Preventing Severe Esophagitis Critical in Chemoradiotherapy for Lung Cancer

PHILADELPHIA—Concurrent chemoradiotherapy seems likely to become standard therapy for treating locally advanced lung cancer. That would make preventing radiation-induced esophagitis even more important, according to Maria Werner-Wasik, MD.

"The esophagus unfortunately is included in most standard radiotherapy fields projecting over the vertebral bodies. Although many of us want to believe that we exclude most of the esophagus in the off-cord fields, that is not the case," she noted. Dr. Werner-Wasik is assistant professor and clinical director, Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia.

"The incidence of acute esophagitis varies with the type of radiochemotherapy used. With standard radiation preceded by induction chemotherapy, incidence of grade 3 or higher esophagitis is a low 1.3%," she said. "With concurrent cisplatin (Platinol)-based regimens and standard radiation, there is 6% to 14% incidence of esophagitis. When radiation intensity increases for hyperfractionated regimens, the incidence of esophagitis rises to 24% to 34%. When the potent radiosensitizer gemcitabine (Gemzar) is added to standard radiation, the esophagitis incidence is as high as 49%."

Phase II Trial

The Jefferson researchers are conducting a phase II trial of induction paclitaxel (Taxol) plus carboplatin (Paraplatin) followed by thoracic radiation therapy with concurrent weekly low-dose paclitaxel for patients with unresectable locally advanced non-small-cell lung cancer.

"In the first 11 evaluable patients, we observed 20% incidence of grade 3 esophagitis. It was also our impression that esophagitis was quite prolonged. Many patients suffered for weeks, in addition to having a high-grade esophagitis. We decided to incorporate amifostine (Ethyol) in treatment of the second cohort of patients because we knew from preclinical data that amifostine provided significant protection against esophagitis in mice treated with radiation. Data from a phase II trial at the University of Wisconsin also suggested that amifostine given during induction and before each fraction of radiation reduced the risk of esophagitis," Dr. Werner-Wasik said.

The second cohort of 12 patients received amifostine 500 mg given on the day paclitaxel was given and again on the following day. For the 6-week chemoradiotherapy cycle, patients receive 12 infusions of amifostine.

Dr. Werner-Wasik reported data on the 11 evaluable patients. Amifostine was well tolerated. One patient developed a skin rash that reappeared on rechallenge, requiring stopping the drug. One patient developed transient hypotension.

All patients in the cohort not treated with amifostine had developed esophagitis: four grade 1, five grade 2, and two grade 3. In the amifostine-treated cohort, two patients had no esophagitis, and there was a shift toward lower grades of esophagitis when it did occur: six grade 1, two grade 2, and one grade 3. The numbers of patients developing esophagitis grade 2 or higher were 7/12 without amifostine and 3/12 with amifostine. Mean values of the esophagitis index were numerically lower with amifostine, although this was not statistically significant.

"The conclusion from our study was that twice weekly amifostine given during standard thoracic radiotherapy with weekly paclitaxel appears to lower the severity of acute esophagitis, as evidenced by less extreme esophagitis index values. In the current cohort of patients, we escalated the dose of amifostine to three times per week, since the lower dose did not eliminate the grade 3 esophagitis," Dr. Werner-Wasik said.

Phase III Trial

This trial is being followed by a phase III (RTOG 98-01) in which patients are randomized to receive amifostine vs no amifostine along with chemoradiation. The regimen includes carboplatin for two cycles of induction and radiotherapy given twice daily to 69.6 Gy, at 1.2 Gy BID with weekly paclitaxel 50 mg/m^², and carboplatin AUC 2. Amifostine is 500 mg four times weekly, given before the afternoon fraction of radiation.

Esophagitis is scored routinely on toxicity forms that the physician is required to fill out once weekly. Monitoring also includes intravenous fluids needed, pneumonitis, steroid requirements, and narcotics needed for pain. The patient fills out a dysphagia log daily. The breadth of data being collected in this trial, Dr. Werner-Wasik noted, should answer several important questions about esophagitis in lung cancer patients receiving combined modality therapy.

"Efforts to minimize severe acute esophagitis are important. Preliminary evidence suggests a role for amifostine in decreasing the incidence and severity of therapy-related esophagitis in patients with lung cancer," Dr. Werner-Wasik said.