Phase I Study of Dose-Escalated Intensity-Modulated Hyperfractionated Radiation Therapy (HFRT) Boost with Concurrent Paclitaxel (P) and Carboplatin (C) to Gross Tumor Volume (GTV) Following Standard-Dose Chemoradiotherapy (SCRT) for Advanced Esophageal Ca

Abstract

Local control rates after SCRT (50 Gy) are very poor in advanced esophageal cancer. Most local failures (LF) occur in the GTV. HFRT allows for delivering a higher total dose without increasing late toxicity. We hypothesized that the use of HFRT boost to the GTV after SCRT using modern image-guided intensity-modulated radiation therapy (IG-IMRT) could potentially intensify local therapy and subsequently improve outcomes. The primary objective of this phase I trial was to define the maximum tolerated dose (MTD) of the HFRT boost with concurrent weekly C/P following SCRT. Patients (pts) who were inoperable or medically unresectable and metastatic with life expectancy ≥ 4 months were eligible. The lower thoracic esophageal cancer involving the stomach was ineligible. Pts were treated with weekly P at 45 mg/m2 and C area under the curve 1.5 with concurrent 50 Gy of IG-IMRT given in 25 fractions for 5 weeks, immediately followed by an image-guided intensity-modulated HFRT boost to the GTV concurrent with the same chemotherapy regimen. The boost doses were escalated ranging from 7.2 to 43.2 Gy in increments of 7.2 Gy delivered in 6 twice daily fractions of 1.2 Gy using a modified Fibonacci design. A minimum of 6 weeks follow-up was required after completion of radiation treatment before proceeding to the next dose. Dose limiting toxicity (DLT) was defined as grade ≥ 4 esophagitis or any other grade ≥ 3 non-hematological toxicity (except nausea and vomiting) or grade ≥ 4 hematological toxicity lasting more than 7 days, which are possibly, probably or definitely associated with protocol treatment occurring during and after completion of the HFRT boost treatment. The MTD was defined as the highest radiation dose at which ≤ 1 pts experienced DLT. Once the MTD was determined, this cohort was expanded to further define the safety profile. Adjuvant chemotherapy was optional. Thirty-four pts were enrolled and 31 were assessable (median age, 62 years; 73% male; 97% T3-4 disease, 65% N1-2 disease; 9% M1 disease; 97% squamous cell carcinoma; 90% PS 0-1).SCRT was well tolerated. The incidence of DLT was 0/3, 0/3, 0/3, 1/6 (grade 4 esophagitis), 0/3, 2/3 (grade 5 esophageal fistula and grade 3 pneumotitis each) at 7.2, 14.4, 21.6, 28.8, 36, and 43.2 Gy, respectively, thus defining the MTD at 36 Gy. In the expansion cohort of 10 pts at the MTD, no DLTs were encountered. The most common acute grade 3 or greater toxicities throughout the entire study period were esophagitis (26%) and neutropenia (19%). Late toxicity included grade 2 esophageal stricture (n = 4). The overall response rate was 84% (95% CI, 42% to 93%; 100% at a dose of ≥ the MTD). With a median follow up of 5 months (range 1 to 12 months), no LF was observed, and distant failure occurred in 3 pts. The MTD of a HFRT boost was determined to be 36 Gy using IG-IMRT with concurrent P and C following 50 Gy of SCRT, resulting in the total combined tumor dose of 86 Gy. Preliminary efficacy data are encouraging. A Phase II study to further evaluate this regimen is underway.