Edmund A. Gehan

The Third Intergroup Rhabdomyosarcoma Study.

PURPOSE The ultimate goal of the Third Intergroup Rhabdomyosarcoma Study (IRS-III, 1984 to 1991) was to improve treatment outcome in children with rhabdomyosarcoma through clinical trials comparing risk-based protocols of surgery and multiagent chemotherapy, with or without irradiation. PATIENTS AND METHODS One thousand sixty-two previously untreated, eligible patients who were entered onto the study after surgery were randomized or assigned to treatment by clinical group (I through IV), histology (unfavorable or favorable), and site of the primary tumor. Initial responses, progression-free survival (PFS), and survival (S) were the end points used in comparisons between randomized groups and between patients treated in IRS-III and IRS-II (1978 to 1984). RESULTS The overall outcome of therapy in IRS-III was significantly better than in IRS-II (5-year PFS, 65% +/- 2% v 55% +/- 2%; P < .001 by stratified testing). Patients with group I favorable-histology tumors fared as well on a 1-year regimen of vincristine and dactinomycin (VA), as did a comparable group treated with VA plus cyclophosphamide (C) (5-year PFS, 83% +/- 3% v 76% +/- 4%; P = .18). Results for patients with group II favorable-histology tumors, excluding orbit, head, and paratesticular sites, were inconclusive regarding the benefit from addition of doxorubicin (ADR) to VA. Patients with group III tumors, excluding those in special pelvic, orbit, and other selected nonparameningeal head sites, fared much better on the more intensive regimens of IRS-III than on pulsed VAC or VAC-VADRC in IRS-II (5-year PFS estimates, 62% +/- 3% v 52% +/- 3%; P < .01); however, there were no significant differences in outcome among the groups treated in IRS-III. Patients with metastatic disease at diagnosis (clinical group IV) did not benefit significantly from the more complex therapies evaluated in IRS-III. CONCLUSION Intensification of therapy for most patients in IRS-III, using a risk-based study design, significantly improved treatment outcome overall. The largest gain from this strategy was realized in patients with gross residual tumor after biopsy (clinical group III). It was also possible to decrease therapy for selected patient subsets without compromising survival.

Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee.

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).

Ewing's sarcoma of soft tissues in childhood: a report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991.

PURPOSE One hundred thirty of 2,792 patients (5%) registered on three Intergroup Rhabdomyosarcoma Study clinical trials (IRS-I, -II, and -III) from 1972 to 1991 had an extraosseous Ewings sarcoma (EOE). We report here the results of multimodality therapy for this tumor. PATIENTS AND METHODS The 130 patients were less than 21 years of age; 70 (54%) were males. Primary tumor sites were on the trunk in 41 patients, an extremity in 34, the head/neck in 23, the retroperitoneum/pelvis in 21, and other sites in 11. One hundred fourteen patients had no metastases at diagnosis. In 21 patients, the tumor was completely resected; in 30, the localized or regional tumor was grossly resected, and in 63 patients, grossly visible sarcoma was left behind. Sixteen patients (12%) had distant metastases at diagnosis. All patients were given multiagent chemotherapy and most received irradiation (XRT); none were treated with bone marrow transplantation. RESULTS One hundred seven patients (82%) achieved a complete response. At 10 years, 62%, 61%, and 77% of the patients were alive after treatment on IRS-I, IRS-II, or IRS-III therapeutic protocols, respectively, similar to figures obtained in all IRS patients. At last follow-up evaluation, 42 patients had died of progressive tumor and one of infection. Survival at 10 years was most likely for patients with tumor that arose in the head and neck, extremities, and trunk, and for those who underwent grossly complete tumor removal before initiation of chemotherapy. For patients with localized, gross residual tumor, adding doxorubicin (DOX) to the combination of vincristine, dactinomycin, cyclophosphamide (VAC), and XRT did not significantly improve survival in 39 patients (62% alive at 10 years) compared with that of 24 patients treated with VAC and XRT without DOX (65% alive at 10 years, P = .93). CONCLUSION This series indicated that EOE in children is similar to rhabdomyosarcoma (RMS) in its response to multimodal treatment. No benefit was apparent from the addition of DOX to VAC chemotherapy in patients with gross residual EOE.

Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee.

PURPOSE We report on long-term health-related problems determined from extended follow-up of 86 children and adolescents who were treated for paratesticular rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Studies I and II (IRS I-II). PATIENTS AND METHODS Patients were treated between 1972 and 1984, and ages at diagnosis ranged from 10 months to 19 years. The majority of these patients had initial retroperitoneal lymph node dissection (RLND) or sampling performed. RESULTS Problems related to surgical procedures included bowel obstruction in nine patients, loss of normal ejaculatory function in eight, development of a hydrocele in five, and lymphedema of the leg in five. Sequelae related to radiotherapy were difficult to assess with the exception of three patients whose remaining testes were in the field of radiotherapy. In general, kidney and bladder function were normal in patients who received radiotherapy to the paraaortic lymph nodes and/or bladder. Four patients who had abdominal radiotherapy had chronic diarrhea. Two patients had urethral strictures and urethritis. Four patients had bone or soft tissue hypoplasia in the field of radiotherapy. Chemotherapy-related late effects were primarily hemorrhagic cystitis or gonadal dysfunction after cyclophosphamide. A third of the patients who received cyclophosphamide developed hemorrhagic cystitis, and half of these had extended periods of gross hematuria after therapy was discontinued. The testicular size was small in children whose testes were irradiated and in some who received cyclophosphamide. Tanner staging was normal in 45 patients for whom it was recorded. Elevated follicle-stimulating hormone (FSH) values or known azoospermia occurred in more than half the patients for whom data were available. CONCLUSIONS A variety of sequelae related to therapy were determined in this patient population. These findings suggest that some aspects of therapy warrant reevaluation and that improved plans for follow-up care need to be provided.

Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma

UNLABELLED Retroperitoneal lymph node dissection (RPLND) was used in 121 Intergroup Rhabdomyosarcoma Study (IRS) III patients with nonmetastatic paratesticular (PT) rhabdomyosarcoma (RMS) to assess retroperitoneal lymph node (RPLN) involvement so as to determine the need for x-ray therapy (XRT). Clinical node evaluation (CNE) was accomplished by a computed tomography (CT) scan in 105 and a sonogram in six. Pathological node evaluation (PNE) was performed in 113: lymphadenectomy (9 bilateral, 85 unilateral) and biopsy in 19. Vincristine and actinomycin D were used for 1 year postoperatively in 89%; all patients who had positive PNE received RPLN XRT. This study compares CNE with PNE and evaluates predictors of relapse and survival. FINDINGS There were clinically negative nodes (cN0) in 81% of the 121 patients. Among cN0 patients, 14% had positive nodes (pN1). Of the clinically positive (cN1) patients, 94% had pN1. RPLN relapse occurred in only two of the 121 patients. Initially both had cN0 and one had PNE that was negative. For all 121 patients, the 5-year survival was 91%. For cN0 patients, the 5-year survival was 96% compared with 69% for cN1 patients (P < .001). Among the children in whom treatment failed, nodes were cN1 in 5 of 11 (45%) compared with 15 of 107 (14%) in those whose treatment did not fail (P < .008). CONCLUSIONS (1) Results of RPLN imaging studies were negative in 81% of patients with PT RMS (specificity 99%, sensitivity 57%). (2) RPLN recurrence is uncommon (even when RPLN are initially involved) if regional XRT and appropriate chemotherapy are used.(ABSTRACT TRUNCATED AT 250 WORDS)