Irinotecan (Camptosar, CPT-11), a member
of the camptothecin family, represents the most active camptothecin available
for clinical use today. Irinotecan is a topoisomerase I inhibitor. Topoisomerase
enzymes support the topologic structure of DNA, thus facilitating translation
and transcription. The enzyme topoisomerase I plays a crucial role in the
relegation of single-strand breaks and in relieving torsional DNA stress.[1,2]
Irinotecan and other camptothecin analogs interfere in this process by
stabilizing the topoisomerase I/DNA cleavable complex. This process is not
compatible with prolonged cell survival.
Irinotecan was approved for use in the second-line therapy of
advanced colorectal carcinoma in the United States in 1996. Since then,
irinotecan has been extensively investigated in a variety of tumor types
(including colorectal carcinoma) with encouraging results. Further developments
in colorectal carcinoma have shown that irinotecan is a highly valuable agent in
either first- or second-line treatment of advanced disease, prolonging survival
and improving quality of life.
Recent developments in the investigation of irinotecan as a
single agent, in combination chemotherapy, or in combined-modality therapy in a
variety of gastrointestinal cancers are described in this supplement. Each
manuscript represents a synopsis of data presented at the symposium sponsored by
The University of Texas M. D. Anderson Cancer Center in Sonoma, California, in
July 1999. The objectives of this endeavor were to provide an update on a number
of strategies currently being explored with irinotecan and to stimulate new
In this issue of Oncology, Royce et al present an
overview of chemotherapy in patients with colorectal carcinoma and point out the
studies performed with agents such as capecitabine (Xeloda), UFT/leucovorin,
eniluracil/fluorouracil (5-FU), oxaliplatin, and irinotecan.
Saltz describes a phase III comparison of
irinotecan/leucovorin/5-FU vs leucovorin/5-FU vs irinotecan administered as
first-line therapy to patients with advanced colorectal carcinoma. The results
of this study demonstrate a markedly higher and statistically significant
increase in response rate, time to progression, and median survival for the
patients who received the three-drug regimen (irinotecan/leucovorin/5-FU). These
positive findings were reviewed by the Oncology Drug Advisory Committee of the
US Food and Drug Administration (FDA) in March 2000. The Committee unanimously
approved the three-drug combination for the first-line therapy of patients with
advanced colorectal carcinoma. In addition, these important findings build a
strong case for the ongoing phase III adjuvant trial for patients with
node-positive colon carcinoma.
On behalf of the V-303 Study Group, Douillard discusses the
European phase III trial in which patients with advanced colorectal carcinoma
received either irinotecan/leucovorin/ 5-FU or leucovorin/5-FU. Their results,
as those of the study reported by Saltz, indicate substantial benefit to the
patients receiving the three-drug combination[3,4]. Taken together, the results
of these two phase III trials in previously untreated patients clearly provide
enough data to support continuing use of this three-drug combination as the
front-line therapy of untreated, advanced colorectal carcinoma, the indication
approved by the FDA in April 2000.
Irinotecan is a radioenhancer. Komaki et al present data from an
ongoing study of irinotecan and concurrent radiotherapy in patients with locally
advanced gastric or esophageal carcinoma. Similarly, Mitchell presents data from
her ongoing study of 5-FU and irinotecan given concurrently with preoperative
radiotherapy in patients with rectal carcinoma. When complete, these studies
will assist in the development of more advanced investigations of
combined-modality therapy with irinotecan.
Kohne et al provide a summary of current options for patients
with advanced carcinoma of the stomach and discuss the results of their
single-agent trial of irinotecan in patients with untreated gastric carcinoma.
Enzinger and Ilson report their study of irinotecan and cisplatin (Platinol) in
patients with either squamous cell carcinoma or adenocarcinoma of the esophagus.
The response rate of approximately 50% reported for this study is very
encouraging. Similar response rates are reported among patients with untreated,
advanced gastric carcinoma by Ajani et al. Green et al discuss their
preliminary, nevertheless intriguing, experience with the combination of
gemcitabine (Gemzar) and irinotecan in the treatment of pancreatic cancer.
Articles pertaining to the management of upper gastrointestinal
tract carcinoma are discussed in the first part of this issue, and are followed
by articles focusing on the management of colorectal carcinoma. All of these
studies demonstrate the broad spectrum of activity of irinotecan in the
treatment of gastrointestinal tract cancers and provide a logical rationale for
continuing investigations with this agent.
1. Liu LF: DNA topoisomerase poisons as antitumor drugs. Ann Rev
Biochem 58:351-375, 1989.
2. Hsiang Y-H, Liu LF: Identification of mammalian DNA
topoisomerase I as an intracellular target of the anticancer drug camptothecin.
Cancer Res 48:1722-1726, 1988.
3. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus
fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study
Group. N Engl J Med 343(13):905-914, 2000.
4. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan
combined with fluorouracil compared with fluorouracil alone as first-line
treatment for metastatic colorectal cancer: A multicentre randomised trial.
Lancet 355:1041-1047, 2000.