The results of treatment of 686, previously untreated patients younger than 21 years with rhabdomyosarcoma or undifferentiated sarcoma, who were entered on Intergroup Rhabdomyosarcoma Study-I (IRS-I) were analyzed after a minimum potential follow-up time of 7 years. Patients in Clinical Group I (localized disease, completely resected) were randomized to receive either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC + radiation. At 5 years, approximately 80% of patients given either treatment were still disease-free and there was no significant difference between treatments in the overall percentages of patients surviving of 93% and 81%, respectively (P = 0.67). Patients in Clinical Group II (regional disease, grossly resected) were randomized to receive either vincristine and dactinomycin (VA) + radiation or VAC + radiation. At 5 years, 72% and 65% of the patients, respectively, were disease-free and there was no evidence of a difference between treatments (P = 0.46). The overall survival percentage at 5 years was approximately 72% for both treatments. Patients in Clinical Groups III (gross residual disease after surgery) and IV (metastatic disease) were randomized to receive either "pulse" VAC + radiation or "pulse" VAC + Adriamycin (doxorubicin) + radiation. The complete remission (CR) rate was 69% in Clinical Group III and 50% in IV, with no statistically significant difference in CR rates between treatments in either group. Those who achieved a CR had a nearly 60% chance of staying in remission for 5 years in Clinical Group III compared with approximately 30% in Clinical Group IV. The overall survival percentage at 5 years was 52% in Clinical Group III compared to 20% in Clinical Group IV (P less than 0.0001). The 5-year survival percentage for the entire cohort of 686 patients was 55%. Survival after relapse was poor, being 32% at 1 year and 17% at 2 years. The risk of distant metastasis was much greater than the risk of local recurrence within each clinical group, and there was no evidence of differing types of relapses between treatments. Primary tumors of the orbit and genitourinary tract carried the best prognosis, whereas tumors of the retroperitoneum had the worst prognosis. The authors conclude that for the therapeutic regimens evaluated there was no therapeutic advantage to including radiation in the treatment of Clinical Group I disease, or cyclophosphamide given as a daily low-dose oral regimen in the treatment of Clinical Group II disease or Adriamycin in the treatment of Clinical Groups III and IV diseases.

Background. Intergroup Rhabdomyosarcoma Study (IRS)‐II, (1978–1984) had the general goals of improving the survival and treatment of children with rhabdomyosarcoma (RMS). Methods. Nine hundred ninety‐nine previously untreated eligible patients entered the study after surgery and were randomized or assigned to therapy by IRS Clinical Group (I‐IV), tumor site, and histologic type. Outcomes were compared between treatments and with results of IRS‐I (1972–1978). Results. Patients in Group I, excluding extremity alveolar (EA) RMS, were randomized to standard vincristine (V), dactinomycin (A), and cyclophosphamide (C) or standard VA. At 5 years, disease‐free survival (DFS) and survival (S) rates were similar between VAC and VA (DFS:80%, 70%, P = 0.47; S:85%, 84%, P = 0.73). Patients in Group II, excluding EA RMS, received radiation and were randomized to intensive VA or repetitive‐pulse VAC. Outcomes were similar for rates of DFS (69%, 74%, P = 0.83) and S (88%, 79%, P = 0.17). Patients in Group III, excluding certain pelvic tumors, received radiation and were randomized to repetitive‐pulse VAC or repetitivepulse VAdrC‐VAC (Adr, Adriamycin [doxorubicin]). Complete remission (CR) rates were close at 74%, 78%, respectively (P = 0.32), as were percentages in CR (73%) and S (66%) rates; the latter outcomes were significantly better than IRS‐I (CR: 56%, P < 0.001; S:50%, P < 0.001). Central nervous system prophylaxis for Group III patients with cranial parameningeal sarcoma increased S rate to 67% from 45% in IRS‐I (P < 0.001). Patients in Group IV received the same regimens as Group III; the CR rate was 53%, 38% remained in CR and S rate was 27% with and 26% without Adr (P = 0.90). At 5 years, S rate for IRS‐II, including EA and all pelvic tumors, was 63%: an 8% increase over IRS‐I (P < 0.001). Outcomes by primary site were as good as, or better than, the IRS‐I experience. Conclusions. Combining all Groups and treatments in IRS‐II, the major improvement in S rate at 5 years between studies was in nonmetastatic patients (71% for IRS‐II versus 63% for IRS‐I, P = 0.01).

Background. There is a need to develop a single prognostically significant classification of rhabdomyosarcomas (RMS) and other related tumors of children, adolescents, and young adults which would be a current guide for their diagnosis, allow valid comparison of outcomes between protocols carried out anywhere in the world, and should enhance recognition of prognostic subsets. Method. Sixteen pathologists from eight pathology groups, representing six countries and several cooperative groups, classified by four histopathologic classification schemes 800 representative tumors of the 999 eligible cases treated on Intergroup Rhabdomyosarcoma Study II. Each tumor was classified according to each of the four systems by each of the pathologists. In addition, two independent subsamples of 200 of the 800 patients were reviewed according to the new system, so that 343 distinct patients were reviewed once, and 57 of these twice. Results. A study of the survival rates of all subtypes in the sample of 800 patients led to the formation of a new system. This was tested on two independent subsets of 200 of the original cases and found to be reproducible and predictive of outcome by univariate analysis. A multivariate analysis of the 343 patients classified according to the new system indicated that a survival model including pathologic classification and known prognostic factors of primary site, clinical group, and tumor size was significantly better at predicting survival than a model with only the known prognostic factors. Conclusion. This new classification, termed International Classification of Rhabdomyosarcoma (ICR) by the authors, was reproducible and predictive of outcome among patients with differing histologies treated uniformly on the Intergroup Rhabdomyosarcoma II protocols. We believe it should be utilized by all pathologists and cooperative groups to classify rhabdomyosarcomas in order to provide comparability among and within multi‐institutional studies. Cancer 1995;76:1073‐85.

Prestudy patient characteristics and specific therapy of all eligible patients with rhabdomyosarcoma entered into Intergroup Rhabdomyosarcoma (RMS) Studies I (IRS-I) (1972 to 1978, n = 686) or II (IRS-II) (1978 to 1984, n = 1,002) were examined for their relationship to survival within each of the four clinical groups using univariate and multivariate analyses. The estimated survival at 5 years from the start of treatment was 56% in IRS-I and 62% in IRS-II (P = .006). The largest survival difference between studies was in patients with group III tumors (52% v 65%). The clinical group was the most important patient characteristic related to survival in both studies. Survival progressively decreased for patients from clinical group I (localized disease, completely resected) to group IV (metastatic disease at the onset). In clinical group I, the only patient characteristic consistently related to survival was histology. Patients with alveolar tumors had the poorest survival, while those with botryoid/embryonal lesions had the best survival. In clinical group II, no characteristic was consistently related to survival. In clinical group III, an orbital primary site was associated with a favorable survival. In clinical group IV, patients with genitourinary tumors had a significant survival advantage. Use of disease-free survival as an end point gave very similar results. This information, from the largest available data base on prognostic indicators in childhood RMS in the context of aggressive multimodal therapies, is being used to plan therapy in the forthcoming study (IRS-IV).

The need for a pretreatment staging system to accurately assess programs of therapy for the various sites and stages of childhood rhabdomyosarcoma has become apparent as detailed analyses of many factors affecting prognosis and treatment choices have been accomplished through the national cooperative trial, the Intergroup Rhabdomyosarcoma Study (IRS). Initiated in 1972, the IRS has thus far used a clinicopathologic grouping system that is based heavily on therapeutic decisions, particularly on whether or not excision is accomplished and the extent of such an operation. The major problem with this and several other staging classifications now in use is that they depend on pathologic data obtained after surgical treatment has been initiated or rejected. In addition, they do not consider histologic variations of this neoplasm which may be important in estimating prognosis. The large body of clinical data now accumulated in the IRS has provided an excellent opportunity for developing a database for evaluating the International Union Against Cancer (UICC) pretreatment staging system and also the potential for using histologic categories in the staging process. The records of 505 eligible patients entered into the IRS between 1978 and 1982 were used to determine the prognostic impact of a number of pretreatment factors. These included local invasiveness of the primary neoplasm on clinical examination, tumor size, clinical status of regional nodes, clinical or radiologic evidence of distant metastases, and favorable or unfavorable histologic categories. A retrospective assessment of the relationship of these pretreatment observations to survival experience has been carried out. This retrospective study indicates definite prognostic significance for all of the individual factors used on the UICC system except clinical status of regional nodes. Also, these data serve as a basis for considering the possibility of including favorable v unfavorable histology in the pretreatment staging system now being tested prospectively in the ongoing IRS protocols.