Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma.

Abstract

Between January and December 1985, 17 children with advanced neuroblastoma who were greater than 1 year old (16 stage IV, one stage III) were administered cisplatin (CPDD, 200 mg/m2) and etoposide (VP-16, 500 mg/m2) as a pilot study of toxicity and response rates for the European Neuroblastoma Study Group (ENSG). The study was designed to assess toxicity of two courses of treatment, and evaluate response rates after this short therapy. The creatinine clearance declined in seven of 15 patients. No patient experienced clinically significant hearing loss, but formal audiometric assessment of nine children revealed characteristic high tone loss in seven patients. Peripheral neuropathy was not seen. Asymptomatic hypomagnesemia (less than 0.7 microEq/L) was frequent, despite routine supplementation. Asymptomatic electrolyte imbalances occurred frequently, but were generally transient. Myelosuppression was severe, but brief. Seven patients required platelet transfusions and seven were readmitted between courses due to febrile episodes while neutropenic. There were no treatment-related deaths. According to strictly defined criteria, 12 of 17 patients showed a partial response (PR), and extensive marrow evaluation showed complete clearing of disease in six of 15 patients. This high-dose regimen, if carefully supervised, is associated with acceptable toxicity, comparable to that seen when the dose of CPDD is spread over several months. The rapidity and degree of response was encouraging and merits further evaluation.

Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution

“…With the high doses of platinum compounds used, a dose-effect relationship has already been shown. 21,22,36 The response rates we observed with these conventional regimens are within the ranges already published. Only 34% of patients entered CR or VGPR following first-line chemotherapy (good responders).…”

“…The protocols used for conventional chemotherapy, which have previously been published, were mostly a combination of vincristine, cyclophosphamide, doxorubicin, etoposide or teniposide, cisplatinum or carboplatin. [20][21][22] High-dose chemotherapy During these two decades, several high-dose drug combinations were used. Throughout the period, all combinations contained high-dose melphalan, 140 to 180 mg/m 2 , and approximately 50% of patients were treated with a busulfan-containing regimen.…”

Amifostine does not protect against the ototoxicity of high‐dose cisplatin combined with etoposide and bleomycin in pediatric germ‐cell tumors

“…[5][6][7][8][9]38,39 Significant concerns regarding the longterm toxicity of cisplatin and bleomycin [11][12][13][14][15] delayed the introduction of cisplatin-based therapy in pediatric patients. After pediatric Phase II studies suggesting that high-dose cisplatin was effective and tolerable in patients with solid tumors and neuroblastoma, 23,24 the POG/CCG Intergroup Germ-Cell Tumor Subcommittee designed a randomized study to evaluate the effect of cisplatin dose intensity on outcome. 25 Unlike the adult study, 7 the pediatric study revealed that using HDPEB improved EFS significantly for pediatric patients with advanced GCT.…”

“…Further, German investigators developed a risk-based approach to PGCT that incorporated the use of both cisplatin and ifosfamide. 18 -20 The adult data suggesting that high-dose cisplatin, etoposide, and bleomycin (HDPEB) was more effective than PEB, 21,22 along with the reports suggesting that high-dose cisplatin was efficacious and had acceptable toxicity, 23,24 prompted the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) to evaluate the impact of cisplatin dose intensity on outcome. The results of that study revealed that unlike in adults with testicular tumors, 7 HDPEB significantly improved the EFS for children with advanced GCT.…”

Where next with therapy in advanced neuroblastoma?

“…High response rates in relapsed patients had been reported several years ago, using conventional dose cisplatinum in combination with VM26 (Hayes et al, 1981), and the demonstration in adults with germ cell tumours that considerable dose escalation of cisplatin was possible if the drug was given in divided doses encouraged enthusiam about this approach in neuroblastoma. Fortunately, children are much less prone to the often crippling peripheral neurotoxicity of high dose cisplatin seen in adults and this regimen was well tolerated in phase III studies (Hartmann et al, 1988). Ifosfamide/adriamycin and high dose platinum/VP16 produces rapid clearing of metastatic disease and, with surgery, produces CR rates around 60% (Pinkerton et al, 1990).…”