Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities

David R. Gandara, William A. Nahhas, Mark D. Adelson, Stuart M. Lichtman, Edward S. Podczaski, Saul Yanovich, Howard D. Homesley, Patricia Braly, Paul S. Ritch, Steven R. Weisberg, Laura Williams, Robert B Diasio, Edith A. Perez, Daniel Karp, Steven D. Reich, Kathleen McCarroll, Julie V. Hoff

Research output: Contribution to journalArticle

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Abstract

Purpose: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. Patients and Methods: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. Results: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose- intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (p < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. Conclusion: This study did not demonstrate a significant chemoprotective effect against cisplatin- induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

Original languageEnglish (US)
Pages (from-to)490-496
Number of pages7
JournalJournal of Clinical Oncology
Volume13
Issue number2
StatePublished - Feb 1995
Externally publishedYes

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Ditiocarb
Cisplatin
Placebos
Ovarian Neoplasms
Lung Neoplasms
Drug Therapy
Small Cell Lung Carcinoma
Etoposide
Therapeutics
Hearing Loss
Non-Small Cell Lung Carcinoma
Hyperglycemia
Cyclophosphamide
Vomiting
Creatinine
Appointments and Schedules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gandara, D. R., Nahhas, W. A., Adelson, M. D., Lichtman, S. M., Podczaski, E. S., Yanovich, S., ... Hoff, J. V. (1995). Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. Journal of Clinical Oncology, 13(2), 490-496.

Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. / Gandara, David R.; Nahhas, William A.; Adelson, Mark D.; Lichtman, Stuart M.; Podczaski, Edward S.; Yanovich, Saul; Homesley, Howard D.; Braly, Patricia; Ritch, Paul S.; Weisberg, Steven R.; Williams, Laura; Diasio, Robert B; Perez, Edith A.; Karp, Daniel; Reich, Steven D.; McCarroll, Kathleen; Hoff, Julie V.

In: Journal of Clinical Oncology, Vol. 13, No. 2, 02.1995, p. 490-496.

Research output: Contribution to journalArticle

Gandara, DR, Nahhas, WA, Adelson, MD, Lichtman, SM, Podczaski, ES, Yanovich, S, Homesley, HD, Braly, P, Ritch, PS, Weisberg, SR, Williams, L, Diasio, RB, Perez, EA, Karp, D, Reich, SD, McCarroll, K & Hoff, JV 1995, 'Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities', Journal of Clinical Oncology, vol. 13, no. 2, pp. 490-496.
Gandara, David R. ; Nahhas, William A. ; Adelson, Mark D. ; Lichtman, Stuart M. ; Podczaski, Edward S. ; Yanovich, Saul ; Homesley, Howard D. ; Braly, Patricia ; Ritch, Paul S. ; Weisberg, Steven R. ; Williams, Laura ; Diasio, Robert B ; Perez, Edith A. ; Karp, Daniel ; Reich, Steven D. ; McCarroll, Kathleen ; Hoff, Julie V. / Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities. In: Journal of Clinical Oncology. 1995 ; Vol. 13, No. 2. pp. 490-496.
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abstract = "Purpose: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. Patients and Methods: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. Results: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9{\%} of PB-treated patients and 23{\%} of DDTC-treated patients (P = .008). The mean cisplatin delivered dose- intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28{\%} of PB-treated patients had completed all six cycles of therapy, compared with only 6{\%} of DDTC-treated patients (p < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. Conclusion: This study did not demonstrate a significant chemoprotective effect against cisplatin- induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.",
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T1 - Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities

AU - Gandara, David R.

AU - Nahhas, William A.

AU - Adelson, Mark D.

AU - Lichtman, Stuart M.

AU - Podczaski, Edward S.

AU - Yanovich, Saul

AU - Homesley, Howard D.

AU - Braly, Patricia

AU - Ritch, Paul S.

AU - Weisberg, Steven R.

AU - Williams, Laura

AU - Diasio, Robert B

AU - Perez, Edith A.

AU - Karp, Daniel

AU - Reich, Steven D.

AU - McCarroll, Kathleen

AU - Hoff, Julie V.

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N2 - Purpose: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. Patients and Methods: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. Results: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose- intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (p < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. Conclusion: This study did not demonstrate a significant chemoprotective effect against cisplatin- induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

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