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Analysis of Prognostic Factors in Patients With Nonmetastatic Rhabdomyosarcoma Treated on Intergroup Rhabdomyosarcoma Studies III and IV: The Children's Oncology Group

Jane L. Meza, James Anderson, Alberto S. Pappo, William H. Meyer

From the Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK; and the Hospital for Sick Children, Toronto, Ontario, Canada

Address reprint requests to Jane L. Meza, PhD, Department of Preventive and Societal Medicine, 984350 Nebraska Medical Center, Omaha, NE 68198-4350; e-mail: jmeza{at}unmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: The outcome for localized rhabdomyosarcoma (RMS) or undifferentiated sarcoma (UDS) is affected by age, histology, primary anatomic site, extent of disease, and therapy.

PATIENTS AND METHODS: We evaluated patient and disease characteristics for their ability to predict outcome for patients with nonmetastatic RMS or UDS treated on Intergroup Rhabdomyosarcoma Study (IRS) -III (1984 to 1991) or IRS-IV (1991 to 1997).

RESULTS: The estimated 5-year failure-free survival (FFS) rate was 90% for patients with embryonal RMS (ERMS) stage 1, group I or IIa; stage 2, group I; or group III orbit. The estimated 5-year FFS rate was 87% for patients with ERMS stage 1, group IIb or IIc; stage 1, group III nonorbit; stage 2, group II; and stage 3, group I or II; and 73% for patients with ERMS stage 2 or 3, group III. The estimated 5-year FFS rate was poor for patients with stage 2 or 3, group III ERMS with invasive (T2) tumors who were age younger than 1 year or 10 years or older (56%) and patients with stage 2 or 3, group III extremity primary tumors (43%). Overall, outcomes for patients with alveolar RMS (ARMS) or UDS were worse than for patients with ERMS. However, the 5-year FFS rate was good for patients with ARMS/UDS at favorable sites with group I or II (80%) or group III (76%) disease. The FFS rate was poorer for patients with ARMS/UDS at unfavorable sites with group I or II (66%) or group III (45%) disease. The estimated 5-year FFS rate was 31% for patients with group III ARMS/UDS at unfavorable sites with regional lymph node disease, which is similar to metastatic RMS.

CONCLUSION: Patient and disease characteristics identify distinct subsets with different outcomes, allowing the Soft Tissue Sarcoma Committee of the Children's Oncology Group to refine risk-adapted therapy assignment.

	INTRODUCTION

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The cure rate for localized rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, has nearly tripled in less than three decades, from 25% in 1970 to approximately 70% with the use of multimodal therapy including surgery and multiagent chemotherapy with or without radiation therapy.^1,2 The Intergroup Rhabdomyosarcoma Study Group (IRSG) (now the Soft Tissue Sarcoma Committee of the Children's Oncology Group [COG]) has conducted four consecutive cooperative group trials (IRS-I, 1972 to 1978; IRS-II, 1978 to 1984; IRS-III, 1984 to 1991; and IRS-IV, 1991-1997). Patient subsets with markedly different risk of treatment failure were identified on IRS-I and IRS-II. IRSG group (Table 1) was identified as the most important predictor of treatment failure, with survival decreasing for patients from group I to group IV. For patients with group I (completely resected) disease, those with RMS of embryonal histology (ERMS) had superior outcomes compared with patients with alveolar histology RMS (ARMS). No additional prognostic factors were identified for patients with group II disease. For group III patients (gross tumor after definitive surgery), orbital primary site was associated with favorable survival.³ More recent IRSG studies, IRS-III and IRS-IV, incorporated more intense therapies, new drug combinations, and refinements in the radiologic assessment of the extent of disease and pathologic classification. Because these changes may have modified the factors that predict clinical outcome, we analyzed the prognostic factors of patients with RMS and undifferentiated sarcoma (UDS) enrolled onto IRS-III and IRS-IV. These data have been used to refine the assignment of patients to specific risk-directed therapies currently used in the COG studies for the treatment of RMS and UDS.

	PATIENTS AND METHODS

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Staging
Staging was determined using the IRS TNM classification (Tables 2 and 3) for pretreatment clinical assessment of disease.⁴ IRS group was assigned at diagnosis according to amount and extent of residual tumor after initial surgery (Table 1).⁵ Central review of initial group, stage, pathologic diagnosis, and adequacy of radiotherapy and chemotherapy was conducted by the IRS Surgery, Pathology, Radiotherapy, and Chemotherapy Subcommittees.

View larger version (12K): [in this window] [in a new window]   Fig 1. Intergroup Rhabdomyosarcoma study-III treatment plan. Regimen 31: dactinomycin (A) 0.015 mg/kg/d intravenously (IV) and vincristine (V) 2 mg/m2 IV; regimen 32: regimen 31 with radiotherapy (RT); regimen 33: regimen 32 with doxorubicin (D) 30 mg/m2/d IV; regimen 34: VA dose as regimen 31 through week 20 with cyclophosphamide (C) 10 mg/kg/d IV x 3; regimen 34: regimen 31 through week 20, cyclophosphamide (C) 10 mg/kg/d IV x 3; regimen 35: regimen 34 with cisplatin (P) 90 mg/m2 IV x 1 and D 30 mg/m2/d IV x 2; and regimen 36: regimen 35 with etoposide (E) 100 mg/m2/d IV x 3. (*)Favorable history. ()Excluding group III favorable histology, orbit, and nonparameningeal head tumors. CR, complete response; PR, partial response; NR, no response; Mx, metastatis.

View larger version (13K): [in this window] [in a new window]   Fig 2. Intergroup Rhabdomyosarcoma Study-IV treatment plan. V, vincristine 1.5 mg/m2 intravenously (IV) x 1 (maximum dose, 2 mg); A, dactinomycin 0.15 mg/kg/d IV x 5 (maximum dose, 0.5 mg/d); C, cyclophosphamide 2.2 g/m2 IV x 1 with mesna; I, ifosfamide 1.8 g/m2/d IV x 5 with mesna; E, etoposide 100 mg/m2/d IV x 5. All courses followed by granulocyte colony-stimulating factor 5 µg/kg/d subcutaneously.

Prognostic Factors
Prognostic factors considered for their relationship to FFS and survival were age, sex, group, stage, tumor size, tumor invasiveness, nodal status, primary site, and study.

End Points and Statistical Methods
Progressive disease, or failure, was defined as increased size of the primary tumor or appearance of disease at a previously uninvolved site. FFS was defined as the time from the start of treatment to disease progression, recurrence, or death as a first event. Survival was defined as the time from start of treatment to death from any cause. FFS and survival for patients who never experienced the event of interest were censored at the time of the patient's last contact date.

FFS and survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test.¹⁰ CIs for estimates of time-to-event distributions were calculated using Greenwood's formula.^{11 2} tests were used to compare frequency distributions of patient characteristics. P < .05 was considered statistically significant. The Cox regression model for censored data was used to examine combinations of patient characteristics predictive of FFS in a multivariate analysis.¹²

	RESULTS

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Patient and Clinical Characteristics
A total of 1,258 eligible patients with nonmetastatic RMS were enrolled onto IRS-III (n = 576) and IRS-IV (n = 682) between 1984 and 1997 and met the eligibility criteria for further analysis. The median follow-up time was 6.4 years (range, 0 months to 15.9 years). Patient and clinical characteristics for patients with EMRS (including spindle cell and botryoid) and ARMS/UDS are listed in Table 4. There were statistically significant differences among histologic types in the distribution of age (P < .001), sex (P = .04), group (P < .001), stage (P < .001), tumor size (P = .004), nodal status (P < .001), and primary site (P < .001). The distribution of study (IRS-III or IRS-IV) was not significantly different for ARMS/UDS and ERMS patients.

Prognostic Factors for ARMS/UDS
In univariate analysis, stage (P < .001) and group (P < .001) were significantly associated with FFS for patients with ARMS/UDS. Because of the strong prognostic influence of stage and group,⁷ multivariate analysis of the prognostic influence of other factors was performed after defining subsets based on stage and group.^6,7,13 Estimated 5-year FFS rates for subsets with differing prognosis were as follows: stage 1 or 2, group I or II, 80% (95% CI, 72% to 87%; n = 119); stage 1 or 2, group III, 76% (95% CI, 63% to 86%; n = 56); stage 3, group I or II, 66% (95% CI, 54% to 76%; n = 73); and stage 3, group III, 45% (95% CI, 36% to 54%; n = 122; P < .001; Fig 3). For each of these four risk categories, Cox proportional hazards regression analysis was used to examine the effects of the remaining factors. For stage 1 or 2, group I or II (n = 119) and stage 3, group I or II (n = 73) ARMS/UDS, no additional significant factors were identified.

View larger version (9K): [in this window] [in a new window]   Fig 3. Failure-free survival for 370 patients with nonmetastatic alveolar rhabdomyosarcoma or undifferentiated sarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV.

For patients with stage 3, group III ARMS/UDS (n = 122), involvement of locoregional lymph nodes (N1) was associated with poorer FFS. One hundred eleven patients had known information on nodal status. Estimated 5-year FFS rate for patients with N1 disease was 31% (95% CI, 19% to 44%; n = 51) compared with 56% (95% CI, 42% to 67%; n = 60) for patients without nodal involvement (N0; P = .01). Estimated 5-year overall survival rate was 34% (95% CI, 21% to 47%) for patients with N1 disease compared with 66% (95% CI, 52% to 77%) for patients with N0 disease (P = .01). Outcomes for patients with ARMS/UDS are listed in Table 5.

Patients identified as low risk were divided into two subsets. Low-risk subset A was defined as patients with ERMS stage 1, group I or IIa; stage 2, group I; and group III orbit disease. Low-risk subset B was defined as patients with ERMS stage 1, group IIb or IIc; stage 1, group III nonorbit; stage 2, group II; and stage 3, group I or II. The remaining patients with stage 2 or 3, group III disease were defined as intermediate-risk ERMS patients. Estimated 5-year FFS rates for patients with ERMS was as follows: low-risk subset A, 90% (95% CI, 86% to 92%; n = 403); low-risk subset B, 87% (95% CI, 77% to 93%; n = 80); and intermediate risk, 73% (95% CI, 69% to 77%; n = 405; P < .001; Fig 4).

View larger version (6K): [in this window] [in a new window]   Fig 4. Failure-free survival for 88 patients with nonmetastatic embryonal rhabdomyosarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV.

Large tumor size (> 5 cm in diameter) was associated with poorer FFS for ERMS subset B patients. For the 79 patients with known tumor size, the estimated 5-year FFS rate for patients with small tumors ( 5 cm in diameter) was 100% (n = 37) compared with 77% (95% CI, 60% to 87%; n = 42) for patients with large tumors (P = .004). The estimated 5-year overall survival rates exceeded 90% (small tumors, 100%; large tumors, 93%).

Patients with intermediate-risk ERMS (unfavorable sites with gross tumor remaining after definitive surgery, n = 405) had varied outcomes. Extremity primary site, invasive (T2) tumors, age younger than 1 year, and age 10 years were associated with poorer FFS. Information on tumor invasiveness was available for 380 patients. Estimated 5-year FFS rate for patients with extremity ERMS was 43% (95% CI, 20% to 64%; n = 18) compared with 75% (95% CI, 70% to 79%) for patients with nonextremity primary sites (P < .001). For patients with nonextremity primary sites, tumor invasiveness and age significantly impacted FFS. Patients with invasive (T2) tumors and age younger than 1 year or 10 years, had a 5-year FFS rate of 56% (95% CI, 43% to 67%; n = 73); patients with invasive tumors and age 1 to 9 years had a 5-year FFS rate of 75% (95% CI, 69% to 81%; n = 197); patients with noninvasive (T1) tumors and age younger than 1 year or 10 years had a 5-year FFS rate of 73% (95% CI, 45% to 88%; n = 19); and patients with noninvasive tumors and age 1 to 9 years had an excellent 5-year FFS rate of 90% (95% CI, 80% to 95%; n = 73; P < .001). The estimated 5-year overall survival rate was 46% (95% CI, 21% to 68%) for patients with extremity ERMS, and the estimated 5-year overall survival rates for subsets of patients with nonextremity primary tumors were as follows: invasive tumors and age younger than 1 year or 10 years, 61% (95% CI, 48% to 71%); invasive tumors and age 1 to 9 years, 81% (95% CI, 74% to 86%); noninvasive tumors and age younger than 1 year or 10 years, 89% (95% CI, 62% to 97%); and noninvasive tumors and age 1 to 9 years, 90% (95% CI, 80% to 95%; P < .001). Outcomes for patients with ERMS are listed in Table 5.

	DISCUSSION

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Treatment outcome for patients with RMS/UDS has improved over the 25-year period during which IRS-I through IRS-IV were conducted, and the overall long-term survival rate for such patients with nonmetastatic disease is expected to exceed 80%. The two major subsets of RMS (alveolar and embryonal) have differing prognostic factors and clinical outcomes. In recognition of this, the presently active COG treatment protocols for patients with nonmetastatic disease deliver risk-directed therapy based on histology and other prognostic factors. With the routine application of myogenin and Myo-D1 histochemical staining, fewer tumors are defined as UDS. In future COG studies, UDS tumors will be eligible for non-RMS soft tissue sarcoma studies.

Low-risk tumors are defined as ERMS tumors at favorable primary sites (stage 1 or 2; Table 2) or as ERMS tumors at unfavorable sites that are grossly completely resected (group I or II; Table 1) and have been classified into two subsets. The favorable subset A patients historically have had excellent outcome with modest therapy. However, subset B patients who received two-drug therapy had a poorer outcome, justifying their exclusion from this analysis and a more aggressive three-drug chemotherapy approach to obtain similar excellent outcome (estimated 5-year survival rate of approximately 95%). Within this group, FFS is poorer for older patients (> 10 years old at diagnosis), although long-term survival is similar, reflecting the ability to salvage the majority of such treatment failures. Patients with large tumors ( 5 cm) had somewhat poorer FFS than patients with small tumors, but the long-term survival rate for both subsets exceeded 90%. In the successor COG protocol for low-risk ERMS (D9602, closed; preliminary results not yet available), subset A patients received VA chemotherapy and subset B patients received VA plus cyclophosphamide (VAC) chemotherapy. A new low-risk protocol has been activated and is aimed at maintaining excellent outcomes while minimizing toxicity. This study uses VAC (with lower dose cyclophosphamide) for both subset A and B patients for four cycles, followed by VA therapy. Subset A patients receive this brief exposure to lower dose alkylator therapy and a dramatic reduction in total length of therapy. For subset B patients, the total length of therapy will be similar to that for D9602 but with substantial decrease in total alkylator exposure. European trials also suggest that a reduction in the length of therapy is safe for patients with low-risk localized RMS.^14,15

Patients with intermediate-risk ERMS (unfavorable sites with gross tumor remaining after definitive surgery) have, overall, a less favorable prognosis than patients with low-risk tumors. Although patients with T1 tumors experienced long-term survival, these patients with group III disease were treated with aggressive chemotherapy using at least three agents and local radiotherapy. At present, we have no data suggesting that a similar excellent outcome would be possible with less aggressive treatment. Patients with T2 tumors do less well (especially those age < 1 year or 10 years); the small number of patients with unresectable embryonal extremity tumors do especially poorly (estimated 5-year survival rate < 50%).

Overall, patients with ARMS/UDS have a less favorable prognosis than patients with embryonal histology tumors. Nevertheless, patients with ARMS/UDS with stage 1 or 2 disease grossly completely resected (group I or II) have relatively favorable outcomes, with long-term survival rates in excess of 85%. Patients with stage 1 or 2, group III ARMS/UDS have similar treatment outcomes, with the exception of the small number of patients younger than 1 year of age (estimated 5-year survival rate of 43%). The patients with ARMS/UDS who remain a challenge to treat include those with primary tumors at unfavorable sites that are either large or have regional lymph node involvement (stage 3). The outcome for such patients with gross residual disease after definitive surgery and regional lymph node involvement is poor (estimated 5-year survival rate of 34%) and is similar to the outcome seen for patients with metastatic RMS.¹⁶ The poor outcome for these patients raises important treatment and research issues. Such poor outcome might justify upstaging these patients and treating them on metastatic disease protocols. However, this is only justified if a different, more aggressive therapy approach is associated with improved outcome or if adding this group to a metastatic research study would enhance our ability to answer an important therapy or biology aim. Unfortunately, we have not impacted the outcome for patients with metastatic RMS; in fact, children with metastatic RMS enrolled onto IRS-III and treated with VAC had a similar outcome when compared with metastatic RMS patients enrolled onto more recent IRS/COG studies.¹⁶ A primary aim for the new COG metastatic RMS trial evaluates whether an aggressive dose-compression treatment strategy will improve outcome compared with historic control patients with metastatic RMS. Accrual of patients with nonmetastatic disease will not enhance our power to address this study aim.

Careful application of these clinical prognostic features should permit more tailored treatment approaches in the future. For the most favorable risk group, further reductions in total chemotherapy exposure, including decreases in alkylator therapy and avoidance of agents with recognized risk of late complications (anthracyclines and epipodophylotoxins), should be explored. Elimination of irradiation and newer radiotherapy techniques that minimize field, dose, and late toxicities should also be explored. However, modifications in treatment may alter the influence of these prognostic factors, and new clinical trials should be carefully designed to monitor for increases in treatment failure as therapy is reduced. An improved understanding of the biologic and genetic diversity of RMS through characterization of gene fusions and gene and protein expression patterns should allow a more precise definition of risk groups. Such evaluations are planned in the next generation of COG RMS studies.

The estimated 5-year FFS rate was better for patients with ERMS (81%) compared with patients with ARMS/UDS (65%; P < .001). After defining risk categories based on stage and group, age was prognostic for patients with stage 1 or 2, group III ARMS/UDS, and nodal status was prognostic for patients with stage 3, group III ARMS/UDS.

The FFS experience was varied for patients with embryonal disease in risk categories defined by stage, group, and primary site. Age was prognostic of FFS for ERMS patients in subset A. Study and tumor size were prognostic of FFS for ERMS patients in subset B, whereas tumor invasiveness, age, and primary site were predictive of FFS for patients with intermediate-risk ERMS.

Future treatment of patients with nonmetastatic RMS whose present outcome is favorable will focus on adjustments in therapy to reduce acute and late adverse effects while maintaining their excellent treatment outcome. New therapeutic approaches are required for the patients whose present outcome is less than optimal.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Alberto S. Pappo Biopharma (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Jane L. Meza, James Anderson, Alberto S. Pappo Provision of study materials or patients: William H. Meyer Data analysis and interpretation: Jane L. Meza, James Anderson, Alberto S. Pappo Manuscript writing: Jane L. Meza, James Anderson, Alberto S. Pappo, William H. Meyer Final approval of manuscript: Jane L. Meza, James Anderson, Alberto S. Pappo, William H. Meyer

 

	NOTES

 
Supported by Grants No. CA-24507 and CA-72989 from the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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13. Raney RB, Anderson JR, Barr FC, et al: Rhabdomyosarcoma and undifferentiated sarcoma in thefirst two decades of life: A selective review of the Intergroup Rhabdomyosarcoma Study Group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23: 215-220, 2001[CrossRef][Medline]

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15. Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German Cooperative Soft Tissue Sarcoma Study, CWS-86. J Clin Oncol 17: 3706-3719, 1999[Abstract/Free Full Text]

16. 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: 334-337, 2001[CrossRef][Medline]

Submitted December 20, 2005; accepted June 15, 2006.

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