Intergroup Rhabdomyosarcoma Study Committee Research Articles

Five-Year Follow-up After Multimodal Treatment Incorporating HDR Brachytherapy for Bladder Prostate Rhabdomyosarcoma in Children

Five-Year Follow-up After Multimodal Treatment Incorporating HDR Brachytherapy for Bladder Prostate Rhabdomyosarcoma in Children

Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Although age <1 year at diagnosis has been associated with a worse prognosis in rhabdomyosarcoma (RMS), the relationship of age at diagnosis to clinical presentation and outcome has not been evaluated carefully. We reviewed data from recent Intergroup Rhabdomyosarcoma Study Committee (later called Group, IRSG) trials to examine this relationship in order to estimate prognosis more accurately and further refine treatment. We used data from IRS-III, -IV Pilot, and -IV (1983-97, N=2,343) to study the relationship of patient age with clinical features and prognosis in a large cohort of patients treated with contemporary therapy. We showed that, after adjusting for important prognostic factors, age was an independent risk factor for treatment failure and patients could be classified into three failure-risk categories based on age (i.e., <1 year; 1-9 years; >10 years). Infants and adolescents were more likely to have unfavorable features, including alveolar or undifferentiated tumors and advanced Group and Stage, and also had significantly poorer failure-free survival (FFS) than did children aged 1-9 (53 and 51% vs. 72%, P<0.001). Although there was a difference in FFS among age categories, there was no evidence that age influences outcome within the three categories. Since age relates independently to outcome after adjustment for known risk factors, it is likely that other factors, including perhaps patients' tolerance of protocol-specified therapy, explain this relationship.

Molecular and surgical advances in pediatric tumors.

Before the 1950s, less than a third of children with Wilms’ tumor, rhabdomyosarcoma (RMS), or neuroblastoma survived. Because of the rarity of these tumors, no single institution could collect enough patients for randomized trials. In the United States, the pediatric cancer study groups joined forces to create the National Wilms’ Tumor Study Group (NWTS) in 1969 and the Intergroup Rhabdomyosarcoma Study Committee (IRS) in 1972. Protocols to treat neuroblastoma have been developed by both the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG). The multinational Societe Internationale d’Oncologie Pediatrique (SIOP) studies form a European counterpart to these groups. The protocols used by these groups that employ multimodality therapy including multiagent chemotherapy, have led to the current long-term survival approaching 40% in neuroblastoma [1], 70% in RMS [2], and 95% in Wilms’ tumor [3]. Each group continues to modify risk-adapted therapy based on identified prognostic factors. Recent identifications of molecular level differences may allow for further stratification of risk and adaptation of therapy to maximize survival while minimizing therapy.

Surgical management of rhabdomyosarcoma in children

This review of the past year's literature summarizes the most relevant advances in the surgical treatment of rhabdomyosarcomas. Improved responses to multimodality therapy and advances in surgical techniques have allowed for more aggressive surgical resection in some patients and less extensive resections in others. The Intergroup Rhabdomyosarcoma Study committee continues to examine prognostic factors in attempts to provide risk-adapted therapy. Development and evaluation of specific recommendations for surgical treatment by site of tumor continue to be a focus of the Intergroup Rhabdomyosarcoma Study. The overall trend is toward less radical surgical intervention with organ preservation.

Second malignant neoplasms in children treated for rhabdomyosarcoma : R. Heyn, V. Haeberlen, W.A. Newton, et al, for the Intergroup Rhabdomyosarcoma Study Committee (IRS). J Clin Oncol 11:262–270, (February), 1993

Second malignant neoplasms in children treated for rhabdomyosarcoma : R. Heyn, V. Haeberlen, W.A. Newton, et al, for the Intergroup Rhabdomyosarcoma Study Committee (IRS). J Clin Oncol 11:262–270, (February), 1993

Tumor-cell DNA content predicts outcome in children and adolescents with clinical group III embryonal rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study Committee of the Children's Cancer Group and the Pediatric Oncology Group.

The prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology. Flow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection. Twelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The probability of progression-free survival at 5 years (+/- SE) was 91% +/- 6% for the hyperdiploid group, compared with 17% +/- 11% for the diploid group (P < .001). Hyperdiploidy was also associated with a significantly higher overall survival rate at 5 years: 96% +/- 4% versus 50% +/- 14% (P = .004). Ploidy retained its prognostic significance after adjustment for tumor site in the Cox regression model. Tumor-cell ploidy strongly correlates with outcome in children with nonmetastic, unresectable embryonal rhabdomyosarcoma. The two biologically distinct groups identified by this measure would benefit from further refinements in risk-directed therapy.

Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the intergroup rhabdomyosarcoma study committee

As increasing numbers of young patients with cancer survive, interest in the late effects of therapy is rising. The sequelae of treatment were reviewed after a minimum of 5 years of observation in 109 surviving patients with sarcoma of the bladder or prostate who were enrolled in the Intergroup Rhabdomyosarcoma Studies I and II (1972-1984). The 82 male and 27 female patients were 3 weeks to 19 years of age when the diagnosis was made (median, 2 years) and were 5-29 years of age at last contact (median, 11 years). Treatment consisted of chemotherapy with vincristine, dactinomycin, and cyclophosphamide and bladder irradiation in nearly all patients. Fifty-four patients underwent total cystectomy, and 10 had a partial cystectomy. Of the 55 patients with bladder preservation, 1 had a urinary conduit with a nonfunctioning bladder. Thus, 54 bladders (50% of the total) remained in place as part of the urinary tract. There was no information regarding bladder function in two patients. Satisfactory bladder function was found in 38 patients (73%), 9 were incontinent, and 5 had urinary frequency with or without nocturia. Posttherapy hematuria was detected in 29% of patients. Nine of the 31 patients (29%) with follow-up renal imaging studies had a structural abnormality, chiefly hydronephrosis, which was more frequent in those with urinary diversion. Positive urine cultures were found mainly among those with enteric urinary conduits, but only two cases of pyelonephritis were documented. Abnormalities of irradiated bone and bowel were observed infrequently. Only one patient had a significantly elevated blood urea nitrogen or serum creatinine value, and only one patient was hypertensive. Most patients were still prepubertal at last follow-up. Of 24 patients who were intrapubertal or postpubertal, 7 (29%) were receiving sex hormone replacement because of delayed pubertal development. Height was decreased by 25% or more in 11 patients, as confirmed by growth chart analysis. Secondary surgical procedures other than repeat biopsy or cystectomy consisted primarily of urinary conduit revisions and repair of bowel adhesions or fistulous tracts. Information about psychosocial status was limited. Overall, 50% of the patients retained their bladders, and 73% of them had satisfactory bladder function. Renal function was preserved in nearly every patient.

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

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). 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. 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). 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.

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

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 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. 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. 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.

Idea analysis: a new approach in using scientific literature

This paper describes a method for identifying the knowledge used by experts in the design of clinical trials. The ideas presented in numerical displays are identified in the medical literature dealing with clinical investigations of the disease. These ideas are extracted, computerized, retrieved, and compared with those in the clinical trial protocol prepared by the experts. The agreements and differences between the two sets of ideas provide insights into the cognitive behavior of experts as they design the therapeutic trial. By tracing the ideas involved, it is possible to estimate the “creation trail” used by the experts. An example is given using the work of the Intergroup Rhabdomyosarcoma Study Committee (IRS). That committee has been the primary contributor of information dealing with the treatment of rhabdomyosarcoma in children. The IRS-III protocol was used in this analysis, because that protocol was adopted by the leading pediatric oncology clinical trial groups in North America and Europe. The Idea Analysis method was found to be useful in identifying most of the ideas used in constructing the IRS-III protocol. Those features which were not direct extensions of the data-supported ideas previously published in the literature could be identified and put into perspective. In most instances, the logic and precursors of the innovative ingredients could be identified.

Tracing expert thinking in clinical trial design

This paper describes a method for the analysis of the clinical trial design process used by experts. With this procedure, the scientific ideas and their sources can be identified and related to the clinical trial protocol actually prepared by the experts. An example is given using the work of the Intergroup Rhabdomyosarcoma Study Committee (IRS). That committee has been the primary contributor of information dealing with the treatment of rhabdomyosarcoma inchildren. The IRS-III protocol was used in this analysis of expert behavior because the protocol was adopted by the leading pediatric oncology clinical trial groups in North America and Europe. The analysis showed that the experts rely heavily, for much of the design, on ideas presented in numerical displays in published documents. Further, those aspects of the design which are innovative can be traced and better understood by applying the new procedure.

Congenital anomalies associated with rhabdomyosarcoma: an autopsy study of 115 cases. A report from the Intergroup Rhabdomyosarcoma Study Committee (representing the Children's Cancer Study Group, the Pediatric Oncology Group, the United Kingdom Children's Cancer Study Group, and the Pediatric Intergroup Statistical Center).

Congenital anomalies were identified in 37 of 115 (32%) children and adolescents autopsied with rhabdomyosarcoma. An analysis of sex, age, site, and histology of cases with or without congenital anomalies showed no significant differences. Of the 45 identified anomalies, 14 were considered major and 31 minor. The distribution of the anomalies by system included central nervous (9), genitourinary (10), gastrointestinal (13), and cardiovascular systems (4). Ten patients had complex or miscellaneous anomalies. There was one child with each of the following: Rubinstein-Taybi syndrome, neurofibromatosis, single horseshoe kidney, hemihypertrophy, and Arnold-Chiari malformation. Aniridia was not noted in any case of rhabdomyosarcoma. Individuals with rhabdomyosarcoma have an increased incidence of genitourinary anomalies similar to that in Wilms' tumor. Recent molecular genetic investigations have suggested that rhabdomyosarcoma, Wilms' tumor, and hepatoblastoma share a common pathogenetic mechanism involving chromosome 11. The uniquely increased association of central nervous system anomalies with rhabdomyosarcoma and absence of aniridia would support a different gene locus operative on chromosome 11 for individuals with rhabdomyosarcoma compared to Wilms' tumor. Extensive epidemiologic studies now in progress in patients with rhabdomyosarcoma should provide the incidence of congenital anomalies and potential linkage with prenatal events.

Localized Orbital Rhabdomyosarcoma: An Interim Report of the Intergroup Rhabdomyosarcoma Study Committee

Children with rhabdomyosarcoma (RMS) (1461 total cases) were included in two prospective, randomized protocols conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Committee from November 1972 to June 1983. Treatment assignment was determined by extent of tumor at diagnosis (clinicopathologic group) and not by primary site. Accordingly, 127 patients with RIVIS confined to the region of the eyelid and orbit were treated by a variety of regimens characterized by initial partial tumor resection followed by concurrent multiagent chemotherapy and orbital radiation therapy. Recurrent tumor developed in ten patients. Seven relapsed initially in the orbit (of whom 4 were salvaged) and three in regional nodes. In addition to the six patients who died of tumor, three died of other causes for a 93% 3-year actuarial survival rate. In 89 children who had subtotal resection or biopsy only, the local control rate with radiotherapy and chemotherapy was 94%.

Intrathoracic soft tissue sarcomas in children: W. M. Crist, R. B. Raney, W. Newton, et al. For the IntergroupRhabdomyosarcoma Study Committee Cancer 50:598–604, (August), 1982

Intrathoracic soft tissue sarcomas in children: W. M. Crist, R. B. Raney, W. Newton, et al. For the IntergroupRhabdomyosarcoma Study Committee Cancer 50:598–604, (August), 1982