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© 2003 American Society for Clinical Oncology Prognostic Factors and Clinical Outcomes in Children and Adolescents With Metastatic Rhabdomyosarcoma—A Report From the Intergroup Rhabdomyosarcoma Study IV
From the Children’s Hospital Medical Center, Cincinnati, OH; University of Nebraska Medical Center, Omaha, NE; Hospital for Sick Children, Toronto, Ontario, Canada; Stanford University Medical Center, Stanford, CA; University of Arkansas, Little Rock, AR; Children’s Hospital of Columbus, Columbus, OH; Johns Hopkins Hospital, Baltimore, MD; University of Oklahoma Health Sciences Center, Oklahoma City, OK; University of Minnesota Cancer Center, Minneapolis, MN; and University of Missouri, Columbia, MO. Address reprint requests to John C. Breneman, MD, Children’s Hospital Medical Center Cincinnati, Division of Radiation Oncology, 234 Goodman Street, ML 0757, Cincinnati OH 45219-0757, email: brenemjc{at}healthall.com, cc: smason{at}childrensoncologygroup.org.
Purpose: To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV). Patients and Methods: Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points. Results: One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P = .026) and increasing number of metastatic sites (P = .028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P = .007 and .006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%. Conclusion: Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.
R HABDOMYOSARCOMA IS THE MOST COMMON malignant soft-tissue tumor of childhood.1 Most children with it present with localized disease, and with multimodal therapy, survival has improved steadily over the last three decades.2–4 Approximately 15% of children with RMS present with metastatic (group IV) disease, and their prognoses have not improved significantly over the last 15 years despite the development of more intensive therapies and the introduction of drugs with novel mechanisms of action.4–7 Several groups have noted that clinical outcomes for children with metastatic RMS might not be uniformly poor. Therefore, intensive or highly experimental therapies might not be justified for all children with metastatic disease.8,9 On the basis of these observations, we conducted a retrospective analysis to identify prognostic factors of clinical outcomes in children with metastatic RMS who were enrolled in IRS-IV.
Patient Population The study population comprised all patients aged 0 to 19 years with diagnoses of metastatic undifferentiated sarcoma, embryonal RMS, or alveolar RMS, as defined by the International Classification,10 who were enrolled in IRS-IV from 1991 to 1997. The treatment protocol was approved by the institutional review boards of participating centers, and informed consent for participation was obtained from the patients, parents, or legal guardians. The Pathology Subcommittee of the Intergroup Rhabdomyosarcoma Study Group centrally reviewed all pathologic specimens, and the Surgical Subcommittee reviewed and confirmed clinical staging. Patients were considered in clinical group IV if there was clinical or radiographic evidence of metastases at one or more sites distant from the primary site. Patients with diffuse involvement of the peritoneal or pleural cavities also were considered in group IV even if a definite primary site could not be identified. Direct invasion into contiguous structures or lymphatic drainage of the primary site were not considered distant metastases. However, involvement of lymph nodes beyond the primary lymphatic drainage was staged as group IV disease. Metastatic sites in a patient were enumerated according to organ system involvement. For example, patients with bone metastases only were classified as having one metastatic site, regardless of the number of bone lesions.
Staging and Treatment After surgery, patients were assigned randomly to one of two up-front phase II window chemotherapy regimens.11 One regimen (VM) consisted of melphalan (30 mg/m2 IV) once every 4 weeks for three doses and vincristine (1.5 mg/m2 IV) weekly for the first 6 weeks. The second regimen (IE) consisted of ifosfamide (1.8 g/m2 per day IV daily x5 with mesna) and etoposide (100 mg/m2 per day IV daily x5) every 3 weeks for a total of four courses. If there was no response at week 6, patients received VAC (vincristine 1.5 mg/m2, dactinomycin 1.5 mg/m2, cyclophosphamide 2.2 g/m2, and mesna 440 mg/m2) for 42 weeks. If there was no response at week 12, patients received VAC for 36 weeks. Patients who showed responses to the phase II regimen received VAC for 36 weeks, except that window chemotherapy agents were substituted for VAC on weeks 25 and 31. In one regimen, patients were treated first with IE for four cycles, followed by VAC with IE added for patients who initially responded to that combination. The alternate regimen was identical, except that VM was substituted for IE. Radiotherapy was specified for primary disease sites and any sites of metastases beginning at week 18.5. Patients with parameningeal tumors received radiation to their primary sites starting on day 0. Primary site radiation dose was determined by the extent of the disease that remained after initial surgery. Patients with gross residual disease received 50.4 Gy at 1.8 Gy per day, those with microscopic residual disease received 41.4 Gy at 1.8 Gy per day, and those with total excisions of the primary lesions received no radiotherapy. Patients with metastases in soft tissue or bone were to receive radiotherapy doses of 50.4 Gy. Patients who had diffuse pleural or peritoneal metastases received 14.4 Gy (whole lung) or 18.0 Gy (whole abdomen) to those cavities. Modification of radiation dose was allowed to keep adjacent critical structures within tolerance.
Statistical Methods
Patient Characteristics One hundred twenty-seven patients were eligible for this analysis (median, age of 7 years). Sixty-eight patients were treated on the VM plus VAC chemotherapy arm, and 59 on the IE plus VAC arm. The distribution of patients by sex, primary site, regional lymph node involvement, tumor size and invasiveness, histology, and number of metastatic sites is listed in Table 1  . Compared with patients without metastatic disease in the IRS-IV study, patients with group IV disease were more likely to be older (median age 7 years v 5 years), have higher incidence of alveolar histology (46% v 22%), have more commonly had invasive tumors (T2: 91% v 49%), have larger tumors (> 5 cm: 82% v 51%), have a higher incidence of regional lymph node involvement (N1: 57% v 16%), and have a greater proportion of extremity and truncal/retroperitoneal primary sites (48% v 25%).
Number and Location of Metastatic Sites Seventy-five patients (59%) had metastases confined to single anatomic sites. Metastases were in two sites in 25 patients (20%), three sites in 20 patients (16%), and four or more sites in seven patients (5%). Sites of metastatic involvement are listed in Table 2 . The most common site of metastasis was the lung (n = 50; 39%); in 31 patients (24%), this was the only metastatic site. The second most common site of metastases was bone marrow (n = 41; 32%), with 12 patients having disease at this site as the sole manifestation of metastatic disease. Other metastatic sites were bone (34 patients, 27%) and distant lymph nodes (38 patients, 30%). Metastatic disease was confirmed pathologically from at least one site in 81 patients (64%).
FFS and OS Estimated 3-year OS and FFS for eligible patients were 39% (95% confidence interval [CI], 30% to 48%) and 25% (95% CI, 17% to 33%), respectively (Fig 1 ). Initial sites of recurrence were primarily metastatic. Fifty-eight of 82 patients (71%) with data available on their relapse types had recurrence at distant sites.
Three-year FFS was influenced significantly by histology, by univariate analysis (P < .001), with embryonal/botryoid/spindle-cell tumors most favorable (Fig 2 ). FFS was influenced negatively by metastatic disease in distant lymph nodes (Fig 3; 17% v 29%; P = .026) and increased number of metastatic sites (Fig 4; P =. 031). Bone involvement seemed to negatively influence 3-year FFS, though this value did not reach statistical significance (25% v 44%; P = .069).
Overall survival at 3 years also was influenced significantly by histology (Fig 5 ; P = .026) and number of metastatic sites (Fig 6; P = .028). The effect on OS of metastatic involvement in lymph nodes (33% v 42%) and bone (25% v 44%) was only marginal (P = .065 and .073, respectively).
According to multivariate analysis, the only factor that correlated significantly statistically with improved FFS and OS was the presence of two or fewer metastatic sites (P = .007 and .006, respectively). Although the influence of histology did not achieve statistical significance in multivariate analysis, using a selection criteria of two or fewer metastases with favorable histology (embryonal) defined a population with a 3-year OS of 47% (Fig 7 ). Estimates of 3-year FFS and OS for the four subsets of patients defined by number of metastatic sites ( 2) and histology (favorable/unfavorable) are listed in Table 3.
Age did not significantly affect survival in this population. Lung involvement did not affect FFS or OS, regardless of whether it was the only site of metastasis or one of many sites. There were no differences in outcomes between patients whose lung metastases were confirmed pathologically and those diagnosed by radiograph only. Metastatic involvement of bone marrow also had no effect on survival, nor did primary tumor site.
The presence of metastatic disease is the strongest predictor of clinical outcomes in patients with RMS. Despite aggressive multimodality treatments, these children fare poorly; only 25% are expected to be free of disease 3 years after diagnosis.2,4 Because of their poor outlook, recent treatment strategies have included escalating doses of cytotoxic agents,4,6,13–15 myeloablative treatments with autologous stem-cell rescue,5,16–20 and up-front window trials to test promising new drugs.7,21 However, many of these alternatives involve significant risks,13,17 and the use of up-front investigational agents could risk the delay of administration of standard therapy that has known, and potentially superior, antitumor activity. Poor prognoses of patients with metastatic RMS have, in part, been used to rationalize acceptance of risks associated with experimental regimens. However, our data and those of others show clearly that not all children with metastatic RMS have uniformly poor prognoses. Raney et al8 analyzed outcomes of children with metastatic RMS and extraosseous Ewing sarcoma treated on the IRS-I protocol. Although overall disease-free survival (DFS) at 2 years for 105 patients was only 14%, patients whose tumors originated in the genitourinary tract, retroperitoneum/pelvis, hepatobiliary tree, or perineum had a 2-year DFS of 29%, compared with 10% for other sites. Also, those children with only one metastasis site had 2-year DFS of 23% compared with 6% for children with multiple sites. In a separate review of prognostic factors of children treated on the IRS-I and IRS-II studies, Crist et al22 found that group IV patients with genitourinary primary sites and those of ages less than 11 years had improved survival. Similarly, analysis of another series of patients with metastatic RMS from the European Cooperative Group Studies found favorable outcomes in subsets of patients with metastatic disease.9 Overall DFS in those patients was only 15% but was better in patients with genitourinary nonbladder/prostate primary sites (50%) and in those who had single rather than multiple sites of metastases. Embryonal histology also was associated with improved survival in that series. In another report, children with metastatic RMS treated on the European Intergroup Study MMT 89 had increased risk of relapse if they had invasive primary tumors (TNM stage T2) or if metastatic disease was in bones or bone marrow.23 In the current analysis, two patient characteristics contributed significantly to better prognoses: two or fewer metastatic sites and embryonal histology. When applied retrospectively to patients treated on IRS studies III, IV Pilot, and IV, those criteria define a population with metastatic disease that had a 5-year FFS of 44% and a 5-year OS of 46%. That is significantly better than outcomes observed in the overall population of children with metastatic disease, and it approaches the 60% to 80% FFS estimates observed in patients with localized disease who are currently categorized as having intermediate-risk RMS.24 Survival in these favorable subgroups of group IV patients cannot be considered adequate, but it does necessitate reevaluating criteria for selecting patients for entry into clinical trials that use highly experimental treatment approaches. This current analysis differs from that reported for group IV patients in the IRS-I study.8 Unlike the IRS I data, analysis of IRS IV data showed no prognostic significance of primary tumor site in patients with metastatic disease. Also, these current data show strong influence of embryonal histology on survival. Histology was not a significant determinant of survival in group IV patients from IRS-I. However, this later result might be somewhat confounded by a change in criteria of embryonal histology classification that occurred between IRS-I/II and IRS III/IV25,26 and the routine use of chest CT scanning for lung metastases in the more recent studies. The reasons for favorable outcomes in patients with two or fewer sites of metastases and the recent emergence of histology as a prognostic factor are not completely clear. Autopsy series of children who died from RMS do not support inherent differences in metastatic potential of different histologic subtypes,27 and though it might be assumed that patients with only one or two metastatic sites have less virulent tumors, resulting in better short-term outcomes compared with children with multiple sites of dissemination, that would not necessarily correlate with a greater sensitivity to treatment that could confer the favorable long-term FFS seen in these patients. It is reasonable to assume that patients with smaller metastatic tumor burdens might have better treatment outcomes. Accurate measurement of tumor burden from existing data for the current patients is not possible, but the number of sites of metastatic disease might be a surrogate for it and could explain the strong correlation between limited number of metastatic sites and survival that we found in this study. The absence of histology as a prognostic factor in earlier studies indicates that recent changes in systemic therapy for group IV patients, which has been intensified progressively, may have differentially improved outcomes for embryonal histology patients. This effect has been seen in IRS-IV nonmetastatic patients when intensified therapy seemed to benefit embryonal histology patients.24,28 Unlike other recent analyses,29 older age was not an independent prognostic factor for the current group of patients. Adolescents are more likely to have alveolar histologies, but that association does not seem to be strong enough to confer inferior outcomes in older patients in the IRS-IV study. This may be a consequence of the relatively small number of these patients analyzed, and it is possible that when additional data become available, age will become significant for survival. Molecular genetic analysis might refine further the identification of prognostic indicators in subgroups of patients with group IV RMS. Detection of PAX3-FKHR fusion protein may be of value in establishing unfavorable histologic subtypes,30 whereas the presence of a PAX7-FKHR fusion protein may indicate a relatively favorable variant of alveolar RMS.31 Various cell membrane markers and oncogenes also have been associated with increased metastatic behavior in cultured RMS cells, including decreased heparin-binding sites on the cell membrane32 and MDR1 expression.33 The clinical significance of these findings is unknown as yet but may someday help further define subgroups of patients with metastatic RMS that have better or worse prognoses.
Supported by Department of Health and Human Services (Washington, DC), United States Public Health Service grants no. CA-24507, CA-30138, CA-30969, CA-29139, CA-13539.
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7. 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 8. Raney RB, Tefft M, Maurer HM, et al: Disease patterns and survival rate in children with metastatic soft-tissue sarcoma: A report from the Intergroup Rhabdomyosarcoma Study (IRS)-I. Cancer 62:1257–1266, 1988[CrossRef][Medline] 9. Koscielniak E, Rodary C, Flamant F, et al: Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: A retrospective European multi-center analysis. Med Pediatr Oncol 20:209–214, 1992[Medline] 10. Newton WA Jr, Gehan EA, Webber BL, et al: Classification of rhabdomyosarcomas and related sarcomas: Pathologic aspects and proposal for a new classification—an Intergroup Rhabdomyosarcoma Study. Cancer 76:1073–1085, 1995[CrossRef][Medline] 11. Breitfeld PP, Lyden E, Raney RB, et al: Ifosfamide and etoposide are superior to vincristine and mephalan 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] 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 13. Felgenhauer J, Hawkins D, Pendergrass T, et al: Very intensive, short-term chemotherapy for children and adolescents with metastatic sarcomas. Med Pediatr Oncol 34:29–38, 2000[CrossRef][Medline] 14. Raney RB, Gehan EA, Maurer HM, et al: Evaluation of intensified chemotherapy in children with advanced rhabdomyosarcoma (clinical groups III and IV). The Intergroup Rhabdomyosarcoma Study (IRS) Committee of the Cancer and Leukemia Group B Children’s Cancer Study Group. Southwest Oncology Group. Cancer Clin Trials 2:19–28, 1979[Medline] 15. Pinkerton CR, Groot-Loonen J, Barrett A, et al: Rapid VAC high dose melphalan regimen, a novel chemotherapy approach in childhood soft tissue sarcomas. Br J Cancer 64:381–385, 1991[Medline] 16. Walterhouse DO, Hoover ML, Marymont MA, et al: High-dose chemotherapy followed by peripheral blood stem cell rescue for metastatic rhabdomyosarcoma: The experience at Chicago Children’s Memorial Hospital. Med Pediatr Oncol 32:88–92, 1999[CrossRef][Medline] 17. Lafay-Cousin L, Hartmann O, Plouvier P, et al: High-dose thiotepa and hematopoietic stem cell transplantation in pediatric malignant mesenchymal tumors: A phase II study. Bone Marrow Transplant 26:627–632, 2000[CrossRef][Medline]
18. Horowitz ME, Kinsella TJ, Wexler LH, et al: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing’s sarcoma and rhabdomyosarcoma. J Clin Oncol 11:1911–1918, 1993 19. Boulad F, Kernan NA, LaQuaglia MP, et al: High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing’s sarcoma, and undifferentiated sarcoma. J Clin Oncol 16:1697–1706, 1998[Abstract] 20. Weigel BJ, Breitfeld PP, Hawkins D, et al: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23:272–276, 2001[CrossRef][Medline] 21. Frascella E, Pritchard-Jones K, Modak S, et al: Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin and vincristine. Eur J Cancer 32A:821–825, 1996[Medline] 22. Crist WM, Garnsey L, Beltangady MS, et al: Prognosis in children with rhabdomyosarcoma: A report of the Intergroup Rhabdomyosarcoma Studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8:443–452, 1990[Abstract] 23. Carli M, Pinkerton P, Frascella E, et al: Risk group analysis in metastatic soft tissue sarcomas (STS) in children: European intergroup study MMT 89. Proc Am Soc Clin Oncol 14:A1438, 1995 (abstr)
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30. Barr FG, Chatten J, D’Cruz CM, et al: Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 273:553–557, 1995 31. Barr FG: The role of chimeric paired box transcription factors in the pathogenesis of pediatric rhabdomyosarcoma. Cancer Res 59:1711s–1715s, 1999[Medline] 32. Moczar E, Raulais D, Poupon MF, et al: Heparin-binding sites of rat rhabdomyosarcoma cells with low and high metastatic capacity. Invasion Metastasis 11:158–165, 1991[Medline] 33. Hanania N, Boyano MD, Mangin C, et al: Oncogene and MDR1 gene expression in rat rhabdomyosarcoma sublines of different metastatic potential. Anticancer Res 11:473–480, 1991[Medline] Submitted June 21, 2002; accepted August 13, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. End points for this analysis were OS and FFS, calculated with the Kaplan-Meier method.
