Laparoscopy for Rectal Cancer: Is the Story Settled?

Abstract

Dear Editor:

Recently, two large, multicenter prospective randomized controlled trials were published in the Journal of the American Medical Association regarding the comparison of the use of laparoscopic and open surgery to achieve an oncologically complete resection of rectal cancer in patients with locally advanced disease (stage II, IIIA, or IIIB) treated with neoadjuvant therapy.^1,2 The American College of Surgeons Oncology Group (ACOSOG) Z6051 study was conducted across 35 institutions in the United States and Canada and enrolled 486 rectal cancer patients. Concurrently, a second trial called the Australasian Laparoscopic Cancer of the Rectum (ALaCaRT) trial enrolled 475 rectal cancer patients from 24 sites across Australia and New Zealand. Both trials used a composite endpoint assessed by histopathology consisting of a complete total mesorectal excision (TME), a negative circumferential resection margin (CRM), and a negative distal margin (DM). All three parameters needed to be satisfied in order for the resection to be deemed complete. These criteria have been shown previously to correlate with long-term outcomes.

In the ACOSOG trial, complete resection was achieved in 81.7% of laparoscopic cases and 86.9% of open cases (P = .41 for noninferiority). Similarly, in the ALaCaRT trial, the primary outcome of a complete resection was achieved in 82% compared to 89% in the open surgery group (P = .38 for noninferiority). Despite a high proportion of complete resection in both the open and laparoscopic arms and a low conversion rate, both studies obviously concluded that the noninferiority endpoint was not met. These results were surprising considering previous multicenter prospective trials demonstrating the efficacy of laparoscopic surgery for colorectal cancers as well as several meta-analyses indicating equivalent oncologic success between laparoscopic and open surgery in the treatment of rectal cancer. Is there a way to reconcile these disparate findings?

The safety and efficacy of laparoscopic surgery in the treatment of colorectal cancer were greatly influenced by the landmark Clinical Outcomes of Surgical Therapy (COST) trial, a noninferiority randomized controlled study carried out at 48 institutions comparing short- and long-term outcomes among 872 colon cancer patients who were randomized to undergo open or laparoscopically assisted colectomy. After a median of 4.4 years of follow-up, no significant difference was seen in the recurrence rate or overall survival between the two surgical techniques.³ With the effectiveness of laparoscopy for colon cancer well supported, the subsequent Conventional versus Laparoscopic Assisted Surgery in Patients with Colorectal Cancer (CLASICC) trial included both colon and rectal cancer patients in a prospective randomized controlled trial. This study was conducted in 27 centers in the United Kingdom from 1996 to 2002 and demonstrated no statistically significant differences in the overall and disease-free survival between laparoscopic and open resection of colon or rectal cancer after 10 years of follow-up. Like the ACOSOG Z6051 and ALaCaRT studies, the CLASICC trial initially used surrogate short-term histopathologic endpoints in an attempt to predict long-term outcomes. In the short-term results of the CLASICC trial, an analysis of the subgroup of rectal cancer patients who received a low anterior resection (LAR) revealed a greater proportion of positive CRM in specimens from laparoscopic compared to open resection (12.1% versus 7.7%, P = .16), but this difference was not statistically significant.⁴ Because positive CRM has been associated with worse long-term outcomes in rectal cancer,⁵ the authors initially concluded that laparoscopic LAR for rectal cancer could be associated with a higher risk of local recurrence and cautioned against the use of laparoscopy for this type of resection. This conclusion was tempered when the 3-year results of the CLASICC trial found no difference in the incidence of local recurrence or OS among rectal cancer patients undergoing laparoscopic compared to open LAR.⁶ Furthermore, no difference in DFS or OS was seen in rectal cancer patients between laparoscopic and open APR at the 3-year mark. These results were echoed at 5 years⁷ and 10 years³ of follow-up.

With the results of the CLASICC trial in mind, it becomes apparent that the findings of the ACOSOG Z6051 and ALaCaRT trials should be interpreted carefully. Specifically, the question remains whether the composite endpoint chosen for these studies will adequately predict long-term outcomes. When looking at CRM positivity alone, neither trial demonstrated a statistically significant difference between laparoscopic and open surgery, although a strong trend favoring open resection was noted in both studies. The ACOSOG trial noted positive CRM in 12.1% of laparoscopically resected specimens versus 7.7% of open resection specimens (P = .11, Table 1). This difference is comparable to that seen in the CLASICC trial among rectal cancer patients who underwent LAR, but who ultimately did not go on to experience statistically significant differences in DFS or OS. However, the ALaCaRT trial achieved much lower positive CRM rates with each technique, with 6.7% of laparoscopically resected specimens having positive CRM compared to 3.8% of open resection specimens (P = .06).

Table 1.

Comparison of Short-Term Pathologic Outcomes

	CRM positive		TME complete or near-complete
Trial	Laparoscopic (%)	Open (%)	Laparoscopic (%)	Open (%)
ACOSOG Z6051¹	12.1	7.7	92.1	95.1
ALaCaRT²	6.7	3.8	96.6	99.1
CLASICC (all rectal cancer pts)⁴	15.5	14.4	—	—
CLASICC (LAR only)⁴	12.4	6.3	—	—
COLOR II⁸	9.5	10.0	97.1	97.3
COREAN¹⁰	2.9	4.1	91.8	88.2

ACOSOG, American College of Surgeons Oncology Group; ALaCaRT, Australasian Laparoscopic Cancer of the Rectum; CLASICC, Conventional versus Laparoscopic Assisted Surgery in Patients with Colorectal Cancer; COLOR II, COlorectal cancer Laparoscopic or Open Resection; CRM, circumferential resection margin; LAR, low anterior resection; TME, total mesorectal excision.

In addition to the CLASICC trial, there are two other large, multicenter prospective randomized controlled trials comparing laparoscopic to open resection for the treatment of rectal cancer. The COlorectal cancer Laparoscopic or Open Resection (COLOR II) trial was a noninferiority phase 3 trial across 30 centers in eight countries that enrolled 1103 rectal cancer patients and randomized 2:1 to laparoscopic or open resection. Like the two more recent trials, the COLOR II trial included pathologic examination of the CRM and DM, as well as completeness of TME, but did not combine them into a composite endpoint. Short-term data indicated no significant difference between laparoscopic and open resection in CRM positivity (9.5% versus 10.0%, P = .850) or completeness of TME (97.1% versus 97.3%, P = .70).⁸ In comparison, the ALaCaRT trial found a strong trend toward lower likelihood of complete or near complete TME in the laparoscopic arm compared to open (96.6% versus 99.1%, P = .11), while the ACOSOG trial found a more modest difference (92.1% versus 95.1%, P = .20). However, in both instances, the more recent trials achieved a higher overall rate of complete TME. After 3 years of follow-up in the COLOR II trial, local recurrence, DFS, and OS were similar between laparoscopic and open resection.⁹

While the COLOR II trial included rectal cancer patients with stage I disease, the comparison of open versus laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy (COREAN) trial enrolled 340 rectal cancer patients from South Korea with cT3N0-2 disease who all received neoadjuvant therapy. As in the other trials, the COREAN trial collected data regarding the involvement of the CRM and TME quality. Analysis of short-term outcomes found no significant difference between laparoscopic and open technique with regard to positive CRM (2.9% versus 4.1%, P = .770) or complete or nearly complete TME (91.8% versus 88.2%, P = .37).¹⁰ While CRM positivity was markedly lower than in the ACOSOG or ALaCaRT trials, the TME findings are similar to those achieved in the more recent trials. Recent publication of the 3-year follow-up from the COREAN trial permits a comparison of short-term data and long-term results. Between the laparoscopic and open technique, there was no significant difference in the rates of local recurrence (2.6% versus 4.9%), disease-free survival (79.2% versus 72.5%), or overall survival (91.7% versus 90.4%), and none of the differences exceeded a 15% noninferiority margin.¹¹

The ACOSOG Z6051 and ALaCaRT trials undoubtedly comprise a significant addition to the surgical treatment of rectal cancer. They are both in agreement that the laparoscopic technique is not noninferior to open resection for the treatment of locally advanced disease based on a composite short-term endpoint. Although this conclusion is at odds with similar high-quality multicenter randomized controlled trials, the long-term results are yet to be reached. In previous trials both with and without differences in short-term oncologic outcomes, the long-term data that are available continue to support the use of laparoscopy as noninferior to open surgery for the treatment of rectal cancer. However, it remains to be seen whether the small, but statistically significant, difference in CRM positivity and TME completeness in these two recent trials has a correspondingly significant impact on long-term outcomes. Without this crucial information, the suitability of laparoscopic resection for stage II and III rectal cancer remains under debate.

Footnotes

Disclosure Statement

No competing financial interests exist.

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