William A. Newton

The intergroup rhabdomyosarcoma study-I: a final report

The results of treatment of 686, previously untreated patients younger than 21 years with rhabdomyosarcoma or undifferentiated sarcoma, who were entered on Intergroup Rhabdomyosarcoma Study‐I (IRS‐I) were analyzed after a minimum potential follow‐up time of 7 years. Patients in Clinical Group I (localized disease, completely resected) were randomized to receive either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC + radiation. At 5 years, approximately 80% of patients given either treatment were still disease‐free and there was no significant difference between treatments in the overall percentages of patients surviving of 93% and 81%, respectively (P = 0.67). Patients in Clinical Group II (regional disease, grossly resected) were randomized to receive either vincristine and dactinomycin (VA) + radiation or VAC + radiation. At 5 years, 72% and 65% of the patients, respectively, were disease‐free and there was no evidence of a difference between treatments (P = 0.46). The overall survival percentage at 5 years was approximately 72% for both treatments. Patients in Clinical Groups III (gross residual disease after surgery) and IV (metastatic disease) were randomized to receive either “pulse” VAC + radiation or “pulse” VAC + Adriamycin (doxorubicin) + radiation. The complete remission (CR) rate was 69% in Clinical Group III and 50% in IV, with no statistically significant difference in CR rates between treatments in either group. Those who achieved a CR had a nearly 60% chance of staying in remission for 5 years in Clinical Group III compared with approximately 30% in Clinical Group IV. The overall survival percentage at 5 years was 52% in Clinical Group III compared to 20% in Clinical Group IV (P < 0.0001). The 5‐year survival percentage for the entire cohort of 686 patients was 55%. Survival after relapse was poor, being 32% at 1 year and 17% at 2 years. The risk of distant metastasis was much greater than the risk of local recurrence within each clinical group, and there was no evidence of differing types of relapses between treatments. Primary tumors of the orbit and genitourinary tract carried the best prognosis, whereas tumors of the retroperitoneum had the worst prognosis. The authors conclude that for the therapeutic regimens evaluated there was no therapeutic advantage to including radiation in the treatment of Clinical Group I disease, or cyclophosphamide given as a daily low‐dose oral regimen in the treatment of Clinical Group II disease or Adriamycin in the treatment of Clinical Groups III and IV diseases.

Bone sarcomas linked to radiotherapy and chemotherapy in children

We estimated the risk of subsequent bone cancer among 9170 patients who had survived two or more years after the diagnosis of a cancer in childhood. As compared with the general population, the patients had a relative risk of 133 (95 percent confidence interval, 98 to 176) and a mean (+/- SE) 20-year cumulative risk of 2.8 +/- 0.7 percent. Detailed data on treatment were obtained on 64 patients in whom bone cancer developed after childhood cancer. As compared with 209 matched controls who had survived cancer in childhood but who did not have bone cancer later, patients who had had radiation therapy had a 2.7-fold risk (95 percent confidence interval, 1.0 to 7.7) and a sharp dose-response gradient reaching a 40-fold risk after doses to the bone of more than 6000 rad. The relative dose-response effect among patients who had been treated for retinoblastoma resembled that among patients with all other types of initial tumors, although the cumulative risk of bone cancer in the retinoblastoma group was higher. Similar numbers of patients were treated with orthovoltage and megavoltage; the patterns of risk among categories of doses did not differ according to the type of voltage. After adjustment for radiation therapy, treatment with alkylating agents was also linked to bone cancer (relative risk, 4.7; 95 percent confidence interval, 1.0 to 22.3), with the risk increasing as cumulative drug exposure rose. We conclude that both radiotherapy and chemotherapy with alkylating agents for childhood cancer increase the subsequent risk of bone cancer.

Second neoplasms after acute lymphoblastic leukemia in childhood.

BACKGROUND Effective forms of treatment for acute lymphoblastic leukemia (ALL) in childhood now result in survival rates above 70 percent at five years, but the treatments are potentially carcinogenic. To determine the magnitude of this risk and identify possible risk factors for the development of second neoplasms, we studied a large cohort of children treated for ALL. METHODS AND RESULTS. We undertook a retrospective cohort study of 9720 children who had been given a diagnosis of ALL between June 1972 and August 1988 and had been treated according to the therapeutic protocols of the Childrens Cancer Study Group. The median follow-up was 4.7 years (range, 2 months to 16 years). We found that 43 second neoplasms occurred among the children in the cohort, including 24 neoplasms of the central nervous system, 10 new leukemias and lymphomas, and 9 other neoplasms. This represented a 7-fold excess of all cancers and a 22-fold excess of neoplasms of the central nervous system. The estimated cumulative proportion of children in whom a second neoplasm developed was 2.53 percent 15 years after diagnosis (95 percent confidence limits, 1.74 percent and 3.38 percent). An even higher risk, particularly of central nervous system tumors, was evident in children five years of age or less at the time of the diagnosis of ALL (P = 0.012). All central nervous system neoplasms developed in children who had previously undergone irradiation. There was no association with exposure to cyclophosphamide or anthracyclines. CONCLUSIONS There is a substantial excess of second neoplasms, especially of the central nervous system, among children treated for ALL. Children five years old or younger and those receiving radiation are at higher risk, especially for second tumors arising in the central nervous system.

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.

Histopathology of childhood sarcomas, Intergroup Rhabdomyosarcoma Studies I and II: clinicopathologic correlation.

Histopathologic material from 1,782 patients registered in the Intergroup Rhabdomyosarcoma Study Committee (IRS)-I and -II were reviewed by the IRS Pathology Committee in order to provide a uniform approach to classification and correlate patient survival with tumor type. Categories considered eligible were the four types of rhabdomyosarcoma (RMS) (criteria of Horn and Enterline), extraosseous Ewings tumor (EOE), and a group of somewhat variable undifferentiated sarcomas designated small round cell sarcoma, type indeterminate (STI). Tumors that were clearly sarcomas but were unclassifiable also were included (NOS). The committee diagnoses were embryonal (Emb) RMS in 877 (54%), alveolar (Alv) RMS in 343 (21%), botryoid (Botr) RMS in 88 (5%), pleomorphic (Pleo) RMS in 11 (1%), STI in 135 (8%), and EOE in 84 (5%). One in nine were mixtures of types, eg, Emb and Alv. Five percent of the sarcomas could not be classified because of inadequate material. In general, there was close agreement (94%) between the review committee and institutional pathologists in the diagnosis of RMS, but not in the specific types, particularly Alv RMS (41%) and STI (36%). This observation is important, since patients with Alv RMS and STI tumors had decreased survival compared with the other histologies. The prognosis varied by histology, with Botr having the best, Alv RMS and STI the worst, and Emb RMS and EOE an intermediate prognosis.

Intergroup Rhabdomyosarcoma Study: Update for Pathologists

ABSTRACT Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, and 75% of such cases in the United States are reviewed at the Pathology Center for the Intergroup Rhabdomyosarcoma Study Group (IRSG). The first four generations of IRSG therapeutic trials (IRS I–IV) and supportive pathologic studies have generated a new International Classification of Rhabdomyosarcoma (ICR) that offers new morphologic concepts to the practicing pathologist. The objective of this report is to clearly define emerging histopathologic categories of RMS as defined by the ICR, and to emphasize correlative immunohistochemical or molecular studies. Emerging ICR variants of RMS place the patient in widely divergent prognostic categories (superior, botryoid or spindle cell variants; poor, solid alveolar or diffusely anaplastic variants). The cardinal histopathologic features of the ICR combined with results of studies of fusion genes seen with t(1;13) and t(2;13) will help delineate therapeutic subgroups of RMS for the fifth generation (IRS V) of IRSG studies. Consequently, it is imperative for the practicing pathologist to be familiar with the practical workup and diagnosis of RMS in childhood.

The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children

Current therapy of rhabdomyosarcoma involves the use of several modalities of treatment: surgery, radiotherapy, and chemotherapy. The present controlled study was designed to evaluate the role of chemotherapy in the control of occult residual disease following surgery and radiotherapy. The results of this study support the adjunctive use of combined chemotherapy with actinomycin D and vincristine sulfate for 1 year in preventing growth of metastatic or recurrent disease when children are made grossly tumor free by surgery and radiotherapy. Twenty‐four (85.7%) of 28 children in this category are disease free for periods greater than 2 years after initial treatment and a year of chemotherapy. Initial staging and the degree to which a patient can be made tumor free with primary definitive therapy are the most significant variables in prognosis. Vinblastine was not useful in the treatment of metastatic rhabdomyosarcoma.

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.

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.

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.