camptothecin analogs have proved to be among the most active anticancer drugs evaluated to date.7 These agents have a unique mechanism of action: inhibition of the enzyme, topoisomerase I, thus preventing relegation of topoisomerase I mediated single-strand breaks.6 This process leads to a collision model in which the replication fork and the drug-stabilized single-strand break results in double-strand breaks and apoptosis. Topotecan was selected for further testing in this trial because of its unique mechanism of action and its high level of activity in xenograft models of childhood RMS and colon carcinoma.6,8 The dose and schedules used in this trial (daily x 5) were adopted from adult clinical trials and directly from a Pediatric Oncology Group phase I study in which the maximum-tolerated dose was defined as 2.0 mg/m2 daily x 5 in patients with refractory solid tumors.9 The clinical implications of the camptothecin’s schedule dependency in preclinical studies was unknown at the time the present trial opened and there was no phase I data using alternative schedules of drug administration available.13,14 Thus the method of drug delivery (daily x 5 x 2) proposed by Houghton et al13 was not incorporated into this trial. However, the current IRSG-V study incorporates this schedule in its front-line irinotecan protocol for the treatment of children with metastatic RMS.15 The toxicity of topotecan in this trial was largely hematopoietic, often causing grade 3 or 4 neutropenia. This effect was manageable with growth factor support; a similar toxicity profile has been reported in other trials using similar schedules.9,14 An unexpected finding in our study was the higher response rate of patients with alveolar RMS (65%) than that observed in patients with embryonal RMS (28%). The reasons for the potential difference in response for alveolar versus embryonal histiotypes of RMS remain unknown. It should be noted that this study was not designed to examine tumor response rates by histiotype, and thus our findings should be viewed as interesting but tentative. Because tumor response rates to single known active agents (eg, vincristine, dactinomycin, cyclophosphamide, doxorubicin, and ifosfamide) have varied between 27% to 86% historically,16-21 we conclude that this agent is sufficiently active against both major histiotypes of RMS to warrant its inclusion in multiagent, multimodal phase III studies. Its novel mechanism of action and likely additive or synergistic effects when given with alkylating agents or vincristine make it especially attractive for further study.22-24 In this trial, the use of topotecan as a single agent before the institution of conventional therapy (VAC) did not seem to jeopardize the rate of survival or of response to subsequent therapy. Our aim in using topotecan in combination with cyclophosphamide and vincristine was to determine the feasibility and safety of this drug combination before evaluating its clinical activity in a prospective randomized phase III trial. Because our study was not designed to demonstrate the potential benefit of topotecan therapy on survival, it is not surprising that we could not show such an effect in the limited patient population presented here. The precise role of camptothecin analogs in the treatment of childhood RMS is prospectively being evaluated in IRSG-V. Patients with metastatic disease will receive a window of irinotecan, a camptothecin analog using a low-dose protracted course as suggested by the xenograft model. Patients with nonmetastatic alveolar-histology tumors and those with unresected embryonal tumors in unfavorable locations will be randomized to receive standard VAC therapy or VAC alternating with VTC. It is hoped that this study will define the potential contribution of topotecan on survival in children with RMS and will help clarify the apparent histiotype-specific activity of this drug in childhood RMS. Our results suggest that preclinical xenograft models of human RMS are able to predict the clinical activity of candidate drugs and can help to identify the dosage and schedule of administration that will produce optimal clinical activity. The high level of activity of topotecan in our study provides a rationale for its incorporation into the front-line therapy of RMS in IRSG-V.
APPENDIX
Supported by grant nos. CA24507 and CA72989 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, and American-Lebanese-Syrian Associated Charities, Memphis, TN.
Members of the Intergroup Rhabdomyosarcoma Study Group are included in the Appendix.
1. Gurney JG, Young JL, Roffers SD, et al: Soft tissue sarcomas, in Gloeckler LA, Smith MA, Gurney JG et al (eds): SEER Pediatric Monograph Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. Bethesda, MD, National Cancer Institute, 1999, pp 111-124
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Crist W, Gehan EA, Ragab AH, et al: The third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13: 610-630, 1995
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Baker S, Anderson JR, Link MP, et al: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18: 2427-2434, 2000 4. Horowitz ME, Etcubanas E, Christensen ML, et al: Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: A model for anticancer drug development. J Clin Oncol 6: 308-314, 1988[Abstract] 5. Houghton PJ, Shapiro DN, Houghton JA: Rhabdomyosarcoma: From the laboratory to the clinic. Pediatr Clin North Am 38: 349-364, 1991[Medline] 6. Stewart C, Zamboni W, Crom W, et al: Topoisomerase I interactive drugs in children with cancer. Invest New Drugs 14: 37-47, 1996[Medline] 7. Thompson J, Stewart C, Houghton P: Animal models for studying the action of topoisomerase-I targeted drugs. Biochim Biophys Acta 1400: 301-319, 1998[Medline] 8. Houghton PJ, Chesire PJ, Myers L, et al: Evaluation of 9-dimethyaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31: 229-239, 1992[Medline] 9. Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 18: 352-361, 1996[Medline] 10. Simon R, Wittes RE: Methodologic guidelines for reports of clinical trials. Cancer Treatment Reports 69: 1-3, 1985[Medline] 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 12. 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 Pediatr Hematol Oncol 20: 315-318, 1998[Medline] 13. Houghton P, Chesire PJ, Hallman J, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low doses in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36: 393-403, 1995[Medline] 14. Santana VM, Zamboni WC, 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 15: 511a, 1997 (abstr 1839) 15. Furman W, Stewart C, Pratt C, et al: A phase I study of irinotecan (CPT-11) in children with relapsed solid tumors. Proc Am Soc Clin Oncol 17: 187a, 1998 (abstr 721) 16. Pappo AS, Etcubanas E, Santana VM, et al: A phase II trial of ifosfamide in previously untreated children and adolescents with unresectable rhabdomyosarcoma. Cancer 71: 2119-2125, 1993[Medline] 17. Sutow WW: Cyclophosphamide (NSC-26271) in Wilms, tumor and rhabdomyosarcoma. Cancer Chemother Rep 51: 407-409, 1967 18. Tan C, Etcubanas E, Wollner N, et al: Adriamycin: An antitumor antibiotic in the treatment of neoplastic diseases. Cancer 32: 9-17, 1973[Medline] 19. Selawry OS, Holland JF, Wolman IJ: Effect of vincristine (NSC-67574) on malignant solid tumors in children. Cancer Chemother Rep 52: 497-500, 1968[Medline]
20.
Sutow WW, Berry DH, Haddy TB, et al: Vincristine sulfate therapy in children with metastatic soft tissue sarcoma. Pediatrics 38: 465-472, 1966 21. Shaw RK, Moore EW, Mueller PS, et al: The effect of actinomycin D on childhood neoplasms. Am Med Assoc J Dis Child 99: 96-103, 1960 22. Meyer WH, Breitfeld P, Lyden ER: The drug pair, topotecan/cyclophosphamide, is active in previously untreated rhabdomysarcoma (RMS): A Report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proc Am Soc Clin Oncol 19: 582a, 2000 (abstr 2288)
23.
Thompson J, George EO, Poquette CA, et al: Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. Clin Cancer Res 5: 3617-3631, 1999 24. Saylors RL, Stewart CF, Zamboni WC: 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] Submitted May 3, 2000; accepted August 2, 2000. 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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TOP
ABSTRACT
INTRODUCTION
grade 3 after the topotecan window was reported to the IRSG chair, and a United States Food and Drug Administration Adverse Drug Reaction Report was to be completed and submitted to the IRSG chair and the National Cancer Institute. 
