Why have patients participated in laparoscopic colectomy trials?

Most patients, and many physicians, assumed that laparoscopic colectomy would offer advantages in recovery similar to those experienced for laparoscopic cholecystectomy. However, it took several years and many carefully conducted clinical trials to precisely define the degree of benefit. Because the oncologic issues were perceived as representing a potential threat to the oncologic outcomes of these patients, several prospective, randomized trials were designed to examine the benefits in the context of the risks. The field had reached a point of equipoise at which the patients and many surgeons preferred the laparoscopic approach, whereas the oncologic risks were uncertain and unknown. This formed the basis of several international clinical trials, as described later. Each of the trials was designed to rigorously investigate the feasibility of laparoscopic colectomy and the cancer risk and recovery benefits in the setting of curable colon cancer.

At least 4 large, prospective, randomized controlled trials from North America, Canada, and Europe have been completed and have reported both short- and long-term outcomes. To date, 3133 patients have been studied by random allocation to laparoscopic versus open surgery and followed for cancer and short-term outcomes. These patients are reported from the Barcelona Trial (219 patients), the Clinical Outcomes of Surgical Therapy (COST) Trial (872 patients), the Colon Cancer Laparoscopic or Open Resection (COLOR) Trial (1248 patients), and the Conventional versus Laparoscopic-Assisted Surgery in Patients with Colorectal Cancer (CLASSIC) Trial (794 patients) ; the novel aspect of the CLASSIC trial is its inclusion of patients with rectal cancer.

Potential Benefits and Short-term Outcomes

Why have thousands of patients accepted participation in laparoscopic trials knowing that they might have an inferior oncologic result?

The driver of laparoscopic colectomy in the setting of cancer was the possibility of gaining patient benefits. It was presumed, but not proved, that a shorter incision would result in less pain, short-duration ileus, and shorter hospital and posthospitalization recovery. To measure these potential benefits, several metrics were developed. Most of the clinical trials measured end points such as length of incision, duration of ileus, the need for analgesia, duration of hospital stay, quality of life (QOL), and complications. Such measurements try to capture the full patient experience, from physiologic factors to the patient’s perception of recovery. In 1993, when many of the international trials were launched, these tools were neither widely accepted nor well developed. Nevertheless, it was possible to identify patient-related benefits, as discussed later.

Data on recovery end points are available, showing the main advantages of the laparoscopic approach: length of hospital stay, duration of ileus, and duration of analgesic use or postoperative pain ( Table 1 ). The COLOR, CLASSIC, and Barcelona trials have found a shorter postoperative ileus with an earlier resumption of fluid intake and a normal diet in the laparoscopic arm. The COST trial showed a significant reduction in duration of narcotic and oral analgesic requirement, and the COLOR trial has shown a lower need for opioid analgesics on postoperative day 2 and 3 in the laparoscopic arm.

Another more recent single-institution, controlled trial from Taiwan randomized 286 patients with more selective entry criteria, including only tumors located in the distal transverse and left colon, requiring mobilization of the splenic flexure. The Taiwan trial is the only one to compare postoperative pain using a visual analog scale, underlying how laparoscopic surgery allows better pain control. Data on postoperative pain control are also available from other studies; in a review article, Tjandra and Chan showed that 7 randomized studies reported significantly less pain, by 12.6%, after laparoscopic procedures, as shown by a reduction of several pain scores, together with a reduction of 30.7% in the use of postoperative narcotics. A Cochrane Database review, based on results from 6 trials, also showed significantly reduced postoperative pain perception on the first postoperative day; however, no significant differences in pain perception were assessed on the second postoperative day.

Data available from the Taiwan trial also demonstrate how laparoscopic surgery–related benefits go beyond enhanced hospital parameters because of better postoperative and posthospital recovery, with a significantly shorter return to partial activity, full activity, and ordinary work.

Intraoperative outcomes were also addressed, showing additional benefits gained through the use of laparoscopic techniques ( Table 2 ). The length of incision was significantly shorter in laparoscopic arms. Investigators from the Taiwan trial argued that, even if open colectomies could be performed in thinner patients through a small incision (<7 cm), the benefits of laparoscopic surgery go beyond the wound size, because there are recovery advantages, a magnified operative field, and a more precise resection of the tumor.

Recovery benefits are gained at the expense of a longer duration of surgery for those treated with laparoscopic colectomy. The duration of surgery in the laparoscopic arm in each of the trials ranged from 24 to 55 minutes more than the open arm, and this difference was significant. Laparoscopic surgery is more costly. The Taiwan trial reported that the overall cost of laparoscopic procedures is significantly higher. However, multicenter randomized data on the costs of the laparoscopic approach are poor. Results are variable on costs, with some studies showing higher overall costs, mostly because of the use of disposable instruments and longer operative times. Other studies show cost saving because of reduced length of hospital stay. Costs seem to be highly practice dependent.

Short-term complications, morbidity, and mortality were investigated and found to be similar between groups in all the trials ( Table 3 ). Thirty-day mortality was not significantly different among trials, although the CLASSIC trial reported higher mortality in both the laparoscopic and open arm compared with the other studies. No significant differences in the rates of intraoperative complications, rates and severity of postoperative complications at discharge, and rates of readmission or reoperation were identified by any of the biggest multicenter randomized trials. However, the Barcelona Trial reported a significant reduction in postoperative complication in the laparoscopic arm.

Other than the main trials mentioned earlier, several studies report on short-term outcomes and morbidity after laparoscopic and open colectomy for colon cancer. One of the most remarkable was led by Bilimoria and colleagues, in which data available from 3059 patients from 121 hospitals were analyzed, using the American College of Surgeons National Surgical Quality Improvement Project database. Although no differences were found in mortality and reoperation rate, the laparoscopic colectomy group showed a significantly lower overall morbidity, attributed to better outcomes for surgical site infections and pneumonia. A significantly lower rate of wound complications (combining wound infection and wound dehiscence) after laparoscopic colectomy was also shown in the pooled analysis of 17 randomized, controlled trials on laparoscopic resection for colon cancer by Tjandra and Chan, although no significant differences in overall complication rates were found between the 2 arms.

Although these findings are likely explained by selection bias, it is also possible that there is some additional benefit to laparoscopic surgery from either the lesser extent of wounding or the better preservation of the immune status.

Potential Benefits and Short-term Outcomes

Why have thousands of patients accepted participation in laparoscopic trials knowing that they might have an inferior oncologic result?

The driver of laparoscopic colectomy in the setting of cancer was the possibility of gaining patient benefits. It was presumed, but not proved, that a shorter incision would result in less pain, short-duration ileus, and shorter hospital and posthospitalization recovery. To measure these potential benefits, several metrics were developed. Most of the clinical trials measured end points such as length of incision, duration of ileus, the need for analgesia, duration of hospital stay, quality of life (QOL), and complications. Such measurements try to capture the full patient experience, from physiologic factors to the patient’s perception of recovery. In 1993, when many of the international trials were launched, these tools were neither widely accepted nor well developed. Nevertheless, it was possible to identify patient-related benefits, as discussed later.

Data on recovery end points are available, showing the main advantages of the laparoscopic approach: length of hospital stay, duration of ileus, and duration of analgesic use or postoperative pain ( Table 1 ). The COLOR, CLASSIC, and Barcelona trials have found a shorter postoperative ileus with an earlier resumption of fluid intake and a normal diet in the laparoscopic arm. The COST trial showed a significant reduction in duration of narcotic and oral analgesic requirement, and the COLOR trial has shown a lower need for opioid analgesics on postoperative day 2 and 3 in the laparoscopic arm.

Another more recent single-institution, controlled trial from Taiwan randomized 286 patients with more selective entry criteria, including only tumors located in the distal transverse and left colon, requiring mobilization of the splenic flexure. The Taiwan trial is the only one to compare postoperative pain using a visual analog scale, underlying how laparoscopic surgery allows better pain control. Data on postoperative pain control are also available from other studies; in a review article, Tjandra and Chan showed that 7 randomized studies reported significantly less pain, by 12.6%, after laparoscopic procedures, as shown by a reduction of several pain scores, together with a reduction of 30.7% in the use of postoperative narcotics. A Cochrane Database review, based on results from 6 trials, also showed significantly reduced postoperative pain perception on the first postoperative day; however, no significant differences in pain perception were assessed on the second postoperative day.

Data available from the Taiwan trial also demonstrate how laparoscopic surgery–related benefits go beyond enhanced hospital parameters because of better postoperative and posthospital recovery, with a significantly shorter return to partial activity, full activity, and ordinary work.

Intraoperative outcomes were also addressed, showing additional benefits gained through the use of laparoscopic techniques ( Table 2 ). The length of incision was significantly shorter in laparoscopic arms. Investigators from the Taiwan trial argued that, even if open colectomies could be performed in thinner patients through a small incision (<7 cm), the benefits of laparoscopic surgery go beyond the wound size, because there are recovery advantages, a magnified operative field, and a more precise resection of the tumor.

Recovery benefits are gained at the expense of a longer duration of surgery for those treated with laparoscopic colectomy. The duration of surgery in the laparoscopic arm in each of the trials ranged from 24 to 55 minutes more than the open arm, and this difference was significant. Laparoscopic surgery is more costly. The Taiwan trial reported that the overall cost of laparoscopic procedures is significantly higher. However, multicenter randomized data on the costs of the laparoscopic approach are poor. Results are variable on costs, with some studies showing higher overall costs, mostly because of the use of disposable instruments and longer operative times. Other studies show cost saving because of reduced length of hospital stay. Costs seem to be highly practice dependent.

Short-term complications, morbidity, and mortality were investigated and found to be similar between groups in all the trials ( Table 3 ). Thirty-day mortality was not significantly different among trials, although the CLASSIC trial reported higher mortality in both the laparoscopic and open arm compared with the other studies. No significant differences in the rates of intraoperative complications, rates and severity of postoperative complications at discharge, and rates of readmission or reoperation were identified by any of the biggest multicenter randomized trials. However, the Barcelona Trial reported a significant reduction in postoperative complication in the laparoscopic arm.

Other than the main trials mentioned earlier, several studies report on short-term outcomes and morbidity after laparoscopic and open colectomy for colon cancer. One of the most remarkable was led by Bilimoria and colleagues, in which data available from 3059 patients from 121 hospitals were analyzed, using the American College of Surgeons National Surgical Quality Improvement Project database. Although no differences were found in mortality and reoperation rate, the laparoscopic colectomy group showed a significantly lower overall morbidity, attributed to better outcomes for surgical site infections and pneumonia. A significantly lower rate of wound complications (combining wound infection and wound dehiscence) after laparoscopic colectomy was also shown in the pooled analysis of 17 randomized, controlled trials on laparoscopic resection for colon cancer by Tjandra and Chan, although no significant differences in overall complication rates were found between the 2 arms.

Although these findings are likely explained by selection bias, it is also possible that there is some additional benefit to laparoscopic surgery from either the lesser extent of wounding or the better preservation of the immune status.

QOL

Regarding QOL parameters, there is now substantial evidence to support modest QOL benefits for patients who have cancer treated with laparoscopic colectomy. The meta-analysis from the Cochrane Database on short-term outcomes after laparoscopic surgery shows that there are only 2 randomized trials that have appropriately investigated QOL after laparoscopic and open colectomy for cancer. The pooled data from these 2 studies failed to show any significant advantage for the laparoscopic versus the conventional technique 60 days after surgery. The COST study, led by Weeks and Nelson, investigated 428 patients, using 3 different QOL scores, evaluating outcomes at 2 days, 2 weeks, and 2 months after surgery. The only statistically significant difference between the 2 arms was identified at 2 weeks after surgery, showing a slightly better overall QOL.

It remains unclear why laparoscopic-assisted colectomy (LAC) has not shown QOL benefits as significant as other parameters of postoperative recovery. One possible explanation could arise from the high conversion rates: data were analyzed by intention-to-treat and this might have masked the favorable effect on QOL of cases that were completed laparoscopically, considering that converted cases were analyzed with the laparoscopic arm. Further gains in QOL in this situation would require substantial reductions in rates of conversion. Another possible explanation for the modest QOL benefits might derive from the inability of the currently available tools to appropriately measure QOL after laparoscopic surgery for carcinoma. Patients who have undergone surgery for carcinoma might evaluate their QOL differently from patients who underwent analogous surgery for benign disease, for which cosmesis, postoperative pain, and limitation of social activity might play a more relevant role.

Data from all relevant trials allow researchers to summarize the main patient-related benefits of the application of laparoscopic techniques in colon cancer resection. These benefits have been established by multicenter, randomized, controlled trials and meta-analysis, and level 1 evidence is now available to support them (see Ref. ):

• 1.
  

  General feasibility

  
  
• 2.
  

  Smaller incision

  
  
• 3.
  

  Lower narcotic usefulness

  
  
• 4.
  

  Reduced postoperative pain

  
  
• 5.
  

  Shorter hospitalization

  
  
• 6.
  

  Improved QOL (at 2 weeks after surgery)

  
  
• 7.
  

  Shorter postoperative recovery

  
  
• 8.
  

  Equivalent morbidity.