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 on new agents, with a particular focus on the broadly used agent irinotecan(Drug information on irinotecan) (CPT-11, Camptosar). Investigators from around the world are invited to present current research. The forums are highly interactive and frank, thus allowing stimulation of new ideas and directions. Seven separate scientific sessions were held, and the respective sessions covered general areas in tumor research, colorectal carcinoma, upper gastrointestinal cancer, lung carcinoma, chemoradiation, other tumor types, and future directions. In addition to stimulating research, another purpose of these workshops is developing enduring material for wider distribution to those who did not attend this workshop. Thus, three publications were planned. Volume 1 (May 2003) previously described new combinations and other tumor types, including glioma, breast cancer, and gynecologic carcinomas, while volume 2 (July 2003) described lung carcinomas. This final volume is devoted to upper gastrointestinal and colorectal carcinomas. Irinotecan/Paclitaxel in Adenomas of the Gastroesophageal Junction
Adenocarcinomas of the gastroesophageal junction comprise adenocarcinomas of the esophagus and gastric cardia. In this volume, J. Randolph Hecht and colleagues discuss a phase II trial of irinotecan and paclitaxel(Drug information on paclitaxel) in the treatment of adenomas of the gastroesophageal junction. The preliminary results demonstrated that the combination shows good tolerability and possesses promising activity, even in previously treated patients Phase I Study of Irinotecan and Gemcitabine(Drug information on gemcitabine): Toxicity and Dose
Weijing Sun and Daniel Haller report on a phase I study designed to test the toxicity of the combination of irinotecan with fixed-dose-rate infusion of gemcitabine (Gemzar), and to determine the dose of the combination for subsequent phase II investigation. Preclinical and clinical data suggest additive or synergistic effects when combining these agents, with few or no overlapping toxicities. It has been suggested that the fixed-dose-rate infusion of gemcitabine increases the concentration of intracellular triphosphate gemcitabine, which may result in more objective responses and longer median survival compared to the standard infusion. Combined-Modality Therapy in Resectable Carcinoma
of the Esophagus or Gastroesophageal Junction The prognosis of patients with local-regional carcinoma of the esophagus is grim, and while preoperative chemoradiotherapy increases the fraction of patients who achieve a pathologic complete response, that fraction is only 25%. In an attempt to increase this percentage, my colleagues and I conducted a study of combined-modality therapy in resectable carcinoma of the esophagus or gastroesophageal junction. The trial used a combination of irinotecan and cisplatin(Drug information on cisplatin) that possesses activity in patients with carcinoma of the esophagus, and also included a regimen of continuous infusion fluorouracil(Drug information on fluorouracil) (5-FU) and paclitaxel with radiotherapy; surgery was performed for patients who completed chemotherapy and had no evidence of metastatic disease. The trial objectives were to increase both the R0 (curative) resection rate and the fraction of patients who have significant pathologic 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 in biliary tract cancers and may possess synergistic activity at clinically relevant doses, this combination may represent a new option in the treatment of biliary tract cancer. Pankaj Bhargava and colleagues describe the results from a phase II study of gemcitabine and irinotecan in patients with advanced or metastatic biliary cancer, and present data showing that the combination possesses moderate activity and is well tolerated in patients with advanced or metastatic biliary cancer. Irinotecan and Docetaxel(Drug information on docetaxel) in Metastatic or Recurrent Esophageal Cancer
The outcomes for patients with metastatic or recurrent esophageal cancer are dismal, with 1-year survival rates of approximately 20%. Ramaswamy Govindan and his coworkers present data from a phase II study examining the combination of docetaxel (Taxotere) and irinotecan in patients with metastatic or recurrent esophageal cancer. The combination resulted in a response rate of 30%, with median survival of 130 days. However, modifications to reduce the incidence of febrile neutropenia need to be undertaken. Role of Irinotecan in Esophageal Cancer
David Ilson and Bruce Minsky review the role of irinotecan in esophageal cancer. Phase II evaluation of weekly irinotecan and cisplatin has shown encouraging response rates in esophageal and gastric cancer. Novel regimens include the combination of irinotecan with mitomycin(Drug information on mitomycin) (Mutamycin), the taxanes, and continuous infusion 5-FU. Trials have also evaluated the combination of irinotecan with concurrent radiotherapy. Phase II evaluation weekly irinotecan, cisplatin, and concurrent radiotherapy as preoperative therapy in locally advanced esophageal cancer is planned at single institutions and in cooperative group trials, as is further phase I and II investigation of this regimen with the addition of targeted agents, ie, celecoxib(Drug information on celecoxib) (Celebrex), cetuximab(Drug information on cetuximab) (Erbitux), and bevacizumab(Drug information on bevacizumab) (Avastin). Alter- native combinations of irinotecan with radiotherapy, including the addition of docetaxel 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 II study in advanced colorectal cancer with irinotecan, 5-FU, and leucovorin (IFL). Irinotecan possesses antitumor efficacy both as a single agent, and incorporated into 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 advocated modifying the standard "Saltz regimen" to weekly for 2 weeks, with repeated cycles every 21 days. Therapy was well tolerated in the 23 patients treated, with a high median relative dose intensity of irinotecan administered in the first 18. These data support the hypothesis that modifying the schedule of IFL administration improves its therapeutic index. If confirmed by randomized studies, this regimen may provide a backbone for use in further investigation of new agents and combinations in the treatment 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 will find the information in this volume relevant, stimulating, and useful in designing new trials.