18 Is it time to rethink the role of hyperfractionated radiotherapy in the management of children with newly-diagnosed brainstem glioma?: Results of a pediatric oncology group phase III trial comparing conventional vs. hyperfractionated radiotherapy

PURPOSE Children less than 1 year of age with metastatic neuroblastoma NB are at high risk of death. The need to identify new and effective chemotherapy agents is clear. A study was conducted by the Pediatric Oncology Group (POG) to determine the efficacy and safety of administering two courses of a single phase II agent before conventional treatment as a means to evaluate new agents in this setting. PATIENTS AND METHODS One hundred seventy-three eligible patients more than 1 year of age with disseminated neuroblastoma received two courses of one of the following: ifosfamide (IFOS) 2 g/m2/d for 4 days intravenously (IV) plus mesna; carboplatin (CARB) 560 mg/m2 i.v. over 1 hour; iproplatin (CHIP) 325 mg/m2 IV over 2 hours; or epirubicin (EPIR) 90 mg/m2 i.v. push. Following evaluation for response and toxicity, eligible patients were randomized to receive either cisplatin 90 mg/m2 i.v. on day 1, etoposide 200 mg/m2 i.v. on day 3, cyclophosphamide 150 mg/m2/d orally on days 7 to 13, doxorubicin 35 mg/m2 i.v. on day 14 (CECA), or cisplatin 40 mg/m2 IV on days 1 to 5 and etoposide 200 mg/m2 i.v. on days 2 to 4 alternating at 3-week intervals with cyclophosphamide 150 mg/m2/d orally on days 1 to 7 and doxorubicin 35 mg/m2 IV on day 8 (HDP/VP/CA). An additional 86 patients were randomized to receive either CECA or HDP/VP/CA without initial phase II therapy. RESULTS After phase II therapy, only 20% of patients experienced grade 3/4 hematopoietic toxicity. No toxic deaths occurred. Objective response rates (partial responses [PRs] plus minor responses [MRs]) following IFOS, CARB, CHIP, and EPIR were 70%, 77%, 67%, and 26%, respectively. Following phase III treatment, there was no statistically significant difference in rates of complete response (CR)/PR or progressive disease (PD), or in time to PD of patients who participated in the phase II window versus those who received only CECA or HDP/VP/CA. CONCLUSION IFOS, CARB, and CHIP are efficacious in neuroblastoma, are well tolerated, and should be incorporated into primary treatment regimens. Combination regimens using these agents may be possible, since most repeat courses were given within 2 weeks. Administering phase II therapy to untreated patients with high-risk tumors provides a unique and sensitive method to assess new agents without compromising patient outcome.

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A Comparison of Hepatotoxicity and Neutropenia in Children Given Oral Mercaptopurine on a Twice-Daily Versus Once-Daily Dosing Schedule for Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study.

Blood ◽

10.1182/blood.v104.11.994.994 ◽

2004 ◽

Vol 104 (11) ◽

pp. 994-994

Author(s):

R. Chesley ◽

B. A. Bell ◽

M. Devidas ◽

B. Bostrom ◽

G. Erdmann ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Phase Iii ◽

Oncology Group ◽

Dose Frequency ◽

Phase Dependence ◽

Continuation Therapy ◽

Pediatric Oncology Group ◽

Grade 3

Abstract Pediatric Oncology Group (POG) protocol 9605, a phase III study of standard risk acute lymphoblastic leukemia (ALL), was designed in part to compare daily (QD) versus twice-daily (BID) mercaptopurine (MP) dosing during intensification and continuation therapy. 1082 patients were enrolled between 1996 and 1999. MP is an important antimetabolite in the treatment of ALL. Due to its S-phase dependence and short half-life, dosing frequency may be crucial to toxicity and/or efficacy. MP is converted into two major metabolites, 6-thioguanine (TGN) and 6-methylthioinosinic acid (mMP). Correlations of toxicity and dose frequency were tabulated. Red blood cell (RBC) TGN and mMP levels measured in a randomized subpopulation (226/1082 patients) on POG 9605 found markedly elevated mMP in the QD versus BID group (2020 versus 1275 ng/8x108 RBC) with slightly higher levels of TGN in the QD group (42 versus 40 ng/8x108 RBC). Toxicity events occurring during treatment were recorded according to toxicity code, grade and week of therapy. Toxicity events for 1037/1082 patients were analyzed. For each toxicity, QD and BID groups were compared based on total number of events, number of individual patients, and average number of events per patient. A comparison of the incidence of neutropenia and hepatotoxicity between QD and BID groups became the focus. 518/1037 patients received 6MP 75 mg/m2 daily and 519/1037 patients received 6MP 37.5 mg/m2 twice daily. Decreased ANC were coded as grade 3 (0.5–0.9 x 103/mm3) or grade 4 (less than 0.5 x 103/mm3). Decreased WBC were coded as grade 3 (1.0–1.9 x 103/mm3) or grade 4 (less than 1.0 x 103/mm3). Elevated aminotransferase (ALT/AST) were coded as grade 3 (5.1–20 x normal) or grade 4 (greater than 20 x normal). For grade 4 neutropenia, the QD group had a significantly higher average number of events per patient than the BID group (4.67 versus 4.22, p=0.021). Also for grade 3 ALT/AST, the QD group had a significantly higher average number of events per patient than the BID group (2.40 versus 2.10, p=0.046). In previous studies, higher mMP levels were found to be correlated with elevated aminotransferases. The subpopulation (n=226/1082) data was analyzed to compare metabolite levels in patients who experienced various toxicities. In the QD arm, TGN was significantly elevated in those patients with grades 3 and 4 WBC (p=0.026) and grades 3 and 4 ANC (p=0.032). MMP was significantly elevated in those with grades 3 and 4 WBC (p=0.0066), grades 3 and 4 ANC (p=0.009) and grades 3 and 4 ALT/AST (p=0.0082). QD administration of 6MP is associated with increased levels of methylated metabolites, elevated ALT/AST and decreased ANC. Neutropenia correlates with elevations of both TGN and mMP. Hepatotoxicity correlates with elevations in mMP. Issues of adherence to dosing may also play a role. Implications for patient outcome await data maturation.

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