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The Evolving Role of Irinotecan: A Broad-Spectrum Chemotherapeutic Agent

The Evolving Role of Irinotecan: A Broad-Spectrum Chemotherapeutic Agent

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.[2] 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 research.

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.

References

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.

 
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