A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group Study

Abstract

The objective of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of irinotecan administered as a 5-day schedule synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation (45 Gy) for primary borderline/unresectable, locally advanced rectal cancer. The study used escalating doses of intravenous irinotecan (6, 8, 10, 12, 14, 16, 18, and 20 mg m À2 ) administered on days 1 -5 and 29 -33 followed by low dose LV (20 mg m À2 ) and 5FU (350 mg m À2 over 1 h) in sequential cohorts. Preoperative pelvic radiotherapy using a three-or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction. Surgery in the form of mesorectal excision was performed 6 -10 weeks later. Histopathological examination of the resected specimen was performed according to techniques of Quirke, and compared with clinical staging. A distance of 1 mm or less between the peripheral extent of the tumour and the radial resection margin defined an involved circumferential resection margin (CRM). The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT) defined as specific grade 3 or 4 toxicities. Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In total, 57 patients received irinotecan at the eight dose levels. The final cohort reached DLT after only four patients had been enrolled. The median age was 62 years (range 26 -75), 37 male and 20 female subjects. The MTD of irinotecan in this schedule was 20 mg m À2 when three out of four patients experienced DLT. Dose limiting grade 3 or 4 diarrhoea was reported in seven out of 57 patients, three at the 20 mg m À2 dose level. Serious haematological toxicity (grade 3) was minimal and reported in only three patients; one grade 3 neutropaenia, one grade 4 neutropaenia and one grade 3 febrile neutropaenia and anaemia. Compliance was good with 93 and 89% of patients completing radiotherapy and chemotherapy, respectively. The remaining patients had only minor deviations from protocol therapy. Eight patients did not proceed to surgery, in six cases because they remained unresectable or had developed metastatic disease, one patient was unfit for surgery and one died as a result of complications from radiotherapy. Forty-nine patients underwent a potentially curative surgical resection. Histopathological examination of the resected specimen demonstrated pCR 12 out of 49 (24%) and 12 out of 57 (21%) overall. A histologically confirmed clear circumferential resection margin (CRM) was achieved in 39 out of 49 (80%) of those resected, and 39 out of 57 (68%) overall. In conclusion, MTD with this scheduled regimen of irinotecan is 20 mg m À2 (days 1 -5 and 29 -33). The acceptable toxicity and compliance at 18 mg m À2 recommend testing this dose in future phase III studies. The tumour downstaging and complete resection rates (negative CRM) are encouragingly high for this very locally advanced group.

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

“…Furthermore, the resection rate achieved in this study is higher than that observed in studies using radiotherapy alone (range, 64 -75%) (Emami et al, 1982;Frykholm et al, 2001) or in some studies of CRT regimens (62 -95%) (de la Torre et al, 1999;Frykholm et al, 2001;Klautke et al, 2006;Glynne-Jones et al, 2007), and it is comparable to that cited in other reports of research with irinotecan (90 -100%) (Minsky et al, 1999;Mitchell et al, 2004;Klautke et al, 2005;Sebag-Montefiore et al, 2005). It is worth noting, that this current trial included only patients with T3/T4 cancers-that is patients with more advanced disease than those included in previously published studies.…”

“…Considering CRM involvement, 81% of patients in this study who underwent TME surgery were classed as R 0 after surgery (CRM-negative). In studies that report data on the number of CRM-negative cases, results range from 61 -74% with radiotherapy (Emami et al, 1982;Frykholm et al, 2001) to 72 -89% with 5-FUbased protocols (de la Torre et al, 1999;Frykholm et al, 2001;Avallone et al, 2006;Klautke et al, 2006;Glynne-Jones et al, 2007) or 88 -89% when irinotecan is given as part of the CRT regimen (Klautke et al, 2005;Sebag-Montefiore et al, 2005). The addition of irinotecan to CRT regimens does not, therefore, seem to increase the high rate of CRM-negative surgery reported previously, but CRT certainly seems to be more successful than radiotherapy alone.…”

“…CRT in patients with nonresectable rectal cancer has been shown to significantly improve disease-free survival compared with radiotherapy alone, and may increase overall survival (Frykholm et al, 2001). Overall survival rates following CRT treatment with 5-FU have been reported to range from 26 to 73% (de la Torre et al, 1999;Frykholm et al, 2001;Avallone et al, 2006;Klautke et al, 2006;Glynne-Jones et al, 2007). Reported rates of disease-free or relapse-free survival range from 54 to 74% (de la Torre et al, 1999;Frykholm et al, 2001;Avallone et al, 2006;Klautke et al, 2006;Glynne-Jones et al, 2007), but again the studies vary in duration of follow-up.…”

“…Clinical staging revealed a complete clinical response rate of 29, and 79% of patients were judged to have downstaged tumours on MRI after treatment. Few studies have reported MR downstaging following CRT, although in a previous study of 31 patients treated with 5-FU and radiotherapy the tumour volume was decreased by at least half in 77% of patients (Glynne-Jones et al, 2007).…”

Developments in Neoadjuvant Chemotherapy and Radiotherapy in Rectal Cancer

“…Irinotecan at 18 mg/m 2 was selected as the recommended dose for future studies. A pCR was observed in 24% patients and tumor downstaging in 41% of patients (Glynne-Jones et al, 2007). The above studies incorporating irinotecan with 5-FU and radiation appear to show promising results, as seen in the pCR rate and the number of patients who eventually had successful surgery.…”