Bruce Webber

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.

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.

Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma.

Clinical and histopathologic features are often inadequate for accurate prediction of relapse or survival of individual patients with rhabdomyosarcoma (RMS). We therefore studied the cellular DNA content (ploidy) of RMS cells in relation to histology and response to therapy in 37 patients with unresectable tumors. Using flow cytometric techniques, we found that about one third of patients had diploid tumor stem lines, regardless of the histologic subtype. In the group with abnormal ploidy, a hyperdiploid classification (1.10 to 1.80 times the DNA content of normal diploid cells) was exclusively associated with embryonal histology (P = .001). By contrast, near-tetraploidy (1.80 to 2.60 times the DNA content of normal cells) was strongly associated with alveolar histology (P = .001). Thus, in these histologic subtypes of RMS, abnormal ploidy appears to arise through different mechanisms. Tumor-cell ploidy had a significant impact on survival that was especially apparent in patients with unresectable, nonmetastatic (group III) tumors. In this subgroup, hyperdiploidy conferred the best prognosis and diploidy the worst (P less than .0001). None of the eight patients with diploid tumors survived for more than 18 months. Tumor-cell ploidy was the best predictor of treatment outcome for patients with either embryonal (P less than .001; relative risk, 25.5) or alveolar (P = .073; relative risk 7.1) RMS and contributed significantly after adjustment for disease stage and anatomic site. Patients with unresectable diploid RMS have an unacceptably high risk of treatment failure, justifying new therapeutic approaches for this distinct subgroup.

Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas. Report of an international study of four pathology classifications

Background. An International Pathology study was conducted to measure the agreement demonstrated among and within groups of pathologists involved in the categorization of childhood rhabdomyosarcoma according to four pathology classifications. Data concerning agreement and survival experience according to pathonew subtypes were used as a basis for selection of a proposed new pathologic classification.

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.

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.

Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy, with or without radiotherapy: A report from the intergroup rhabdomyosarcoma study (IRS) committee

Purpose Children with bladder rhabdomyosarcoma (RMS) are currently treated with primary chemotherapy and usually with local irradiation. More than 30% of this group ultimately require total cystectomy. The purpose of this study was to review the results of the use of partial as opposed to total cystectomy in 40 patients with bladder RMS during Intergroup Rhabdomyosarcoma Study (IRS)-I, -II, and -III (1972–1989). Patients and Methods A total of 171 children with primary RMS of the bladder were enrolled in the IRS during this interval. Partial cystectomy was performed in 40, in 33 before any other therapy and in seven after 10–57 weeks of chemotherapy (primarily vincristine, actinomycin-D, and cyclophosphamide, i.e., VAC) radiotherapy. Surviving patients have been observed for 4–22 years. Results Thirty-one of 40 patients (78.5%) have been disease free for 2–16 years. Survival among all other IRS cases with bladder RMS during the same interval was 79.5%. Of the 31 surviving patients, one required secondary total cystectomy and two required bladder augmentation procedures for benign bladder contracture. Three quarters of the total group of living patients who have undergone partial cystectomy are without bladder-related symptoms or demonstrable lower urinary tract disease. The remaining patients have a history of functional bladder problems related to contracture or incontinence. Conclusions Partial cystectomy is an alternative to total cystectomy for bladder RMS when the tumor site makes it anatomically feasible. In such patients, it should be considered before total cystectomy and in patients with persistent areas of questionable residual tumor after otherwise apparently successful regimens of primary chemotherapy radiotherapy.

Risk of subsequent contralateral breast carcinoma in a population of patients with in-situ breast carcinoma

One hundred ninety‐one cases of unilateral noninvasive breast carcinoma were studied with regard to the development of subsequent cancers in the contralateral breast. The majority of patients were treated by mastectomy and have been followed for an average of nine years. Their overall survival did not differ significantly from that of age‐specific population survival figures for U. S. women. Among all cases, 13 or 6.8% subsequently developed contralateral carcinoma; 3.1% of these contralateral tumors were invasive. The authors found only one histological type, namely lobular carcinoma in‐situ for which the development of subsequent contralateral carcinomas was statistically significant. Seven of the 68 women with this type developed second breast cancers (10.3%; 4.4% of these were invasive). These data suggest that the occurrence of clinically apparent subsequent cancers developing in the opposite breast following the diagnosis of in‐situ carcinoma is relatively small.

Undifferentiated sarcomas of children: pathology and clinical behavior--an Intergroup Rhabdomyosarcoma study.

Undifferentiated soft tissue sarcoma (UND-STS) is the most poorly defined tumor eligible for intergroup Rhabdomyosarcoma Studies (IRS). Recent IRS UND-STS experience was reviewed to assess the histologic characteristics and clinical behavior of undifferentiated sarcomas. Of the 1,527 patients entered on IRS-III and IRS pilot-IV, 96 had tumors classified by the IRS Pathology Committee as UND-STS. Of these, 52 had adequate histologic material for this study. After application of immunohistochemistry, 18 tumors were reclassified, mostly as embryonal rhabdomyosarcomas (RMS), primitive neuroectodermal tumors, and intraabdominal desmoplastic small found cell tumors. The remaining 34 UND-STS had a diffuse hypercellular histologic pattern made up of sheets of medium-sized cells. The tumor cells had a minimal to moderate amount of cytoplasm and a variable nuclear morphology, predominately vesicular with finely granular chromatin. Except for reactivity with antibodies against vimentin, most tumors had a negative immunohistochemical profile. The 5 year Kaplan-Meier survival estimate for patients with non-metastatic disease was 72%, a significant improvement when contrasted with patients diagnosed to have UND-STS in IRS-I and IRS-II.