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Journal of Clinical Oncology, Vol 22, No 20 (October 15), 2004: pp. 4119-4126 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.174 Response to Paclitaxel, Topotecan, and Topotecan-Cyclophosphamide in Children With Untreated Disseminated Neuroblastoma Treated in an Upfront Phase II Investigational Window: A Pediatric Oncology Group StudyFrom the Department of Pediatrics, Boston Floating Hospital for Infants and Children, Boston, MA; Department of Hematology/Oncology, Children's Memorial Medical Center at Chicago, Chicago, IL; Department of Radiation Oncology, Midwest Children's Cancer Center, Milwaukee, WI; Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT; Department of Radiation Oncology, Children's Healthcare of Atlanta at Egleston, Atlanta, GA; Department of Surgery, University of Texas Southwestern, Dallas, TX; Children's Oncology Group Statistics Department, University of Florida, Gainesville, FL; and the Department of Pediatric Hematology/Oncology, University of Alabama, Birmingham, AL Address reprint requests to Cynthia S. Kretschmar, MD, Boston Floating Hospital for Infants and Children, Department of Pediatrics, Division of Pediatric Oncology, 750 Washington St, Box 14, Boston, MA 02111; e-mail: ckretschmar{at}tufts-nemc.org
PURPOSE: Most children older than 1 year of age with metastatic neuroblastoma (NB) die despite intensive chemotherapy and bone marrow transplantation. The Pediatric Oncology Group conducted a study of paclitaxel, topotecan, and topotecan-cyclophosphamide (topo-cyclo) in newly diagnosed children with stage IV NB. PATIENTS AND METHODS: There were 102 patients enrolled between September 1993 and October 1995; two of them were later shown to be ineligible. Of the remaining 100 patients, the first cohort of 33 patients received paclitaxel 350 mg/m2 intravenously (IV) over 24 hours every 14 to 21 days; the next 33 patients received topotecan 2 mg/m2/d for 5 days IV every 21 days; a third cohort of 34 patients were treated with IV cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 each day for 5 days every 21 days. Patients were re-evaluated after two courses and then treated with intensive induction therapy and bone marrow transplantation. RESULTS: Objective responses (complete response + partial response + mixed response) were documented in 67% of children who received topotecan, 76% after topo-cyclo, and 25% after paclitaxel. Four patients had grade 3 to 4 allergic reactions to paclitaxel; most patients developed grade 3 to 4 marrow suppression after topotecan or topo-cyclo. Neither disease-free survival nor overall survival differed significantly between children who received a phase II agent and those who did not. The 6-year disease-free survival and overall survival rates for all 100 children were 18% ± 5% and 26% ± 5%, respectively. CONCLUSION: Topotecan and topo-cyclo are active in children with NB, are well tolerated, and should be evaluated further in combination regimens.
Neuroblastoma is the most common extracranial solid malignancy of childhood, and most patients have metastatic disease at diagnosis. Long-term disease-free survival (DFS) for children with advanced neuroblastoma (International Neuroblastoma Staging System [INSS] stage IV) has improved from less than 10% in conventional chemotherapy studies before the mid-1980s,1-3 to approximately 25% in ablation chemotherapy and autologous marrow transplant trials over the past decade.4-7 Two recent trials of high-dose therapy with marrow rescue have reported improved event-free survivals of 34% at 3 years8 and 29% at 7 years9 for patients who initially responded to induction chemotherapy. Antiproliferative therapies, such as retinoic acid8,10 and anti-GD2 monoclonal antibody,11,12 have also shown to benefit children with minimal residual disease; however, most children with stage IV neuroblastoma still succumb to their disease, which necessitates the search for new therapies. The Pediatric Oncology Group (POG) showed that administering phase II therapy to untreated patients with high-risk tumors is a sensitive and safe method to assess new agents without compromising outcome.13,14 From March 1994 to November 1995, POG undertook successive new-agent studies of paclitaxel, topotecan, and combination topotecan-cyclophosphamide (topo-cyclo) given to newly diagnosed stage IV patients as primary chemotherapy for two courses in an upfront phase II window followed by re-evaluation of all disease (POG 9340). Children subsequently were treated with induction chemotherapy (POG 9341) followed by autologous bone marrow transplant (ABMT; POG 9342); those with refractory disease during phase II therapy began induction therapy immediately at investigator discretion. The first phase II agent evaluated was paclitaxel, which has activity in adult malignancies such as breast and ovarian cancer.15,16 Paxlitaxel's ability to promote rigidity in the microtubule network causes resistance to depolymerization and inhibits cell replication in G2 and M phases.17 Because this inhibition is similar to the effect on cellular assembly caused by vincristine, paxlitaxel was chosen for phase II evaluation despite a lack of preclinical or relapsed data in childhood neuroblastoma. Topotecan, a topoisomerase I inhibitor and water-soluble analog of camptothecin, was chosen as the second phase II agent because of early clinical responses noted in children with neuroblastoma treated in the phase I trials.18,19 The combination of topotecan and cyclophosphamide was chosen for the third patient cohort because of preclinical reports of synergistic stabilization of topoisomerase I-DNA adducts formed after cyclophosphamide-induced DNA damage.20 POG's phase I trial of this combination included two patients with neuroblastoma who achieved complete response (CR) or partial response (PR).21
Eligible patients were from 1 to 21 years of age and had untreated INSS stage IV neuroblastoma. Patients underwent staging evaluations with computed tomography (CT) scan or magnetic resonance imaging of primary site disease, bone scan, skeletal survey, bone marrow aspirate and biopsy, serum ferritin, urine catecholamines, and renal and liver function studies. Pathology was confirmed by central review of initial primary biopsy or marrow positive for neuroblastoma cells with elevated urine catecholamines (homovanillic and vanillylmandelic acid). MYCN amplification studies were performed in POG reference laboratories on primary tumor tissue or bone marrow obtained at diagnosis. MYCN copy number was determined by Southern blot analysis using standard methodology22 in tumor samples obtained before July 1993, which were studied at least in duplicate, and copy numbers of amplified samples (> three gene copies) were determined by serial dilution and laser densitometry (KLB-Ultroscan SL; Pharmacia LKB, Piscataway, NJ). After July 1993, fluorescent in situ hybridization was used to determine amplification (> 10 copies) using described methods.23Written informed consent was obtained according to National Cancer Institute guidelines after local institutional review board approval. Response status was assessed after two courses of phase II therapy according to INSS criteria24 Responses were measured and submitted by the institutional investigators. Patients who achieved a mixed response (MR) were included as responders for the purpose of evaluating possible activity after two cycles of each phase II agent. If disease progression was suspected, and confirmed, at any time during the phase II window, patients could proceed directly to induction chemotherapy on POG 9341.
Treatment
Toxicities during the phase II window were managed such that a 25% dose reduction in the second course was required for: grade 4 hematopoietic toxicity associated with sepsis or life threatening hemorrhage, or treatment delay of greater than 1 week; grade 3 neurologic myalgias or arthralgias from paxlitaxel; and grade 4 mucositis or diarrhea, or a delay of greater than 1 week. The study coordinator was to be notified immediately for all such toxicities. Paxlitaxel was to be discontinued for any grade 3 toxicity, and the study coordinator and the POG Executive Officer were to be notified. For all other grade 3 toxicities, phase II therapy was to be held pending immediate discussion with the study coordinator and POG Executive Officer. After completion of the POG 9340 phase II window, patients were registered on POG 9341 for intensive multi-agent induction therapy with second-look surgery and local radiation therapy, to be followed by ablation chemotherapy with purged marrow rescue on POG 9342.
Statistical Methods Descriptive analyses of response rates and toxicity rates were performed. Inferential analyses of DFS and overall survival (OS) were performed using a log-rank test to compare the phase II window treatment groups. Because treatment groups were not randomized, it was not possible to determine whether differences in survival rates were caused by the treatments alone. The outcome for all patients who received phase II window therapy (N = 100) also was compared with the outcome of the 40 patients who would have met eligibility criteria for POG 9340 but enrolled directly on POG 9341, either due to temporary closure of the window (n = 18) or parent or physician preference (n = 22). Because of concern regarding selection bias, whereby these 22 patients might have skipped the phase II window because of more advanced disease, the DFS and OS curves for the two non-window groups were compared using a log-rank test. The DFS and OS curves were not found to be statistically significantly different (P = .458 and P = .663, respectively), and analysis proceeded using a single combined group of non-window patients (n = 40). The 95% CI on the response rates were calculated using the formula for a normal approximation to the binomial distribution. The Kaplan-Meier method26 was used to estimate the 6-year DFS and OS rates, expressed as the rate ± SE. Duration of OS was calculated from study entry date to date of death. If the patient did not die, then the date of last reported contact was used. Duration of DFS was calculated from study entry date to date of the earliest of these events: relapse, progressive disease, secondary malignancy, or death. If the patient experienced none of these events, then date of last reported contact was used. P values < .05 were considered to be statistically significant, though the critical value was lower for the pair-wise comparisons of treatment groups, after a Bonferroni adjustment was applied for multiple comparisons.
Patient characteristics are shown in Table 2. One hundred two patients were registered on POG 9340 between September 1993 and October 1995. Two patients lacked pathologic confirmation of neuroblastoma and were ineligible, leaving 100 eligible patients.
In the phase II window cohort, there were 46 females and 54 males, with a median age at diagnosis of 3 years 4 months (range, 13 months to 17 years 8 months). Fifty-nine children had adrenal primary tumors, 29 retroperitoneal, four pelvic, seven mediastinal, and one unknown primary. Ninety-one children had bone scans positive for metastatic disease, 86 had marrows positive for neuroblastoma cells, 38 had distant nodal disease, 13 had liver and an equal number had lung or pleural involvement, seven had cranial bone metastases, and one patient each had scalp metastases, contralateral adrenal tumor, and opsoclonus-myoclonus. Fifty-six patients had an initial biopsy of the primary tumor or of involved nodal disease; eight children underwent gross total resection and two children partial resection of the primary tumor mass; and 34 children had central review of marrow biopsy in conjunction with elevated urine catecholamines. Analysis of amplification of MYCN was performed on tumor specimens from 87 of the 100 eligible patients and was amplified in tumors from 26 patients and not amplified in 61.
Response
PD after two courses of paclitaxel was documented by routine evaluations in the primary site (three patients) and/or metastatic sites (six patients). Of the five patients who received only one course, three developed worsening periorbital disease, and one patient each had new nodal or liver disease. After two courses of topotecan, progressive disease was documented by routine evaluations in the primary site (two patients) and/or metastatic sites (five patients). One child developed PD on bone scan after one course of topotecan and did not receive the second course. The only child with PD receiving topo-cyclo was noted to have increased primary tumor on routine CT scans. In no case were there any delays in starting induction chemotherapy for any of the patients treated with upfront phase II therapy. There was no evidence that lack of response to phase II therapy affected the response to subsequent induction chemotherapy on POG 9341. Of the 24 patients who were nonresponders to paclitaxel, 17 were then treated with POG 9341 induction therapy, and all responded (the other seven were not registered on POG 9341). Similarly, nine of 10 patients who had not responded to topotecan, and five of seven whose disease progressed while they were being treated with topo-cyclo, responded to subsequent therapy on POG 9341.
Toxicity of Phase II Therapy
Topotecan was administered every 21 days to the second group, 22 of whom also received G-CSF; two patients without interim blood work were not assessable for toxicity. As expected, most children had myelotoxicity, including four with transient bacteremia. The only other significant toxicities were in three children who developed mild skin rash thought attributable to topotecan, and in three children who had transient pulmonary infiltrates and dyspnea from a concurrent pneumonic process. Topo-cyclo was administered to 34 patients every 21 days for two cycles followed by G-CSF. Approximately 75% of patients had grade 3 to 4 marrow suppression; fever of unknown origin was more common with longer duration of neutropenia associated with the cyclophosphamide. Because G-CSF was used selectively by treating physicians, hematologic toxicity data should be interpreted with caution. No other unusual toxicities were noted. No patient required a dose reduction at the second course of phase II therapy.
Survival
We also compared DFS and OS for each phase II treatment in a pair-wise fashion. In pair-wise comparisons, DFS and OS rates for these groups were not statistically significantly different from one another, although the DFS curve for topo-cyclo (6-year DFS, 23% ± 12%) was somewhat higher than the DFS curve for paclitaxel (6-year DFS, 9% ± 5%; Figs 2A and B). Similarly, the OS for all 20 patients with PD on the phase II window, which included 12 patients on paclitaxel, seven on topotecan, and one on topo-cyclo, was lower (15% ± 10%) than for the patients who did not progress early (29% ± 6%, n = 78; P = .0231).
Overall, 21 of 33 children who received paclitaxel, 26 of 33 who received topotecan, and 22 of 34 who received topo-cyclo completed ablation chemotherapy with marrow rescue. Because of the unusual triple registration process for this combined study, eight patients who were treated during the early months with paclitaxel were inadvertantly not registered on induction therapy POG 9341 and could not be evaluated for tumor response, progression, or treatment with subsequent bone marrow transplant. Of those 25 paclitaxel patients registered on POG 9341, five patients were identified who had responded and were eligible for POG 9342, but developed new metastatic disease during delays before transplant. Subsequent to the topotecan and topo-cyclo windows, seven of 33 patients and 11 of 34 patients, respectively, developed PD before transplant (one patient's parents refused ABMT). Eight of 40 patients not treated with the phase II window were NR/PD and did not go on to transplant. There was no statistical evidence that phase II window treatment influenced development of PD before transplant.
We found that topotecan and topo-cyclo have significant activity in children with newly diagnosed neuroblastoma when given as a 5-day infusion schedule every 3 weeks. The percent of patients achieving CR/PR was slightly higher in patients treated with topotecan than with topo-cyclo, although the number of patients with frank PD was higher on topotecan (seven patients) versus topo-cyclo (one patient). If patients with MR are included, objective response rates were slightly higher for topo-cyclo (76%) than for topotecan (67%). This may reflect the lower population of children on topo-cyclo with blast-positive marrows (85%) or with MYCN amplification (25%) than for children treated with topotecan alone (89% and 33%, respectively) or with paclitaxel (97% and 31%, respectively). It should be noted that any comparison of response results must be interpreted cautiously as the study was not powered to detect differences between the two regimens. Toxicity on the topotecan regimens was mainly limited to expected marrow suppression. Paclitaxel was found active in only 25% of patients, with four children having allergic or anaphylactic reactions. The poor response rate for paclitaxel mandates that future phase II window studies consider only agents that have shown disease-specific activity in the preclinical or relapsed setting. While the paclitaxel response rate was not trivial in terms of phase II single-agent activity, the comparative results of this study indicate that addition of paclitaxel is unlikely to improve response in current multi-agent regimens. Topotecan stabilizes the DNA-topoisomerase I covalent complex created during DNA replication, such that the collision of the advancing DNA replication forks with the drug-enzyme-DNA complex produces DNA damage that results in cell cycle arrest and cell death. Randomized trials in adults confirmed that a daily for 5 days infusion schedule every 3 weeks had greater activity than either 24- or 72-hour continuous infusion.27,28 A pediatric phase I trial at St Jude Children's Research Hospital (Memphis, TN) evaluated a 72-hour continuous infusion of topotecan, with a maximum tolerated dose of 1 mg/m2/d, and reported only one response among 27 children (CR in a patient with neuroblastoma).19 POG's phase I trial of the 5-day infusion schedule in heavily pretreated patients reported a maximum tolerated dose of 2 mg/m2/d (+G-CSF) with dose-limiting toxicities of neutropenia and thrombocytopenia. Objective responses were seen in three patients, all of whom had neuroblastoma, with an additional two patients who had stable disease for greater than 6 months.20 Phase II pediatric trials of topotecan given as a single 24-hour or 72-hour infusion failed to show significant activity in patients with a variety of solid tumors and CNS malignancies.29-31However, when POG evaluated phase II response in 141 patients treated with the 5-day schedule (2 mg/m2/d), responses were seen in seven of 20 patients with neuroblastoma (two CR, five MR),32 thus supporting the rationale for a 5-day schedule in this study. Because topotecan appears to stabilize topoisomerase I-DNA adducts formed after cyclophosphamide-induced DNA damage, the combination of topo-cyclo may result in synergistic cell killing, possibly augmented by unscheduled DNA synthesis induced by cyclophosphamide.21 After preclinical reports of synergy in rhabdomyosarcoma xenografts,33 POG undertook a phase I study of escalating topotecan in conjunction with cyclophosphamide 250 mg/m2/d over 5 days.21 Neutropenia was the dose-limiting toxicity at 0.75 mg/m2/d + G-CSF with one CR and one PR in patients with neuroblastoma. The Children's Oncology Group (COG) recently has completed a phase II study (POG 9462) comparing response to topotecan alone versus topo-cyclo in patients with relapsed neuroblastoma. The clinical characteristics of patients in the three phase II strata evaluated in this window study were comparable in terms of high-risk features which might affect drug responsiveness. Despite poorer response to paclitaxel, the overall survivals of children treated with or without a phase II agent were not statistically different. Patients with early progression during any of the phase II windows had a lower OS than patients who did not (P = .0231). Overall, the phase II window approach allows for the rapid evaluation of new agents, with no significant risk to children with newly diagnosed advanced-stage disease.13,34,35 A similar phase II window trial of topo-cyclo in untreated children with rhabdomyosarcoma was completed recently by the Intergroup Rhabdomyosarcoma Group36 (now part of the COG). Further evaluation of topotecan has been based in part on preclinical studies of more prolonged dosing schedules that suggest increased sensitivity in neuroblastoma xenografts.37 Since there are numerous reports of prolonged stable disease (6 to 18+ months) in multiple relapsed patients treated with topoisomerase inhibitors,19,20,31,32 several institutions evaluated continuous oral dosing schedules,38,39 as well as a 21-day continuous-infusion regimen.40 Such continuous topotecan regimens may be valuable in the post-ABMT setting of minimal residual disease. Topotecan and topo-cyclo have shown upfront response rates comparable to those reported for ifosfamide (70%) and carboplatin (77%).13 Topotecan should be considered for primary inclusion in multi-agent regimens, or in phase I trials of ablation chemotherapy with stem-cell rescue.41 As a result of the response rates documented in this phase II trial, COG is currently evaluating combination therapies with camptothecin derivatives in trials of solid tumors in children.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Rosen EM, Cassady JR, Frantz CN, et al: Neuroblastoma: The Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Childen's Hospital experience. J Clin Oncol 2: 719-732, 1984[Abstract] 2. Hartmann O, Scopinaro M, Tournade MF, et al: Neuroblastomas treated at the Gustave-Roussy Institute from 1975 to 1979. 173 cases. Arch Fr Pediatr 40: 15-21, 1983[Medline] 3. Shafford EA, Rogers DW, Pritchard J: Advanced neuroblastoma: Improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. J Clin Oncol 2: 742-747, 1984[Abstract] 4. Dini G, Lanino E, Garaventa A, et al: Unpurged ABMT for neuroblastoma: AIEOP-BMT experience. Bone Marrow Transplant 7: 92, 1991 (suppl 2)
5. Pole JG, Casper J, Elfenbein G, et al: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 9: 152-158, 1991 6. Matthay KK: Neuroblastoma: Biology and therapy. Oncology (Huntingt) 11: 1857-1866, 1997 7. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16: 953-965, 1988
8. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341: 1165-1173, 1999
9. Frappaz D, Michon J, Coze C, et al: LMCE3 treatment strategy: Results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 18: 468-476, 2000 10. Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation. J Clin Oncol 13: 894-901, 1995[Abstract] 11. Yu AL, Batova A, Alvarado C, et al: Usefulness of a chimeric anti-GD2 (ch14.18) and G-CSF for refractory neuroblastoma: A POG phase II study. Proc Am Soc Clin Oncol 16: 1846, 1997 (abstr 1846) 12. Yu AL, Uttenreuther-Fischer MM, Huang CS, et al: Phase I trial of a human-mouse chimeric anti-disaloganglioside monoclonal antibody ch14.l8 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol 16: 2169-2180, 1998[Abstract]
13. Castleberry RP, Cantor AB, Green AA, et al: Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 12: 1616-1620, 1994
14. Pappo AS, Lyden E, Breneman J, et al: Upfront window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An Intergroup Rhabdomyosarcoma Study. J Clin Oncol 19: 213-219, 2001 15. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111: 273-279, 1989
16. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83: 1797-1805, 1991
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20. Slichenmyer WJ, Rowinsky EK, Donehower RC, et al: The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85: 271-291, 1993 21. Saylors RL 3rd, Stewart CF, Zamboni WC, 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]
22. Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224: 1121-1124, 1984 23. Shapiro DN, Valentine MB, Rowe ST, et al: Detection of N-myc gene amplification by fluorescence in situ hybridization. Diagnostic utility for neuroblastoma. Am J Pathol 142: 1339-1346, 1993[Abstract]
24. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11: 1466-1477, 1993 25. Gee AP, Graham-Pole J, Lee C, et al: Transplantation for neuroblastoma using immunomagnetically purged autologous marrow, in Dicke KA, Spitzer G, Jagannath S, et al (eds): Proc 3rd Internat Symp Autologous Bone Marrow Transplantation, The University of Texas M.D. Anderson Hospital and Tumor Institute, Houston, TX, 1987, pp. 425-431 26. Kaplan EL, Meier P: Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 27. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 16: 2233-2237, 1998[Abstract] 28. Weitz JJ, Jung SH, Marschke RFJ, et al: Randomized phase II trial of two schedules of topotecan for the treatment of advanced stage non-small cell lung carcinoma (NSCLC): A North Central Cancer Treatment Group (NCCTG) trial. Proc Am Soc Clin Oncol 14: 1053, 1995 (abstr 1053) 29. Blaney SM, Phllips PC, Packer RJ, et al: Phase II evaluation of topotecan for pediatric central nervous system tumors. Cancer 78: 527-531, 1996[CrossRef][Medline] 30. Kadota RP, Stewart CF, Horn M, et al: Topotecan for the treatment of recurrent or progressive central nervous system tumors—a Pediatric Oncology Group phase II study. J Neurooncol 43: 43-47, 1999[CrossRef][Medline]
31. 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 32. 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[CrossRef][Medline] 33. Houghton PJ, Stewart CF, Zamboni WC, et al: Schedule-dependent efficacy of camptothecins in models of human cancer. Ann N Y Acad Sci 803: 188-201, 1996[Medline]
34. Saylors RL 3rd, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A Pediatric Oncology Group phase II study. J Clin Oncol 19: 3463-3469, 2001 35. Harris MB, Cantor AB, Goorin AM, et al: Treatment of osteosarcoma with ifosfamide: Comparison of response in pediatric patients with recurrent disease versus patients previously untreated: A Pediatric Oncology Group study. Med Pediatr Oncol 24: 87-92, 1995[Medline]
36. Waterhouse DO, Lyden ER, Breitfeld PP, et al: Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: A Children's Oncology Group Study. J Clin Oncol 22: 1398-1403, 2004
37. 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 38. Zamboni WC, Bowman LC, Tan M, et al: Interpatient variablilty in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43: 454-460, 1999[CrossRef][Medline]
39. Gerrits CJ, Schellens JH, Burris H, et al: A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin). Clin Cancer Res 5: 69-75, 1999
40. 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 41. Park J, Slattery J, Gooley T, et al: Phase I topotecan preparative regimen for high risk neuroblastoma and advanced pediatric solid tumors. Proc Am Soc Clin Oncol 19: 591, 2000 (abstr 2326) Submitted August 27, 2003; accepted July 27, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
