Dose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial

Abstract

Background: This prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year.

Methods: Eligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1-6, 8-13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals.

Results: Between 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48-66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59-100], 53% [34-83], 41% [23-73], and 29% [14-61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40-88], 35% [19-67], and 29% [14-61], corresponding cumulative incidences of loco-regional progressions were 18% [4-39%], 35% [14-58%], and 41% [17-64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%).

Conclusions: Dose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound. Trial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE ) and authorized to proceed on 2006-09-25.

Keywords: Definitive chemoradiation; Dose-escalation; Esophageal cancer; Squamous cell carcinoma.

Fig. 1

a Study scheme. b CONSORT diagram

Fig. 2

a Overall survival of all patients (n = 17). b Overall survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median pretreatment gross tumor volume (≤ 33.2 ml vs > 33.2 ml). c Overall survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median metabolic response to induction chemotherapy (deltaSUV = SUV_{max[postinduction]}/SUV_{max[pretreatment]} ≤ 0.39 vs deltaSUV > 0.39)

Fig. 3

a Loco-regional progression-free survival of all patients (n = 17). b Loco-regional progression-free survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median pretreatment gross tumor volume (≤ 33.2 ml vs > 33.2 ml). c Loco-regional progression-free survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median metabolic response to induction chemotherapy (deltaSUV ≤ 0.39 vs deltaSUV > 0.39)

Fig. 4

Competing risk analysis. a Cumulative incidences of the events: death without relapse (black), distant metastases (red), or loco-regional recurrence (green), all patients (n = 17). b cumulative incidences of death without relapse (black), distant metastases (red), or loco-regional recurrence (green), grouped by radiotherapy dose (≤ 60 Gy [solid lines] versus > 60 Gy [dashed lines])