Frederick B. Ruymann

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.

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.

High Risk of Subsequent Neoplasms Continues With Extended Follow-Up of Childhood Hodgkin’s Disease: Report From the Late Effects Study Group

PURPOSE We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkins disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up. PATIENTS AND METHODS Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years. RESULTS An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy. CONCLUSION Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.

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).

Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study.

PURPOSE The objectives of this study were to determine if the addition of etoposide, thioguanine, and dexamethasone to daunorubicin and cytarabine (five-drug regimen) during induction would improve remission induction rates and survival of children with acute myeloid leukemia (AML) when compared with the standard regimen of cytarabine and daunorubicin (7 + 3) and whether allogeneic bone marrow transplantation (BMT) or intensive chemotherapy consolidation with or without maintenance would give a superior outcome. PATIENTS AND METHODS A total of 591 assessable children with AML entered Childrens Cancer Group (CCG) trial 213 between January 1986 and February 1989. The status of patients as of September 1, 1992 forms the basis of this report. The results were compared with previous AML studies. RESULTS The projected survival rate of all patients at 5 years is 39% (event-free survival [EFS] rate, 31%), which is superior to that of the prior CCG study (P = .01). The induction rate was 79% for 7 + 3 and 76% for the five-drug regimen (not significant). Comparisons of BMT to chemotherapy favored BMT, but these differences do not always reach statistical significance (eg, 5-year disease-free survival [DFS] rate, 46% v 38% [P = .06] with donor available and 54% v 37% [P = .002] if treated according to protocol intent). No benefit for maintenance therapy was found and, in some comparisons, it was inferior to discontinuation of therapy (5-year survival rate, 46% v 68%, P < .01). CONCLUSION The 5-year EFS rate of patients with AML is 31% and has improved. The five-drug induction regimen is no better than standard induction, BMT appears superior to chemotherapy, and maintenance therapy was not beneficial.

Successful Treatment of Disseminated Central Nervous System Malignant Rhabdoid Tumor

Purpose Malignant rhabdoid tumor (MRT) of the central nervous system (CNS) is pathologically identical to MRT of the kidney. CNS MRTs have the clinicopathological behavior of a high-grade intracranial sarcoma, and the children have a very poor prognosis. We report on three cases of primary CNS MRT with a review and summary of the pediatric literature with respect to demographic features and multidisciplinary management. Patients and Methods The 18 cases reviewed had a male to female ratio of 1.0 and an extremely young median age of 32 months. Our three cases of CNS MRT were treated with surgery, chemotherapy, radiotherapy, and triple intrathecal (TIT) chemotherapy similar to the Intergroup Rhabdomyosarcoma Study III guidelines for parameningeal primary tumors with intracranial extension. Results The three patients described in this report are surviving with no evidence of disease at 5 years, 2 years, and 9 months from diagnosis. Before these three cases, only four of 16 reported patients were known to have survived. One unique case in our report involved disease in the cerebral cortex, sinuses, and orbit with metastases to the subarachnoid space. This metastatic MRT responded to treatment with TIT, multiagent chemotherapy and cranial-spinal radiation after partial resection of only the cortical portion of the MRT. Conclusions Disseminated CNS MRTs can be treated using multidisciplinary management with an approach similar to that used to treat rhabdomyosarcoma.

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.

Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: A report from the Childhood Cancer Survivor Study

Limited data exist on the comprehensive assessment of late medical and social effects experienced by survivors of childhood and young adult acute myeloid leukemia (AML).

Pregnancy Outcome of Partners of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE This study was undertaken to determine the effect, if any, on pregnancy loss, live births, and birthweight of treatment for cancer diagnosed during childhood or adolescence. PATIENTS AND METHODS We reviewed pregnancy outcome among sexually active male Childhood Cancer Survivor Study (CCSS) participants who responded to a questionnaire before February 3, 2000. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered, the cumulative dose of drug administered for several drugs of interest, and the doses, volumes, and dates of administration of all radiotherapy. RESULTS There were 4,106 sexually active males; 1,227 reported they sired 2,323 pregnancies (69% live births, 1% stillbirths, 13% miscarriages, 13% abortions, 5% unknown or in gestation). The male-to-female ratio of the offspring of the partners of the male survivors was significantly different from that of the offspring of the partners of the male siblings of the survivors (1.0:1.03 v 1.24:1.0) (P =.016). The proportion of pregnancies of the partners of male survivors that ended with a liveborn infant was significantly lower than for the partners of the male siblings of the survivors who were the control group for comparison (relative risk = 0.77, P =.007). There were no significant differences in pregnancy outcome by treatment. CONCLUSION This large study did not identify adverse pregnancy outcomes for the partners of male survivors treated with most chemotherapeutic agents. The reversal of the sex ratio and the association observed for procarbazine warrant further investigation.

Variables influencing end-of-life care in children and adolescents with cancer.

Background The purpose of this study was to describe the variables influencing end-of-life care in children and adolescents dying of cancer. Materials and Methods Records of 146 children with cancer who died at Childrens Hospital were reviewed for demographics, diagnosis, location of death, withdrawal of life support, use of “do not resuscitate” (DNR) orders, and the length of time that those orders were in effect. Results Ninety-five patients were evaluated. Fifty-nine died of progressive disease and 36 deaths were therapy-related. Sixty-four percent of disease-related deaths occurred at home with support from home care or hospice. Only 10% of all patients died while receiving maximal aggressive support in the intensive care unit. Age, diagnosis (solid tumor vs. leukemia), cause of death, length of last hospital admission, and the duration of DNR orders had a significant correlation with the place of death and referral to and use of hospice. Thirty-five percent of all patients had hospice support. Conclusions Most children who die of cancer die because of progressive disease at home with hospice support. Do not resuscitate orders were written for most patients who died. End-of-life decisions are influenced by patient diagnosis, cause of death, and age.