Marc E. Horowitz

Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors

BACKGROUND Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Therefore, in 1986, the Pediatric Oncology Group began a study in which postoperative chemotherapy was given in order to permit a delay in the delivery of radiation to the developing brain. METHODS Children under 36 months of age with biopsy-proved malignant brain tumors were treated postoperatively with two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. This sequence was repeated until the disease progressed or for two years in 132 children 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis. After this, the patients received radiation therapy. The response to the first two cycles of chemotherapy was measured in 102 patients with residual postoperative disease. RESULTS The first two cycles of cyclophosphamide and vincristine produced complete or partial responses in 39 percent of the 102 patients who could be evaluated. The response rates were highest among patients with medulloblastomas, malignant gliomas, or ependymomas. Patients with brain-stem gliomas or embryonal tumors (primitive neuroectodermal tumors) had little or no response. The progression-free survival rate was 41 percent at one year for children who were 24 to 36 months old at diagnosis and 39 percent at two years for those under 24 months of age at diagnosis. Multivariate analysis identified embryonal tumors as a significant adverse prognostic feature (relative risk, 2.2; 95 percent confidence interval, 1.4 to 3.4) and complete resection as a favorable feature (relative risk, 0.33; 95 percent confidence interval, 0.20 to 0.54). Complete responses to chemotherapy were associated with a progression-free survival rate approaching that achieved with gross total resection. A comparison of cognitive evaluations obtained at base line and after one year of chemotherapy revealed no evidence of deterioration in cognitive function. CONCLUSIONS Chemotherapy appears to be an effective primary postoperative treatment for many malignant brain tumors in young children. Disease control for one or two years in a large minority of patients permitted a delay in the delivery of radiation and, on the basis of preliminary results, a reduction in neurotoxicity. For patients who had undergone total surgical resection or who had a complete response to chemotherapy, the results are sufficiently encouraging to suggest that radiation therapy may not be needed in this subgroup of children after at least one year of chemotherapy.

Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas.

BACKGROUND An excess risk of second malignancies has been reported in survivors of Ewings sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewings sarcoma and to identify possible causal factors. METHODS Information was derived from a data base that included 266 survivors of Ewings sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated. RESULTS After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P = .002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy. CONCLUSION The overall risk of second malignancies after Ewings sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.

Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation.

One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.

Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma.

PURPOSE In an effort to improve outcome in patients with metastatic or high-risk localized Ewings sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT. RESULTS Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008). CONCLUSIONS Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.

Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

PURPOSE Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. PATIENTS AND METHODS A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. RESULTS The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. CONCLUSIONS The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

Prognostic Factors in Infants and Very Young Children with Intracranial Ependymomas

The Pediatric Oncology Group (1986–1990) conducted a study in which 48 children <3 years of age with intracranial ependymomas were treated with prolonged postoperative chemotherapy (CT) and delayed RT. Thirty-one children, 0–23 months of age at diagnosis (Gp A) received 2 years of CT followed by RT; while 17 children, 24–36 months of age at diagnosis (Gp B) received CT for 1 year followed by radiation. One-year survivals were 87% (Gp A) and 94% (Gp B) and 2-year survivals were 67% (Gp A) and 82% (Gp B). In subsequent years a significant divergence in survivals according to age has been noted (p = 0.04). Five-year survivals were 25.7% (Gp A) vs. 63.3% (Gp B). The curves began to diverge 1 year following diagnosis. Other than age, the only significant prognostic factor was degree of surgical resection: 5-year survivals were 66% (total resection) vs. 25% (subtotal resection). Neither the presence of metastases, degree of anaplasia nor the degree of surgical resection varied significantly according to age at diagnosis. The most likely reason for the difference in survivals between the two age groups relates to the timing of radiation following CT, i.e., 1-year delay in children 24–36 months of age compared to a 2-year delay in children 0–23 months of age. An alternative but less likely hypothesis is that ependymomas in the younger children have a more aggressive biology. In contrast, survivals in the 24- to 36-month group are much better than previous reports in the literature suggesting that prolonged postoperative CT may allow both a delay in CRT as well as provide improved survivals. Based on these results, future treatment trials should emphasize maximal surgical resection and a delay in radiation of no more than 1 year.

Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study.

The multiinstitutional osteosarcoma study (MIOS), a randomized trial of adjuvant therapy for osteosarcoma with a concurrent control group, registered 113 patients from June 1982 to August 1984. Preliminary analysis of the study indicated a significant event-free survival advantage favoring immediate adjuvant chemotherapy, (P less than .001). For patients treated with surgery alone or with surgery and adjuvant chemotherapy, the lungs were involved in more than 80% of the relapses. Patients relapsing after surgery alone tended to relapse earlier (P less than .01), had more pulmonary nodules (P less than .01), and had more frequent bilateral pulmonary involvement (P less than .01) than those treated with immediate postsurgical adjuvant chemotherapy. However, patients relapsing after treatment with surgery alone experienced a significantly longer interval to further disease progression (P less than .01) and improved survival after relapse (P = .01) when compared with patients who relapsed after treatment with immediate adjuvant chemotherapy. The only factor predictive of survival after relapse was if the patient could be made surgically disease-free after initial relapse (P = .03).

Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna.

Ifosfamide/mesna treatment of 50 patients with pediatric malignant solid tumors was associated with the development of neurotoxic signs and symptoms in 11 of these individuals who received 29 courses of treatment. Neurologic toxicity included changes in mental status, cerebellar function, cranial nerve, and cerebellar and motor system function, including seizures. All symptoms, signs, and EEG abnormalities were transient. Some of the affected individuals failed to develop acute neurotoxic signs of symptoms when retreated with ifosfamide. A grading system for scoring these neurologic abnormalities is presented for comparison of acute neurotoxic effects of other agents. Recommendations are made regarding early termination or delay of ifosfamide/mesna treatments in the presence of significant neurotoxicity.

Long-term follow-up of Ewing's sarcoma of bone treated with combined modality therapy

Between 1968 and 1980, 107 consecutive patients with Ewings sarcoma of bone were entered on three sequential combined modality treatment protocols (S2, S3, S4) at the National Cancer Institute (NCI). Protocol treatment involved 4 cycles of two drug [cyclophosphamide (CTX) and vincristine (VCR)] or three drug [CTX and VCR with either actinomycin-D (ACT-D) or doxorubicin (ADR)] regimens and local irradiation (50 Gy) to the involved bone. Eighty patients presented with localized disease and 27 patients had metastatic disease at presentation, including 11 patients with multiple metastatic sites. With a median potential follow-up of greater than 15 yrs (range 8-20 yrs), 28 pts (27%) remain alive. Disease-free (DFS) and overall survival (OS) decreased most rapidly during the initial 5 yrs of follow-up with 5-yr DFS of 29% and 5-yr OS of 39%. Only two patients with metastases at presentation are long term (greater than 5 yr) survivors. For localized disease patients, the 2, 5, 10, and 15 yr DFS and OS are 52%, 37%, 35%, and 33% DFS and 68%, 51%, 39%, and 34% OS, respectively. Eleven patients relapsed locally as the first site of failure. Using the Cox proportional hazards model, four significant variables for both DFS and OS were recognized, including metastatic disease at presentation, age greater than 25 yrs, high LDH in localized disease patients, and central primary tumor in localized disease patients in decreasing order of significance. We conclude that a majority of these patients with Ewings sarcoma of bone relapsed within 5 yrs of presentation although late relapse (5-15 yrs) did occur. Local failure occurred in 20% of patients using these combined modality treatments but had no impact on overall survival.