Abdelsalam H. Ragab

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.

The intergroup rhabdomyosarcoma study. A preliminary report

Four hundred and twenty‐three children with newly diagnosed rhabdomyosarcoma have been entered to date in the Intergroup Rhabdomyosarcoma Study (IRS), which began in 1972. Patients were classified into Clinical Disease Groups (Stages) I‐IV, based on disease extent and resectability, and treatment regimens were randomly assigned according to group. Two hundred and seventy‐eight of 423 patients are evaluable for this analysis. Thus far, for Group I disease (localized/completely resected), disease control achieved by vincristine, dactinomycin, and cyclophosphamide (VAC) given in combination for 2 years has not been enhanced by the administration of postoperative radiation to the tumor bed. To date, 92% of patients in both irradiated and nonirradiated groups exhibit no evidence of disease, and 92‐96% are still alive, with the median time of follow‐up being 72 weeks. For Group II disease (microscopic residual/nodal involvement), VAC given for 2 years has not been found to be more effective than vincristine plus dactinomycin given for 1 year, both groups also having received postoperative irradiation. Thus far, over 85% of patients on either treatment have no evidence of disease and 90% are still alive. Survival and complete remission durations range from 1+ to 143+ weeks and the median duration of follow‐up is 45 weeks. Chemotherapy as initial treatment has been studied in Group III (localized sarcoma not treated initially by gross total resection) and Group IV (metastases present at diagnosis) patients. They have received either intensive “pulse” VAC or “pulse” VAC plus Adriamycin, and radiation has been administered after 6 weeks. Eighty‐one percent of patients in Group III and 81‐83% in Group IV have responded favorably, with complete regression of disease having been observed in over one‐fourth of patients even before the start of radiation and in approximately one‐half of all the patients after receiving radiation therapy. There is no indication as yet that one treatment regimen is superior to the other. Seventy‐nine percent of patients in Group III are still alive (0+ to 154+ weeks) and 69% remain in continuous response (0+ to 139+ weeks) with the median duration of follow‐up being 41‐44 weeks. Fifty percent of patients in Group IV are still alive (0+ to 127+ weeks) with a median time of follow‐up of 41‐44 weeks. Tumors arising either from genitourinary sites or the extremities have had a higher incidence of lymphatic spread than tumors in all other primary sites of origin.

Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee.

PURPOSE This study was performed to determine the incidence and risk factors involved in the development of a second malignant neoplasm (SMN) after treatment of primary rhabdomyosarcoma (RMS) in patients enrolled onto Intergroup Rhabdomyosarcoma Studies I and II (IRS I and II). PATIENTS AND METHODS There were 1,770 patients with primary RMS entered onto IRS I and II between 1972 and 1984. They were treated with chemotherapy and, in most instances, radiotherapy according to randomized or assigned regimens based on clinical grouping. Median follow-up time for these patients was 8.4 years. Incidence density (ID) was calculated for each study and for treatment and age groups. The 10-year cumulative incidence was estimated for each study. RESULTS Twenty-two SMNs have been reported through 1991. The most common tumor type was a bone sarcoma followed by acute nonlymphoblastic leukemia (ANLL). The median time to the development of an SMN was 7 years (range, 1 11/12 to 15 9/12 years). The 10-year cumulative incidence rate was 1.7% for both studies. ID and cumulative incidence estimates were highest for patients who received both an alkylating agent and radiotherapy. The majority of patients for whom family histories were available had either neurofibromatosis themselves or a family history that suggested the Li-Fraumeni syndrome (LFS). CONCLUSION The results of this study suggest that genetic abnormalities play a prominent role in the development of an SMN after therapy for a primary RMS. Chemotherapy with an alkylating agent and radiotherapy play significant roles in the development of an SMN compared with patients who received only one of these therapeutic modalities.

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.

Cisplatin in recurrent pediatric brain tumors A pog phase II study a pediatric oncology group study

Forty‐six evaluable pediatric patients with primary recurrent brain tumors resistant to standard therapy were treated with cisplatin, 60 mg/m2/day, X2 days every 3 to 4 weeks, to study the efficacy and toxicity of this drug. Complete and partial responses, documented by computed tomography (CT) scan, were demonstrated in 4 of 10 patients with medulloblastoma and 3 of 15 patients with ependymoma. No activity was documented in astrocytic tumors. Dose limiting major toxicities were renal and auditory. It is recommended that the new analogues of cisplatin with less toxicity be studied in these tumors.

Neonatal rhabdomyosarcoma: The IRS experience

Neonatal rhabdomyosarcoma is rare, and the characteristics and optimal therapy for patients with this condition have not been well described. Of 3,217 eligible patients entered in the Intergroup Rhabdomyosarcoma Study (IRS), 14 were less than 30 days old at the time of diagnosis. Among these patients, male gender, Caucasian race, caudal tumors, and embryonal/botryoid and undifferentiated histology predominate. Although half the neonates survived, neither histology, tumor size, nor type of surgery were predictive of outcome. The presence of necrosis and small round cell configuration coincides with a poor prognosis, regardless of histological diagnosis. Neonatal rhabdomyosarcoma of caudal origin has a favorable prognosis.

Phase I Trial of Paclitaxel in Children With Refractory Solid Tumors: A Pediatric Oncology Group Study

PURPOSE A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.

Occult testicular leukemia: Testicular biopsy at three years continuous complete remission of childhood leukemia: A Southwest Oncology Group study

Between June 1977 and December 1978, occult testicular leukemia (OTL) was discovered at three years of continual complete remission (CCR) from the time of diagnosis of acute lymphoblastic leukemia (ALL) in 5 of 59 (8.5%) of males undergoing bilateral wedge testicular biopsy at 1 of 15 participating Southwest Oncology Group (SWOG) institutions. Forty‐six of the 54 males with normal biopsies (78% of the total group of 59) have remained free of recurrent ALL at a median of 18 months (range 13 to 23 months) since the biopsy procedure, whereas eight have relapsed for the first time—five bone marrow (BM), one sclera, one simultaneous BM and testes, and one testes—at a median of 12.5 months (range 4 to 22 months) after the normal testicular biopsy. With aggressive therapy after biopsy in the five boys with OTL, one has died 19 months after biopsy (after two BM relapses), one is alive 21 months after biopsy (after two BM relapses), and three are alive and free of recurrent ALL 13, 16, and 19 months, respectively, since the diagnosis of OTL.

Clinical characteristics and treatment outcome of children with acute lymphocytic leukemia and Down's syndrome. A Pediatric Oncology Group study.

Of 2947 children with acute lymphocytic leukemia (ALL), treated during three consecutive studies of the Pediatric Oncology Group (1974–1986), 52 (1.8%) had Downs Syndrome (DS). Comparison of clinical and laboratory characteristics showed no significant differences in leukocyte count, racial distribution, sex ratio, platelet count, incidence of mediastinal mass, lymphadenopathy or hepatosplenomegaly, or percentage of blood or bone marrow blasts for children with ALL with or without Downs Syndrome (DS‐ALL or NDS‐ALL, respectively). However, children with DS‐ALL were slightly older at the time of presentation and had higher hemoglobin values. The relative frequency of each major immunophenotype (early pre‐B, pre‐B, T, or B) was also comparable for patients with or without DS. For this report, treatment regimens were categorized as either conventional (no consolidation therapy) or intensive. Cox regression analysis revealed that the presence of DS, a higher leukocyte count, black race, or age older than 10 years was independently associated with a poorer event‐free survival (EFS) for children treated with conventional chemotherapy. However, for the cohort of children who received intensive chemotherapy, DS was no longer an independent risk factor. In fact, event‐free survival (EFS) was markedly improved to a level comparable with that observed in the children diagnosed as having NDS‐ALL. On the other hand, serious toxicity, requiring interruption of treatment, was significantly more frequent in the intensively treated children with DS compared with similarly treated patients with NDS‐ALL, although deaths resulting from toxicity occurred infrequently.

Soft-tissue sarcoma of the trunk in childhood: Results of the intergroup rhabdomyosarcoma study

Disease‐free survival data were obtained on 30 children with soft‐tissue sarcoma of the trunk. The children were clinically grouped and treated in accord with the IRS protocol (Cancer 1977; 40:2015) from November 1972 through December 1976. Histologically, 40% of the tumors were alveolar rhabdomyosarcoma (RMS), 20% were embryonal RMS, 20% were extraosseous Ewings sarcoma, 17% were undifferentiated sarcoma, and 3% were pleomorphic RMS. In 14 patients with primary tumors of the chest wall, the male‐to‐female (M:F) ratio was 3:11, and the median age was 12.5 yr. Five of the ten patients (50%) with localized tumor (Groups I‐III) were disease‐free at a median of 4.7 yrs. after diagnosis; two died of locally recurrent tumor, two died of metastases to lungs or bones, and 1 died of intracranial hemorrhage. None of the four with chest wall tumors and distant metastases (Group IV) survived. In ten patients with localized paraspinal primary tumors, the M:F ratio was 8:2, and the median age was 3.5 yrs. None had metastases. Seven of ten (70%) were disease‐free at a median of 4.7 yrs. after diagnosis. Two died after regional recurrence developed (one retroperitoneal, one meningeal), and one died of lung metastases. In six patients with primary tumors of the abdominal wall, the M:F ratio was 3:3 and the median age was 9.5 yrs. Three of five with localized tumor (Groups I‐III) were disease‐free at a median of 5 yr. after diagnosis; one died after regional recurrence, and one died from accidental trauma. The one Group IV patient died of tumor. Overall, 15 of 30 patients (50%) are alive and free of recurrent disease at a median of 5+ yr. after initiation of treatment. The authors conclude that prognosis is most favorable for patients with paraspinal tumors, least favorable for those with chest wall tumors, and intermediate in patients with abdominal wall tumors. Prognostic differences appeared to be influenced by extent of disease at diagnosis and histologic subtype of the sarcoma.