Clinical Status and Future Directions of Irinotecan

August 1, 1998
Richard Pazdur, MD

Oncology, ONCOLOGY Vol 12 No 8, Volume 12, Issue 8

Nearly a decade ago, irinotecan (CPT-11 [Camptosar]) began clinical development in Japan. Early clinical trials in that country recognized its anti-tumor activity in a variety of advanced malignancies, including stomach, colon, cervical, and lung

Nearly a decade ago, irinotecan (CPT-11 [Camptosar]) began clinical development in Japan. Early clinical trials in that country recognized its anti-tumor activity in a variety of advanced malignancies, including stomach, colon, cervical, and lung cancers. The anti-tumor activity observed on 5-fluorouracil (5-FU) refractory colorectal cancer patients fulfilled a unique niche in medical oncology, however, since no other agent had consistent clinical activity in this refractory disease setting. Clinical development of this agent proceeded outside of Japan in the United States and Europe examining different doses and schedules than were originally investigated in Japan. In 1996, irinotecan received conditional approval by the United States Food and Drug Administration (FDA) and became commercially available for the treatment of patients with metastatic carcinoma of the colon and rectum that has recurred or progressed following 5-FU-based therapy.[1]

This supplement to oncology focuses on the development of irinotecan, summarizing a conference which was held at The University of Texas M. D. Anderson Cancer Center in January, 1998. The purpose of this conference was to provide a focused discussion of irinotecan’s international development with investigators who had performed either preclinical or clinical evaluations.

Two European phase III trials were presented at this investigators’ meeting by Dr. David Cunningham from the Royal Marsden Hospital who was a principal investigator. These trials provide insight into irinotecan’s clinical benefit in the treatment of metastatic 5-FU refractory colorectal cancer. End points of these trials clarified the drug’s impact on survival, quality of life, and control of disease-related symptoms compared to either best supportive care or infusional regimens of 5-FU. In a randomized trial comparing irinotecan to best supportive care, the group receiving irinotecan had prolonged survival, improved quality of life, and better control of disease-related symptoms.[2] During the trial comparing irinotecan to infusional 5-FU, investigators noted a survival advantage associated with irinotecan with a comparable effect on quality of life and control of disease-related symptoms.[3]

In addition to a discussion of the above phase III trials, four major sessions were held at this symposium. The first focused on the preclinical and early clinical development of the drug. A review of preclinical models which may be useful in designing future schedules and combinations of irinotecan was presented, followed by discussions of phase I trials and irinotecan’s pharmacology.

The second session reviewed trials which were performed primarily in colorectal cancer. These trials included an analysis of the pivotal trials presented for irinotecan’s conditional approval by the FDA, irinotecan’s role in the first-line treatment of colorectal cancer, and trials examining combinations of irinotecan with 5-FU and leucovorin. These latter trials attempt to integrate irinotecan in colorectal cancer treatment strategies in earlier staged patients. In addition, a review of irinotecan’s toxicities, especially diarrhea, and potential methods to reduce this toxic effect are presented.

Although the initial interest in irinotecan emphasized its unique activity in the treatment of colorectal cancers, this agent has a wide spectrum of clinical anti-tumor activity. The third part of the symposium reviewed phase II trials performed in advanced non-small-cell lung, cervical and gastric cancer in the United States, as well as trials performed in Japan, examining the activity of this agent in lymphomas, leukemias, pancreas, ovarian, and small-cell lung cancers. The symposium’s final presentation focused on future uses of this agent: combination chemotherapy regimens incorporating irinotecan, the role of irinotecan in radiation sensitization, and clinical evaluations necessary to more fully assess its palliative role.

This conference brought the experiences of both preclinical and clinical investigators together to review past experiences with irinotecan and to focus collectively on new directions. Since its introduction into clinical practice almost 2 years ago, we now have a clearer understanding of irinotecan’s clinical benefits in colorectal cancers in improving survival and symptoms, its activity in additional malignancies, and insights for future clinical development.


1. Von Hoff DD, Rothenburg ML, Pitot HC, et al: Irinotecan (CPT-11) therapy for patients with previously treated metastatic colorectal cancer: Overall results of FDA-reviewed pivotal US clinical trials (abstract 803). Proc Am Soc Clin Oncol 16:228a, 1997.

2. Cunningham DD, Pyrchonen S, James RD, et al: A phase III multicenter randomized study of CPT-11 vs supportive care alone in patients with 5-FU-resistant metastatic colorectal cancer (abstract 1). Proc Am Soc Clin Oncol 17:1a, 1998.

3. Van Custem E, Bajetta E, Niederle N, et al: A phase III multicenter randomized trial comparing CPT-11 to infusional 5-FU regimen in patients with advanced colorectal cancer (ACRC) after 5-FU failure. Proc Am Soc Clin Oncol 17:256a, 1998.

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