A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma

Mace L. Rothenberg, John V. Cox, Russell F. DeVore, John D. Hainsworth, Richard Pazdur, Saul E. Rivkin, John S. Macdonald, Charles E. Geyer, John Sandbach, Daniel L. Wolf, J. Scott Mohrland, Gary L. Elfring, Langdon L. Miller, Daniel D. Von Hoff

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

BACKGROUND. This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5- fluorouracil (5-FU)based chemotherapy. METHODS. CPT-11 was given as a 90- minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS. A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicides between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age ≥ 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS. CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicides. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

Original languageEnglish (US)
Pages (from-to)786-795
Number of pages10
JournalCancer
Volume85
Issue number4
DOIs
StatePublished - Feb 15 1999

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irinotecan
Carcinoma
Diarrhea
Confidence Intervals
Neutropenia
Fluorouracil
Vomiting
Colorectal Neoplasms

Keywords

  • Clinical trial
  • Colorectal carcinoma
  • CPT-11
  • Irinotecan
  • Topoisomerase I

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma. / Rothenberg, Mace L.; Cox, John V.; DeVore, Russell F.; Hainsworth, John D.; Pazdur, Richard; Rivkin, Saul E.; Macdonald, John S.; Geyer, Charles E.; Sandbach, John; Wolf, Daniel L.; Mohrland, J. Scott; Elfring, Gary L.; Miller, Langdon L.; Von Hoff, Daniel D.

In: Cancer, Vol. 85, No. 4, 15.02.1999, p. 786-795.

Research output: Contribution to journalArticle

Rothenberg, ML, Cox, JV, DeVore, RF, Hainsworth, JD, Pazdur, R, Rivkin, SE, Macdonald, JS, Geyer, CE, Sandbach, J, Wolf, DL, Mohrland, JS, Elfring, GL, Miller, LL & Von Hoff, DD 1999, 'A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma', Cancer, vol. 85, no. 4, pp. 786-795. https://doi.org/10.1002/(SICI)1097-0142(19990215)85:4<786::AID-CNCR5>3.0.CO;2-9
Rothenberg, Mace L. ; Cox, John V. ; DeVore, Russell F. ; Hainsworth, John D. ; Pazdur, Richard ; Rivkin, Saul E. ; Macdonald, John S. ; Geyer, Charles E. ; Sandbach, John ; Wolf, Daniel L. ; Mohrland, J. Scott ; Elfring, Gary L. ; Miller, Langdon L. ; Von Hoff, Daniel D. / A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma. In: Cancer. 1999 ; Vol. 85, No. 4. pp. 786-795.
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abstract = "BACKGROUND. This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5- fluorouracil (5-FU)based chemotherapy. METHODS. CPT-11 was given as a 90- minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS. A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8{\%}; 95{\%} confidence interval [CI], 6.1-15.6{\%}). An additional 67 patients (40.4{\%}) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1{\%} (9 of 64 patients; 95{\%} CI, 5.5-22.6{\%}). Among patients given a starting dose of 100 mg/m2, the RR was 8.8{\%} (9 of 102 patients; 95{\%} CI, 3.3-14.3{\%}). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1{\%}], nausea [15.1{\%}], emesis [9.6{\%}], abdominal cramping [22.2{\%}], and neutropenia [19.9{\%}]). There were no significant differences in the frequencies of Grade 3/4 toxicides between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9{\%} vs. 2{\%}; P < 0.001). Patients age ≥ 65 years were twice as likely (38.6{\%} vs. 18.8{\%}; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0{\%} vs. 14.7{\%}; P = 0.106). CONCLUSIONS. CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicides. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.",
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TY - JOUR

T1 - A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma

AU - Rothenberg, Mace L.

AU - Cox, John V.

AU - DeVore, Russell F.

AU - Hainsworth, John D.

AU - Pazdur, Richard

AU - Rivkin, Saul E.

AU - Macdonald, John S.

AU - Geyer, Charles E.

AU - Sandbach, John

AU - Wolf, Daniel L.

AU - Mohrland, J. Scott

AU - Elfring, Gary L.

AU - Miller, Langdon L.

AU - Von Hoff, Daniel D.

PY - 1999/2/15

Y1 - 1999/2/15

N2 - BACKGROUND. This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5- fluorouracil (5-FU)based chemotherapy. METHODS. CPT-11 was given as a 90- minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS. A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicides between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age ≥ 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS. CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicides. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

AB - BACKGROUND. This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5- fluorouracil (5-FU)based chemotherapy. METHODS. CPT-11 was given as a 90- minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS. A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicides between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age ≥ 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS. CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicides. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

KW - Clinical trial

KW - Colorectal carcinoma

KW - CPT-11

KW - Irinotecan

KW - Topoisomerase I

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