R. Beverly Raney

Intergroup Rhabdomyosarcoma Study-IV: Results for Patients With Nonmetastatic Disease

PURPOSE The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy. PATIENTS AND METHODS Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT). RESULTS Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P =.42). No significant difference in outcome was noted with HF-RT versus C-RT (P =.85 and P =.90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%. CONCLUSION VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.

The intergroup rhabdomyosarcoma study‐II

Background. Intergroup Rhabdomyosarcoma Study (IRS)‐II, (1978–1984) had the general goals of improving the survival and treatment of children with rhabdomyosarcoma (RMS).

Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life : a selective review of intergroup rhabdomyosarcoma study group experience and rationale for intergroup rhabdomyosarcoma study V

Purpose To review the importance of prognostic factors in developing new protocols for children with rhabdomyosarcoma (RMS). Patients and Methods Four studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group from 1972 through 1991. Results Favorable prognostic factors are: (1) undetectable distant metastases at diagnosis; (2) primary sites in the orbit and nonparameningeal head/neck and genitourinary nonbladder/prostate regions; (3) grossly complete surgical removal of localized tumor at the time of diagnosis; (4) embryonal/botryoid histology; (5) tumor size ≤5 cm; and (6) age younger than 10 years at diagnosis. The IRS-V protocols are risk-based and refine therapy by reducing exposure to cyclophosphamide and radiation therapy (XRT) in patients at low risk while adding new, active agents such as topotecan or irinotecan to the standard therapy of vincristine, actinomycin D, and cyclophosphamide (VAC) plus XRT for patients with unfavorable histology or advanced disease. Collection of biologic specimens from patients with newly diagnosed disease continues to identify other factors that may distinguish patients with favorable features from those who need more intensive therapy. A new protocol that takes into account their previous treatment is needed for patients with recurrent disease. This program (being planned) does not include bone marrow/stem cell reconstitution because this strategy has thus far failed to improve survival rates of patients with metastases at diagnosis. Conclusion Better understanding of biologic differences and new, active agents are needed to improve outcome of patients with unfavorable features at presentation.

Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck : A descriptive report from the intergroup rhabdomyosarcoma studies (IRS)-II and - III

Background. This review of children and adolescents with nonorbital soft-tissue sarcoma of the head and neck was undertaken to describe late sequelae of treatment, as manifested primarily by problems with statural growth, facial and nuchal symmetry, dentition, vision and hearing, and school performance, Procedure. Four hundred sixty-nine patients entered the IRS-II and -III protocols with localized, nonorbital soft-tissue sarcomas of the head and neck from 1978 through 1987, Their overall survival rate was 53% (250/469) at 5 years. Two hundred thirteen patients were surviving relapse free 5 or more years after diagnosis, for whom there were serial height measurements at 2 or more years after initiation of therapy. Their me dian age at diagnosis was 5 years; the median length of follow-up was 7 years. All received multiple-agent chemotherapy, and all but 3 received irradiation to the primary tumor volume Sixty-eight percent of the tumors arose in cranial parameningeal sites, 22% in nonparameningeal sites, and 10% in the neck. We reviewed flow sheets submitted to the IRS Group Statisti cal Office to ascertain which late sequelae were recorded. Results. One hundred sixty-four patients (77%) had one or more problems recorded. One hundred ninety of the two hundred thirteen patients (89%) were under 15 years of age at study entry, and at follow-up 92 (48%) had failed to maintain their initial height velocity, which had decreased by more than 25 percentile points from the original value. Thirty-six of the one hundred ninety patients (19%) were receiving growth hormone injections.

Rhabdoid tumors of soft tissues: A clinicopathologic study of 26 cases enrolled on the intergroup rhabdomyosarcoma study

Twenty-six cases of malignant soft tissue tumors with features similar to renal rhabdoid tumors were identified among approximately 3,000 childhood sarcomas entered on Intergroup Rhabdomyosarcoma Studies I-III. The tumors consisted of polygonal cells with vesicular nuclei and prominent nucleoli and cytoplasmic intermediate filament inclusions as identified by electron microscopy and immunohistochemistry. The growth pattern was predominantly solid or solid-trabecular. Immunohistochemistry showed vimentin, wide spectrum keratin, and epithelial membrane antigen to be the most consistent antigenic phenotypes. Eleven patients were infants less than 1 year of age. The tumors affected predominantly soft tissues of proximal extremities, trunk, and retroperitoneum/pelvis/abdomen. Nineteen patients died within 1 to 82 months (median, 6 months) from the start of treatment. Five patients have survived the disease for 2 to 13 years. When compared with the survival analysis of 991 Intergroup Rhabdomyosarcoma Study II patients, it was obvious that this group of tumors fares very poorly (P less than .001). The tumor belongs to the group of soft tissue neoplasms showing mesenchymal and subtle epithelial differentiation, similar to epithelioid sarcoma. Because of its identifiable histology, site and age distribution, and poor outcome, it warrants a status as an independent entity.

The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major Lessons From the IRS-I Through IRS-IV Studies as Background for the Current IRS-V Treatment Protocols

Purpose. To enumerate lessons from studying 4292 patients with rhabdomyosarcoma (RMS) in the Intergroup Rhabdomyosarcoma Study Group (IRSG, 1972–1997). Patients. Untreated patients < 21 years of age at diagnosis received systemic chemotherapy, with or without irradiation (XRT) and/or surgical removal of the tumor. Methods. Pathologic materials and treatment were reviewed to ascertain compliance and to confirm response and relapse status. Results. Survival at 5 years increased from 55 to 71% over the period. Important lessons include the fact that extent of disease at diagnosis affects prognosis. Re-excising an incompletely removed tumor is worthwhile if acceptable form and function can be preserved. The eye, vagina, and bladder can usually be saved. XRT is not necessary for children with localized, completely excised embryonal RMS. Hyperfractionated XRT has thus far not produced superior local control rates compared with conventional, once-daily XRT. Patients with non-metastatic cranial parameningeal sarcoma can usually be cured with localized XRT and systemic chemotherapy, without whole-brain XRT and intrathecal drugs. Adding doxorubicin, cisplatin, etoposide, and ifosfamide has not significantly improved survival of patients with gross residual or metastatic disease beyond that achieved with VAC (vincristine, actinomycin D, cyclophosphamide) and XRT. Most patients with alveolar RMS have a tumor-specific translocation. Mature rhabdomyoblasts after treatment of patients with bladder rhabdomyosarcoma are not necessarily malignant, provided that the tumor has shrunk and malignant cells have disappeared. Discussion. Current IRSG-V protocols, summarized herein, incorporate recommendations for risk-based management. Two new agents, topotecan and irinotecan, are under investigation for patients who have an intermediate or high risk of recurrence.

Three-year relapse-free survival rates in childhood rhabdomyosarcoma of the head and neck: Report from the intergroup rhabdomyosarcoma study

In 202 patients with rhabdomyosarcoma of the head and neck who registered in the first Intergroup Rhabdomyosarcoma Study, the primary lesions arose about the eye and orbit in 26%, in parameningeal sites in 46%, and in other head and neck areas in 28%. Histopathologically, 78% were embryonalbotryoid, 9% alveolar, 10% undifferentiated, and 3% extraosseous Ewings types. Actual three‐year relapse‐free survival rates were calculated from data on 103 of these patients who were free of distant metastases at diagnosis and in whom follow‐up had been completed for a three‐year period. The actual relapse‐free survival rates were 91% (21/23) for those with eye/orbit primaries, 46% (20/44) for those with parameningeal primaries, and 75% (27/36) for those with other head and neck sites affected. Among those with no clinical evidence of tumor activity at two years, 8% (6/75) had subsequent relapses.

What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract

Factors affecting outcome for rhabdomyosarcoma (RMS) of the female genital tract in patients treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols I–IV were evaluated to define optimal therapy.

Results of the Intergroup Rhabdomyosarcoma Study Group D9602 Protocol, Using Vincristine and Dactinomycin With or Without Cyclophosphamide and Radiation Therapy, for Newly Diagnosed Patients With Low-Risk Embryonal Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group

PURPOSE Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients. PATIENTS AND METHODS Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients. RESULTS Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77). CONCLUSION Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.

Primary chemotherapy with or without radiation therapy and/or surgery for children with localized sarcoma of the bladder, prostate, vagina, uterus, and cervix. A comparison of the results in Intergroup Rhabdomyosarcoma Studies I and II.

A major objective of the second Intergroup Rhabdomyosarcoma Study (IRS‐II) (1978 to 1984) was to preserve the bladder without compromising the survival of children with localized genitourinary sarcomas arising in or near the bladder. After incisional biopsy, 109 patients with localized, gross residual sarcoma of the prostate (43 patients), bladder (43 patients), vagina (20 patients), or cervix/uterine corpus (3 patients) were treated with vincristine, dactinomycin, and cyclophosphamide (VAC). After two to four drug courses, radiation therapy and/or surgery were used to treat patients with residual or recurrent tumor. the 3‐year survival rate of patients treated on this primary chemotherapy regimen (70%) was similar to that of the primary surgery regimens of IRS‐I (78%; P = 0.46), but the 3‐year disease‐free survival rate was significantly inferior (52% versus 70%; P = 0.02). Since the IRS‐II encouraged bladder preservation at the onset of therapy, the percentage of patients with bladder and prostate tumors who retained the bladder was initially substantially higher in IRS‐II (97%) than in IRS‐I (58%). However, the percentages of 95 patients with bladder‐prostate (BP) tumors in IRS‐II who retained the bladder and were alive at 2 and 3 years after starting treatment were only 33% and 22%, respectively, compared with 26% and 23%, respectively, in the 66 patients with BP tumors in IRS‐I. Thus, sequential treatment with primary chemotherapy, followed by radiation therapy and/or surgery as given in IRS‐II, failed to improve the eventual bladder salvage rate.