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Gastrointestinal (Colorectal) Cancer
Rectal Cancer: New Paradigms beyond Standard Chemotherapy and Radiation
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Minimally Invasive Surgery of Rectal Cancer: Current Evidence and Options
Abstract
Minimally invasive surgery (MIS) of colorectal cancer has become more popular in the past two decades. Laparoscopic colectomy has been accepted as an alternative standard approach in colon cancer, with comparable oncologic outcomes and several better short-term outcomes compared to open surgery. Unlike the treatment for colon cancer, however, the minimally invasive approach in rectal cancer has not been established. In this article, we summarize the current status of MIS for rectal cancer and explore the various technical options.
MIS HAS become the standard procedure in some operations, such as cholecystectomy and appendectomy. Several short-term benefits are associated with MIS, including reduced postoperative pain and decreased need for analgesic drugs, more cosmetically pleasing incisions, shorter length of hospital stay, and earlier return to functionality. These are the major reasons for the increasing popularity of the minimally invasive surgical approach.
KEY POINTS
Minimally invasive colon surgery for cancer has become standard.
Rectal surgery is more challenging than colon surgery because of anatomic limitation of the pelvis and need to preserve autonomic nerves while maintaining a clear margin.
Minimally invasive rectal cancer surgery has proven feasible.
The UK MRC CLASICC trial demonstrated equivalent long-term recurrence and survival results between laparoscopic and open rectal surgery, and the results of several ongoing trials (the COREAN, COLOR II, JCOG 0404, and ACOSOG-Z6051 trials) are awaited.
Greater degree of rotation and instrument movement along with three-dimensional optics has led to the use of robotic technology in rectal cancer surgery. The UK MRC ROLARR trial is currently comparing laparoscopic to robotic resection.
The optimal learning curve and method to train surgeons in minimally invasive surgery is still in flux and include surgeon mentoring and didactic sessions.
Jacobs and colleagues1 first reported a case series of successful laparoscopic colectomies in 1990. In the beginning, its application was limited to treatment of benign lesions. However, the use of MIS in colon cancer raised concerns about the possibility of port site metastases and inadequate oncologic resection. Early reports indicated that the incidence of port site metastasis was approximately 4% in the laparoscopic group compared with 1% in the open group.2,3 This contentious question was resolved by a large meta-analysis of several controlled studies, which concluded that the incidence of port site metastasis was 0.87% in the laparoscopic group compared with 0.34% in the open group (p = 0.16).4 Correspondingly, concerns regarding oncologic outcome were dispelled by several well-designed large, randomized, controlled studies that demonstrated the equivalence of laparoscopic colectomy to the conventional open approach in terms of recurrence and survival.5–8 Undoubtedly, laparoscopic colectomy is now considered an alternative standard approach in the treatment of colon cancer.
Obviously, surgery of the rectum is more challenging for several reasons, mostly because dissection of the mesorectal plane is limited by the confines of the bony pelvis and the goal of preserving the autonomic nerves. Moreover, neoadjuvant treatment sequelae, especially those secondary to radiotherapy, may affect the surgical field. Thus, the role of MIS for rectal cancer is still controversial and substantial evidence is lacking. We summarize the current status of MIS in rectal cancer, the findings of contemporary published studies, and the appropriate application of various existing techniques.
At present, the American Society of Colon and Rectal Surgeons (ASCRS) has not endorsed laparoscopic proctectomy for rectal cancer because of concerns about achieving adequate mesorectal excision and clear surgical margins using this technique.9 ASCRS has encouraged well-designed trials to examine the safety, efficacy, and benefits of MIS in rectal cancer surgery, especially in regard to long-term oncologic outcomes. A majority of these prospective randomized, controlled trials are ongoing, and the results have not yet been defined. Thus, MIS for rectal cancer has not become standard treatment in the United States.10 Based on evidence presented in European trials, however, several countries in Europe and Asia have endorsed MIS as an alternative to standard open surgery in rectal cancer.
The United Kingdom Medical Research Council Trial of Conventional vs. Laparoscopic-Assisted Surgery in Colorectal Cancer (United Kingdom MRC CLASICC) was a prospective randomized trial that included both patients with colon cancer and patients with rectal cancer.7 Of the 794 enrolled patients, 381 had rectal cancer and the conversion rate was 34%. Within the actual treatment group, 87 patients underwent open total mesorectal excision (TME) and 189 had laparoscopic-assisted TME. The primary endpoints were rate of positive-circumferential and longitudinally resected margins. No significant difference in either margin of resection was identified when comparing the two procedures. Among patients undergoing anterior resection, the rate of positive circumferential resection (CRM) was slightly higher in the laparoscopic than in the open group (12% vs. 6%; p = 0.80). In-hospital mortality rates between laparoscopic and open surgery were not significantly different (4% vs. 5%; p = 0.57), but the mortality rate was higher in patients who were converted to open surgery.
Regarding long-term outcomes, 5-year results of the United Kingdom MRC CLASICC have already been published.11 There was no significant difference in 5-year overall survival (OS) between the laparoscopic and open groups (60.3% vs. 52.9%; p = 0.132). Five-year disease-free survival did not differ either (53.2% vs. 52.1%, respectively; p = 0.953). In converted patients, the overall survival rate was significantly worse, compared to the other patients who initially received randomized treatment (p = 0.05). There was no difference in rate of local recurrence between patients who had laparoscopic compared with open anterior resection, although as previously noted, the rate of positive CRM was slightly higher in the laparoscopic group (9.4% vs. 7.6%; p = 0.74). No data was shown on local recurrence in patients who had abdominoperineal resection.
An important finding of this study was the high rate of conversion from laparoscopic to open surgery intraoperatively (34%), and the poorer outcomes in patients who were converted. The reasons for intraoperative conversion included tumor fixation, patient obesity, technical difficulty, practitioner uncertainty regarding adequate tumor clearance, and uncertainty regarding anatomic landmarks.
The Comparison of Open vs. laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial is a multicenter randomized, controlled trial comparing open with laparoscopic surgery in Korean patients with mid- or low-rectal cancer (i.e., tumor within 9 cm of the anal verge) following preoperative chemoradiotherapy.12 The primary endpoint was 3-year disease-free survival. Seven high-volume surgeons were qualified to enroll in the study. Three hundred and forty patients with T3/N0–2 rectal cancer were randomly assigned to laparoscopic and open groups in a ratio of 1:1. The conversion rate was 1.2% (2 in 170 patients), secondary to difficult dissection in the narrow pelvis and/or bleeding. The rates of coloanal anastomosis and abdominoperineal resection were equivalent between the laparoscopic and open surgery groups (19.4% vs. 19.4% and 11.2% vs. 14.1%, respectively; p = 0.7085). Operative time was significantly longer in the laparoscopic group (244.9 min vs. 197 min, p = 0.006), but estimated blood loss was significantly less (217.5 mL vs. 200 mL, p < 0.0001). The rate of positive CRM did not differ significantly between the two groups (2.9% laparoscopic vs. 4.1% open; p = 0.770), nor did distal resection margin or pathologic stage. The short-term benefits of laparoscopic surgery were notable: speedier return of bowel function, less postoperative pain, and less need for/use of analgesic drugs.
The COREAN trial is the first study to compare laparoscopic with open TME in patients who have undergone neoadjuvant chemoradiotherapy. The promising short-term outcomes of laparoscopic surgery for rectal cancer include a low rate of conversion and small number of positive CRMs. Both may be the result of neoadjuvant treatment, combined with optimal resection technique employed by experienced surgeons. Long-term follow-up data regarding recurrence and survival are awaited, and will be important factors in this large trial.
The European Colon Cancer Laparoscopic or Open Resection (COLOR) II trial is an international randomized, multicenter study comparing the outcomes of curative laparoscopic and conventional open surgery for rectal cancer.13 The primary endpoint is 3-year locoregional recurrence. Secondary endpoints are recurrence-free and OS at 3, 5, and 7 years; rate of port- and wound-site metastases; distant metastases; morbidity and mortality within 8 weeks following resection; macroscopic evaluation of the resected specimen; quality of life; and cost. Currently, the final results have been obtained but are not yet reported.
The Japanese Clinical Oncology Group Study (JCOG 0404) is a multicenter randomized, controlled trial comparing laparoscopic and open surgery in Japanese patients with colon or rectal cancer.14 This study was activated in October 2004. The planned sample size is 818 cases; 409 cases per arm with 5 years of follow-up after 3 years of accrual. The primary endpoint is OS. Secondary endpoints are relapse-free survival, short-term clinical outcomes, adverse events, and rates of conversion.
The American College of Surgeons Oncology Group (ACOSOG)-Z6051 trial is a prospective, randomized trial aimed at evaluating the noninferiority of laparoscopic compared with open surgery for rectal cancer.15 Primary measurements include completeness of TME and circumferential and distal resection margins. The secondary endpoints are short-term benefits; disease-free and overall survival; pelvic recurrence rates; and quality of life, including sexual and bowel function. The results are awaited.
The data on laparoscopic resection for mid- and low-rectal cancers are limited in predominantly retrospective series, prospective nonrandomized, controlled trials, and small randomized, controlled studies. As predicted, the conclusion from all meta-analyses is that patients in the laparoscopic group have better short-term outcomes than patients in the open surgery group. This is similar to the results of laparoscopic procedures in other diseases.16–19 In terms of recurrence and survival, one meta-analysis (including a 5-year follow-up of the MRC CLASICC trial) evaluated 2,095 patients with rectal cancer (1,096 undergoing laparoscopic; 999 undergoing open surgery) from 12 randomized, controlled studies.20 Less blood loss, a more rapid return to oral diet, and briefer hospital stay were identified as short-term benefits of laparoscopic versus open surgery. Long-term outcomes; local, wound-site, and distant recurrences; 5-year overall and disease-free survival; and urinary and sexual function did not differ significantly between the two groups.
The United Kingdom MRC CLASICC trial finding of increased CRM positivity within the laparoscopic anterior resection group raised questions about the oncologic competence of this procedure. The question of adequacy is answered by the 5-year follow-up results. The COREAN trial concludes that laparoscopic surgery for rectal cancer, performed by skillful laparoscopic surgeons in high-volume centers, is feasible and has promising short-term results. As we await the long-term results of the aforementioned ongoing trials (the COREAN, COLOR II, JCOG 0404, and ACOSOG-Z6051 trials), one topic must be considered before applying the results to general practice: how to prepare and qualify operators so that patients receive the maximum benefits of MIS.
As previously noted, rectal resection is more demanding than colectomy because of the anatomy of the pelvis, the desirability of preserving autonomic nerve function, and the sequelae of neoadjuvant treatment. In conventional open surgery, the retractor is a key factor in achieving adequate exposure, especially in male patients with a bulky mesorectal tumor and narrow pelvis. Appropriate TME should be performed by sharp (not blunt) dissection to achieve the best oncologic outcome. All of these considerations make laparoscopic rectal resection more challenging.
One study from Japan analyzed the learning curve for laparoscopic low anterior resection.21 Single surgeons performed 250 operations, with patients divided into five groups. The learning curve analysis demonstrated that operative time stabilized after 50 cases. The conversion rate was significantly lower after 150 cases (p < 0.05), correlating with male sex and advanced T stage. Other studies have suggested that an adequate learning curve is passed at somewhere between 20 and 60 cases.6,7,22,23 In laparoscopic TME, adequacy of exposure without use of the retractor is necessary. Therefore, not only the experience of the surgeon but the aptitude of the entire surgical team is important. The mirror image from the camera and the alignment of the first assistant's working instruments in opposite positions may disorient the assistant operator. One study concluded that assisting in more than 30 to 40 cases is sufficient to overcome mirror-image movements.24
Existing published reports show no final agreement regarding the optimal number of cases necessary to achieve technical expertise. Extrapolated from the COST study, ASCRS and the Society of Gastrointestinal and Endoscopic Surgeons (SAGES) recommend that a practitioner complete at least 20 laparoscopic resections of benign colon lesions before being credentialed for colon cancer resection.9 Undoubtedly, completing a large number of operations correlates with better outcomes. One good example is the correlation between high-volume surgeons (all ranked among the top one-third in operative experience in their respective cancer centers) and impressive short-term results shown in the COREAN trial.12 This begs the question: How can operators pass the learning curve without putting patients at risk? Simulation and animal and cadaveric training courses are currently available worldwide; however, it is not known if this kind of training sufficiently qualifies a surgeon to perform resection in human patients. From our perspective, the answer is still uncertain. Intraoperative supervision by an experienced surgeon as well as appropriate case selection should be major considerations in any training program, even at an advanced level. This is essential to safe clinical practice.25
It has been suggested that hand-assisted laparoscopic colectomy has potential benefits, including a shorter learning curve for the practitioner, less operative time, and lower conversion rate compared to conventional laparoscopic surgery. This may be especially true in complex procedures such as total proctocolectomy.26–28 Unfortunately, several difficult issues are associated with hand-assisted laparoscopy. Placing a hand into the abdominal cavity may have iatrogenic effects including a traumatic affect on the immune system, which may eliminate the long-term benefits of MIS (such as fewer postoperative adhesions). Interleukin 6 (IL-6) and C-reactive protein (CRP) are sensitive markers of the immune system's acute inflammatory response, and exaggeration of these may actually have a deleterious effect on wound healing and increase the risk of postoperative infection.29,30 Several human studies have shown significant lowering of IL-6 and CRP in laparoscopic compared with open surgery (p < 0.05, p < 0.007, and p < 0.001).29 In two animal studies comparing hand-assisted laparoscopic surgery (HALS) with laparoscopic surgery, slightly higher levels of IL-6 and CRP were reported with HALS; however, the levels of these cytokines were significantly lower than the levels seen in open surgery (p = 0.04 and p < 0.05).30,31 No comparative human study has been reported.
Regarding long-term complications, one retrospective study compared 266 hand-assisted operations with 270 laparoscopic operations for colorectal disease. After a 27-month median follow-up, the incidence of small bowel obstruction was not significantly different between the hand-assisted versus laparoscopic groups (4.1% vs. 7.4%; p = 0.10), nor was the rate of postoperative incisional hernia (6% vs. 4.8%; p = 0.54).32 Based on these results, we may conclude that hand-assisted surgery does not appear to be inferior to laparoscopic surgery, and retains the potential benefits of MIS.
HALS for rectal cancer is challenging because, as noted above, the pelvic space is restricted by its bony anatomic structure. On the positive side, the hand may be used as an effective retractor to achieve adequate exposure. Unfortunately, in a deep and narrow pelvis, the hand may not be a useful tool because of the limited anatomic space. A multicenter prospective, randomized study comparing hand-assisted with straight laparoscopic-assisted proctectomy for rectal cancer is currently in the recruitment phase.33 The planned sample size is 128 cases; estimated accrual will end by December 2012. The primary outcome is operative time. The secondary outcomes include adequacy of resection margins; in-hospital mortality and morbidity; and preoperative as well as 3- and 6-month postoperative follow-ups of urinary and sexual function. The investigators hypothesize that HALS results in shorter operative time while retaining the benefits associated with laparoscopic surgery.
As we await the results of this trial, several publications have reported on the role of robotic-assisted laparoscopic TME. A prospective randomized, controlled trial comparing robotic-assisted and laparoscopic TME is also ongoing. Comparative analysis, based on the ultimate data comparing hand-assisted and robotic-assisted laparoscopic surgery for rectal cancer, will be challenging. Only one three-arm retrospective study comparing HALS, robotic-assisted, and laparoscopic TME has been reported (with 30 patients with rectal cancer per arm).34 No significant differences in pathologic outcome or complications were identified. To ascertain the equivalence of HALS and robotic surgery, however, a prospective randomized, controlled trial is needed.
Robotic-assisted laparoscopic prostatectomy has become extremely popular. An excellent three-dimensional visual system using EndoWrist instruments eliminates many of the limitations of operating with straight laparoscopic instruments in a restricted anatomic area. The extraperitoneal part of the rectum is situated in the pelvic cavity. Thus, the idea of robotic-assisted laparoscopic surgery for rectal cancer appeals to surgeons. Loss of free movement to several quadrants of the abdomen, as well as increases in cost without benefits when compared to laparoscopic surgery, limits the use of robotic-assisted laparoscopic colectomy for colon cancer. A retrospective study comparing 40 robotic-assisted to 135 laparoscopic right hemicolectomies reported no significant difference in short-term benefits, including estimated blood loss, rate of conversion, complications, and hospital stay. Moreover, operative time and costs were significantly higher in the robotic versus the laparoscopic group (p < 0.001 vs. p = 0.003, respectively).35 In concurrence with the findings of a meta-analysis of seven nonrandomized studies, the average operative time was 39 minutes longer and $792 more expensive than in conventional laparoscopy, with no improvement in short-term benefits.36
As noted, however, the rectum seems suited to robotic surgery and the learning curve is less steep. Data on 50 robotic-assisted laparoscopic rectal surgery cases suggest that the learning curve is passed after 15 to 25 operations.37 Unfortunately, the utilization of this technology has been limited by cost. Most of the current evidence regarding the benefits of robotic-assisted laparoscopic rectal cancer surgery consists of case series. Case-match and nonrandomized studies conclude that robotic-assisted surgery is feasible and comparable to laparoscopic TME.38–40 A large prospective, randomized, controlled trial is needed, however, to assess the equivalence of robotic surgery to conventional laparoscopic surgery.
The United Kingdom Medical Research Council Trial of Robotic compared with Laparoscopic Resection for Rectal cancer (ROLARR) trial is a multicenter prospective, randomized, controlled trial of robotic-assisted compared with laparoscopic surgery in the curative treatment of rectal cancer.41 Four hundred patients will be recruited and randomly assigned with a 1:1 ratio. This trial is currently in the randomization phase, which will end by mid-2012. The primary endpoint is conversion rates to open surgery. Secondary endpoints are intraoperative and postoperative complications; oncologic outcomes, including circumferential margin, 3-year overall and disease-free survival; and quality of life.
There is debate over port placements, docking techniques, and techniques for take-down of the splenic flexure in robotic-assisted laparoscopic TME. The two major techniques are 1) totally robotic surgery and 2) a hybrid approach, depending on which instrument is used in take-down. Some surgeons are practicing a hybrid approach consisting of a robotic surgical system for vessel control and pelvic dissection, and straight laparoscopy for splenic flexure mobilization. The idea is to decrease the prolonged operative time caused by multiple dockings of the robot.
The technique of totally robotic surgery is challenging because of limitations in port placement and positioning of the robot. Most of the time, more than one docking of the robot is needed to complete the operation. Some centers have proposed the feasibility of a single-stage technique.42,43 However, there are currently no published studies comparing docking techniques. Surgeon preference and experience are still the main factors in selecting an operation. From our perspective, there is no single ideal technique that will fit all patients. Knowledge of the benefits and limitations of each technique is crucial, and the surgeon must be prepared to tailor surgery to each individual patient.
Minimally invasive surgery for rectal cancer is challenging because of the anatomic restrictions of the bony pelvis and the necessity of autonomic nerve preservation. Various techniques have been proposed, including straight laparoscopic, hand-assisted, and robotic-assisted laparoscopic surgery. In laparoscopic rectal cancer surgery, the short-term benefits are similar to those associated with other minimally invasive techniques. Current data indicate that long-term oncologic outcomes are similar in terms of recurrence and survival. Several additional prospective, randomized, controlled trials are in progress. We believe that the results will demonstrate the noninferiority of laparoscopic surgery compared to open surgery.
The data from small case series and one nonrandomized, controlled trial indicate that the emerging techniques of hand-assisted and robotic-assisted laparoscopy are feasible and comparable to the results achieved with conventional laparoscopic surgery. Prospective randomized, controlled trials of both techniques are ongoing. At this time, it is not possible to determine which procedure is “best.” Surgeon preference and availability of instruments are crucial in choosing the right procedure for each individual patient.
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