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10.1245/s10434-006-9135-4
Annals of Surgical Oncology 14:109-117 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Oncologic Results of Laparoscopic Versus Conventional Open Surgery for Stage II or III Left-Sided Colon Cancers: A Randomized Controlled Trial

Jin-Tung Liang, MD, PhD1,4, Kuo-Chin Huang, MD, PhD2, Hong-Shiee Lai, MD, PhD1, Po-Huang Lee, MD, PhD1 and Yung-Ming Jeng, MD3

1 Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
2 Department of Family Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
3 Department of Pathology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
4 Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, R.O.C.

Correspondence: Address correspondence and reprint requests to: Jin-Tung Liang, MD, PhD, Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan, R.O.C.; E-mail: jintung{at}ha.mc.ntu.edu.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Minimal invasive surgical approach can achieve quick functional recovery. However, the oncologic outcome for cancer is still a concern. This study aims to compare the oncologic outcome between laparoscopic and open methods in the curative resection of Stage II or III left-sided colon cancers.

Methods: In consideration of statistical power up to 90%, 286 eligible patients with curable left-sided colon cancer (Tumor-Node-Metastasis Stage II and Stage III disease) requiring the takedown of colonic splenic flexure to facilitate a curative left hemicolectomy were recruited randomly and equally allocated to the laparoscopic and open group. The primary endpoint was time-to-recurrence of tumor. Data was analyzed according to intention-to-treat principle.

Results: Postrandomization exclusion occurred because of metastatic disease detected intraoperatively occurred in 13 patients and because of patient withdrawal from trial in 4. Therefore, 135 and 134 patients actually comprised the laparoscopic and open group, respectively. The median follow-up of patient was 40 months (range: 18–72 months). The oncologic results were similar (P = 0.362, one-sided log-rank test) in laparoscopic and open group of patients, with the estimated cumulative recurrence rate of 13.2% (9/68) versus 17.2% (11/64) in Stage II disease and 20.9% (14/67) versus 25.7% (18/70) in Stage III disease, respectively. The recurrence patterns were similar between the two groups. Both open and laparoscopic groups were comparable in the number of dissected lymph node (15.6 ± 3.0 vs. 16.0 ± 6.0, P = 0.489), various demographic and clinicopathologic parameters.

Conclusions: The estimated cumulative recurrence rate for the surgery of Stage II or III left-sided colon cancers was the same between laparoscopic and open methods.

Key Words: Laparoscopic surgery • Left colon cancer • Randomized trial • Laparoscopic left hemicolectomy for cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Laparoscopic technique has been enthusiastically applied to the resection of colorectal tumor for more than 10 years. Currently, more and more colorectal surgeons believe that laparoscopic approach gains quicker functional recovery and achieves comparable1–3 and even better oncologic results4,5 for the treatment of patients with colorectal malignancy. However, even to date, laparoscopic colectomy is still by no means common in surgical practice. Beart et al.6 pointed out that laparoscopic abdominal surgery was most commonly used in France (28% patients), compared with only 1–11% patients in Germany, Italy, Spain, United Kingdom, and the United States. This is because for most colorectal surgeons the oncologic outcome of laparoscopic approach is still a concern. Furthermore, widespread adoption of laparoscopic colectomy was jeopardized by its inherent disadvantages, such as steeper learning curve, longer operation time, and much more expense,7 as compared with the traditional open procedure.

Laparoscopic left hemicolectomy, involving the takedown of colonic splenic flexure, has been more challenging than the other laparoscopic colorectal procedures. Because of the technical variability between colorectal surgeons, the clinical trial of laparoscopic left hemicolectomy that required the takedown of colonic splenic flexure for the curative resection of cancers and tension-free colonic anastomosis has been rare. It was not until 2000 that the laparoscopic medial-to-lateral approach for the takedown of colonic splenic flexure was mastered and well established in our institution.8–13 Based on this standardized technique, we thereafter further conducted this randomized controlled prospective study to compare the oncologic results between laparoscopic and traditional open surgery in patients with Tumor-Node-Metastasis (TNM) Stage II or III colon cancer undergoing a curative left hemicolectomy. We believe that the role of laparoscopic surgery for the treatment of advanced colon cancer located at this specific anatomic location will be better clarified through this study.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
The consecutive patients with TNM Stage II or III left-sided colon cancer under the care of a single surgeon (J.-T. Liang) between January 2000 and June 2004 were recruited according to appropriate eligibility criteria. This study was performed with the approval of the ethics committee of National Taiwan University Hospital. Written informed consent was obtained from all patients who agreed to undergo this clinical trial. By block randomization method with random block sizes ranging from 2 to 10, the patients were prospectively and equally allocated to either laparoscopic or open group. The patients were randomized the day before surgery. To prevent selection bias, the random numbers were generated by a research assistant who was not involved in enrollment of participants with randomization allocation software. This clinical trial has been registered in ICMJE (International Committee of Medical Journal Editors) and designated as No. 9100017028.

Before the study entry, patients had to meet certain inclusion and exclusion criteria. The inclusion criteria were: (1) Primary colon cancers located at the specific anatomic location, including distal transverse colon, colonic splenic flexure, descending colon, sigmoid-descending colonic junction, and proximal sigmoid colon that required the mobilization of colonic splenic flexure to facilitate a curative resection and tension-free anastomosis of bowel; (2) TNM Stage II or III adenocarcinomas; (3) Curative and elective surgery; (4) American Society of Anesthesiology (ASA) class I to III patients; and (5) Age >18 years. The exclusion criteria were: (1) Cecal, ascending, proximal transverse, middle and distal sigmoid, and rectal cancers; (2) Emergency or palliative surgery; (3) Evidence of disseminated disease or adjacent organ invasion; (4) Primary tumor mass >8 cm in diameter; (5) Morbidly obese patients, that is, body mass index (BMI) ≥40 kg/m2; and (6) Previous major surgery of upper abdomen.

Preoperative staging work-up
All patients admitted first underwent colonoscopy with a biopsy to confirm the diagnosis, followed by a barium enema, abdominal ultrasonography, computed tomography (CT) of the abdomen and pelvis, and a chest radiograph to fully stage the extent of tumor before surgery. Whole-body magnetic resonance imaging (MRI), multislice spiral CT, and positron emission tomography (PET) scanning were selectively used in some patients. Additionally, serum level of carcinoembryonic antigen (CEA) was routinely quantified before operation.

Operative strategy
All patients underwent extended D2 resection for left-sided colon cancers, as defined by Japanese Society for Cancer of the Colon and Rectum;14 this involved excision of the left half of greater omentum, and en-bloc resection of mesocolon and lymph nodes within the territory of left branch of middle colic artery, left colic artery, and inferior mesenteric vein. The involved blood vessels were ligated at the root. The technical details of laparoscopic approach were shown in our previous multimedia article.13,15

Evaluation of surgical efficacy
The surgical efficacy was evaluated by the number of regional lymph nodes harvested and time-to-recurrence of cancer after surgery. The experienced pathologist (Y.M. Jeng), blinded to both surgical approaches, was in charge of the evaluation of pre-and postoperative surgical histopathology, and the determination of the final TNM stage of the resected tumor.

Postoperatively, the patients received regular follow-up at the outpatient department. Adjuvant chemotherapy with 5-Fu (450 mg/m2/week) and leucovorin (25 mg/m2/week) was routinely given to patients with TNM stage III disease for 6 months in both assigned groups. The tumor recurrence was determined by various diagnostic modalities including simple history and physical examination, digital examination, stool occult blood test, quantification of CEA level and liver function tests at 1-month intervals, chest radiography and abdominal ultrasonography at 3-month intervals, and colonoscopy or barium enema examination every 6 months. Suspected recurrent lesions were assessed further by selective use of traditional CT, multislice spiral CT, MRI, bone scan, intravenous pyelography (IVP), endoscopic ultrasonography, and PET scan. In equivocal cases, endoscopic biopsy, ultrasonographically guided biopsy and exploratory laparotomy were used selectively to confirm the diagnosis of a recurrent tumor.

Evaluation of surgical efficiency
We assessed the surgical efficiency using parameters including length of operation time (counted from the beginning of skin incision to the final skin closure), blood loss (measured by the amount of blood in suction bottle and the number of blood-soaked gauzes), conversion rate, intraoperative and postoperative complications, wound size, and degree of surgical stress. The wound size was measured by summation of the length of one major wound (generally 5 cm in size) for tumor retrieval and four working ports (5–12 mm in diameter) in the laparoscopic group, and by the length of the major laparotomy wound plus one minor wound for indwelling drain tube in open group. The operative complications, if present, were individually listed. We evaluated the severity of surgical stress using the proinflammatory factors including serum concentration of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and immunosuppressive factors including blood lymphocyte counts and CD4+ to CD8+ ratio. The quantification of various immunologic factors was detailed in our previous articles.8,9 Briefly, the CRP was quantified by an immunoturbidimetric method. The ESR was measured by the Westergren method. The CD4+ to CD8+ ratio was determined by flow cytometry. For the quantitative analysis of all these proinflammatory and immunosuppressive factors, each patient’s peripheral blood was sampled twice at 24 h before and after surgery, respectively. The quotient for the alteration of each factor was individually calculated by dividing the postoperative value with the preoperative baseline value.

Evaluation of functional recovery
The functional recovery was compared by length of postoperative ileus and hospitalization, degree of postoperative pain, and disability. The visual analogue scale was used in assessing postoperative pain on the first postoperative day. A standardized questionnaire was given to patients to assess disability that included the number of days until return to partial activity, full activity, and work on the basis of their subjective responses.8,9 All parameters of functional recovery were evaluated by research assistants blinded to the study groups. To facilitate blinding, the wound was wrapped by abdominal bandage until the start of oral feeding, generally on the fifth postoperative day.

Calculation of overall costs
The overall costs of the laparoscopic surgery were calculated by the summation of operation fee, anesthesia fee, surgical equipment costs, the price of disposable laparoscopic instruments, hospital stay and pharmacy costs, and miscellaneous expenses.

Statistics
All patients were prospectively followed-up till December 2005. The primary endpoint of this study was time to recurrence of cancer after curative resection. The secondary endpoints included variables related to surgical efficiency, functional recovery, disability, and overall costs. Data were assessed according to intention-to-treat principle. Patients who died without a reported tumor recurrence was assumed to have had a recurrence at death unless it was clearly documented otherwise, in which case the patients’ data were censored on the date of death in the analysis of the time-to-recurrence. Kaplan-Meier curves were constructed to estimate the distribution of the disease-free survival. The primary analysis consisted of a one-sided log-rank test comparing time with recurrence in the two randomized group. We assumed that a difference in tumor recurrence rate of less than 10% between treatment arms indicates an equivalent efficacy. Assuming a 25% recurrence rate in the traditional open group, approximately 143 patients per group was required to show that both surgical techniques were equivalent with an {alpha} level of 0.05 and ß error of 0.10. In evaluating secondary endpoints, two-tailed Fisher’s exact test or Chi-square test was appropriately used to analyze the categoric data, whereas the continuous data was compared by Student’s t-test. The significance level of all tests was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The profile of this surgical trial is shown in Fig. 1Go. During the entire follow-up period (median: 40 months; range: 18–72 months), there was no significant difference (P = 0.362) in time to tumor recurrence between laparoscopic and open groups of patients with the estimated cumulative recurrence rate of 17.0% (23/135) in the laparoscopic group versus 21.6% (29/134) in the open group (Fig. 2AGo). When stage-to-stage comparison was done, there was still no significant difference between both surgical approaches, with 13.2% (9/68, laparoscopic group) versus 17.2% (11/64, open group) in Stage II disease and 20.9% (14/67, laparoscopic group) versus 25.7% (18/70, open group) in Stage III disease, respectively (Fig. 2B,CGo). The recurrence patterns were similar (P = 0.974) between open and laparoscopic groups of patients (Table 1Go). Remarkably, one patient in the laparoscopic group developed port-site recurrence. However, recurrence over laparotomy wound was also noted in one patient of the open group. With regard to surgical efficacy, we found that the extent of tumor extirpation, as evaluated by the number of dissected lymph nodes, was the same between both the groups (Table 2Go).


Figure 1
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  		FIG. 1. Randomization, treatment, and inclusion of patients in analysis.

 

Figure 2
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  		FIG. 2. Cumulative incidence of recurrence in the tumor-node-metastasis Stage II and III patients assigned to laparoscopic and conventional open surgery. (A) Overall patients; (B) Stage II patients; (C) Stage III patients.

 

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  		TABLE 1. Comparison of recurrence patterns of advanced left-sided colon cancer in laparoscopic and open group of patients
 

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  		TABLE 2. Comparison of surgical outcomes between laparoscopic and open groups
 
In scrutiny of various demographic and clinicopathologic parameters, we found that both groups of patients were well matched (Table 3Go). Although the BMI and tumor size were statistically different between the laparoscopic and open group patients, they were deemed clinically insignificant as the difference of mean was very small. The comparisons of various parameters of surgical outcome between laparoscopic and open groups of patients are shown in Table 2Go. The operation time was moderately higher (P < 0.001) in the laparoscopic group of patients by an average of 40.4 min. The blood loss and wound sizes were significantly lower (P < 0.001) in the laparoscopic group. Remarkably, however, four patients of the laparoscopic group were converted to open surgery and their wound sizes were up to approximately 20 cm and, in contrast, nine patients of the open group were operated on a total wound size of approximately 10 cm. The postoperative complication rates and patterns were similar between both the groups (Table 2Go). The postoperative proinflammatory response, evaluated by CRP and ESR, and postoperative immunosuppression, assessed by alterations of lymphocyte counts and the CD4+/CD8+ ratio, were significantly less (P < 0.001) in the laparoscopic group of patients. These favorable factors imply that this laparoscopic technique can accomplish similar technical efficiency and induced minimal surgical invasiveness, as compared with the open technique. With regard to the functional recovery, it was obvious that the patients undergoing laparoscopic procedure were lower in the length of postoperative ileus and hospitalization, degree of postoperative pain, and disability (P < 0.001). However, the overall cost of the laparoscopic technique was significantly higher (P < 0.001).


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  		TABLE 3. Comparison of demographic and clinicopathologic data between laparoscopic and open groups of patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Compared with the previous randomized trials in the literature, the present study posed some weak and strong points that needed to be further addressed.

First, randomization of patients to evaluate surgical procedures involved problems in addition to those associated with medical experimentation.16 Surgery, unlike a pill, is not a standardized, reproducible entity, but rather a unique product whose details are defined by variables which include, for example, the skill of the surgeon.17,18 Any surgical trial is ethically problematic if it was conducted by surgeons on a learning curve.19 Our study was started in January 2000. Only after that time was the laparoscopic technique for colon cancer well established and was the clinical trial approved by the institutional review board of National Taiwan University Hospital. This clinical trial was conducted by a single surgeon because at that time only very few surgeons in Taiwan were experienced in laparoscopic colectomy and hard to organize. Theoretically, the greater the number of surgeons who have been involved and the more representative they are of those who will implement the findings, the safer the generalization.20 However, although several randomized trials of laparoscopic colectomy in the literature were multi-institutional, despite serious attempts at standardization, deviations from the protocol were not uncommon, for example, the high technical variability among institutions21 and the high percentage of intention-to-treat patients,3 thereby blurring the distinction between the laparoscopic and open surgical procedures. Therefore, although the generalization for the results of this study is questionable, it does reflect the current status of laparoscopic colectomy for cancer in Taiwanese context.

Second, previous randomized trials in the literature incorporate all colon cancers located at various locations into the analysis of oncologic results and functional outcomes.1,3–5,7,21 This was deemed unreasonable, because the route of lymphatic drainage, extent of dissection during radical extirpation of tumor, surgical technique, and even the biologic behavior were quite different in various colonic anatomic positions. For example, the right colon embryologically belongs to the territory of the midgut and the right-sided colon cancers are with more familial tendency in comparison with the left-sided colon cancers.22 Technically, it was generally accepted that the laparoscopic sigmoidectomy was much easier than the laparoscopic right and left hemicolectomy. This issue was further confounded by the definition of rectosigmoid junction that has been controversial and therefore the results from studies on this anatomic position should be taken very cautiously.2 The present study investigated only patients with left-sided colon cancers that required the routine takedown of colonic splenic flexure.

Third, in surgery, blinding of surgeons to the procedure is obviously impossible. However, the lack of blinding is unlikely to distort the objective outcomes such as time-to-recurrence (the primary endpoint of the present study) and the final overall survival of patients, whereas lack of blinding of patients and assessors may affect subjective outcomes (the secondary endpoints of this study) owing to a "placebo effect." In this study, the abdominal wound was dressed in the same way in both intervention groups until oral feeding was started, thereby ensuring that patients and the ward staff were blind to the type of intervention. Therefore, the subjective data such as postoperative ileus and pain were evaluated in the way of double blindness. However, the length of hospitalization and disability were inevitably assessed without blindness. The postoperative stress was evaluated by the measurements of immune status, which is an excellent objective method of detecting a possible advantage of laparoscopic approach. However, the concept of surgical efficacy as based on immune sparing has not been confirmed.23 It needs to be mentioned that many parameters measuring functional outcomes in the present clinical trial were usually skew to one side. When these data were doubly checked by nonparametric method, that is, using median and interquartile range in comparing the two groups, the results were the same.

Fourth, the present study shows that the oncologic results of both intervention groups were equal, based on the median follow-up time of 40 months. Our previous report showed that most recurrence of tumor happened within 2 years after operation.24 The recent report from Sargent et al.25 has shown that 3-year disease-free survival is an appropriate endpoint to replace 5-year overall survival as an endpoint in adjuvant colon cancer clinical trials of fluorouracil-based regimens. Actually, the time-to-recurrence analysis in this series showed that the recurrent tumor detected after 3 years of follow-up only constituted a very small percentage (3.7%, 11/269) of patients. Therefore, it is highly probable that the present results can be the surrogate for the final outcomes of this patient population whose long-term follow-up for more than 5 years will be completed in the near future.

Besides the equivalent time-to-recurrence, this study showed the similar recurrence patterns between open and laparoscopic patient groups. Furthermore, the present study confirmed that port-site recurrence did exist, but its incidence was very rare, and when the laparoscopic colectomy was performed according to strict oncologic principles, laparoscopic technique does not increase the risk of intraperitoneal cancer spillage.26–29

Some well-experienced colorectal surgeons advocated that the majority of colectomies could be accomplished by an incision of less than 7 cm and thus argumented against the advantages of laparoscopic approach.30 In this study, a few thinner patients (n = 9, 6.7%) were assigned to open groups whose colon cancers were resected by minilaparotomy, with a total wound size of approximately 10 cm. However, the functional recovery of these patients was skewed to the side of open laparotomy (data not shown). Our findings implied that the benefits of laparoscopic surgery for colon cancer seems to be beyond wound size, that is, additionally, taking advantage of the properties of laparoscopy, the operation field is magnified and the tumor was resected in the way of more precision and minimal invasiveness.

In conclusion, with regard to the surgical treatment for Stage II or III left-sided colon cancers, the oncologic results of laparoscopic approach were similar to those of traditional open surgery seeing that the extent of tumor extirpation and the tumor recurrence rate were the same in both the methods.

Received for publication March 27, 2006. Accepted for publication June 26, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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