Role of Selective Dose Escalation and Addition of Cytoprotection Evaluated in Patients With Esophageal Cancer

PORTLAND, OR-A treatment- intensification study in esophageal cancer patients that includes an additional boost of radiotherapy in combination with fluorouracil(Drug information on fluorouracil) (5-FU), carboplatin(Drug information on carboplatin) (Paraplatin) and paclitaxel(Drug information on paclitaxel) (Taxol), and amifostine(Drug information on amifostine) (Ethyol) has met with early difficulties, and accrual has been stopped pending longer follow-up, reports Steven K. Seung, MD, PhD, a radiation oncologist at the Oregon Clinic, in Portland. The addition of amifostine is an attempt to build on promising results of an earlier selective dose-escalation study in patients with esophageal cancer by using cytoprotection to reduce treatment- related morbidity and mortality. Dr. Seung first discussed the earlier INT-0123 study, which increased the radiation dose to 64.8 Gy vs the standard 50.4 Gy. In this trial, 31% of patients survived 2 years, but less than 50% of patients had local control, and mortality in the high-dose arm was greater owing to complications. "High-dose chemoradiotherapy may be too toxic, perhaps because prolonging the chemothera- py may have been too arduous for these patients," Dr. Seung said. "We decided first to try a fast-andhard approach by giving a shorter course of intensified chemoradia- tion and then selectively escalating the dose for patients who do not have a good clinical response to standard-dose radiotherapy." Radiation Dose Escalation
The prospective study design assessed survival and failure patterns of patients treated with conventional 50.4 Gy radiotherapy and carboplatin/5-FU/paclitaxel, then selectively escalated the radiation dose in patients who had less than a complete response (CR) or partial response (PR) to initial treatment, with a PR defined as a 50% reduction in maximal dimension of tumor and negative biopsy. The researchers enrolled 18 patients with T1-4, N0-1, M0-1a esophageal cancer. "Most were adenocarcinomas, reflecting the change in the natural history of this disease," Dr. Seung said. Approximately 6 to 8 weeks after initial chemoradiotherapy, patients underwent repeat staging with computed tomography (CT) scan, esophageal ultrasound, and biopsy. Those with less than a PR received a boost dose of 900 cGy with concurrent paclitaxel/ carboplatin/continuous infusion 5-FU. Patients were followed every 4 months with CT and endoscopy for the first year and every 6 months thereafter. With a median follow-up of 19 months, 11 of 18 patients had attained CR or PR, Dr. Seung reported. Six of 18 received a boost. One patient died of heart failure prior to completing the initial course. Overall survival was 30% at 3 years, with a median survival duration of 25 months, despite 39% of the patients having stage IVA disease. "Patients with weight loss greater than 10% had lower survival in this study and in other trials," Dr. Seung said (see Figure 1). One factor in weight loss was acute esophagitis. One patient had grade 4 esophagitis, 7 patients had grade 3 esophagitis (none required feeding tubes), and 16 had grade 2 esophagitis. Amifostine Added
"This protocol allows screening of patients at risk for local failure, allowing selection of high-risk patients to undergo dose-escalation. Reducing the acute side effects may further improve compliance and outcome, which raised the question of a role for amifostine," Dr. Seung said. The investigators then decided to add amifostine 500 mg SC prior to each dose of radiotherapy, which was given at 1.8 Gy 5 days per week for 5.5 weeks (50.4 Gy in 28 fractions). The first four patients treated with this approach all had to stop receiving amifostine prior to completion of treatment. Two had generalized rash, one had nausea and hypotension, and one had arrhythmia. Tumor recurred within 4 months in one of these four patients but has not recurred at 2, 6, and 7 months of follow-up in the other three patients.