Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma.

PURPOSE: Patients with medulloblastoma are exposed to ototoxic treatments including radiation therapy and platinum chemotherapy. The favorable toxicity profile of carboplatin led us to substitute this chemotherapeutic agent for cisplatin in the HIT-1991, HIT-MED-1999, and HIT-2000 chemotherapy protocols. We retrospectively investigated its consequences in terms of overall survival and ototoxicity rates. METHODS: Twenty-four medulloblastoma patients were treated according to HIT protocols with carboplatin substitution between April 1999 and June 2006. Nineteen (79%) patients had adequate baseline and post-treatment audiological data. Mean age at diagnosis was 9.3 (range 3.5-18.9) years with a mean follow-up time of 30.8 (8.1-111.3) months. Patients received a mean carboplatin cumulative dose of 2,131 (830-4312) mg/m(2). RESULTS: Twenty-three patients were alive at the time of assessment. Hearing loss greater than 20 dB was observed in two (10.5%) of 19 patients. Both had grade 2 ototoxicity according to Brock's scale. There were no significant differences between the patients' baseline and post-treatment audiograms at any frequency. The observed hearing loss was significantly correlated to younger age at diagnosis and cumulative carboplatin dose (p<0.05). CONCLUSIONS: The encouraging overall survival and low hearing loss rates in this medulloblastoma patient cohort suggest that protocols containing carboplatin may offer a viable alternative to standard cisplatin protocols and warrant further investigation.

Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma.

BACKGROUND: Current standard therapy for high-grade osteosarcoma is neoadjuvant chemotherapy and complete resection of the primary tumour. Irradiation can improve local control if complete tumour resection is not possible or refused, but data on long-term outcome are not available. PATIENTS AND METHODS: We report on long-term results for overall survival, occurrence of local recurrence and metastasis, joint function and side-effects in 13 patients with high-grade osteosarcoma having been treated with a combination of local irradiation and polychemotherapy (median follow-up of 13.5 years). RESULTS: Ten of the 13 patients were alive 4-23 years after diagnosis. Three patients suffered local recurrence, in 2 of them tumour control and long-term survival could be achieved by secondary salvage surgery and polychemotherapy. In 5 patients pathological fractures of the irradiated bones occurred, none of them was associated with local recurrence. In 7 of the 10 long-term survivors good or fair joint function was achieved. CONCLUSIONS: We conclude that combination of chemotherapy and intensive local irradiation can achieve long-term local control and even cure in high-grade osteosarcoma. Thus radiation therapy may represent an alternative to definite surgery in selected patients, in particular in those with good response to chemotherapy, when surgery is not feasible or refused.

High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia.

High-dose methotrexate (MTX) has been extensively used for treatment of acute lymphoblastic leukemia (ALL). To determine the optimal dose of MTX in childhood relapsed ALL, the ALL Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group performed this prospective randomized study. A total of 269 children with a first early/late isolated (n = 156) or combined (n = 68) bone marrow or any isolated extramedullary relapse (n = 45) of precursor B-cell (PBC) ALL (excluding very early marrow relapse within 18 months after initial diagnosis) were registered at the ALL-REZ BFM90 trial and randomized to receive methotrexate infusions at either 1 g/m(2) over 36 hours (intermediate dose, ID) or 5 g/m(2) over 24 hours (high dose, HD) during 6 (or 4) intensive polychemotherapy courses. Intensive induction/consolidation therapy was followed by cranial irradiation, and by conventional-dose maintenance therapy. Fifty-five children received stem-cell transplants. At a median follow-up of 14.1 years, the 10-year event-free survival probability was .36 (+/- .04) for the ID group (n = 141), and .38 (+/- .04) for the HD group (n = 128, P = .919). The 2 groups did not differ in terms of prognostic factors and other therapeutic parameters. In conclusion, methotrexate infusions at 5 g/m(2) per 24 hours, compared with 1 g/m(2) per 36 hours, are not associated with increased disease control in relapsed childhood PBC acute lymphoblastic leukemia.

Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87.

PURPOSE: Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria. PATIENTS AND METHODS: Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed. RESULTS: The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses. CONCLUSION: With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.

Pain in pediatric oncology--children's and parents' perspectives.

There is a lack of valid epidemiological data on malignancy-associated pain in modern pediatric oncology. Pediatric oncology patients (self-assessment) and their parents from 28 hospitals were questioned using age-adapted, structured interviews and validated pain assessment tools. Pain intensity was measured by the NRS and Bieri faces scale. We conducted 363 interviews with patients and their parents, and 46 with the parents alone (if patients <2.5 years). Pain was reported at the time of the interview or within the last 24 h, 7 d, or 4 weeks in 15%, 28%, 50% and 58% of cases, respectively. The proportion of patients suffering severe to maximal pain (NRS>3; Bieri>2) increased significantly (p=0.001, chi2 test). The median pain intensity for the most severe pain episode within the last 4 weeks was 6.7 (NRS 0-10). Adverse effects of anti-tumor therapy were the most frequent cause of pain. Multivariate analyses depicted general physical condition either "severely reduced" (ASA status 3) (OR 4.0, 95% CI 1.1-14.7, p=0.037) or "moderately reduced" (ASA status 2) (OR 1.8, 95% CI 1.1-2.9, p=0.018), "in-patient status" (OR 1.8, 95% CI 1.2-2.9, p=0.010), and "co-morbidity present" (OR 3.5, 95% CI 1.1-10.7, p=0.030) as risk factors for severe to maximal pain. General anesthesia was the only factor significantly (OR 0.14, 95% CI 0.05-0.39, p<0.01) associated with a reduction in the proportion of patients suffering severe to maximal pain during bone marrow aspiration. Our data emphasize both the importance of in-house acute pain control and the need for general anesthesia during painful procedures in pediatric oncology.