A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer

Abstract

The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3 -4 N0 -2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4 -6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m À2 day À1 (n ¼ 3), 1000 mg m À2 day À1 (n ¼ 6), 1250 mg m À2 day À1 (n ¼ 3), 1650 mg m À2 day À1 (n ¼ 3), 1800 mg m À2 day À1 (n ¼ 8) and 2000 mg m À2 day À1 (n ¼ 5). The mean age was 62.3 years (range: 33 -80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1 -11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m À2 day À1 (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m À2 day À1 had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m À2 day À1 after reaching MTD. None of the eight patients at dose level 1800 mg m À2 day À1 developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m À2 day À1 , given as 1000 mg m À2 twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m À2 day À1 when given in this schedule.

Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer

“…In the current trial, even though we performed meticulous pathologic examination described previously, 11 our ypCR rate or other histologic parameters were comparable with other studies that used capecitabine, [16][17][18][23][24][25][26] and our ypCR rate was higher than that of the German trial (17% vs 8%) in spite of more adverse factors (Table 7). 2 The exact reason for these differences is not clear, but we propose the following 2 explanations.…”

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

“…Phase I studies of radiotherapy with capecitabine have established dose levels in the range of 800–900 mg/m 2 given twice daily throughout radiotherapy. The DLT was either grade 3 hand-foot syndrome or diarrhea [21,22,23]. In phase II studies, pCR rates in the range of 12–31% were achieved, with diarrhea and hand-foot syndrome as the main symptoms of grade 3 toxicity [24,25,26].…”

Preoperative chemoradiation in rectal cancer: Retrospective comparison between capecitabine and continuous infusion of 5‐fluorouracil

“…Only a few studies have used capecitabine in the preoperative treatment of rectal cancer [9,10,15]. Kim et al [9] administered capecitabine with leucovorin in two cycles of 14 days each, concomitant with preoperative irradiation.…”