Irinotecan and Other Agents in Lung Carcinoma

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).

Investigators from around the world were invited to present current research. The forums were highly interactive and frank, thus allowing stimulation of new ideas and directions. The meetings were more like a workshop rather than didactic sessions. Six separate scientific sessions were held, and the respective sessions covered colorectal carcinoma, upper gastrointestinal/genitourinary carcinoma, lung carcinoma, and new combinations and other tumor types.

In addition to stimulating research, another purpose of these workshops is to develop enduring material for wider distribution to those who did not attend. Thus, four volumes have been published. This fourth and final volume is devoted to lung carcinomas. The three previous volumes focused on colorectal cancers, upper gastrointestinal/genitourinary carcinomas, and new combinations and other tumor types.

Treatment Options in Small-Cell and Non-Small-Cell Lung Cancer

In this volume, Hong-Gyun Wu and Hak Choy review current treatment options for patients with non-small-cell lung cancer and small-cell lung cancer, and note that the combination of chemotherapy and radiation therapy has improved outcomes in patients with non-small-cell lung cancer. Phase I/II studies have demonstrated the single-agent activity of irinotecan against advanced non-small-cell lung cancer, similar to that reported for other new active agents such as vinorelbine (Navelbine), gemcitabine (Gemzar), paclitaxel, and docetaxel (Taxotere). The synergistic effect of irinotecan and cisplatin was also observed in both in vitro and clinical studies, and phase I/II studies of thoracic radiation therapy and concurrent irinotecan and cisplatin demonstrated encouraging response and survival rates with acceptable toxicities.

Studies in small-cell lung cancer have demonstrated that concurrent chemotherapy and radiation therapy is more efficacious than sequential chemotherapy and radiation therapy, early thoracic radiotherapy is better than late radiotherapy, and twice-daily radiation is more beneficial than once-daily treatment. While the cisplatin/etoposide combination is currently the standard chemotherapy regimen for patients with limited-disease small-cell lung cancer, trials are needed to explore the potential role of irinotecan in these patients.

Agents Targeting Specific Biologic Pathways

Although treatment of advanced non-small-cell lung cancer has improved with the availability of new agents such as the taxanes, topoisomerase inhibitors, vinorelbine, and gemcitabine, platinum-based combination therapy has appeared to have reached a threshold of therapeutic effectiveness. Roy Herbst discusses the development of agents targeting specific biologic pathways in tumor development. These agents include endothelial growth factor receptor (EGFR) inhibitors (eg, monoclonal antibody trastuzumab [Herceptin]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774 [Tarceva]), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-a).

A number of these agents have entered advanced-phase clinical investigation, and Dr. Herbst notes that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment.

Topoisomerase I Inhibitor/Nonplatinum Combinations

Caio Max S. Rocha Lima and Marcos Joppert review topoisomerase I inhibitor/nonplatinum combinations in the management of advanced non-small-cell lung cancer. Topoisomerase I inhibitors, such as irinotecan, are active both as single agents and in combination with platinums in non-small-cell lung cancer. Investigators have begun assessing non-platinum-based doublet combinations in an attempt to reduce toxicity and improve efficacy. The available data on nonplatinum doublets that include topoisomerase I inhibitors suggest that these regimens provide efficacy equal to that achieved with platinum-based doublets.

Camptothecins and Taxanes

For more than 2 decades, combination chemotherapy has been the standard therapy for patients with small-cell lung cancer. However, despite high initial response rates in both extensive- and limited-stage disease, long-term survival rates are only 10% to 20%. Myron Kwong, Eric Bleickardt, and John Murren review the role of camptothecins and taxanes, newer classes of agents that have shown significant activity against small-cell lung cancer.

In one randomized multicenter study, patients with metastatic small-cell lung cancer treated with irinotecan and cisplatin achieved better survival than patients receiving standard therapy. The combination of irinotecan and a taxane holds promise as an active regimen that may be better tolerated than cisplatin and irinotecan. Other approaches that might improve survival in this chemotherapy-sensitive disease include intensification of dose and/or better use of clinical and genotypic data to optimize dose in the individual patient, allowing maximal doses without increasing toxicity.

Irinotecan/Cisplatin Combination

Alan Sandler concludes volume 4 with a review of the use of the irinotecan/cisplatin combination in patients with small-cell lung cancer. Until recently, no one regimen of combination chemotherapy had emerged as superior in extensive-stage small-cell lung cancer. A recent Japanese phase III study demonstrated that irinotecan in combination with cisplatin significantly improved the survival of previously untreated patients with extensive-stage small-cell lung cancer compared with standard etoposide/cisplatin therapy. Two additional phase III trials are planned to confirm these results in the United States, and to investigate how the irinotecan/cisplatin administration schedule may be modified to improve the therapeutic index.

Conclusion

In conclusion, I believe that the data presented at The University of Texas M. D. Anderson Cancer Center Investigators’ Workshop provided current insights, trends, and practices in relevant areas of oncology. I hope you, the reader, find the information in all four volumes useful in designing new investigations and educating your colleagues, in addition to contributing to the better management of all patients.