Preoperative oxaliplatin with chemoradiation therapy

The ACCORD 12/0405-Prodige 2 trial (NCT00227747), which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible by digital rectal examination to either preoperative radiation therapy (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily 5 of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly). Total mesorectal excision was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation therapy was completed.[39]

The ACCORD 12/0405-Prodige 2 trial (NCT00227747), which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible by digital rectal examination to either preoperative radiation therapy (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily 5 of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly). Total mesorectal excision was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation therapy was completed.[39]

Pathological complete response was the primary end point (albeit never validated as a true surrogate of OS). A higher percentage of patients achieved a pathological complete response in the oxaliplatin-treated group (19.2% vs. 13.9%). However, the difference did not reach statistical significance (P = .09).

The ACCORD 12/0405-Prodige 2 trial (NCT00227747), which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible by digital rectal examination to either preoperative radiation therapy (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily 5 of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly). Total mesorectal excision was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation therapy was completed.[39]

The rate of grade 3 or 4 toxicity was significantly higher in the oxaliplatin-treated group (25% vs. 11%; P < .001), and there was no difference in the rate of sphincter-sparing surgery (75% vs. 78%).

Similarly, the STAR-01 trial investigated the role of oxaliplatin combined with 5-FU chemoradiation therapy for locally advanced rectal cancer.[40][Level of evidence A1] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation therapy or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary end point was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported.

Similarly, the STAR-01 trial investigated the role of oxaliplatin combined with 5-FU chemoradiation therapy for locally advanced rectal cancer.[40][Level of evidence A1] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation therapy or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary end point was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported.

The rate of pathological complete response was equivalent at 16% in both arms (odds ratio, 0.98; 95% CI, 0.66–1.44; P = .904).

Similarly, the STAR-01 trial investigated the role of oxaliplatin combined with 5-FU chemoradiation therapy for locally advanced rectal cancer.[40][Level of evidence A1] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation therapy or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary end point was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported.

There was no difference noted in the rate of pathologically positive lymph nodes, tumor infiltration beyond the muscularis propria, or the rate of circumferential margin positivity.

Similarly, the STAR-01 trial investigated the role of oxaliplatin combined with 5-FU chemoradiation therapy for locally advanced rectal cancer.[40][Level of evidence A1] This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation therapy or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary end point was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported.

An increase in grades 3 to 4 treatment-related acute toxicity was noted with the addition of oxaliplatin (24% vs. 8%; P <.001). Longer-term outcomes including OS have not yet been reported.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

Intravenous (IV) continuous infusion 5-FU with radiation therapy.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

Capecitabine with radiation therapy.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

IV continuous infusion 5-FU plus weekly oxaliplatin with radiation therapy.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

Capecitabine plus weekly oxaliplatin with radiation therapy.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

There was no significant difference in the rates of pathological complete response, sphincter-sparing surgery, or surgical downstaging between the 5-FU and capecitabine regimens or between the regimens with and without oxaliplatin.

The NSABP-R-04 trial (NCT00058474) randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:The primary objective of this study is locoregional disease control.[41][Level of evidence B1] Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated the following results:

Patients treated with oxaliplatin had significantly higher rates of grade 3 and grade 4 acute toxicity (15.4% vs. 6.6%; P < .001).

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical lymph node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation therapy with 5-FU (week 1 and week 5) or concurrent chemoradiation therapy with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[42][Level of evidence B1]

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical lymph node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation therapy with 5-FU (week 1 and week 5) or concurrent chemoradiation therapy with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[42][Level of evidence B1]

In contrast to the previous studies, a significantly higher rate of pathological complete response was achieved in patients who received oxaliplatin (17% vs. 13%; P = .038).

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical lymph node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation therapy with 5-FU (week 1 and week 5) or concurrent chemoradiation therapy with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[42][Level of evidence B1]

There was no significant difference in rates of overall grades 3 and 4 toxicity; however, diarrhea and nausea and vomiting were more common among those treated with oxaliplatin.

The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical lymph node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation therapy with 5-FU (week 1 and week 5) or concurrent chemoradiation therapy with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2).[42][Level of evidence B1]

The 5-FU schedules in this study differed between the two arms, which may have contributed to the difference in outcomes noted. Longer follow-up will be necessary to determine the effect on the primary end point of the study, DFS.