A phase I study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non‐hematopoietic solid tumors

Abstract

Background The combination of a platinum agent and anthracycline has shown activity in pediatric solid tumors. This trial evaluated the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin combined with doxorubicin in pediatric patients with recurrent solid tumors. Methods Oxaliplatin was administered on day 1 and Doxorubicin on days 1–3 of each 21 day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels were evaluated: 1) oxaliplatin 105 mg/m2 and doxorubicin 20 mg/m2, 2) oxaliplatin 130 mg/m2 and doxorubicin 20 mg/m2, and 3) oxaliplatin 130 mg/m2 and doxorubicin 25 mg/m2. Dexrazoxane was administered at 10 times the doxorubicin dose prior to doxorubicin infusion. Results Seventeen patients were enrolled. Dose level 1 was the determined MTD. Grade 2 cardiac DLT was seen in 1 of 6 patients on dose level 1, grade 4 thrombocytopenia in 2 of 5 patients on dose level 2, and 1 each of grade 2 cardiac and grade 4 thrombocytopenia in 5 patients on dose level 3. Cardiac DLT was only noted in patients with prior exposure to both anthracycline and chest radiation. No grade 3 or 4 neurotoxicity or mucositis was seen. Objective responses were noted in 2 patients with neuroblastoma and 1 each of mixed germ cell tumor, thymic neuroendocrine carcinoma and nasopharyngeal carcinoma. Conclusions Oxaliplatin 105 mg/m2 on day 1 combined with doxorubicin 20 mg/m2 days 1–3 was the MTD. This combination shows sufficient activity to justify further studies in select pediatric tumors.

Risk–Benefit of Dexrazoxane for Preventing Anthracycline-Related Cardiotoxicity: Re-Evaluating the European Labeling

“…The overall tolerability and safety of dexrazoxane has been established in extensive reviews [22,28]. Several recent investigations highlighted the incidence of adverse hematological events in children after dexrazoxane treatment (Table 3) [6,8,12,14,16]. The COG P9404 trial found similar rates of infection, hematologic toxicity and central nervous system toxicity in patients who did and did not receive dexrazoxane [6].…”

“…The only grade 3/4 event to differ significantly between groups was mucositis, which had a lower incidence in the dexrazoxane group (33/273 [12.1%] patients) than in the no-dexrazoxane group (52/264 [19.7%] patients; p = 0.02). Other nonrandomized studies have reported adverse hematological events after dexrazoxane treatment [8,12,14,16]. Despite the hematological toxicity observed in some studies, overall treatment with dexrazoxane appears to be well tolerated.…”

“…The only randomized trial showed that the incidence of grade 3/4 hematological toxicity was virtually identical in patients treated with (89.0%) or without (89.8%) dexrazoxane (p = 0.26) [6]. The myelosuppressive changes observed in nonrandomized studies [8,12,14,16] may have been caused by the complex chemotherapy being administered. The Cochrane Group meta-analysis found no differences in the incidences of grade 3/4 thrombocytopenia, abnormal platelet counts (nadir or at recovery), neutropenia, abnormal granulocyte counts (nadir or at recovery) or white blood cell counts at recovery in patients treated with or without dexrazoxane [22].…”

“…When we limited the results to publications consistent with the revised label for Cardioxane, 13 clinical trials [6][7][8][9][10][11][12][13][14][15][16][17][18] and four meta-analyses or systematic reviews remained [19][20][21][22]. These meta-analyses and systematic…”

“…Dexrazoxane is an effective cardioprotectant in children Since the CHMP review, 11 relevant publications have examined the use of dexrazoxane in children [6,7,[9][10][11][12][14][15][16][17][18]. The Children's Oncology Group (COG) P9404 randomized trial evaluated oncologic efficacy, cardioprotective effectiveness and safety following dexrazoxane therapy in 537 children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic non-Hodgkin lymphoma (Table 1) [6].…”