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.
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 irinotecans
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 irinotecans clinical benefit in the
treatment of metastatic 5-FU refractory colorectal cancer. End points
of these trials clarified the drugs 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. 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.
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 irinotecans pharmacology.
The second session reviewed trials which were performed primarily in
colorectal cancer. These trials included an analysis of the pivotal
trials presented for irinotecans conditional approval by the
FDA, irinotecans 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 irinotecans 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 symposiums 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 irinotecans 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.