International journal of radiation oncology, biology, physics 1994-06-15
Combined-modality therapy of esophageal cancer with radiotherapy, etanidazole, and cisplatin-fluorouracil, with or without surgery: neurotoxicity, other toxicities and outcome.   
To investigate whether etanidazole and cisplatin can be given safely together and to evaluate the relationship between incidence of peripheral neuropathy and cumulative exposure to etanidazole and cisplatin, as well as other toxicities and treatment outcome.
Thirty-two previously untreated patients with locally advanced esophageal cancer were entered on a Phase I study of etanidazole combined with radiation therapy and chemotherapy. Cisplatin/5-FU (two cycles, weeks 1 and 4) and etanidazole (weeks 2, 3 and 5) were given concurrently with radiation therapy. Eligible patients then underwent surgical resection. All patients were scheduled to receive two additional cycles of cisplatin/5-FU chemotherapy after completion of radiation therapy (definitive arm) or surgery (preoperative arm).
Of 19 fully evaluable patients, nine (47%) developed peripheral neuropathy. Six of six patients, 65 years or older, experienced peripheral neuropathy, compared with three of 13 patients less than 65 years old (p = .003). For patients younger than 65 years, two of the two patients with single dose area under the curve (AUC) > 4.0 mMhr experienced peripheral neuropathy, compared with one of 11 patients with single-dose AUC < 4.0 mMhr (p = .03). Grade 4 toxicity included neutropenia (23%) and thrombocytopenia (26%). No other Grade 4 toxicity was observed. The pathologic complete response rate in patients who underwent surgical resection was 29%.
This regime of chemotherapy, radiotherapy, and etanidazole had acceptable toxicity. However, combining etanidazole and cisplatin appears to increase the risk of developing peripheral neuropathy for at least some categories of patients. Further studies of these interactions are needed.

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