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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4909-4913 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.4257 Assessment of Response to Induction Therapy and Its Influence on 5-Year Failure-Free Survival in Group III Rhabdomyosarcoma: The Intergroup Rhabdomyosarcoma Study-IV Experience—A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group
From the Children's Hospital Cleveland Clinic, Cleveland; Children's Hospital, Columbus, OH; University of Nebraska Medical Center, Omaha, NE; University of Iowa College of Medicine, Iowa City, IA; Children's Hospital, Pittsburgh, PA; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Oklahoma Medical Science Center, Oklahoma City, OK; Duke University Medical Center; EMD Pharmaceuticals Inc, Durham, NC; and the Children's Oncology Group, Arcadia, CA 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 Initial response to induction chemotherapy predicts failure-free survival (FFS) in osteosarcoma and Ewing's sarcoma. For Intergroup Rhabdomyosarcoma Study (IRS) IV patients with group III rhabdomyosarcoma, we assessed whether reported response assessed by anatomic imaging at week 8 predicted FFS. Patients and Methods We studied 444 group III patients who received induction therapy, had response assessed at week 8 by anatomic imaging, and continued with protocol therapy. Induction chemotherapy was generally followed by radiation therapy (RT) starting after week 9. Response to induction therapy was determined at weeks 0 and 8. Local institutions coded response. Results Response rate for the entire cohort at week 8 was 77% (95% CI, 73% to 81%; complete response [CR], 21%; partial response [PR], 56%) but response had no influence on FFS (P = .57). Two hundred seventy-two patients received standard-timing RT at week 9 and thus only chemotherapy during induction. Response rate was 81% (95% CI, 76% to 86%; CR, 22%; PR, 59%). In these patients, response did not influence FFS except for those with alveolar histology. One hundred thirty-two other patients received chemotherapy and RT during induction (up-front RT). Response rate was 65% (95% CI, 57% to 73%; CR, 12%; PR, 53%), but response had no influence on FFS (P = .69). Forty patients received no RT at all (protocol violation) and response to induction therapy had no effect on FFS. Conclusion In IRS-IV, response rate to induction therapy was 77% in group III patients, was independent of histology, and had no influence on FFS overall.
Initial response to chemotherapy is predictive of outcome in many childhood malignancies. Examples include acute lymphoblastic leukemia (ALL),1,2 Hodgkin's lymphoma,3 Ewing's sarcoma4,5, and osteosarcoma.6 In most of these examples, histologic response to chemotherapy was assessed. Assuming that early response to chemotherapy is predictive of outcome in children with rhabdomyosarcoma, European studies used early response defined by anatomic methods to tailor subsequent treatment in these clinical trials.7-8 The association between initial response and outcome has further been supported by observations in adults with rhabdomyosarcoma in the United States.9 Multiple variables are known to be predictive of outcome in childhood rhabdomyosarcoma including age, stage, group, location of primary, and histology.10 Whether response to induction therapy influences failure-free survival (FFS) in children with rhabdomyosarcoma treated on Intergroup Rhabdomyosarcoma Study (IRS) group protocols has not been evaluated. IRS-IV collected data for response at week 8 of induction, and all patients received the same consolidation chemotherapy and local control regardless of week 8 response. IRS-IV data presented us with the opportunity to examine whether response to induction therapy influenced 5-year FFS in a large cohort of patients with group III rhabdomyosarcoma.
IRS-IV enrolled patients from 1991 to 1997. Group III was defined as incomplete resection with gross residual disease either after biopsy only or after incomplete resection. The details of therapy have been described previously.11 Briefly, patients with group III disease were randomly assigned one of three chemotherapy regimens (vincristine, dactinomycin, cyclophosphamide [VAC]; vincristine, ifosfamide, etoposide; vincristine, dactinomycin, ifosfamide) during weeks 0 to 28. All patients received VAC chemotherapy from week 29 to the end of therapy. Those patients with pre-existing renal abnormalities received VAC chemotherapy (Fig 1). 11 All patients were to receive radiation therapy (RT). Patients were randomly assigned to conventional RT (CRT; 50.4 Gy, as a single daily fraction of 1.8 Gy), or hyperfractionated RT (59.4 Gy, in two daily fractions, 1.1 Gy each) beginning at week 9. For those patients with parameningeal primary tumors with evidence of intracranial extension, CRT was started as soon as possible, usually by week 2. Results of IRS-IV have been previously published and no effect on FFS was noted by randomized chemotherapy regimen or randomized RT fractionation schedule.11,12
By protocol, all patients were to receive three cycles of induction chemotherapy during the initial 9-week period and disease evaluation was mandated at week 8. Standard timing for radiation therapy was scheduled to begin at week 9. Because our goal was to understand the relationship of FFS to response to induction therapy, patients for this analysis must have had their diagnosis confirmed by central pathology review; completed induction therapy; undergone disease evaluation at the end of induction (around week 8) before continuing with consolidation; and proceeded on with consolidation therapy. Patients were divided into three subsets that depended on the timing of RT. Standard timing RT patients were defined as those receiving protocol defined RT at week 9. Up-front RT patients were defined as those receiving protocol-defined radiotherapy during induction usually for intracranial extension associated with a parameningeal primary. No RT patients were defined as patients that received no RT during any portion of the treatment. This circumstance represented a protocol violation and most of these patients were younger than 3 years of age. Response at week 8 was determined using standard anatomic imaging modalities available at the treating institution. Thus, response was determined using the results of conventional computed axial tomography (CT) or magnetic resonance (MR) imaging as reported by each institution. Modality of assessment, such as CT or MR, was not coded in the IRS-IV database. A complete response (CR) was defined in the protocol as complete resolution of disease. A partial response (PR) was defined as a decrease of 50% or more 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 (NR) was less than a 50% decrease and less than a 25% increase in the sum of the products of the maximum perpendicular diameters of all measurable lesions. Progressive disease 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 the appearance of new lesions. FFS was defined as the interval from study entry to the first occurrence of disease progression or death. FFS for patients alive without progression of their rhabdomyosarcoma were censored at the time of last reported contact. Estimates of the distribution of FFS were calculated using the Kaplan-Meier method.
Patient Population In IRS-IV, there were 548 patients who were classified as group III. A total of 49 of these patients were off study before completion of induction chemotherapy or did not have disease evaluation at week 8 according to protocol guidelines. Of the remaining 499 patients who completed induction chemotherapy, had disease evaluation, and continued on therapy, 55 patients were excluded from further analysis because centralized pathology review did not confirm a diagnosis of embryonal/alveolar rhabdomyosarcoma (n = 41), or because the start date for RT could not be determined in the IRS-IV database (n = 14). This resulted in 444 patients who are included in our analysis. Patient characteristics are described in Table 1. 12
Response Rate to Induction Chemotherapy As Measured at Week 8 Response rate for all 444 patients was 77% (95% CI, 73% to 81%;CR, 21%; PR, 56%) at week 8 (Table 2). Among 272 patients receiving standard timing RT, response rate to induction chemotherapy at week 8 was 81% (95% CI, 76% to 86%) and consisted of 22% CR and 59% PR. Within this subset of patients, histology had no influence on response rate to induction chemotherapy. Those with embryonal tumors had an 81% response rate at week 8 (95% CI, 75% to 86%; CR, 21%; PR, 60%), while those with alveolar tumors also had an 81% response rate at week 8 (95% CI, 71% to 89%; CR, 24%; PR, 57%). The subset of patients with embryonal histology tumors and standard timing RT was large enough to assess whether tumor size at diagnosis affected week 8 response. No statistically significant difference in week 8 response rate was seen comparing those with primary tumors smaller than 5 cm to those with tumors  5 cm (data not shown). There were 132 patients receiving up-front RT and for 125 of these, the indication for up-front RT was a parameningeal primary with intracranial extension. The response rate for this subset was 65% (95% CI, 57% to 73%; CR, 12%; PR, 53%). Forty patients did not receive RT as part of their therapy (a protocol violation) and had comparable response rates (Table 2). In addition, we found that response did not vary significantly by randomized chemotherapy regimen (data not shown).
5-Year FFS Table 3 demonstrates that there was no significant difference in 5-year FFS by response at week 8 among the entire cohort of 453 patients. Patients in CR, PR, and NR had 5-year FFS rates of 75%, 71%, and 78%, respectively (P = .57). When analyzed by RT timing, there was no difference in survival based on initial response in either the up-front RT patient subset or in those receiving standard timing. Standard timing patients had FFS rates of 81%, 72%, and 84% (P = .20) for CR, PR, and NR, respectively (Table 3). Patients receiving up-front RT had 5-year FFS rates of 75%, 66%, and 76% (P = .69) for patients with CR, PR, and NR, respectively (Table 3). Patients who received standard timing RT and had embryonal tumors had similar 5-year FFS rates regardless of response as assessed at week 8 to induction chemotherapy (Table 3). However, for those patients with alveolar tumors who received standard-timing RT, response had an unexpected influence on 5-year FFS. Patients with PR in this subgroup demonstrated inferior outcome to patients with CR or NR (39%, 71%, 81%, respectively; P = .04; Table 3). Finally, when patients were analyzed based on chemotherapy regimen, there was no significant influence of response on 5-year FFS (data not shown).
Patients with group III rhabdomyosarcoma enrolled onto IRS-IV were likely to respond to the initial 8-week induction regimen, as we observed a response rate of 77%. Response at week 8 to induction chemotherapy was independent of histology subtype. Finally, response rate as assessed at week 8 in IRS-IV did not influence 5-year FFS. We were surprised that response as assessed by anatomic imaging at week 8 had no influence on 5-year FFS. Response assessment can be performed in several ways. In ALL where bone marrow aspirate morphology or flow cytometric analyses are used to assess response, response to the first 7 to 14 days of induction therapy has been shown to influence outcome.1,2 Likewise, in osteosarcoma and Ewing's sarcoma, response as assessed by histopathology examination of tumor necrosis after initial neoadjuvant chemotherapy influences outcome.4-6 Anatomic imaging techniques such as CT and MR have been used to assess response to therapy in non-Hodgkin's and Hodgkin's lymphoma, and these have been predictive of outcome in defined settings.3 Functional imaging techniques also have demonstrated value in assessing response to treatment. For example, recent studies have suggested that metaiodobenzylguanidine uptake in neuroblastoma13 and changes in glucose uptake as assessed by positron emission tomography (PET) in soft tissue14 and bone sarcomas15 hold promise as predictors of outcome. Finally, molecular techniques designed to detect very low levels of disease (minimal residual disease) have value in predicting outcome when assessed early in therapy for ALL.16 Because response to therapy in rhabdomyosarcoma is routinely assessed using anatomic imaging methods, we utilized these data in our study. We could not use histopathologic assessment in our setting. In IRS-IV, RT was the mandated primary modality for local control; surgical excision of disease after induction therapy was rarely used. In addition, at the time of the study, functional imaging such as PET, was not readily available and not mandated by the IRS-IV protocol. Why did response assessed by anatomic imaging at week 8 fail to predict outcome? It is possible that week 8 is the wrong time to assess response. Perhaps outcome is influenced by response determined at an earlier time point as in ALL. Alternatively, it is possible that outcome is influenced by local control; thus, a better time to assess treatment response may be after induction and local control periods. Our observation that response had no impact on 5-year FFS in the up-front RT subset would argue against this however. In addition, assessment of response by anatomic imaging may not reflect tumor necrosis in rhabdomyosarcoma. Our observation that patients with tumor responses classified as NR enjoy outcomes as favorable as those classified as CR strongly supports this hypothesis. In osteosarcoma and Ewing's sarcoma, anatomic imaging methods are generally inferior to direct assessment of tumor necrosis by histopathology in regard to their value as predictors of outcome.4,17-19 In this sense, our findings in rhabdomyosarcoma may not be surprising. It may be that functional imaging such as PET may provide a truer assessment of treatment effect and thus a better predictor of outcome. Future studies in rhabdomyosarcoma should assess the value of PET in assessing response and predicting outcome. Nevertheless, other investigators have provided evidence that anatomic imaging in rhabdomyosarcoma provides prognostic information. For example, in the Cooperative Soft Tissue Sarcoma Study (CWS-81 and CWS-86), patients achieving a poor response (more than one third tumor volume reduction but < two thirds volume reduction) or NR to induction with VACA (vincristine, dactinomycin, cyclophosphamide, and doxorubicin in CWS-81) or VAIA (vincristine, dactinomycin, ifosfamide, and doxorubicin in CWS-86) had poorer event-free survival than those achieving a CR or good response (greater than two thirds reduction in tumor volume).20 However, in the CWS-86 study, patients with a poor response or NR received alternative therapy after induction and this alteration may have influenced outcome. A single institution retrospective report noted that in adults with rhabdomyosarcoma who received neoadjuvant chemotherapy, responders to chemotherapy had significantly better metastatic-free survival and local control than nonresponders.9 What could account for our findings that response had no bearing on outcome in contrast to these reports? First, our report includes many more patients than any prior reported experience. Second, our report is more contemporary than the CWS reports. Thus, contemporary imaging and RT techniques (dependent on accurate anatomic imaging) may account for some of the difference. Our report is on patients younger than 21 years of age and the relationship between response and outcome may be different in older patients. The chemotherapy regimens in all of the reports and ours were similar and would not likely account for the findings. Patients with alveolar group III disease experienced a significantly worse 5-year FFS if they achieved a PR (FFS, 39%) compared with either a CR (FFS, 71%) or NR (FFS, 81%). Further examination of this cohort revealed that induction response was not significantly influenced by primary site. In addition, patients classified as PR at week 8, regardless of tumor size, had worse outcome than those with NR. There was no evidence that the patients classified as PR had more radiation guideline deviations. Finally, because multiple analyses were performed, it is possible that this finding is one of chance. There are multiple potential limitations to our findings. This is a retrospective analysis of IRS-IV data since the IRS-IV trial was not designed to answer the question posed in this analysis. Nevertheless, the data were collected prospectively. The IRS-IV study was a cooperative group study involving more than 200 institutions and no central review of imaging response was mandated. The patients with group III disease were randomly assigned to one of three different chemotherapy regimens and randomly assigned to CRT or hyperfractionated RT. These factors could have influenced our results. However, patient outcome was not significantly influenced by chemotherapy regimen or fractionation of RT.11,12 In addition, we found that randomized chemotherapy regimen in IRS-IV did not influence response rates. Therefore, it is unlikely that poor responders were rescued by type of chemotherapy or RT received. Finally, we do not know if the local treating institution in some way may have influenced further therapy in patients without response at week 8 that might bias these results. What are the implications of our finding that response to induction chemotherapy as assessed by anatomic imaging at week 8 does not impact outcome in group III rhabdomyosarcoma? These data do not support the practice of modifying therapy after induction for those patients who do not achieve a CR or PR to induction therapy. Similarly, clinical trial designs that tailor postinduction therapy based on response to induction therapy should be carefully constructed and justified. Finally, additional methods of response assessment should be formally tested to assess their value as predictors of outcome in rhabdomyosarcoma.
The author(s) indicated no potential conflicts of interest.
Conception and design: James R. Anderson, Philip P. Breitfeld Administrative support: William H. Meyer Provision of study materials or patients: William H. Meyer, Philip P. Breitfeld Collection and assembly of data: Megan Burke, David Rodeberg, Stephen J. Qualman, Suzanne L. Wolden Data analysis and interpretation: James R. Anderson, David Rodeberg, Stephen J. Qualman, Suzanne L. Wolden, William H. Meyer, Philip P. Breitfeld Manuscript writing: Megan Burke, James R. Anderson, Simon C. Kao, David Rodeberg, William H. Meyer, Philip P. Breitfeld Final approval of manuscript: Megan Burke, James R. Anderson, Simon C. Kao, David Rodeberg, Stephen J. Qualman, Suzanne L. Wolden, William H. Meyer, Philip P. Breitfeld
We thank all participating institutions and their investigators.
Supported by Grants No. IRS NIH U10 CA24507 and IRS NIH U10 CA24507, COG Statistics and Data Center Grant No. NIH U10 CA098413, and COG Grant No. CA 98543. A complete list of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
