Thus, the COG adopted treatment with C5V as the standard. Even though tumor responses to CD were superior, this arm was associated with a higher percentage of drug-associated cardiac toxicities, and there was no statistical difference in outcomes. 12 Tumor progression accounted for 86% of the events among patients treated with C5V but for only 50% of the events among those treated with CD. The Pediatric Intergroup Study INT-0098 randomized patients to receive treatment with 4 to 8 cycles of either C5V or cisplatin and doxorubicin (CD) to compare the efficacy of these 2 regimens. 4, 8 Successive trials from these groups as well as the Japanese Liver Tumor Group and the German Society for Pediatric Oncology have tried to optimize the use of these agents to maximize tumor response, increase resection rates, and improve survival, 9- 11 but because the disease stratification and risk classification used in each trial have varied, no regimen has been shown to be clearly superior. 2 Cisplatin, 5-flourouracil, and vincristine (C5V) have been the standard regimen used in the North American cooperative group/Children's Oncology Group (COG) protocols, whereas the International Childhood Liver Tumors Strategy Group (SIOPEL) has routinely included cisplatin in combination with doxorubicin (PLADO). 7, 8 5-Flououracil, vincristine, carboplatin, ifosfamide, and etoposide have also been used in various combinations with modest improvements in outcomes. 1- 4 However, these most active drugs are dose-limited because of renal, auditory, and cardiac toxicities. Over the last 2 decades, advances in both surgical techniques and chemotherapeutics, including the use of cisplatin and doxorubicin, have resulted in increased survival for children with HB. 3, 4 Historically, approximately two-thirds of such tumors are amenable to conventional resection after several cycles of neoadjuvant chemotherapy. 1, 2 Surgical resection of the primary tumor is the foundation of curative therapy, but only approximately one-third of newly diagnosed children have conventionally resectable tumors at diagnosis. Hepatoblastoma (HB) is the most common malignant liver tumor in children and typically presents in the first few years of life. The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials. The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. The most common adverse events were febrile neutropenia (n = 55 ), infection (n = 48 ), mucositis (n = 31 ), hypokalemia (n = 39 ), and elevated aspartate aminotransferase (n = 28 ). Toxicity was within expectations, with death as a first event in 1 patient. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. Patients were eligible if they had unresectable, nonmetastatic disease. In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin.
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