Irinotecan and Other Agents in Upper Gastrointestinal and Colorectal Carcinomas

The 5th University of Texas M. D. Anderson Cancer Center Investigators'Workshop was held on July 24-28, 2002, in San Diego, California.The purpose of these annual workshops has been to review the latest data onnew agents, with a particular focus on the broadly used agent irinotecan (CPT-11,Camptosar).Investigators from around the world are invited to present current research. Theforums are highly interactive and frank, thus allowing stimulation of new ideas anddirections. Seven separate scientific sessions were held, and the respective sessionscovered general areas in tumor research, colorectal carcinoma, upper gastrointestinalcancer, lung carcinoma, chemoradiation, other tumor types, and future directions.In addition to stimulating research, another purpose of these workshops isdeveloping enduring material for wider distribution to those who did not attend thisworkshop. Thus, three publications were planned. Volume 1 (May 2003) previouslydescribed new combinations and other tumor types, including glioma, breastcancer, and gynecologic carcinomas, while volume 2 (July 2003) described lungcarcinomas. This final volume is devoted to upper gastrointestinal and colorectalcarcinomas.Irinotecan/Paclitaxel in Adenomas of the Gastroesophageal Junction
Adenocarcinomas of the gastroesophageal junction comprise adenocarcinomasof the esophagus and gastric cardia. In this volume, J. Randolph Hecht and colleaguesdiscuss a phase II trial of irinotecan and paclitaxel in the treatment ofadenomas of the gastroesophageal junction. The preliminary results demonstratedthat the combination shows good tolerability and possesses promising activity, evenin previously treated patientsPhase I Study of Irinotecan and Gemcitabine: Toxicity and Dose
Weijing Sun and Daniel Haller report on a phase I study designed to test thetoxicity of the combination of irinotecan with fixed-dose-rate infusion of gemcitabine(Gemzar), and to determine the dose of the combination for subsequent phase IIinvestigation. Preclinical and clinical data suggest additive or synergistic effectswhen combining these agents, with few or no overlapping toxicities. It has beensuggested that the fixed-dose-rate infusion of gemcitabine increases the concentrationof intracellular triphosphate gemcitabine, which may result in more objectiveresponses and longer median survival compared to the standard infusion.Combined-Modality Therapy in Resectable Carcinoma
of the Esophagus or Gastroesophageal JunctionThe prognosis of patients with local-regional carcinoma of the esophagus isgrim, and while preoperative chemoradiotherapy increases the fraction of patientswho achieve a pathologic complete response, that fraction is only 25%. In anattempt to increase this percentage, my colleagues and I conducted a study ofcombined-modality therapy in resectable carcinoma of the esophagus or gastroesophagealjunction. The trial used a combination of irinotecan and cisplatin thatpossesses activity in patients with carcinoma of the esophagus, and also includeda regimen of continuous infusion fluorouracil (5-FU) and paclitaxel with radiotherapy;surgery was performed for patients who completed chemotherapy andhad no evidence of metastatic disease. The trial objectives were to increase boththe R0 (curative) resection rate and the fraction of patients who have significantpathologic response, and to evaluate morbidity and mortality.Irinotecan and Gemcitabine in Advanced or Metastatic Biliary Cancer
Because irinotecan and gemcitabine possess good single-agent activity inbiliary tract cancers and may possess synergistic activity at clinically relevantdoses, this combination may represent a new option in the treatment of biliarytract cancer. Pankaj Bhargava and colleagues describe the results from a phase IIstudy of gemcitabine and irinotecan in patients with advanced or metastatic biliarycancer, and present data showing that the combination possesses moderate activityand is well tolerated in patients with advanced or metastatic biliary cancer.Irinotecan and Docetaxel in Metastatic or RecurrentEsophageal Cancer
The outcomes for patients with metastatic or recurrent esophageal cancer aredismal, with 1-year survival rates of approximately 20%. Ramaswamy Govindanand his coworkers present data from a phase II study examining the combinationof docetaxel (Taxotere) and irinotecan in patients with metastatic or recurrentesophageal cancer. The combination resulted in a response rate of 30%, withmedian survival of 130 days. However, modifications to reduce the incidence offebrile neutropenia need to be undertaken.Role of Irinotecan in Esophageal Cancer
David Ilson and Bruce Minsky review the role of irinotecan in esophagealcancer. Phase II evaluation of weekly irinotecan and cisplatin has shown encouragingresponse rates in esophageal and gastric cancer. Novel regimens include thecombination of irinotecan with mitomycin (Mutamycin), the taxanes, and continuousinfusion 5-FU. Trials have also evaluated the combination of irinotecan withconcurrent radiotherapy. Phase II evaluation weekly irinotecan, cisplatin, andconcurrent radiotherapy as preoperative therapy in locally advanced esophagealcancer is planned at single institutions and in cooperative group trials, as is furtherphase I and II investigation of this regimen with the addition of targeted agents, ie,celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab (Avastin). Alter-native combinations of irinotecan with radiotherapy, including the addition ofdocetaxel and continuous infusion 5-FU, are also undergoing evaluation.Phase II Study of IFL in Advanced Colorectal Cancer
Jimmy Hwang and colleagues conclude the volume with a report of a phase IIstudy in advanced colorectal cancer with irinotecan, 5-FU, and leucovorin (IFL).Irinotecan possesses antitumor efficacy both as a single agent, and incorporatedinto the IFL regimen. Randomized studies confirmed the superiority of IFL over 5-FU and leucovorin alone based on objective response, survival, and time to progression.To improve the tolerability of IFL, some investigators have advocatedmodifying the standard "Saltz regimen" to weekly for 2 weeks, with repeatedcycles every 21 days.Therapy was well tolerated in the 23 patients treated, with a high medianrelative dose intensity of irinotecan administered in the first 18. These data supportthe hypothesis that modifying the schedule of IFL administration improves itstherapeutic index. If confirmed by randomized studies, this regimen may provide abackbone for use in further investigation of new agents and combinations in thetreatment of advanced colorectal cancer.Conclusion
In conclusion, I believe that the data presented at the University of Texas M. D.Anderson Cancer Center Investigators' Workshop provided new insights and perspectives,trends, and practices in various areas of oncology. I hope the reader willfind the information in this volume relevant, stimulating, and useful in designingnew trials.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.