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The Medical Research Council Conventional versus Laparoscopic-Assisted Surgery In Colorectal Cancer (MRC CLASICC) trial was designed to determine the long-term oncological safety and efficacy of laparoscopically assisted surgery in comparison with conventional open surgery for the treatment of colorectal cancer. Earlier diagnosis of colorectal cancer, and changes in surgical technique, chemotherapy and radiotherapy, have led to substantially improved survival over recent years.
Surgical resection of colorectal cancer remains the only curative modality. The laparoscopic approach is now increasingly being used for colorectal cancer, and the UK National Institute for Health and Clinical Excellence guidance was updated in 2006 to recommend laparoscopic resection in patients in whom both open and laparoscopic approaches were deemed suitable1. CLASICC, along with similar trials, was instrumental in promoting the uptake of laparoscopic surgery, demonstrating improved short-term outcomes including reduced hospital stay, fewer wound complications and expedited return to normal function2–4.
Adequacy of technique was initially a criticism of laparoscopically assisted surgery; however, studies showing comparable outcomes in terms of resection margins and lymph node harvest have suggested equal short-term oncological efficacy4, 5. Studies examining long-term follow-up, including CLASICC 3- and 5-year analyses, have generally shown comparable outcomes between open and laparoscopic surgery in terms of disease-free survival (DFS) and overall survival3, 6–8.
CLASICC differed from other similar trials conducted at the time, with the inclusion of both colonic and rectal tumours, and also the requirement for central pathological review of all resection specimens. This paper reports long-term follow-up data from CLASICC, now exceeding 10 years, and provides further insight into the long-term outcomes and comparability of open versus laparoscopically assisted resection.
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Laparoscopically assisted surgery has been established previously as a recognized option for the surgical management of colorectal cancer. Evidence from randomized clinical trials, including CLASICC, has consistently shown comparable outcomes between open and laparoscopically assisted surgery in terms of overall survival and DFS6, 7. Reassuringly, pathological data from CLASICC, showing non-significantly raised circumferential resection margin positivity rates with laparoscopically assisted AR compared with open AR2, did not translate into survival differences at either 3- or 5-year follow-up6, 7. The present long-term follow-up of CLASICC has further demonstrated that laparoscopically assisted surgery is oncologically safe, and a suitable alternative to open surgery in the treatment of colorectal cancer, reporting no differences in long-term overall survival and DFS. There were no significant differences in local recurrence rates between randomized groups, and in particular the rectal cancer subgroups, a finding supported by recent meta-analyses9, 10.
In terms of survival, patients with colonic cancer appeared to do better than those with rectal cancer, a finding at odds with trends reported at the time of data collection in the general UK surgical population. However, CLASICC has demonstrated that survival of patients with rectal cancer is equivalent to that of the general UK surgical population, and improved survival in patients with colonic cancer in CLASICC is most likely explained by selection in terms of higher social class and lower stage of disease11.
On multivariable analysis, there was a statistically significant difference in DFS when right-sided cancers were compared with left-sided and sigmoid colonic cancers, with a non-statistically significant trend towards increased local recurrence in patients with cancers of the right colon. Recent evidence suggests that complete mesocolic excision (CME) with central vessel ligation (CVL) may improve oncological outcomes following right-sided resections12, 13. Although equivalence in terms of resection has been suggested14, there are no randomized data comparing laparoscopic and open surgery from which to draw any firm conclusions. It should be noted, however, that neither CME nor CVL was practised in the laparoscopic arm of CLASICC.
The present study has confirmed the observation that rectal cancers, in particular those subjected to APR, are at a higher risk of distant recurrence than colonic cancers. The local recurrence rates were similar in both the open and laparoscopic groups for AR and APR. CLASICC was undertaken before popularization of the extralevator APR (EL-APR) technique15, and it is interesting to speculate what impact the EL-APR might have on local recurrence rates following APR (15·3 per cent at 10 years with APR in CLASICC compared with 7–10 per cent reported with EL-APR)16, 17.
Higher local recurrence rates may also reflect the lower use of radiotherapy during the trial period compared with current practice. Further recent advances in this field include the introduction of robotic-assisted surgery. Early data from non-randomized sources suggest that robotic assistance may help to reduce the conversion rates in laparoscopic surgery18, 19. Other potential advantages include better autonomic nerve preservation, which may impact on the previously high rates of postoperative sexual and urinary dysfunction following total mesorectal excision20, 21.
There remains conflicting evidence regarding the impact of conversion on postoperative outcomes, with a number of studies suggesting that conversion does not influence survival adversely22, 23. In contrast, CLASICC previously reported worse outcomes associated with conversion, although this was statistically significant only in terms of overall survival6, 7. In the present analysis of long-term follow-up data, only patients with colonic cancer appeared to suffer adverse survival following conversion, which was associated with a statistically significant reduction in both overall survival and DFS following adjustment for key prognostic factors. The finding of poor DFS after conversion in patients with colonic cancer suggests that the disease process itself adversely influenced survival rather than conversion per se. As advanced cancer is the most commonly cited reason for conversion, this would appear to be the most likely explanation24. The DFS data showed gradually worsening survival in patients whose procedures had been converted compared with those who had a planned open procedure. This suggests a long-term process, that is advanced cancer pathology affecting survival. The more rapid initial decline seen in overall survival is explained by the presence of factors such as increased stress owing to a prolonged operation, in addition to adverse prognostic factors including, but not limited to, surgical experience, and inherent patient factors such as advanced disease, obesity and anatomical variation. These are likely to increase early morbidity and adversely affect recovery, thus primarily affecting overall survival.
Neither overall survival nor DFS appeared to be influenced adversely by intraoperative conversion in patients with rectal cancer. The reason for this is unclear, and the limited patient numbers preclude further subgroup analysis.
Interestingly, there was a trend towards improved early survival associated with laparoscopic surgery in patients with rectal cancer. Although this has not been reported elsewhere, it may be due to improved functional recovery resulting from the minimally invasive nature of the surgery2, 4, 25. This finding in particular should encourage surgeons to use laparoscopic surgery in patients with rectal cancer.
Overall, there were no statistically significant differences in overall survival or DFS between surgical techniques when analysed by TNM stage. A trend favouring survival following laparoscopic resection of stage III colonic cancer has been reported previously26, although these findings have since been explained as an outlier effect owing to underpowered subgroup analysis. The long-term follow-up of CLASICC has shown a converse trend, favouring open surgery in patients with stage III colonic cancer. Although this appears to suggest worse oncological outcomes associated with laparoscopic surgery, the numbers at risk are small and no confirmatory reports have been found. Any real effect therefore remains speculative, and it is evident that caution should be employed pending further research in this group of patients.
The long duration of follow-up examined here provides evidence to support the use of laparoscopically assisted surgery for colonic and rectal cancer. Laparoscopic surgery should be the treatment of choice, enabling patients to benefit from earlier functional recovery with no detriment to long-term survival outcomes.