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

December 3, 2000

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 (Camptosar, CPT-11), a memberof the camptothecin family, represents the most active camptothecin availablefor clinical use today. Irinotecan is a topoisomerase I inhibitor. Topoisomeraseenzymes support the topologic structure of DNA, thus facilitating translationand transcription. The enzyme topoisomerase I plays a crucial role in therelegation of single-strand breaks and in relieving torsional DNA stress.[1,2]Irinotecan and other camptothecin analogs interfere in this process bystabilizing the topoisomerase I/DNA cleavable complex.[2] This process is notcompatible with prolonged cell survival.

Irinotecan was approved for use in the second-line therapy ofadvanced 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 developmentsin colorectal carcinoma have shown that irinotecan is a highly valuable agent ineither first- or second-line treatment of advanced disease, prolonging survivaland improving quality of life.

Recent developments in the investigation of irinotecan as asingle agent, in combination chemotherapy, or in combined-modality therapy in avariety of gastrointestinal cancers are described in this supplement. Eachmanuscript represents a synopsis of data presented at the symposium sponsored byThe University of Texas M. D. Anderson Cancer Center in Sonoma, California, inJuly 1999. The objectives of this endeavor were to provide an update on a numberof strategies currently being explored with irinotecan and to stimulate newresearch.

In this issue of Oncology, Royce et al present anoverview of chemotherapy in patients with colorectal carcinoma and point out thestudies performed with agents such as capecitabine (Xeloda), UFT/leucovorin,eniluracil/fluorouracil (5-FU), oxaliplatin, and irinotecan.

Saltz describes a phase III comparison ofirinotecan/leucovorin/5-FU vs leucovorin/5-FU vs irinotecan administered asfirst-line therapy to patients with advanced colorectal carcinoma. The resultsof this study demonstrate a markedly higher and statistically significantincrease in response rate, time to progression, and median survival for thepatients who received the three-drug regimen (irinotecan/leucovorin/5-FU). Thesepositive findings were reviewed by the Oncology Drug Advisory Committee of theUS Food and Drug Administration (FDA) in March 2000. The Committee unanimouslyapproved the three-drug combination for the first-line therapy of patients withadvanced colorectal carcinoma. In addition, these important findings build astrong case for the ongoing phase III adjuvant trial for patients withnode-positive colon carcinoma.

On behalf of the V-303 Study Group, Douillard discusses theEuropean phase III trial in which patients with advanced colorectal carcinomareceived either irinotecan/leucovorin/ 5-FU or leucovorin/5-FU. Their results,as those of the study reported by Saltz, indicate substantial benefit to thepatients receiving the three-drug combination[3,4]. Taken together, the resultsof these two phase III trials in previously untreated patients clearly provideenough data to support continuing use of this three-drug combination as thefront-line therapy of untreated, advanced colorectal carcinoma, the indicationapproved by the FDA in April 2000.

Irinotecan is a radioenhancer. Komaki et al present data from anongoing study of irinotecan and concurrent radiotherapy in patients with locallyadvanced gastric or esophageal carcinoma. Similarly, Mitchell presents data fromher ongoing study of 5-FU and irinotecan given concurrently with preoperativeradiotherapy in patients with rectal carcinoma. When complete, these studieswill assist in the development of more advanced investigations ofcombined-modality therapy with irinotecan.

Kohne et al provide a summary of current options for patientswith advanced carcinoma of the stomach and discuss the results of theirsingle-agent trial of irinotecan in patients with untreated gastric carcinoma.Enzinger and Ilson report their study of irinotecan and cisplatin (Platinol) inpatients with either squamous cell carcinoma or adenocarcinoma of the esophagus.The response rate of approximately 50% reported for this study is veryencouraging. Similar response rates are reported among patients with untreated,advanced gastric carcinoma by Ajani et al. Green et al discuss theirpreliminary, nevertheless intriguing, experience with the combination ofgemcitabine (Gemzar) and irinotecan in the treatment of pancreatic cancer.

Articles pertaining to the management of upper gastrointestinaltract carcinoma are discussed in the first part of this issue, and are followedby articles focusing on the management of colorectal carcinoma. All of thesestudies demonstrate the broad spectrum of activity of irinotecan in thetreatment of gastrointestinal tract cancers and provide a logical rationale forcontinuing investigations with this agent.

References:

1. Liu LF: DNA topoisomerase poisons as antitumor drugs. Ann RevBiochem 58:351-375, 1989.

2. Hsiang Y-H, Liu LF: Identification of mammalian DNAtopoisomerase 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 plusfluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan StudyGroup. N Engl J Med 343(13):905-914, 2000.

4. Douillard JY, Cunningham D, Roth AD, et al: Irinotecancombined with fluorouracil compared with fluorouracil alone as first-linetreatment for metastatic colorectal cancer: A multicentre randomised trial.Lancet 355:1041-1047, 2000.