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

Abstract

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. 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, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150 mg m À2 ) were given on days 2 and 30, followed by low-dose LV (20 mg m À2 ) and 5FU (350 mg m À2 ), both given on days 1 -5 and 29 -33. Surgery was performed 6 -10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31 -79), 24 males and eight females. . In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR þ Tmic 5 out of 27 (19%), pT0 -2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150 mg m À2 given days 2 and 30 when added to the described 5FU LV and 45 Gy radiation preoperatively. The acceptable toxicity and compliance at 130 mg m À2 recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group.

Biweekly oxaliplatin, raltitrexed, 5-fluorouracil and folinic acid combination chemotherapy during preoperative radiation therapy for locally advanced rectal cancer: a phase I–II study

“…Indeed, several recent phase I -II trials have explored the activity of a combination of OXA and fluoropyrimidines (i.v. FU or oral capecitabine) during preoperative pelvic RT (Gerard et al, 2003;Rodel et al, 2003;Aschele et al, 2005;Sebag-Montefiore et al, 2005). Although all these trials have demonstrated the feasibility of such combinations, we would underline that the reported pCR rates (ranging between 7 and 28%) were clearly lower than that achieved in our study.…”

“…Furthermore, the addition of OXA to a biweekly regimen of RTX and FU/FA proved manageable and active in heavily pretreated patients (Comella et al, 2002). Recently, several investigators have reported encouraging results with the addition of OXA to fluoropyrimidines during pelvic preoperative radiotherapy in LARC (Gerard et al, 2003;Rodel et al, 2003;Gambacorta et al, 2004a;Aschele et al, 2005;Sebag-Montefiore et al, 2005). For all these reasons, the combination of OXA, RTX and FU/FA with pelvic RT represents an attractive perspective in the preoperative setting of LARC.…”

Adjuvant chemotherapy after neoadjuvant chemoradiation and surgery: A quest to improve survival for stage II and III rectal cancer

“…In colon cancer, the addition of oxaliplatin to 5-FU as adjuvant therapy after curative resection of stage II/III disease resulted in signifi cant improvement in disease-free survival (P = 0.0002) [34]. The tolerability of oxaliplatin added to 5-FU with concomitant radiotherapy in rectal cancer was established in the Lyon R 97-03 phase 1 trial in 2001 [35] and the CCOG study [36]. With weekly oxaliplatin (60 mg/m 2 ) added to continuous infusion 5-FU (225 mg/m 2 per day) and radiotherapy (1.8 Gy over 28 fractions for a total dose of 50.4 Gy) preoperatively in patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum, Aschele et al [37] found an impressive 21 of 24 patients (84%) with tumor downstaging and 7 of 24 patients (28%) with pathologic complete responses.…”

Recent advances in the treatment of localized rectal cancer

“…Combinations of two drugs (capecitabine and oxaliplatin; protracted venous infusions of 5-FU plus capecitabine; 5-FU/leucovorin plus capecitabine; 5-FU/leucovorin plus irinotecan), in combination with preoperative RT, have been tested in numerous phase 1/2 studies [15][16][17]. Results have shown good tolerability profiles, and the combinations have appeared to significantly increase R0 resection and tumor sterilization rates.…”