Phase III Trials Fail to Show Noninferiority of Surgical Outcome for Laparoscopic vs Open Resection in Rectal Cancer
Two phase III trials, reported in JAMA by Fleshman et al and Stevenson et al, failed to show noninferiority of surgical outcome for laparoscopic vs open resection in patients with rectal cancer.
ACOSOG Z6051 Trial
In the American College of Surgeons Oncology Group (ACOSOG) Z6051 trial, reported by Fleshman et al, 486 patients with stage II or III rectal cancer within 12 cm of the anal verge from 35 institutions in the United States and Canada were randomly assigned between October 2008 and September 2013 to undergo laparoscopic resection (n = 240 evaluable patients) or open resection (n = 222 evaluable patients) by credentialed surgeons after neoadjuvant chemotherapy. The primary outcome measure was successful resection as a composite of circumferential radial margin > 1 mm, distal margin without tumor, and completeness of total mesorectal excision. The noninferiority margin was 6%.
The laparoscopic and open surgery groups were generally balanced for age (mean = 58 and 57 years), sex (65% and 66% male), race (83% and 87% white, 9% and 5% black), planned procedure (abdominoperineal resection in 23% and 24%, low anterior resection in 77% and 76%), tumor location (high in 14% and 12%, middle in 35% and 40%, low in 51% and 48%), Zubrod performance score (0–1 for 99% and 98%), clinical stage (IIa in 41% and 39%, IIIA in 4.5% and 4.6%, IIIB in 47% and 48%, IIIC in 6.6% and 7.9%), and prior therapy (chemotherapy and radiotherapy in 95% and 91%, radiotherapy alone in 3.3% and 5.5%, chemotherapy alone in 1.7% and 3.4%).
Successful resection occurred in 81.7% of patients undergoing laparoscopic resection (95% confidence interval [CI] = 76.8%–86.6%) vs 86.9% of those undergoing open resection (95% CI = 82.5%–91.4%); the difference was −5.3%, with a one-sided 95% CI of −10.8% to ∞ and P for noninferiority = .41. Conversion to open resection occurred in 11.3% of patients in the laparoscopic resection group. Mean operation time was 266.2 vs 220.6 minutes (mean difference = 45.5 minutes, P < .001). There were no significant differences in length of hospital stay (mean = 7.3 vs 7.0 days), readmission within 30 days (3.3% vs 4.1%), or severe complications (22.5% vs 22.1%).
Overall, quality of the total mesorectal excision specimen in the 462 evaluable cases was complete (77%) or nearly complete (16.5%) in 93.5% of patients (92.1% vs 95.1%, P = .20). A negative circumferential radial margin was observed in 90% of patients overall (87.9% vs 92.3%, P = .11). The distal margin result was negative in > 98% of patients irrespective of type of surgery (P = .91).
The investigators concluded: “Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients.”
ALaCaRT Trial
In the Australasian Laparoscopic Cancer of the Rectum (ALaCaRT) trial, reported by Stevenson et al, 475 patients with stage T1 to T3 rectal cancer < 15 cm from the anal verge from 24 sites in Australia and New Zealand were randomly assigned between March 2010 and November 2014 to undergo laparoscopic (n = 238) or open resection (n = 237) by credentialed surgeons. The primary outcome measure was successful resection as a composite of complete total mesorectal excision, clear circumferential margin (≥ 1 mm), and clear distal resection margin (≥ 1 mm). The noninferiority margin was 8%.
The laparoscopic and open resection groups were generally balanced for age (median = 65 years in both), sex (67% and 64% male), Eastern Cooperative Oncology Group performance status (0 or 1 for 98% in both), preoperative radiotherapy (50% and 49%), planned procedure (abdominoperineal resection in 8% and 7%, low anterior resection in 92% and 93%), tumor location (high in 22% and 21%, middle in 43% and 44%, low in 35% in both), stage (T1 in 8% and 5%, T2 in 29% in both, T3 in 63% and 66%), nodal status (N0 in 45% and 53%, N1 in 39% and 34%, N2 in 16% and 13%), and distant metastasis (4% in both).
Resection was successful in 82% of the laparoscopic surgery group vs 89% in the open surgery group; the difference was −7.0%, with a 95% CI of −12.4% to ∞ and P = .38 for noninferiority. Conversion to open resection occurred in 9% of the laparoscopic group. Circumferential resection margin was clear in 93% vs 97% (difference = −3.7%, P = .06), distal margin was clear in 99% vs 99% (difference = −0.4%, P = .67), and total mesorectal excision was complete in 87% vs 92% (difference = −5.4%, P = .06).
Median operation time was 210 vs 190 minutes (P = .007). There were no significant differences between groups in length of hospital stay or rates of major complications.
The investigators concluded: “Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired.”
James Fleshman, MD, of Baylor University Medical Center, is the corresponding author for the JAMA article reporting the ACOSOG Z6051 trial. Andrew R. L. Stevenson, MB BS, FRACS, of University of Queensland, is the corresponding author for the JAMA article reporting the ALaCaRT trial.
The ACOSOG Z6051 trial was supported by a grant from the National Cancer Institute, and the Covidien Company provided unrestricted research support to the ACOSOG infrastructure for the trial. The ALaCaRT Trial was supported by grants from the Colorectal Surgical Society of Australia and New Zealand Foundation and the National Health and Medical Research Council. For full disclosures of the study authors, visit jama.jamanetwork.com.
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