Combined-Modality Therapy in Lung Cancer Yields Encouraging Results

NASHVILLE,Tennessee—"The significant discovery of the 1980s was that chemoradiotherapy is better than radiation alone for treating locally advanced non-small-cell lung cancer," stated Hak Choy, MD. "In the 1990s we learned that concurrent chemoradiotherapy is better than a sequential schedule. Our task now is to discover which drug regimen is best." Dr. Choy is professor and vice-chair of the Vanderbilt University Medical Center in Nashville, Tennessee.

Dr. Choy reviewed data on irinotecan-based chemoradiotherapy, mostly from studies done in Japan. "The main toxicities were pulmonary toxicity and esophagitis, and response rates were over 60%, with an encouraging 2-year survival of nearly 55%," he said. This work was extended in three US-based phase I trials.

Dose-Finding Study

Dr. Choy discussed his own group’s phase I pilot study of a 6-week regimen of irinotecan (Camptosar)/carboplatin (Paraplatin), and radiation for medically and/or surgically inoperable non-small-cell lung cancer. This dose-finding trial was coordinated through Vanderbilt University Medical Center and conducted through the Vanderbilt Cancer Center Affiliate Network (VCCAN).

There was little hematologic toxicity, according to Dr. Choy. The maximum tolerated dose was 40 mg/m²/wk of irinotecan with carboplatin at AUC (area under the curve) 2. Dose-limiting toxicities were esophagitis, nausea, and vomiting. Responses were observed in 15 of the 26 patients on this study (61.5%).

Modest Survival Benefit

According to Dr. Choy, "Combined-modality therapy provides a modest survival benefit, increasing median survival from 11 to 15 months and 2-year survival from about 20% to about 30%. New drugs are likely to further increase survival a few more months, raising median survival to 18 months and 2-year survival to 40%. New agents, in addition to irinotecan, currently under investigation include paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and gemcitabine (Gemzar). Since combined-modality regimens tend to add toxicity, more studies are needed."

Future studies are expected to combine chemoradiation with molecular targeted agents. These include cyclooxygenase-2 (COX-2) inhibitors, tyrosine kinase inhibitors, endothelial growth factor receptor inhibitors, and integrin antagonists.

"Seventy percent to 90% of lung cancers overexpress COX-2, and this expression is linked to poor prognosis," Dr. Choy said. "There is little expression of COX-2 in normal tissues, and preclinical studies show that radiotherapy plus a COX-2 inhibitor can greatly increase apoptosis in COX-2-expressing tumor cells. In lung cancer and colon cancer cell lines, this delays tumor growth."

This finding has been carried forward in a phase II study of concurrent chemoradiotherapy plus celecoxib (Celebrex). Dr. Choy showed impressive images of lung cancer shrinkage in the first patient treated on this regimen.