A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer

Abstract

We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N þ were recruited to receive irinotecan (50 mg m À2 weekly) and capecitabine (500 mg m À2 bid days 1 -38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4 -6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/À/À; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/À, nausea/vomiting 9/10/2/À, and increased activity of transaminases 3/3/1/À. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n ¼ 25; abdomino-perineal resection n ¼ 6; Hartmann's procedure n ¼ 3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy. Advances in surgical technique, including total mesorectal excision and thorough pathohistological work-up of the resected specimen have significantly improved the prognosis of patients with localised rectal cancer during the past two decades. Nevertheless, preoperative radiotherapy further improves local recurrence rates (Kapiteijn et al, 2001). The German CAO/AIO/ARO-94 trial, which compared pre-and postoperative chemoradiation in resectable rectal cancer, established the neoadjuvant approach as a new standard of care given it's superiority with respect to local failure rates and toxicity (Sauer et al, 2004). Moreover, the MRC CR07 trial, which compared short-course preoperative radiotherapy (5 Â 5 Gy) in resectable rectal cancer with selective postoperative chemoradiation in patients with compromised circumferential resection margins, showed a significant reduction in local recurrence and improved disease-free survival in favour of the short-course preoperative radiotherapy . Finally, bot...

Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study

“…However, the rate of grade III/IV toxicity (10%) noted in this study is comparable with that reported for oxaliplatin regimes (18 -30%) (Alonso et al, 2004(Alonso et al, , 2007Casado et al, 2004;Tucci et al, 2004;Fakih et al, 2005;Machiels et al, 2005;Avallone et al, 2006;Rutten et al, 2006;Rödel et al, 2007). Indeed, the findings of this study suggest a safety profile for irinotecan, 5-FU and radiotherapy that is comparable with previously reported findings with capecitabine and radiotherapy (rate of grade III/IV diarrhoea 12 -28%) (Mehta et al, 2003;Navarro et al, 2003;Mitchell et al, 2004;Mohiuddin et al, 2006;Willeke et al, 2007), but using a lower radiation dose (45 Gy as opposed to 50.4 Gy in the capecitabine regimen).…”

“…Six small studies are published as full papers (Kalofonos et al, 2003;Mehta et al, 2003;Klautke et al, 2005;Mohiuddin et al, 2006;GlynneJones et al, 2007;Willeke et al, 2007). To conclude, the combined RCT regimen irinotecan plus 5-FU with radiation therapy appears to be a tolerable adjuvant therapy (Kalofonos et al, 2003) that results in a good tumour response when given pre-operatively to patients with rectal cancer in whom resection is either possible or uncertain (Mehta et al, 2003;Klautke et al, 2005).…”

A phase II study of cetuximab, capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer

“…21 The addition of a second chemotherapeutic agent to neoadjuvant capecitabine-based CRT with cetuximab has not demonstrated a marked improvement to the rates of pCR or tumor downstaging in LARC, 24 which remain similar to those reported from studies of neoadjuvant capecitabine-based CRT, 12,13,25 or capecitabine-based CRT with irinotecan or oxaliplatin. 26,27 In the present study an assessment of radiological tumor response according to RECIST criteria was made. An overall response rate of 71% was recorded, which was similar to the that reported for patients with locally advanced SCCHN receiving cetuximab in combination with radiotherapy.…”

Inhibitory effects of oxaliplatin in experimental radiation treatment of colorectal carcinoma: does oxaliplatin improve 5-fluorouracil-dependent radiosensitivity?

“…• Irinotecan: Phase II trials have found a dose-dependent improved pCR rates (0-24%) with irinotecan implemented in CRT with acceptable toxicity (184,185), and a German study found pCR of 15% (186). A recent phase III trial reported no improved efficacy and increased toxicity of irinotecan when implemented in postoperative CRT after a 3-year follow-up (187).…”