Irinotecan and Other Agents in Upper Gastrointestinal and Genitourinary Tumors

May 2, 2002

The 4th Investigators’ Workshop sponsored by The University of Texas M. D. Anderson Cancer Center was held on July 25-29, 2001, in Colorado Springs, Colorado. 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 (CPT-11, Camptosar).

The 4th Investigators’ Workshop sponsored by TheUniversity of Texas M. D. Anderson Cancer Center was held on July 25-29, 2001,in Colorado Springs, Colorado. The purpose of these annual workshops has been toreview the latest data on new agents, with a particular focus on the broadlyused agent irinotecan (CPT-11, Camptosar).

Investigators from around the world were invited to present current research.The forums were highly interactive and frank, thus allowing stimulation of newideas and directions. The meetings were more like a workshop rather thandidactic sessions. Six separate scientific sessions were held, and therespective sessions covered colorectal carcinoma, uppergastrointestinal/genitourinary carcinoma, lung carcinoma, and new combinationsand other tumor types.

In addition to stimulating research, another purpose of these workshops is todevelop enduring material for wider distribution to those who did not attend.Thus, four publications are intended. This second volume is devoted to uppergastrointestinal/genitourinary malignancies. Successive volumes will be devotedto new combinations and other malignancies (volume 3) and lung malignancies(volume 4). Last month, the first volume focused on colorectalcancers.

Gastric Carcinoma

In this volume, David Ilson and colleagues report on a phase I trial ofweekly irinotecan, cisplatin, and concurrent radiotherapy in patients withlocally advanced esophageal cancer—an aggressive cancer with a poor prognosis.Among the 13 evaluable patients, there were 5 clinical complete responses (38%),including 3 pathologic complete responses in 10 patients undergoing surgery(30%). These data indicate that full doses of weekly irinotecan (65 mg/m²) andcisplatin (30 mg/m²) can be combined safely with concurrent radiotherapy inpatients with locally advanced esophageal cancer.

Gastric carcinoma continues to be a significant health problem despite itsdecreasing incidence, and it remains the second most common malignant disorderin the world. In our article, my colleagues and I summarize our data from aphase II study that assessed the response rate and toxicity profile of theirinotecan/cisplatin combination administered weekly to patients who have had atleast one previous chemotherapy for advanced adenocarcinoma of the stomach orgastroesophageal junction. A 29% response rate was achieved in the study.Modifications in doses and schedule are warranted to increase the tolerabilityof the regimen in further investigation.

Pancreatic Cancer

Caio Max Rocha Lima et al discuss a phase I study of the combination ofirinotecan and gemcitabine in 19 patients with solid tumors, includingpancreatic cancer. Three patients—one with pancreatic cancer at irinotecan 100mg/m² and another with pancreatic and one with metastatic carcinoma of unknownprimary at 115 mg/m²—had documented partial responses. The recommended phaseII dose of irinotecan is 100 mg/m2 in combination with gemcitabine at 1,000mg/m² days 1 and 8 every 3 weeks, and a multicenter phase II trial is under wayin patients with previously untreated pancreatic cancer.

William Blackstock and coworkers report the preliminary results of an ongoingphase II trial in patients with locally advanced, unresectable pancreatic cancerwho received induction gemcitabine/irinotecan followed by twice-weeklygemcitabine and concurrent radiation. The observed grade 3/4 toxicities(primarily gastrointestinal and hematologic) were limited to those expected inpatients receiving irinotecan and gemcitabine. No local tumor progression wasdemonstrated during induction chemotherapy in the eight assessable patients.Based on these early results, the regimen of gemcitabine/irinotecan followed bygemcitabine with concurrent radiation appears safe and efficacious.

Ovarian and Cervical Cancers

Ovarian cancer, the second most common gynecologic malignancy, accounts forapproximately 14,000 deaths annually in the United States. In general, recurrentovarian cancer is incurable, partly because of the relative inefficacy ofsalvage therapy. David Gershenson discusses trials of new active drugs, such asirinotecan as a single agent and irinotecan in combination with cisplatin, inthe treatment of epithelial ovarian cancer. The data suggest that irinotecanappears to have moderate activity and acceptable toxicity in patients withrecurrent epithelial ovarian cancer.

Claire Verschraegen reviews various trials of topoisomerase inhibitors,including irinotecan, in the treatment of refractory or recurrent cervicalcancer. Irinotecan administered in varying schedules has achieved response ratesranging from 13% to 26%. The combination of irinotecan/cisplatin has also beenstudied in first-line therapy (78% response) and in patients with refractorydisease (59%). In the treatment of refractory disease, hematologic andgastrointestinal toxicities have been observed; gastrointestinal toxicities havebeen particularly problematic at high irinotecan doses. Further studies ofirinotecan in combination with other drugs and radiotherapy are warranted.

Rectal Cancer

Bruce Minsky reviews studies of fluorouracil (5-FU)- and irinotecan-basedregimens in combination with preoperative or postoperative pelvic radiation inpatients with rectal cancer. Although 5-FU-based combined-modality therapyremains the standard of care in adjuvant treatment for patients with T3/4 rectalcancer, results from phase I/II trials suggest that preoperative irinotecan plusradiation therapy appears most effective when used in combination with 5-FU.

Preoperative chemoradiation has become a common treatment for stage II andIII rectal cancers at many institutions, including The University of Texas M. D.Anderson Cancer Center. Christopher Crane and colleagues review pertinent data.Patients with rectal cancer who respond to preoperative chemoradiation havebetter pelvic control, sphincter preservation, and overall survival than thosewho do not respond. However, additional improvements in the treatment of rectalcancer are needed, including the study of irinotecan as radiosensitizing agentand cyclooxygenase-2 (COX-2) inhibitors as targeted therapy.

Al Benson et al conclude the volume with a review of trials conducted by theUS National Cancer Institute Gastrointestinal Intergroup that investigatedchemotherapy (ie, 5-FU, leucovorin, levamisole [Ergamisol]; semustine[methyl-CCNU], vincristine, and 5-FU [MOF]) and radiation regimens in thetreatment of stage II and III rectal cancer. European trials in this arena arealso summarized. Future trials will explore the use of newer agents, includingcapecitabine (Xeloda), irinotecan, and oxaliplatin, as well as the utility intrial design of laboratory correlates, especially molecular markers.

In conclusion, I believe that the data presented at The University of TexasM. D. Anderson Cancer Center Investigators’ Workshop provided currentinsights, trends, and practices in relevant areas of oncology. I hope you willfind the information in this and the other volumes useful in designing newinvestigations and educating your colleagues, in addition to contributing to thebetter management of all patients.