Phase III Trials Fail to Show Noninferiority of Surgical Outcome for Laparoscopic vs Open Resection in Rectal Cancer


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James Fleshman, MD, and colleagues

Andrew R. Stevenson, MBBS, FRACS, and colleagues

Laparoscopy vs Open Surgery for Rectal Cancer

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.

—James Fleshman, MD, and colleagues
Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery.

—Andrew R. Stevenson, MBBS, FRACS, and colleagues

Two phase III trials, reported in JAMA by James Fleshman, MD, of Baylor University Medical Center, Dallas, and colleagues1 and Andrew R. Stevenson, MBBS, FRACS, of the University of Queensland, Brisbane, Australia, and colleagues,2 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 and colleagues, 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 all baseline characteristics assessed, including age, sex, race, planned procedure, tumor location, Zubrod performance score, clinical stage, and prior therapy.

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% confidence interval 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 Trial ­(ALaCaRT), reported by Stevenson and colleagues, 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 all baseline characteristics assessed, includin age, sex, ECOG performance status, preoperative radiotherapy, planned procedure, tumor location, stage, nodal status, and distant metastasis.

Resection was successful in 82% of the laparoscopic surgery group vs 89% of the open surgery group; the difference was −7.0%, with a 95% confidence interval 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.” ■

Disclosure: 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. The American Society of Colon and Rectal Surgeons provided funding for the quality-of-life secondary endpoint evaluation during the study. For full disclosures of the study authors, visit jama.jamanetwork.com.

References

1. Fleshman J, Branda M, Sargent DJ, et al: Effect of laparoscopic-assisted resection vs open resection of stage II or III rectal cancer on pathologic outcomes: The ACOSOG Z6051 randomized clinical trial. JAMA 314:1346-1355, 2015.

2. Stevenson AR, Solomon MJ, Lumley JW, et al: Effect of laparoscopic-assisted resection vs open resection on pathological outcomes in rectal cancer: The ALa­CaRT randomized clinical trial. JAMA 314:1356-1363, 2015.


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