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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3415-3422 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.9497 Pooled Analysis of Phase II Window Studies in Children With Contemporary High-Risk Metastatic Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group
From the Duke University Medical Center, Durham, NC; University of Nebraska Medical Center, Omaha, NE; University of Oklahoma Health Sciences Center, Oklahoma City, OK; Children's Oncology Group, Arcadia, CA; and the Hospital for Sick Children, Toronto, Ontario, Canada Address reprint requests to Philip P. Breitfeld, MD, Pediatric Hematology-Oncology, Box 2916, Duke University Medical Center, Durham, NC 27710; e-mail: breit003{at}mc.duke.edu
PURPOSE: The Soft Tissue Sarcoma Committee of the Children's Oncology Group has conducted five upfront window trials in patients with newly diagnosed metastatic rhabdomyosarcoma to identify promising new treatment agents. PATIENTS AND METHODS: This pooled analysis identified a total of 420 patients (115 from Intergroup Rhabdomyosarcoma Study III [IRS-III] and 305 from the five window trials). We assessed window therapy response rate, failure-free survival (FFS), and overall survival (OS). RESULTS: Response rates (complete + partial response) assessed at week 6 of window therapy ranged from 41% to 55% and did not predict FFS (P = .073) or OS (P = .31). FFS was influenced by trial (P = .048); patients enrolled onto IRS-III and the ifosfamide/etoposide and ifosfamide/doxorubicin trials fared best. When grouped and compared with topoisomerase I poison trials, ifosfamide/topoisomerase II inhibitor trials had superior FFS (P = .013). However, there was no difference in survival. CONCLUSION: Upfront phase II window trials can efficiently provide robust estimates of activity for new agents and combinations in newly diagnosed patients with high-risk rhabdomyosarcoma. Our data indicate that, for some phase II window trials, the risk of treatment failure may be increased but that the trend towards lower survival for some of the window trials compared with IRS-III is not statistically significant. Window nonresponders did not suffer worse FFS or OS than patients who responded to window therapy. Finally, these results provide a rationale for incorporating ifosfamide, etoposide, doxorubicin, and topoisomerase I poisons in future trials of high-risk metastatic rhabdomyosarcoma.
Phase II window design involves administration of an investigational drug or combination to newly diagnosed patients for a short period (4 to 12 weeks) before standard chemotherapy. This design has been used in populations with high failure rates on standard therapy. Its primary goal is to test new agents in untreated patients who are less likely to have multiple drug–resistant tumors. In 1988, Horowitz et al1 reported that melphalan, which had no activity in a traditional phase II study in heavily pretreated rhabdomyosarcoma patients, was active in newly diagnosed patients with poor-risk rhabdomyosarcoma. Since 1988, phase II window trials have been designed and executed for patients with many pediatric tumors.2-6 Most children with high-risk metastatic rhabdomyosarcoma die of disease, and their outcomes have not improved for 30 years. In the Intergroup Rhabdomyosarcoma Studies (IRS) IRS-I (1972 to 1978), IRS-II (1978 to 1984), and IRS-III (1984 to 1991), strategies for improving these patients' outcomes included cyclophosphamide dose intensification and addition of active agents including doxorubicin, cisplatin, dacarbazine, and etoposide to standard therapy with vincristine, dactinomycin, and cyclophosphamide (VAC).7-9 Still disease-free survival and overall survival (OS) for high-risk rhabdomyosarcoma patients remain disappointingly poor. To rapidly identify new active single agents or combinations of agents and define their toxicity profiles alone and with standard VAC therapy, a series of upfront phase II window studies was conducted.10-13 Starting in 1988, the Intergroup Rhabdomyosarcoma Group (IRSG), now part of the Children's Oncology Group (COG), conducted these studies with high-risk rhabdomyosarcoma patients. Critics argued that the ability of phase II window studies to identify clinically useful new agents has yet to be proven and that participation in a phase II window study places patients at risk compared with initiation of therapy with standard multiagent regimens.14 The purpose of this pooled analysis was to examine the Intergroup Rhabdomyosarcoma Group's initial 12-year experience with the phase II window design and assess how currently defined high-risk patients have fared from IRS-III to present with respect to response rate, failure-free survival (FFS), and OS.
We analyzed five phase II window studies of high-risk rhabdomyosarcoma performed between 1988 and 2000 by pooling individual patient data. These data were compared with data of individual patients treated on IRS-III.9 The six clinical trials (IRS-III trial plus five window trials containing six window regimens) are listed in Table 1.
Eligible patients were younger than 21 years old and had newly diagnosed stage IV/group IV pathologically proven rhabdomyosarcoma or undifferentiated sarcoma. They had to have normal hepatic and renal function and no exposure to chemotherapy or radiotherapy. Those on topoisomerase I poison trials (topotecan [Topo], topotecan/cyclophosphamide [TC], and irinotecan [Irino]) had to have normal bone marrow function, unless there was evidence of bone marrow tumor infiltration. After March 1998, children younger than 10 years old who had embryonal rhabdomyosarcoma were excluded from the high-risk group because they had more favorable outcomes.15 Thus, eligibility for this analysis required either metastatic alveolar rhabdomyosarcoma or metastatic embryonal rhabdomyosarcoma and age  10 years. Chemotherapy regimens in all studies were based on VAC on a 21-day cycle, but components' dosages varied (Table 2). In all studies, dactinomycin was held during radiotherapy. In alkylator window studies (ifosfamide/doxorubicin [ID], ifosfamide/etoposide [IE], and vincristine/melphalan [VM]), response to window therapy was assessed at 6 and 12 weeks. Patients who had no response or progressive disease (PD) at 6 weeks proceeded to VAC alone. After week 12, all patients proceeded to continuation therapy; those who had complete or partial responses at 12 weeks were treated with a VAC regimen that incorporated window agents at week 25 and week 31. The rest received VAC alone. In the topoisomerase I poison window studies (Topo, TC, and Irino), window therapy response was assessed at 6 weeks. Patients who had no response or PD at 6 weeks proceeded to VAC alone, whereas those who had complete or partial responses at 6 weeks were administered a VAC regimen that incorporated window agent(s). In the Topo and TC window trials, the window agent(s) was incorporated in the VAC regimen at weeks 26, 32, and 38. In the Irino window trial, it was incorporated at weeks 9 to 10, 26 to 27, 32 to 33, and 38 to 39.
Response was the primary end point in all studies. Complete response was defined as disappearance of all tumors with no evidence of disease. Partial response was defined as 50% or greater decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no evidence of progression in any lesion, and no new lesions. Objective improvement was defined as 25% or greater decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no evidence of progression in any lesion, and no new lesions. No response was defined as less than 25% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no evidence of progression in any lesion, and no new lesions, or as a steady-state that did not qualify for progression definition. PD was defined as a 25% or greater increase in the sum of the products of the maximum perpendicular diameters of measurable lesions at any involved site and/or appearance of new lesions. For this analysis, patients were classified as window responders if they had complete response or partial response at the end of window therapy. All other patients were classified as window nonresponders. FFS was the interval from enrollment to progression or death. Progression during the upfront window was not an event in this analysis. OS time was the interval from enrollment to death. Estimates of time-to-event distributions were calculated using the Kaplan-Meier method. Comparisons of outcome among patient subsets were made using the log-rank test. A P < .05 was considered statistically significant.
Patient Characteristics Among the six studies (Table 1), 420 patients were eligible. As presented in Table 3, patients were predominantly white, greater than 9 years old, and evenly distributed by sex. The most common tumor sites were the extremities and the retroperitoneum. More than 70% of patients had tumors more than 5 cm, and more than 80% had invasive tumors.
Response to Window Therapy Response to therapy at week 6 in the window studies ranged from 41% to 55% (Table 4). When grouped by type of window agents, trials with alkylating agents (ID, IE, and VM) had response rates from 41% to 55%, and those with topoisomerase I poisons (Topo, TC, and Irino) had similar rates (45% to 50%). PD rates varied widely among the trials. The PD rates were higher for trials of topoisomerase I poisons (T, TC, and Irino) and highest for single-agent trials (Topo and Irino). We also examined deaths during window therapy. There were two treatment-related deaths during ID, two tumor-related deaths on VM, two treatment-related deaths on Topo, and two deaths due to intracranial hemorrhage (one tumor and one nontumor) on Irino. Thus, of the 305 patients enrolled onto phase II window trials, a total of eight patients (2.6%) died from any cause during the window period prescribed by the trial.
Response to VAC in Window Nonresponders Patients whose tumors had no response or progressed during window therapy received VAC as prescribed. Overall, they had a 33% response (21 of 63 patients) to VAC prospectively assessed at weeks 15 (T, TC, and Irino) or 18 (IE and VM; Table 5). Nonresponders to window therapy that did not contain an alkylating agent (Topo and Irino) had higher response rates to subsequent VAC (53% or 11 of 21 patients) than patients whose window therapy did contain alkylating agents (24% or 10 of 42 patients; Table 5; P = .05, Fisher's exact test). It should be noted that the length of window therapy was 12 weeks for the patients who experienced IE and VM failure but 6 weeks for all others. Because data regarding response to VAC after window failure were not prospectively evaluated in the ID trial, this was not included in this analysis.
Chemotherapy Efficacy by Trial When data from all six studies were combined, 4-year estimated FFS rate was 19% (95% CI, 15% to 23%) and 4-year estimated OS rate was 23% (95% CI, 19% to 27%; Fig 1). When the trials were considered separately, a difference in FFS was seen (P = .048), with IRS-III and the ifosfamide-based window (ID and IE) patients faring the best (Fig 2). No statistical difference was seen in OS between trials (Fig 3). When studies combining ifosfamide with a topoisomerase II inhibitor (ID and IE) were grouped and compared with outcomes of the studies involving topoisomerase I poisons (T, TC, and Irino), the topoisomerase II inhibitor studies had superior FFS (P = .013), but no significant difference was observed in OS between these groups of studies (P = .14). When compared with IRS-III, the topoisomerase I poison trials were inferior with regard to FFS (P = .0092), with FFS in the topoisomerase II trials being similar to IRS-III. However, there was no observed significant difference in OS between IRS-III, topoisomerase II inhibitor, and topoisomerase I poison trials (P = .12).
Chemotherapy Efficacy by Window Response Window responders did not seem to have improved FFS (P = .073) or OS (P = .31) compared with nonresponders (Figs 4 and 5). When window responders were analyzed separately, there were no statistically significant differences in FFS or OS between individual trials or when topoisomerase II inhibitor window trials were compared with topoisomerase I poison window trials (data not shown). Similarly, no significant differences by trial or type of trial were observed in FFS or OS for window nonresponders (data not shown).
To our knowledge, this was the largest reported clinical trial experience with upfront window trial design and the largest reported clinical trial experience with metastatic rhabdomyosarcoma. Patients who participated in window therapy had similar outcomes for FFS and OS, regardless of window therapy response. We also found that FFS was slightly better for patients in IE and ID window trials and on IRS-III, where no therapeutic windows were used. The upfront window trial design delays standard regimens for patients who receive window therapy. There has been reasonable concern that this could harm patients in these trials, so we examined the results of our consecutive phase II window studies in metastatic rhabdomyosarcoma patients to shed light on the issue. We did note that certain phase II window trials (VM, Topo, and TC) were associated with an inferior FFS compared with IRS-III, although the survival differences were not statistically significant. We also noted that the highest rates of initial tumor progression during the window portion of therapy were observed in single-agent window trials (Irino and Topo). This suggests that single-agent window studies may pose a greater initial risk to patients than combination studies because of the potential for prolongation of tumor-related symptoms noted at the time of diagnosis. In addition, we found that patients who did not achieve complete or partial responses to therapy had OS similar to patients who achieved at least partial responses. Although this finding supports the safety of window trials in patients with rhabdomyosarcoma, it is somewhat surprising. In this experience, many tumors that did not respond to window therapy failed to respond to VAC therapy (Table 5), suggesting that these tumors may have intrinsic global chemotherapy resistance. Often, pediatric patients with malignancies that are resistant to initial therapies have much poorer overall outcomes, even when many other active agents are administered subsequently.16,17 Finally, although the OS curves for the IRS-III and IE trials seem superior to the other window studies (Fig 3), the differences are not statistically significant. It is possible that a larger study would find these differences statistically significant. Another criticism of the window approach has been that it is unproductive and little has been gained through it. However, the current report amply demonstrates that reliable response data can be captured efficiently for many single agents and combinations in a much shorter span than would be required to conduct similar phase II studies in relapsed patients. Window studies also have demonstrated the predictive capacity of the preclinical xenograft model system.18 Finally, data from these studies have been used to design trials in intermediate- and high-risk rhabdomyosarcoma. The current COG intermediate-risk rhabdomyosarcoma trial (COG D9803), under data monitoring committee review, incorporates the TC combination into the experimental arm. The concept protocol for the next high-risk rhabdomyosarcoma trial incorporates many agents that were active in this series of window studies. Some criticize the window approach in rhabdomyosarcoma because agents active in the window have not improved outcome when added to or substituted for standard therapy. However, to date, the only completed test of this hypothesis in rhabdomyosarcoma is the IRS-IV trial, in which vincristine, ifosfamide, and dactinomycin (VIA) and vincristine plus IE were substituted for VAC.19 Besides substantial activity in the window, IE also had significant activity against rhabdomyosarcoma in standard phase II studies, yet failed to improve outcome in intermediate-risk rhabdomyosarcoma patients when substituted for VAC in the first 28 weeks of therapy.19 It is possible that other study designs incorporating IE in an alternating fashion with standard VAC therapy would lead to different results. Nevertheless, several other agents with substantial activity in the relapse setting, including doxorubicin and cisplatin, also failed to improve outcome in previous IRS studies.9 The comparator trial in this analysis, IRS-III, was in the top tier of outcomes for FFS and OS compared with the window trials. Addition of the window agents to the VAC backbone did not seem to provide additional survival benefit over the regimen used in IRS-III. Nevertheless, these historical comparisons must be interpreted with caution. It is possible that some investigators may have selectively limited entry of more prognostically favorable patients in some window trials. Such patients might have been more likely to enter regimens seen as more mainstream (as with IRS-III) or that incorporated agents with known activity in relapsed rhabdomyosarcoma (ID and IE). If true, studies that included topoisomerase I poisons might have had poorer outcomes simply by nature of patients selected for them. Alternatively, it is possible that some investigators avoided enrollment of unstable patients on single-agent window trials (Topo or Irino) or on trials of agents without known activity in traditional phase II studies (Topo, TC, and Irino). Plans for development of clinical research studies in the COG incorporating topoisomerase I poisons are based, in part, on evidence reported here that exposure/resistance to topoisomerase I poisons does not confer absolute cross resistance to VAC-based therapy. In this analysis, response to subsequent VAC therapy was higher in patients who had no response in topoisomerase I poison window trials than patients who had no response in window trials that contained alkylators. The upfront phase II window design, like traditional phase II designs, uses response rate as a primary outcome. Response rate is used as a surrogate end point for survival benefit. In this analysis of window trials, response to window therapy did not predict improved outcome with regard to FFS or OS. It was reported recently that response at week 8 was not predictive of survival in patients with group III rhabdomyosarcoma.20 Early response to therapy has been predictive of survival outcomes in many other pediatric cancers.21,22 It remains unclear whether increases in survival are directly attributable to early decrease in tumor burden or whether other factors account for association between response and survival in other tumors. It may also be that our current methods of assessing tumor response (ie, computed tomography and magnetic resonance imaging scans) in rhabdomyosarcoma inadequately assess true tumor response to therapy. This pooled analysis was limited by several factors that could have influenced results. The trials were not randomized comparisons; they were also not run concurrently and, instead, conducted over 12 years. Only patients who met the current definition of high-risk disease were included, so other changes over time, such as modification of definition of alveolar rhabdomyosarcoma and changes in detection of metastatic disease could have influenced apparent differences in survival among the trials. In addition, accrual numbers in the individual trials were small, ranging from 20 to 96 patients. This limited our detection of differences in outcomes among trials. Our analysis included phase window trials that tested single as well as pairs of agents. Some researchers have made the distinction that phase II window studies of single agents may pose different safety concerns compared with studies using two or more agents.23 Thus the Topo and Irino trials involving single agents contribute the most to the discussion of the safety and value of single-agent upfront phase II window trials. Furthermore, it can be argued that, if there are no data in humans regarding the activity of a proposed phase II window agent (usually derived from traditional phase II studies in recurrent patients), safety concerns are heightened. For example, ifosfamide,24 etoposide,24 doxorubicin, and melphalan1 were known to be active agents either in traditional phase II studies or in small numbers of newly diagnosed patients with rhabdomyosarcoma when the ID, IE, and VM windows were conceived. However, there were no phase II activity data regarding Topo, the combination TC, or Irino when the respective phase II window studies summarized here were initiated These agents were nevertheless pursued in a phase II window given their known activity in a well-established preclinical model of rhabdomyosarcoma xenografts.1 Our experience with the three window trials initiated without traditional phase II activity data (T, TC, and Irino) potentially shed the most light on safety concerns of phase II window studies. The onus is on the investigator in such settings to provide ample preclinical evidence of activity. Likewise, it is acknowledged that such phase II window studies pose the greatest potential risk to patients. We believe that any phase II window trial must properly inform patients of the potential risks of delaying standard therapies and include a priori monitoring rules for tumor progression, tumor- and nontumor-related death, and agent-specific toxicity. Finally, the observed response rates for the window trials reported here were similar. This begs the question of what is the minimum response rate that would prompt further investigation of the agent in a classic randomized phase III trial. On the basis of best available treatment for high-risk rhabdomyosarcoma, one could argue that response rates of 50% or more and progression rates of 15% or less are reasonable criteria that new agents or combinations must meet for consideration for phase III trials in rhabdomyosarcoma. Nevertheless, as in traditional phase II studies in patients with recurrent tumors, it remains unclear how response data should be used in making decisions about proceeding to phase III trials. Ultimately, the value of this approach will be apparent when active agents identified in this way are found to be effective in randomized phase III trials. Thus, this analysis provides important information about safety of upfront phase II design and activity of agents tested in the 12-year experience with phase II window studies in high-risk rhabdomyosarcoma. Caution should be exercised in extrapolating this experience to other tumor systems, especially those that lack a reliable preclinical model for assessing the activity of candidate new agents.
The authors indicated no potential conflicts of interest.
We acknowledge the work of Drs Sandler and Walterhouse for their primary manuscripts describing the results of certain studies summarized here. We also acknowledge the work of the laboratory of Dr Peter Houghton. This work established the scientific rationale for many of the window studies described here.
A complete listing of grant support for research conducted by the Children's Cancer Group and Pediatric Oncology Group before initiation of the Children's Oncology Group grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm. The D9802 study of irinotecan was supported in part by a grant from Pharmacia. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Kadota RP, Kun LE, Langston JW, et al: Cyclophosphamide for the treatment of progressive low-grade astrocytoma: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 21:198-202, 1999[CrossRef][Medline] 6. 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 7. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study-I: A final report. Cancer 61:209-220, 1988[CrossRef][Medline] 8. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71:1904-1922, 1993[CrossRef][Medline] 9. Crist W, Gehan EA, Ragab AH, et al: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13:610-630, 1995 10. Breitfeld PP, Lyden E, Raney RB, et al: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: A report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23:225-233, 2001[CrossRef][Medline] 11. Pappo AS, Lyden E, Breneman J, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An intergroup rhabdomyosarcoma study. J Clin Oncol 19:213-219, 2001 12. Sandler E, Lyden E, Ruymann F, et al: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37:442-448, 2001[CrossRef][Medline] 13. Walterhouse 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 14. Smith MA, Anderson B: Phase II window studies: 10 years of experience and counting. J Pediatr Hematol Oncol 23:334-337, 2001[CrossRef][Medline] 15. Anderson JR, Ruby E, Link M, et al: Identification of a favorable subset of patients (pts) with metastatic (MET) rhabdomyosarcoma (RMS): A report from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Proc Am Soc Clin Oncol 16:510a, 1997 (abstr 1836) 16. Silverman LB, Gelber RD, Young ML, et al: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85:1395-1404, 1999[CrossRef][Medline] 17. Lieskovsky YE, Donaldson SS, Torres MA, et al: High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: Results and prognostic indices. J Clin Oncol 22:4532-4540, 2004 18. Peterson JK, Houghton PJ: Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 40:837-844, 2004[CrossRef][Medline] 19. Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091-3102, 2001 20. Breitfeld PP, Anderson JR, Kao S, et al: Assessment of response to induction therapy and its influence on 5-year failure-free survival (FFS) in group III rhabdomyosarcoma (RMS): Intergroup Rhabdomyosarcoma Study (IRS)-IV experience. J Clin Oncol 22:802s, 2004 (suppl; abstr 8513) 21. Gaynon PS, Desai AA, Bostrom BC, et al: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: A review. Cancer 80:1717-1726, 1997[CrossRef][Medline] 22. Picci P, Bohling T, Bacci G, et al: Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities. J Clin Oncol 15:1553-1559, 1997[Abstract] 23. Smith MA, Anderson BD: A window on reality? J Clin Oncol 22:1360-1362, 2004 24. Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna uroprotection and etoposide: An effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5:1191-1198, 1987 Submitted March 9, 2005; accepted May 1, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
