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An 8 year experience of laparoscopic TME for low and mid rectal cancer

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16/10/2010

Laparoscopic total mesorectal excision can be performed on a non-selective basis in patients with rectal cancer with excellent medium-term results

 

D G Glancy, B Choudhary, GL Greenslade, A R Dixon

 

Department of Colorectal Surgery

Frenchay Hospital

North Bristol NHS Trust

Bristol

UK

 


Abstract

 

Aim: Concerns exist regarding laparoscopic rectal cancer surgery due to increased rates of open conversion / complications and circumferential resection margin positivity (a surrogate for local recurrence). This study reports medium-term results from consecutive unselected cases in a single-surgeon series.

 

Method: The results of laparoscopic total mesorectal excison (TME) for rectal cancer over a 9 year period were reviewed from analysis of a prospectively maintained database. No patients with advanced disease or unfavourable histology were excluded.

 

Results: One hundred and fifty patients (91 males, median age 69 years and median BMI 26) underwent laparoscopic TME over 10 years. Median length of follow-up was 28.5 months (range 0-88). Sixteen patients (10.6%) underwent neo-adjuvant radiotherapy. 6 patients (4.0%) required open conversion and 13 patients (8.6%) developed an anastomotic leak. Breakdown by Duke’s Stage was A 33.3%, B 30.7%, C 31.3% and D 4.7%.  Five patients (3.3%) had an R1 and one patient an R2 resection. Median length of post-operative stay was 6 days. Three patients (2.0%) died within 30 days. Four patients (2.7%) developed local recurrence and 14 patients (9.3%) developed distant metastases. Predicted 5 year disease-free and overall survival rates were 85.8% and 78.7% respectively.

 

Conclusions: Despite concerns in the literature, laparoscopic TME surgery can safely be offered to unselected patients with rectal cancer with excellent medium-term results.

 

Introduction

 

The role of laparoscopic surgery in the treatment of colonic cancer has been well established, with short-term benefits over open surgery and oncological equivalence in the longer-term 1-3. However, concerns still exist regarding laparoscopic rectal cancer surgery. Whilst no multi-centre randomised trial has specifically addressed this topic, the CLASICC trial did include rectal cancer resections, including 85 anterior resections with total mesorectal excision (TME) 4 and has reported its 3 year follow-up data 5. In particular, there were worries regarding the high rate (57%) of open conversion (with an associated increase in complications), together with a higher rate (12%)  of circumferential resection margin (CRM) positivity (a surrogate marker for local recurrence) compared with 6% after an open operation 4. However, no difference in oncological outcome at 3 years was seen 5.

 

A 2006 Cochrane review of laparoscopic versus open TME for rectal cancer included 3 individual randomised trials, 12 cohort studies and 33 case-control or case-series. It concluded that laparoscopic rectal cancer surgery may have short-term advantages with respect to blood loss, return to normal diet and post-operative pain without any significant differences in anastomotic leak rate, lymph node harvest, resection margin positivity, morbidity or mortality (although with longer operation times and higher costs).  However, the limited numbers of patients or duration of follow-up in many studies precluded any conclusions regarding longer-term oncological outcomes 6. Concern has also been raised about whether or not the RCTS were truly randomised and how many cases were true rectal cancer (Bergamaschi, CD 2009, 11, 1-2

 

More recent studies of laparoscopic rectal cancer surgery may still suffer variously from low numbers, heterogeneity of tumour location and hence type of operation (abdomino-perineal resection or high anterior resection without TME), length of follow-up and retrospective design or case selection 7-13. Three larger recent series with between 80-202 patients that underwent laparoscopic anterior resection with TME and 29-48 months mean follow-up reported acceptable rates of anastomotic leak (9.6-16.8%), open conversion (6.1-12.7%), 30 day morbidity (31.8-39.3%), R1 resection (2.6-6.7%) and local recurrence (4.78-5.79%) 14-16. The paper by Staudacher et al is notable for reporting a consecutive unselected series of 226 patients exclusively undergoing TME (including 24 abdomino-perineal resections).

 

The purpose of laparoscopic surgery is not feasibility but rather complete histological resection.  This paper reports the medium-term results of our experience in treating unselected patients with mid to low rectal cancers by laparoscopic TME. Abdomino-perineal resections have been excluded in order to highlight a specific group of patients, which by itself is comparable to the other larger series in the literature.


Patients and methods

 

All patients attending our institution with a histologically confirmed new diagnosis of rectal cancer and referred to a single-surgeon were included. Patients underwent local and distant staging with a pelvic MRI and CT scan of the chest, abdomen and pelvis before discussion at the local multi-disciplinary team meeting. Long-course pre-operative chemoradiotherapy (CRT) was offered to patients with locally advanced T3 / T4 disease who were predicted to have a threatened CRM. Short-course pre-operative radiotherapy (RT) was offered to some patients with T2 / early T3 disease and adverse prognostic features.

 

Surgery took place within the context of an evolving enhanced recovery protocol 17. All patients were considered for laparoscopic resection and no patients with advanced disease were excluded. A standard 3 port technique with a 30o laparoscope was used for all resections (open 12mm infra-umbilical port insertion with further 12mm and 5mm right iliac fossa ports). A medial to lateral dissection was performed using an ultrasonic dissector.  The inferior mesenteric artery and vein were divided separately using 10mm Hem-o-Loc clips (Wyek).  An ATG articulated stapler (Ethicon Endosurgery, Bracknel, UK) was used to divide the rectum at the pelvic floor. The mobilized bowel was then exteriorized via a 4-6cm midline skin incision, centred on the umbilical port, in order to complete the proximalresection of the tumour and insert the anvil of a CDH circular stapler (Ethicon Endosurgery, Bracknel, UK) for subsequent intra-corporeal anastomosis. Open conversion was defined by an incision longer than that required for specimen extraction. A defunctioning loop ileostomy was performed selectively in high risk patients such as those that had received pre-operative radiotherapy, with nutritional failure or with significant co-morbidity. A pelvic drain was used whenever the dissection had been difficult. In the early post-operative period, patients were investigated for an anastomotic leak if there was clinical concern.

 

Patients were followed up for a minimum of 5 years post-operatively. A prospective database was maintained and updated at each outpatient visit (surgical, oncology or endoscopy). Results for consecutive patients undergoing laparoscopic TME for mid to low rectal cancers were analysed using the database on an intention-to-treat basis. This included low anterior resection (LAR) or TME Hartmann’s procedure (TMEH). High anterior resection (HAR) for recto-sigmoid tumours and abdomino-perineal resection (APER) for tumours involving the sphincters were specifically excluded.

 

Statistical analysis was performed using Graphpad Prism 3.0. (Needs a reference) Quantitative data were expressed as medians and ranges and qualitative data as frequency and percentage. Kaplan Meier survival analysis was used to estimate 5 year disease-free and overall survival.

 

 

 


Results

 

One hundred and fifty patients underwent laparoscopic TME surgery for rectal cancer over a 9 year period between April 2000 and October 2009 (144 LAR, 6 TMEH). A further 147 HAR and 34 APER were excluded. Patient demographics and overall outcomes are presented in Tables 1-2. Six patients (4.0%) required open conversion (one for equipment failure, one for pelvic bleeding and 4 for adhesions or technical difficulty). Median length of follow-up was 28.5 months (range 0-88). One patient was lost to follow-up.

 

Median lymph node harvest was 13 (inter-quartile range 9-17). Breakdown by TNM and Duke’s stage is shown in Table 3. Patients with an R1 or R2 resection all had T3 N2 or T4 disease. A total of 51 patients (34.0%) suffered some form of morbidity as detailed in Table 4. Thirteen patients (8.6%) developed an anastomotic leak; two patients (without a defunctioning ileostomy) were managed conservatively, one patient died and the remaining 10 patients (5 with a defunctioning ileostomy) returned to theatre for washout and / or Hartmann’s procedure or other defunctioning procedure. Overall, 15 (10.0%) patients returned to theatre at a median of 6 days post-operatively (range 2-11) as detailed in Table 5. Three patients (2.0%) died within 30 days from multi-organ failure (2 patients following an anastomotic leak and one following pelvic bleeding).

 

Four patients (2.7%) developed local recurrence at a median of 12 months (range 10-13), as detailed in Table 6. All were R0 resections. Seven patients (4.7%) had known metastases (6 hepatic and one peritoneal) at the time of initial surgery. A further 7 (4.7%) patients subsequently developed distant metastases (4 hepatic, 2 hepatic / pulmonary and one bone) at a median of 22 months (range 2-28) post-operatively.

In addition to the three early deaths, a further 17 patients (11.3%) subsequently died at a median of 24 months (range 0-70) post-operatively. This included one patient with local recurrence and 8 with distant metastases (2 of which had known metastases at the time of surgery). Predicted 5 year disease-free survival by Kaplan Meier analysis was 85.8% (95% CI 79.4-92.2%) and overall survival was 78.7% (95% CI 69.4-88.0%), as shown in Figures 1-2.

 

 

 


Discussion and conclusions

 

This study reports medium-term results for laparoscopic TME in patients with rectal cancer from a single-surgeon series and is one of the largest in terms of both patient numbers and duration of follow-up in the literature.

 

Despite this being an unselected series, there was a very low conversion rate of 2.8%, which compares very favourably with rates of 6.1-12.7% in other recent studies 14-16. The anastomotic leak rate was within accepted guidelines, especially considering these were all mid to low rectal cancers 18. The overall morbidity rate of 34.0% may not be dissimilar to that which would be seen with open surgery, but was in keeping with the published rates of 31.8-39.3% from other recent large laparoscopic series 14-16. The rates of major morbidity, 30 day mortality (2.0%) and readmission (7.3%) were all low. The oncological adequacy of the surgery was reflected in the median lymph node yield (13) and low rate of margin positivity (4.0%), compared with figures of 12 and 12.0%  respectively in the CLASSIC trial 4.

 

The post-operative staging of patients by TNM and Dukes stage showed a reasonable spread, although with more early disease than in other series (Dukes A 33.3%, B 30.7%, C 31.3% and D 4.7% compared with 16.7%, 34.6%, 29.5% and 7.6% respectively in CLASSIC) 4. This was not accounted for by a selection bias by the multi-disciplinary team towards sending patients with less advanced tumours to the dedicated laparoscopic specialist.  However, the proportion of patients that required neo-adjuvant radiotherapy compared with other studies may have affected the results. Local recurrence rates were certainly low (2.7% compared with 9.7% in the CLASICC trial) 4, but unexpectedly the majority of patients that developed local recurrence did not have particularly advanced tumours or adverse prognostic features: all were Ro resections (table 6). The reasons for this are uncertain. The number that went on to develop distant metastases was also low, comprising only 7/143 patients (4.9%) that were clear at initial presentation. This data translates into predicted 5 year disease-free and overall survival rates of 85.8% and 78.7% respectively. Despite the possibility of selection bias, 93 patients (62.0%) had T3 or T4 disease and 49 patients (32.7%) had nodal involvement and so perhaps the impressive rates of local recurrence and survival may in part reflect a benefit of laparoscopic surgery itself, although the usual caveats regarding a single-surgeon series apply.  Faster recovery times may allow earlier adjuvant treatment to be instigated, with a median time of only 4 weeks from date of surgery to outpatient oncology review.

 

The likelihood of tumour metastases depends on the balance between the metastatic potential of the tumour and the anti-metastatic host defences, of which cell-mediated immunity, and natural killer (NK) cell function in particular, is a critical component.  It is becoming increasingly recognised that anaesthetic technique and other peri-operative factors have the potential to effect long term outcome and cancer survival.  Surgery can inhibit host defences for several days (Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosupression: could they reduce recurrence rates in oncological patients? ANN Surg Oncol 2003; 10: 972-92)., especially NK cell activity (Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G.  Evidence that stress and surgical interventions promote tumour development by suppressing natural killer cell activity. Int.J.Cancer 1999; 80: 880-8) and promote the development of metastases.  Laparoscopic surgery itself has also been shown to diminish the level of post-operative immunosuppression that is usually associated with the surgical stress response following open surgery 6, 19. This may in turn translate into long-term oncological benefit. (ref LaceyAM, Garcia-Valdecasas JC, Delgado S et al. Lapaaroscopy-assisted colectomy versus open colectomy fro treatment of non-metastatic colon cancer: a randomised trial. Lancet 2002; 359: 2224-9).

The move towards ERP, regional anaesthesia and inhibition of the stress response, and the avoidance of morphine may also be influencing outcome; morphine inhibits both cell-mediated and humoral immunity and this includes NK cell activity, production of immune-stimulating cytokines, phagocytic activity and antibody production (Sessler DI. Does regional analgesisia reduce the risk of cancer recurrence? A hypothesis. Eur J.Cancer Prev 2008; 17: 269-72; Vallejo R deLeon-Casasola O, benyamin R. Opiod therapy and immunosupression: a review. Am J.Ther 2004; 11: 354-65.).  Tramadol, which has noradrenergic and serotonergic activity in addition to its action at opiod receptors, stimulates NK cell activity (Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonisation in rats. J Neuroimmunol 2002; 129: 18-24 as well as enhancing NK activity in humans post hysterectomy  (Sacerdote P, Bianchi M, Gaspani L et al., The effect of tramadol and morphine on immune responses and pain after surgery in cancer patients.  Anaesth Analg 2000; 90: 1411-4).  Acute pain also suppresses NK cell activity (Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001; 90: 191-9.

With this data in mind, the Outcomes Research Consortium (Cleveland Clinic USA) has initiated a multicentre RCT looking at epidural and analgesia for laparoscopic colorectal cancer surgery (NCT00684229) with a primary endpoint of cancer recurrence.

 

In conclusion, despite concerns in the literature, we feel that laparoscopic TME surgery can safely be offered to unselected patients with rectal cancer with excellent medium-term results.  The improved metastatic free and overall survival may in part be influenced by the laparoscopic technique and its effects on stress response as well as our move towards “Accelerated” ERP using regional anaesthesia, oral tramadol and the avoidance of morphine.

 


Table 1: Patient Demographics

 

 

 

Male / female

91 (60.7%) / 59 (39.3%)

Median age (years)

69 (range 20-90)

Median BMI (kg/m2)

26 (range 19-55)

Neo-adjuvant radiotherapy

RT 4 (2.7%)

CRT 12 (8.0%)

 

 

Table 2: Outcome data

 

 

Median operating time (min)

140 (range 45-260)

Conversion to open

6 (4.0%)

Defunctioning loop ileostomy

56 (37.3%)

Median length of stay (days)

6 (1-37)

Return to theatre

15 (10.0%)

Readmission

11 (7.3%)

Morbidity

51 (34.0%)

30 day mortality

3 (2.0%)

Median time from operation to first oncology outpatient appointment (weeks)

4 (range 1-8)

 

Table 3: Post-operative staging of patients by TNM and Dukes stage

Staging

Patients

%

TNM

 

 

T1

15

10.0

T2

42

28.0

T3

81

54.0

T4

12

8.0

N0

101

67.3

N1

33

22.0

N2

16

10.7

R1

5

3.3

R2

1

0.7

Dukes

 

 

A

50

33.3

B

46

30.7

C

47

31.3

D

7

4.7


Table 4: Postoperative complications

(includes readmissions, some patients had more than one complication)

Complication

Patients

Anastomotic leak

13 (8.6%)

Anastomotic bleed

1 (0.7%)

Pelvic haematoma

1 (0.7%)

Ischaemic colon

1 (0.7%)

Prolonged ileus

14 (9.3%)

Small bowel obstruction

2 (1.3%)

High output ileostomy

2 (1.3%)

Ischaemic ileostomy

1 (0.7%)

Urinary retention

5 (3.3%)

Urinary tract infection

2 (1.3%)

Myocardial infarction

3 (2.0%)

Atrial fibrilation

4 (2.7%)

Pulmonary embolism

1 (0.7%)

Early incisional hernia

1 (0.7%)

Clostridium difficile infection

1 (0.7%)

Opiate overdose

1 (0.7%)

Phlebitis

1 (0.7%)

Wound abscess

1 (0.7%)

Wound infection

6 (4.0%)

Wound dehiscence (superficial)

1 (0.7%)

Wound haematoma (superficial)

1 (0.7%)

 

 

Table 5: Patients returned to theatre

(includes readmissions)

Reason

Patients

Anastomotic leak

10

Pelvic bleed

1

Small bowel obstruction

2

Prolonged ileus

1

Wound abscess

1

 

 

Table 6: Patients with local recurrence

Original histology

Extramural vascular invasion

Time to recurrence (months)

T2 N0

No

12

T3 N0

No

10

T3 N0

No

12

T4 N1

Yes

13


 Figure 1: Kaplan Meier disease-free survival (95% confidence intervals)

 

 

 

 

 


Figure 2: Kaplan Meier overall survival (95% confidence intervals)

 

 

 

 

 


References

 

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2. Lourenco T, Murray A, Grant A, McKinley A, Krukowski Z, Vale L. Laparoscopic surgery for colorectal cancer: safe and effective? - A systematic review. Surg Endosc 2008;22(5):1146-60.

3. Tjandra JJ, Chan MK. Systematic review on the short-term outcome of laparoscopic resection for colon and rectosigmoid cancer. Colorectal Dis 2006;8(5):375-88.

4. Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 2005;365(9472):1718-26.

5. Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol 2007;25(21):3061-8.

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8. Hiep PN, Vu PA, Thien HH. Laparoscopic surgery in rectal cancer: a retrospective analysis. Int J Colorectal Dis 2009;24(12):1465-9.

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10. Ng SS, Leung KL, Lee JF, Yiu RY, Li JC, Hon SS. Long-term morbidity and oncologic outcomes of laparoscopic-assisted anterior resection for upper rectal cancer: ten-year results of a prospective, randomized trial. Dis Colon Rectum 2009;52(4):558-66.

11. Laurent C, Leblanc F, Wutrich P, Scheffler M, Rullier E. Laparoscopic versus open surgery for rectal cancer: long-term oncologic results. Ann Surg 2009;250(1):54-61.

12. Gonzalez QH, Rodriguez-Zentner HA, Moreno-Berber JM, et al. Laparoscopic vs. open total mesorectal excision for treatment of rectal cancer. Rev Invest Clin 2008;60(3):205-11.

13. Strohlein MA, Grutzner KU, Jauch KW, Heiss MM. Comparison of laparoscopic vs. open access surgery in patients with rectal cancer: a prospective analysis. Dis Colon Rectum 2008;51(4):385-91.

14. Fernandez-Cebrian JM, Gil P, Hernandez-Granados P, et al. Initial surgical experience in laparoscopic total mesorectal excision for middle and lower third rectal cancer: short-term results. Clin Transl Oncol 2009;11(7):460-4.

15. Pugliese R, Di Lernia S, Sansonna F, et al. Laparoscopic resection for rectal adenocarcinoma. Eur J Surg Oncol 2009;35(5):497-503.

16. Staudacher C, Di Palo S, Tamburini A, Vignali A, Orsenigo E. Total mesorectal excision (TME) with laparoscopic approach: 226 consecutive cases. Surg Oncol 2007;16 Suppl 1:S113-6.

17. Zafar N, Davies R, Greenslade GL, Dixon AR. The evolution of analgesia in an 'accelerated' recovery programme for resectional laparoscopic colorectal surgery with anastomosis. Colorectal Dis 2010;12(2):119-24.

18. Guidelines for the Management of Colorectal Cancer. The Association of Coloproctology of Great Britain and Ireland 2007.

19. Vittimberga FJ, Jr., Foley DP, Meyers WC, Callery MP. Laparoscopic surgery and the systemic immune response. Ann Surg 1998;227(3):326-34.

 

 

 

 


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