Surg Endosc DOI 10.1007/s00464-013-3286-8
and Other Interventional Techniques
Long-term oncologic outcome after laparoscopic surgery for rectal cancer Ayman Agha • Volker Benseler • Matthias Hornung • Michael Gerken • Igors Iesalnieks • Alois Fu¨rst • Matthias Anthuber • Karl-Walter Jauch • Hans J. Schlitt
Received: 28 May 2013 / Accepted: 11 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Recent studies demonstrated favorable shortand mid-term results after laparoscopic surgery for rectal cancer. However, long-term results from large series are lacking. The present study analyses long-term results of laparoscopic rectal cancer surgery from a large-volume center. Methods From January 1998 until March 2005, 225 patients underwent laparoscopic rectal resection due to carcinoma at the Medical Centre of the University of Regensburg. From 224 patients, a follow-up over 10 years was performed using the A. Agha V. Benseler (&) M. Hornung I. Iesalnieks A. Fu¨rst M. Anthuber K.-W. Jauch H. J. Schlitt Department of Surgery, University Medical Centre Regensburg, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany e-mail: [email protected] M. Gerken Tumour Center Regensburg, Regensburg, Germany Present Address: I. Iesalnieks Department of Surgery, Marienhospital Gelsenkirchen, Gelsenkirchen, Germany Present Address: A. Fu¨rst Department of Surgery, Caritas-Krankenhaus St. Josef, Regensburg, Regensburg, Germany Present Address: M. Anthuber Department of Surgery, Klinikum Augsburg, Augsburg, Germany Present Address: K.-W. Jauch Department of Surgery, University of Munich Campus Grosshadern, Munich, Germany
data of the Tumour Centre of the University of Regensburg. The data were analysed using oncological data (tumour recurrence) as well as overall survival. In addition, the effect of conversion to open resection on overall survival was analysed. Results With a median of 10 years at follow-up, the overall and disease-free survival was 50.5 and 50.1 %, respectively. Local recurrence of all patients was 5.8 % and none of the converted patients was within this group. The median time interval for the development of local recurrence was 30 months. Six of the 13 patients with local recurrence (46.1 %) had received neoadjuvant radiochemotherapy before surgery. Patients with a conversion to open surgery had primarily a significantly worse outcome than patients resected completely laparoscopically (p = 0.003). However, this difference was no longer apparent using a multivariant analysis (hazard ratio 1.221; p = 0.478). Conclusions Overall survival and local recurrence rate of patients undergoing laparoscopic resection of rectal cancer are comparable to open surgery. However, in our analysis, patients undergoing laparoscopic anterior resection had a higher survival rate compared with patients with abdominoperineal resection. Keywords Laparoscopic rectal surgery Conversion Rectal cancer Abbreviations AR Anterior resection APR Abdominoperineal resection
Several studies have shown that laparoscopic rectal resection for carcinoma of the rectum is feasible and safe [1–3]. However, in contrast to carcinoma of the colon, rectal resection often is considered to be too challenging for the
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laparoscopic approach and is therefore not accepted as a standard procedure for all patients. Instead, patients are selected for gender, localisation of the tumour, and tumour stage to meet adequate oncological criteria [4]. For prognostic reasons, the oncological outcome is related to the fulfilment of oncological criteria, including quality of mesorectal resection, sufficient aboral and lateral distance, and sufficient lymphadenectomy, leading to a minimum of local recurrence and improved overall and disease-related survival. Several studies that compared laparoscopic and conventional open rectal resection showed no difference with respect to local recurrence or overall and disease-free survival after 3 and 5 years, respectively [5–8]. However, long-term results after laparoscopic rectal resection for carcinoma of the rectum are still missing. Until now, only a few studies reported long-term complications and oncological outcome after conventional open and laparoscopic rectal resection over a 10-year period [9, 10]. So far, data are not sufficient to show clear evidence that both methods are similar with respect to oncological outcome. In 2008, we published the 5-year results from 225 patients undergoing laparoscopic rectal resection for carcinoma of the rectum [2]. Here, we report the 10-year follow-up of these patients with respect to oncological outcome with a retrospective subgroup analysis of patients converted from laparoscopic to open resection.
Methods From January 1998 to March 2005, 225 patients underwent laparoscopic surgery for rectal cancer. All patients had tumours within 16 cm from the anal verge. Patients’ characteristics and oncological results median 5 years after surgery were published previously [2]. The quality of total mesorectal excision (TME) was assessed regularly and documented by the hospital pathologist according to the MERCURY classification system [11, 12]. Exclusion criteria for laparoscopic surgery were locally advanced T4 tumors, multivisceral resections, emergency resections, and patients with previous major abdominal surgeries. These operations were either performed or assisted by three surgeons with extensive experience in colorectal surgery (more than 50 laparoscopic colorectal surgeries). The criteria for neoadjuvant radiochemotherapy were patients with rectal cancer of the lower and middle third of the rectum and suspected T3 or T4 tumours and patients with pathological lymph nodes as demonstrated by endosonography or MRI-scan. Follow-up Clinical examination included rectoscopy and assessment of tumour markers, such as carcinoembryonic antigen
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(CEA). Colonoscopy was conducted 1 year after primary surgery and then after every 3 years. Patients with suspected local recurrence were further evaluated with CT scans of the pelvis, and in cases with unclear results positron-emission tomography (PET) was performed. Definition of outcome For long-term outcome, we assessed local tumour recurrence and overall survival. Local recurrence was divided into extra- and intraluminal recurrence and diagnosed either radiologically (CT scan, PET) or after biopsy and histological examination. For analysis of the survival curves, overall and disease-free survival was assessed. In addition, a subgroup analysis of patients with conversion from laparoscopic to open resection was conducted and compared to patients undergoing complete laparoscopic resection. As previously reported, conversion is the unplanned change of the operative technique from laparoscopic to open resection [2]. Because this was a retrospective analysis, the intraoperative time point of conversion could not be analysed, as it was not documented. Statistical analysis Overall survival was analysed using the Kaplan–Meier method. The log-rank test was applied to calculate the prognostic value of various parameters by univariate analysis. Multivariate analysis of factors related to outcome was performed using the Cox’s proportional hazards model. All data were analysed using the statistical software IBM SPSS version 20.
Results The follow-up information was available from 224 of 225 cases. The median follow-up was 10 (range 7.3–13.6) years at the time of data collection (June 2012). The mean age was 64.6 (range 35–91) years, and the mean body mass index (BMI) was 26.5 kg/m2. Sixty-eight percent of the patients had BMI [25 kg/m2. The ASA scores (anaesthesiological risk according to the classification of American Society of Anaesthesiologists) varied from I to IV, whereby the majority of included patients (82.2 %) had an ASA score II or III. Ninety-seven patients (43.1 %) had carcinoma localized in the middle rectum, 94 patients (41.7 %) in the distal rectum, and 34 patients (15.1 %) in the proximal third of the rectum. The tumour stages according to UICC-classification were as follows: stage I, 85 patients (37.7 %); stage II, 46 patients (20.5 %); stage III, 56 patients (24.9 %); and stage IV, 38 patients (16.9 %) [2]. Overall, negative resection margins were documented
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Fig. 1 UICC stage-related and disease-free survival after laparoscopic rectal resection
in 216 patients (96 %); however, the distal resection margin was less than 2 cm in four cases (1.7 %). In patients operated in curative intention, the circumferential resection margin was [ 1 mm in 182 cases (98 %). Eight-three patients (37 %) received neoadjuvant chemoradiation. Overall and disease-free survival Synchronous metastases were present in 30 patients (13.3 %), whereas 21 patients (9.4 %) subsequently developed metachronous metastases. Overall and diseasefree survivals were 50.5 % and 50.1 % at 10 years, respectively (Fig. 1). The 10-year overall survival was 69 % for UICC stage I disease, 58.4 % for stage II disease, 42 % for stage III disease, and 12 % for stage IV disease. Overall survival was 58.4 % at 10 years in patients undergoing resection with curative intent as compared to 12.8 % after palliative surgery. There was a statistically significant survival difference between patients undergoing laparoscopic anterior resection (AR) compared with abdominoperineal resection (APR) (54.8 % vs. 41.8 % at 10 years, p = 0.029). Using Cox’s regression model for multivariate analysis, no difference could be found between the first and second half of patients regarding the overall (hazard ratio (HR) 1.08; 95 % confidence interval (CI) 0.937–1.244, p = 0.288) and diseasefree survival (HR 1.07; 95 % CI 0.933–1.226, p = 0.333).
5.8 % (13/224). There were no new cases of local recurrence between 5 and 10 years of follow-up (Fig. 2). The local recurrence rate was 6.6 % (11/165) for patients after AR compared with 3.7 % (2/54) for patients undergoing APR (p = 0.328). The median time between surgery and diagnosis of a local recurrence was 30 (range 5.5–112) months. The timeframe to develop a local recurrence was similar between the first (1998–2002) and the second (2002–2005) half of patients in a multivariate analysis using Cox’s regression model (HR 1.008; 95 % CI 0.721–1.429; p = 0.963). Of all patients suffering local recurrence, ten (77 %) patients underwent second AR, and three patients (23 %) underwent APR. The second surgery revealed negative resection margins in 12 of 13 cases. Using a multivariate Cox regression analysis, we found significant differences between patients treated with and without preoperative radiochemotherapy (p = 0.039) and R0 versus R1 resection (p = 0.034) as well as concerning the tumour location from the anal verge (p = 0.022). Regarding the different surgical procedures, we could not find any significant differences (AR vs. APR, p = 0.62; Table 2). During surgery, none of the tumours were perforated and no patient developed port site metastases. Distant metastases occurred in 30 patients. Seven patients developed metastasis in liver and lung, 13 in liver only, 8 in lung only, 1 patient in liver and brain, and another patient in liver and spleen. Conversion
Local and distant recurrence The demographic data of patients with local recurrence are shown in Table 1. The overall local recurrence rate was
The conversion rate was 10.2 % (n = 23). In all cases, conversion was due to technical and not oncological reasons (obesity and narrow pelvis n = 10; adhesions n = 4;
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Surg Endosc Table 1 Characteristics of patients with local tumour recurrence (n = 13)
Causes of death
Characteristics
Variable
Age (year), mean (range)
61 (42–76)
Of the 75 patients who died, 66 patients were in the laparoscopic and 9 patients in the converted group. In the laparoscopic group, rectal cancer-related deaths occurred in 34 (45 %) patients. The remaining patients died due to cardiovascular (n = 22), development of a second malignoma (n = 5), or unknown (n = 5) reasons. In the converted group, cancer-related deaths occurred in four (44 %) cases. One patient developed a second malignoma and four patients died because of cardiovascular reasons.
Gender, n (%) Female
4 (31)
Male
9 (69)
UICC, n (%) 1
6 (46)
II III
3 (23) 3 (23)
IV
1 (8)
Tumour size, n (%) \5 cm
Discussion 9 (69)
[5 cm
4 (31)
Tumour location from anal verge, mean in cm (range, SD)
6.7 (1–12, 3.4)
Aboral distance to tumour, mean in cm (range, SD) Surgery, n (%)
2.7 (0.3–9.0, 2.5)
Anterior rectal resection—LAR
10 (77)
Abdominoperineal resection—APR
3 (23)
Symptoms, n (%) No symptoms
12 (92)
Ileus
1 (8)
Location of recurrence, n (%) Intraluminal
4 (31)
Extraluminal
7 (54)
Intra- and extraluminal
2 (15)
Time to recurrence, mean in months (range, SD) Resection margins, n (%)
30 (5.5–112)
RO
8 (61.5)
R1
3 (23.1)
R2
2 (15.4)
SD standard deviation
bleeding during splenic flexure mobilisation n = 3; dysfunction of the stapler device n = 2; injury of the ureter n = 2; anaesthetic issues n = 2). After 10 years, overall survival was 30.4 % in converted cases, but it was 53.1 % in laparoscopically completed cases (p = 0.003; Fig. 3). In the multivariate analysis, however, when the hazard ratios were calculated using Cox’s regression model, factors associated with an inferior outcome were age, tumour stage, and surgical complications. For the localisation of the tumor and neoadjuvant radiochemotherapy, the overall survival rate was similar between converted and nonconverted patients. The previously described highly significant difference (HR 2.129, p = 0.004) was no longer apparent when adjusted for these variables (HR 1.221, p = 0.478). In addition, none of the converted patients developed local tumor recurrence.
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Overall and disease-free survival To the best of our knowledge, this study is one of the largest reporting on long-term follow-up of patients undergoing laparoscopic surgery for rectal cancer. The 10-year overall and disease-free survival were 50.5 and 50.1 %, respectively. Considering that most patients underwent complete laparoscopic rectal resection (86.6 %) and 36.9 % received preoperative radiochemotherapy, our data are comparable with overall survival of 59.6 % in patients treated by preoperative radiochemotherapy and open rectal resection [13]. To assess a possible learning curve, we compared the first (1998–2002) and second (2002–2005) half of patients undergoing laparoscopic resection. In a multivariate analysis with Cox’s regression model, we could not find a difference in the overall survival, disease-free survival, or local recurrence rate between the two groups, indicating a consistent expertise in laparoscopic surgery likely due to standardization of the resections in our hospital. Most of the published studies that address laparoscopic surgery describe long-term results up to 5 years after surgery. The CLASICC trial, a multicenter study comparing open to laparoscopic resection in rectal cancer, has just published its 5-year and, just recently, 10-year results, respectively [3, 10]. The 5-year overall survival for patients resected laparoscopically was 60.3 %. The analysis of 326 patients of the CLASICC trial showed a disease-free survival of 52.1 % after 5 years [3]. The 10-year follow-up described an overall survival of 82.7 months with no difference between patients undergoing AR or APR [10]. Our results showed an inferior outcome with reduced overall survival in the APR group compared with AR. However, this finding might be a bias and due to patient selection for laparoscopic surgery. Ng et al. [9] published in 2009 the analysis of 74 patients undergoing laparoscopic rectal resection for cancer of the upper third of the rectum. They reported an overall and disease-free survival of 63.9 and 82.9 % after 10 years. However, a major limitation of this study was inclusion of upper rectal cancer only.
Surg Endosc Fig. 2 Incidence of local recurrence for low anterior (n = 157) and abdominoperineal (n = 67) resection
Table 2 Multivariate Cox regression analysis of all patients (n = 224)
Variable
n
%
HR
95 % CI
p
Age
224
100
0.988
0.928–1.051
0.704
Male
143
63.8
1.000
Female
81
36.2
0.449
0.126–1.599
0.217
1
83
37.1
1.000
II
46
20.5
2.727
0.530–14.019
0.230
III
56
25
2.276
0.580–8.928
0.238
IV
39
17.4
0.580
0.043–7.838
0.682
No
142
63.4
1.000
Yes
82
36.6
0.126
0.02–0.805
0.029
Distal Medial
93 97
41.5 43.3
1.000 0.157
0.036–0.688
0.014
Proximal
34
15.2
0.060
0.006–0.622
0.018
Anterior rectal resection
157
70.1
1.000
Abdominoperineal resection
67
29.9
0.191
0.034–1.084
0.62
0.801–146.423
0.073
Gender
UICC stage
Treatment received Preoperative CRT
Tumour location from anal verge
Type of resection
Completeness of local resection CRT chemoradiotherapy, HR hazard ratio, CI confidence interval
RO
219
97.8
1.000
R1/2
5
2.2
10.831
Local recurrence In our study, the rate of local recurrence was 5.8 % after 5 and 10 years. Regarding the local recurrence rate, no difference could be found between the first and second
half of surgeries using Cox’s regression model of multivariate analysis (p = 0.963). Ng et al. [9] reported a local recurrence rate of 7.1 % after laparoscopic rectal resection for carcinoma of the upper third of the rectum after 10 years.
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Conversion and its influence on oncological outcome
Fig. 3 Ten-year overall survival for converted and nonconverted patients (p = 0.003, log-rank test)
The development of local recurrence is depended on several factors. These include radiochemotherapy (neoadjuvant/adjuvant), the type of resection conducted, the aboral distance of the tumour from the anal verge as well as the distance to the circumferential resection margin. A multivariate Cox analysis showed significant differences in tumour localisation, preoperative radiochemotherapy, and, as expected, R0 versus R1 tumour resection. With a local recurrence rate of 6.6 % for AR and 3.7 % for APR (p = 0.62), we could not find a statistical difference between these two groups consistent with the data reported in the CLASICC trial (AR 9.9 % and APR 15.3 %, p = 0.078) [3, 10]. The positive impact of neoadjuvant radiochemotherapy to prevent local tumour recurrence has been demonstrated by several studies [5, 6, 14]. In total, neoadjuvant radiochemotherapy was performed in 36.9 % of our patients. From the patients who developed local recurrence, 6 patients (46.1 %) received adjuvant/neoadjuvant radiochemotherapy and another 7 of 13 (53.9 %) were treated without radiochemotherapy. In the era of neoadjuvant radiochemotherapy, the time-point of development of local recurrence is of great interest as, in theory, this might occur later than in patients only treated surgically. In our study, the median time for the development of local recurrence was 30 months. Interestingly, none of the patients who were converted to open resection developed local tumour recurrence. In this respect, the long-term data of the COLOR-II, a large prospective, randomized, multicenter trial, will be of great interest [15].
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In 2008, we have published our results on conversion from laparoscopic to open rectal resection in patients with rectal cancer [16]. We could demonstrate that the conversion rate is based on a learning curve and correlated with an increased morbidity compared with patients operated completely laparoscopically (61.2 % vs. 36.8 %, p = 0.025). This finding is concurrent with the results of a recent multicenter study confirming that conversion of laparoscopic to open resection is associated with a significantly higher rate of intra- and postoperative complications [17]. In addition, patients converted to open resection had significantly longer operation time (p = 0.001) and required more blood transfusions (p = 0.001) than nonconverted patients. In all our patients, conversion to open surgery was due to technical but not oncological (e.g., perforation of the tumour, insufficient distance to the tumour) reasons. Nevertheless, we could detect a significant difference between converted and nonconverted patients regarding overall (p = 0.003) and disease-free survival (p = 0.004). Several studies had demonstrated a significant association between postoperative morbidity and overall and disease-free survival rate in patients undergoing colorectal cancer surgery [18–20], probably due to a profound immunosuppression and a catabolic state caused by septic complications [21]. Thus, we believe, an increased postoperative morbidity rate in converted patients might be the reason for the impaired longterm outcome. This suggestion was confirmed by the Cox regression analysis. Our data are consistent with the results published in the CLASICC trial showing a statistically inferior overall survival rate in patients who had to be converted to open surgery [3, 10]. In the CLASICC trial, the negative effect of conversion was also related to technical events. Contrary to it, in a German multicenter study, which included 237 patients with laparoscopic rectal resection, no difference between converted and nonconverted patients was reported with respect to overall and disease-free survival after 5 years [22]. This analysis demonstrates the long-term results of one of the biggest series after laparoscopic rectal resection due to rectal carcinoma. Our data confirm previous reports that oncological criteria established in open rectal surgery can be preserved in laparoscopic surgery. Although surgery was performed by several surgeons, we could show that using a standardised technique, laparoscopic rectal resection can reveal similar longterm results compared to the open procedure.
Conclusions Our study demonstrates that surgery for rectal cancer can reveal good long-term outcome using the laparoscopic
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approach. However, because this is a technically challenging procedure, we recommend that laparoscopic resection of the rectum should be performed in centers with sufficient expertise and standardized procedures in laparoscopic surgery. Acknowledgments The authors thank Richard John Heald for critical reading of the manuscript.
11.
12.
Disclosures Drs. Agha, Benseler, Hornung, Gerken, Iesalnieks, Fu¨rst, Anthuber, Jauch and Schlitt have no conflict of interest or financial ties to disclose.
13.
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and Other Interventional Techniques
Long-term oncologic outcome after laparoscopic surgery for rectal cancer Ayman Agha • Volker Benseler • Matthias Hornung • Michael Gerken • Igors Iesalnieks • Alois Fu¨rst • Matthias Anthuber • Karl-Walter Jauch • Hans J. Schlitt
Received: 28 May 2013 / Accepted: 11 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Background Recent studies demonstrated favorable shortand mid-term results after laparoscopic surgery for rectal cancer. However, long-term results from large series are lacking. The present study analyses long-term results of laparoscopic rectal cancer surgery from a large-volume center. Methods From January 1998 until March 2005, 225 patients underwent laparoscopic rectal resection due to carcinoma at the Medical Centre of the University of Regensburg. From 224 patients, a follow-up over 10 years was performed using the A. Agha V. Benseler (&) M. Hornung I. Iesalnieks A. Fu¨rst M. Anthuber K.-W. Jauch H. J. Schlitt Department of Surgery, University Medical Centre Regensburg, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany e-mail: [email protected] M. Gerken Tumour Center Regensburg, Regensburg, Germany Present Address: I. Iesalnieks Department of Surgery, Marienhospital Gelsenkirchen, Gelsenkirchen, Germany Present Address: A. Fu¨rst Department of Surgery, Caritas-Krankenhaus St. Josef, Regensburg, Regensburg, Germany Present Address: M. Anthuber Department of Surgery, Klinikum Augsburg, Augsburg, Germany Present Address: K.-W. Jauch Department of Surgery, University of Munich Campus Grosshadern, Munich, Germany
data of the Tumour Centre of the University of Regensburg. The data were analysed using oncological data (tumour recurrence) as well as overall survival. In addition, the effect of conversion to open resection on overall survival was analysed. Results With a median of 10 years at follow-up, the overall and disease-free survival was 50.5 and 50.1 %, respectively. Local recurrence of all patients was 5.8 % and none of the converted patients was within this group. The median time interval for the development of local recurrence was 30 months. Six of the 13 patients with local recurrence (46.1 %) had received neoadjuvant radiochemotherapy before surgery. Patients with a conversion to open surgery had primarily a significantly worse outcome than patients resected completely laparoscopically (p = 0.003). However, this difference was no longer apparent using a multivariant analysis (hazard ratio 1.221; p = 0.478). Conclusions Overall survival and local recurrence rate of patients undergoing laparoscopic resection of rectal cancer are comparable to open surgery. However, in our analysis, patients undergoing laparoscopic anterior resection had a higher survival rate compared with patients with abdominoperineal resection. Keywords Laparoscopic rectal surgery Conversion Rectal cancer Abbreviations AR Anterior resection APR Abdominoperineal resection
Several studies have shown that laparoscopic rectal resection for carcinoma of the rectum is feasible and safe [1–3]. However, in contrast to carcinoma of the colon, rectal resection often is considered to be too challenging for the
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laparoscopic approach and is therefore not accepted as a standard procedure for all patients. Instead, patients are selected for gender, localisation of the tumour, and tumour stage to meet adequate oncological criteria [4]. For prognostic reasons, the oncological outcome is related to the fulfilment of oncological criteria, including quality of mesorectal resection, sufficient aboral and lateral distance, and sufficient lymphadenectomy, leading to a minimum of local recurrence and improved overall and disease-related survival. Several studies that compared laparoscopic and conventional open rectal resection showed no difference with respect to local recurrence or overall and disease-free survival after 3 and 5 years, respectively [5–8]. However, long-term results after laparoscopic rectal resection for carcinoma of the rectum are still missing. Until now, only a few studies reported long-term complications and oncological outcome after conventional open and laparoscopic rectal resection over a 10-year period [9, 10]. So far, data are not sufficient to show clear evidence that both methods are similar with respect to oncological outcome. In 2008, we published the 5-year results from 225 patients undergoing laparoscopic rectal resection for carcinoma of the rectum [2]. Here, we report the 10-year follow-up of these patients with respect to oncological outcome with a retrospective subgroup analysis of patients converted from laparoscopic to open resection.
Methods From January 1998 to March 2005, 225 patients underwent laparoscopic surgery for rectal cancer. All patients had tumours within 16 cm from the anal verge. Patients’ characteristics and oncological results median 5 years after surgery were published previously [2]. The quality of total mesorectal excision (TME) was assessed regularly and documented by the hospital pathologist according to the MERCURY classification system [11, 12]. Exclusion criteria for laparoscopic surgery were locally advanced T4 tumors, multivisceral resections, emergency resections, and patients with previous major abdominal surgeries. These operations were either performed or assisted by three surgeons with extensive experience in colorectal surgery (more than 50 laparoscopic colorectal surgeries). The criteria for neoadjuvant radiochemotherapy were patients with rectal cancer of the lower and middle third of the rectum and suspected T3 or T4 tumours and patients with pathological lymph nodes as demonstrated by endosonography or MRI-scan. Follow-up Clinical examination included rectoscopy and assessment of tumour markers, such as carcinoembryonic antigen
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(CEA). Colonoscopy was conducted 1 year after primary surgery and then after every 3 years. Patients with suspected local recurrence were further evaluated with CT scans of the pelvis, and in cases with unclear results positron-emission tomography (PET) was performed. Definition of outcome For long-term outcome, we assessed local tumour recurrence and overall survival. Local recurrence was divided into extra- and intraluminal recurrence and diagnosed either radiologically (CT scan, PET) or after biopsy and histological examination. For analysis of the survival curves, overall and disease-free survival was assessed. In addition, a subgroup analysis of patients with conversion from laparoscopic to open resection was conducted and compared to patients undergoing complete laparoscopic resection. As previously reported, conversion is the unplanned change of the operative technique from laparoscopic to open resection [2]. Because this was a retrospective analysis, the intraoperative time point of conversion could not be analysed, as it was not documented. Statistical analysis Overall survival was analysed using the Kaplan–Meier method. The log-rank test was applied to calculate the prognostic value of various parameters by univariate analysis. Multivariate analysis of factors related to outcome was performed using the Cox’s proportional hazards model. All data were analysed using the statistical software IBM SPSS version 20.
Results The follow-up information was available from 224 of 225 cases. The median follow-up was 10 (range 7.3–13.6) years at the time of data collection (June 2012). The mean age was 64.6 (range 35–91) years, and the mean body mass index (BMI) was 26.5 kg/m2. Sixty-eight percent of the patients had BMI [25 kg/m2. The ASA scores (anaesthesiological risk according to the classification of American Society of Anaesthesiologists) varied from I to IV, whereby the majority of included patients (82.2 %) had an ASA score II or III. Ninety-seven patients (43.1 %) had carcinoma localized in the middle rectum, 94 patients (41.7 %) in the distal rectum, and 34 patients (15.1 %) in the proximal third of the rectum. The tumour stages according to UICC-classification were as follows: stage I, 85 patients (37.7 %); stage II, 46 patients (20.5 %); stage III, 56 patients (24.9 %); and stage IV, 38 patients (16.9 %) [2]. Overall, negative resection margins were documented
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Fig. 1 UICC stage-related and disease-free survival after laparoscopic rectal resection
in 216 patients (96 %); however, the distal resection margin was less than 2 cm in four cases (1.7 %). In patients operated in curative intention, the circumferential resection margin was [ 1 mm in 182 cases (98 %). Eight-three patients (37 %) received neoadjuvant chemoradiation. Overall and disease-free survival Synchronous metastases were present in 30 patients (13.3 %), whereas 21 patients (9.4 %) subsequently developed metachronous metastases. Overall and diseasefree survivals were 50.5 % and 50.1 % at 10 years, respectively (Fig. 1). The 10-year overall survival was 69 % for UICC stage I disease, 58.4 % for stage II disease, 42 % for stage III disease, and 12 % for stage IV disease. Overall survival was 58.4 % at 10 years in patients undergoing resection with curative intent as compared to 12.8 % after palliative surgery. There was a statistically significant survival difference between patients undergoing laparoscopic anterior resection (AR) compared with abdominoperineal resection (APR) (54.8 % vs. 41.8 % at 10 years, p = 0.029). Using Cox’s regression model for multivariate analysis, no difference could be found between the first and second half of patients regarding the overall (hazard ratio (HR) 1.08; 95 % confidence interval (CI) 0.937–1.244, p = 0.288) and diseasefree survival (HR 1.07; 95 % CI 0.933–1.226, p = 0.333).
5.8 % (13/224). There were no new cases of local recurrence between 5 and 10 years of follow-up (Fig. 2). The local recurrence rate was 6.6 % (11/165) for patients after AR compared with 3.7 % (2/54) for patients undergoing APR (p = 0.328). The median time between surgery and diagnosis of a local recurrence was 30 (range 5.5–112) months. The timeframe to develop a local recurrence was similar between the first (1998–2002) and the second (2002–2005) half of patients in a multivariate analysis using Cox’s regression model (HR 1.008; 95 % CI 0.721–1.429; p = 0.963). Of all patients suffering local recurrence, ten (77 %) patients underwent second AR, and three patients (23 %) underwent APR. The second surgery revealed negative resection margins in 12 of 13 cases. Using a multivariate Cox regression analysis, we found significant differences between patients treated with and without preoperative radiochemotherapy (p = 0.039) and R0 versus R1 resection (p = 0.034) as well as concerning the tumour location from the anal verge (p = 0.022). Regarding the different surgical procedures, we could not find any significant differences (AR vs. APR, p = 0.62; Table 2). During surgery, none of the tumours were perforated and no patient developed port site metastases. Distant metastases occurred in 30 patients. Seven patients developed metastasis in liver and lung, 13 in liver only, 8 in lung only, 1 patient in liver and brain, and another patient in liver and spleen. Conversion
Local and distant recurrence The demographic data of patients with local recurrence are shown in Table 1. The overall local recurrence rate was
The conversion rate was 10.2 % (n = 23). In all cases, conversion was due to technical and not oncological reasons (obesity and narrow pelvis n = 10; adhesions n = 4;
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Surg Endosc Table 1 Characteristics of patients with local tumour recurrence (n = 13)
Causes of death
Characteristics
Variable
Age (year), mean (range)
61 (42–76)
Of the 75 patients who died, 66 patients were in the laparoscopic and 9 patients in the converted group. In the laparoscopic group, rectal cancer-related deaths occurred in 34 (45 %) patients. The remaining patients died due to cardiovascular (n = 22), development of a second malignoma (n = 5), or unknown (n = 5) reasons. In the converted group, cancer-related deaths occurred in four (44 %) cases. One patient developed a second malignoma and four patients died because of cardiovascular reasons.
Gender, n (%) Female
4 (31)
Male
9 (69)
UICC, n (%) 1
6 (46)
II III
3 (23) 3 (23)
IV
1 (8)
Tumour size, n (%) \5 cm
Discussion 9 (69)
[5 cm
4 (31)
Tumour location from anal verge, mean in cm (range, SD)
6.7 (1–12, 3.4)
Aboral distance to tumour, mean in cm (range, SD) Surgery, n (%)
2.7 (0.3–9.0, 2.5)
Anterior rectal resection—LAR
10 (77)
Abdominoperineal resection—APR
3 (23)
Symptoms, n (%) No symptoms
12 (92)
Ileus
1 (8)
Location of recurrence, n (%) Intraluminal
4 (31)
Extraluminal
7 (54)
Intra- and extraluminal
2 (15)
Time to recurrence, mean in months (range, SD) Resection margins, n (%)
30 (5.5–112)
RO
8 (61.5)
R1
3 (23.1)
R2
2 (15.4)
SD standard deviation
bleeding during splenic flexure mobilisation n = 3; dysfunction of the stapler device n = 2; injury of the ureter n = 2; anaesthetic issues n = 2). After 10 years, overall survival was 30.4 % in converted cases, but it was 53.1 % in laparoscopically completed cases (p = 0.003; Fig. 3). In the multivariate analysis, however, when the hazard ratios were calculated using Cox’s regression model, factors associated with an inferior outcome were age, tumour stage, and surgical complications. For the localisation of the tumor and neoadjuvant radiochemotherapy, the overall survival rate was similar between converted and nonconverted patients. The previously described highly significant difference (HR 2.129, p = 0.004) was no longer apparent when adjusted for these variables (HR 1.221, p = 0.478). In addition, none of the converted patients developed local tumor recurrence.
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Overall and disease-free survival To the best of our knowledge, this study is one of the largest reporting on long-term follow-up of patients undergoing laparoscopic surgery for rectal cancer. The 10-year overall and disease-free survival were 50.5 and 50.1 %, respectively. Considering that most patients underwent complete laparoscopic rectal resection (86.6 %) and 36.9 % received preoperative radiochemotherapy, our data are comparable with overall survival of 59.6 % in patients treated by preoperative radiochemotherapy and open rectal resection [13]. To assess a possible learning curve, we compared the first (1998–2002) and second (2002–2005) half of patients undergoing laparoscopic resection. In a multivariate analysis with Cox’s regression model, we could not find a difference in the overall survival, disease-free survival, or local recurrence rate between the two groups, indicating a consistent expertise in laparoscopic surgery likely due to standardization of the resections in our hospital. Most of the published studies that address laparoscopic surgery describe long-term results up to 5 years after surgery. The CLASICC trial, a multicenter study comparing open to laparoscopic resection in rectal cancer, has just published its 5-year and, just recently, 10-year results, respectively [3, 10]. The 5-year overall survival for patients resected laparoscopically was 60.3 %. The analysis of 326 patients of the CLASICC trial showed a disease-free survival of 52.1 % after 5 years [3]. The 10-year follow-up described an overall survival of 82.7 months with no difference between patients undergoing AR or APR [10]. Our results showed an inferior outcome with reduced overall survival in the APR group compared with AR. However, this finding might be a bias and due to patient selection for laparoscopic surgery. Ng et al. [9] published in 2009 the analysis of 74 patients undergoing laparoscopic rectal resection for cancer of the upper third of the rectum. They reported an overall and disease-free survival of 63.9 and 82.9 % after 10 years. However, a major limitation of this study was inclusion of upper rectal cancer only.
Surg Endosc Fig. 2 Incidence of local recurrence for low anterior (n = 157) and abdominoperineal (n = 67) resection
Table 2 Multivariate Cox regression analysis of all patients (n = 224)
Variable
n
%
HR
95 % CI
p
Age
224
100
0.988
0.928–1.051
0.704
Male
143
63.8
1.000
Female
81
36.2
0.449
0.126–1.599
0.217
1
83
37.1
1.000
II
46
20.5
2.727
0.530–14.019
0.230
III
56
25
2.276
0.580–8.928
0.238
IV
39
17.4
0.580
0.043–7.838
0.682
No
142
63.4
1.000
Yes
82
36.6
0.126
0.02–0.805
0.029
Distal Medial
93 97
41.5 43.3
1.000 0.157
0.036–0.688
0.014
Proximal
34
15.2
0.060
0.006–0.622
0.018
Anterior rectal resection
157
70.1
1.000
Abdominoperineal resection
67
29.9
0.191
0.034–1.084
0.62
0.801–146.423
0.073
Gender
UICC stage
Treatment received Preoperative CRT
Tumour location from anal verge
Type of resection
Completeness of local resection CRT chemoradiotherapy, HR hazard ratio, CI confidence interval
RO
219
97.8
1.000
R1/2
5
2.2
10.831
Local recurrence In our study, the rate of local recurrence was 5.8 % after 5 and 10 years. Regarding the local recurrence rate, no difference could be found between the first and second
half of surgeries using Cox’s regression model of multivariate analysis (p = 0.963). Ng et al. [9] reported a local recurrence rate of 7.1 % after laparoscopic rectal resection for carcinoma of the upper third of the rectum after 10 years.
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Conversion and its influence on oncological outcome
Fig. 3 Ten-year overall survival for converted and nonconverted patients (p = 0.003, log-rank test)
The development of local recurrence is depended on several factors. These include radiochemotherapy (neoadjuvant/adjuvant), the type of resection conducted, the aboral distance of the tumour from the anal verge as well as the distance to the circumferential resection margin. A multivariate Cox analysis showed significant differences in tumour localisation, preoperative radiochemotherapy, and, as expected, R0 versus R1 tumour resection. With a local recurrence rate of 6.6 % for AR and 3.7 % for APR (p = 0.62), we could not find a statistical difference between these two groups consistent with the data reported in the CLASICC trial (AR 9.9 % and APR 15.3 %, p = 0.078) [3, 10]. The positive impact of neoadjuvant radiochemotherapy to prevent local tumour recurrence has been demonstrated by several studies [5, 6, 14]. In total, neoadjuvant radiochemotherapy was performed in 36.9 % of our patients. From the patients who developed local recurrence, 6 patients (46.1 %) received adjuvant/neoadjuvant radiochemotherapy and another 7 of 13 (53.9 %) were treated without radiochemotherapy. In the era of neoadjuvant radiochemotherapy, the time-point of development of local recurrence is of great interest as, in theory, this might occur later than in patients only treated surgically. In our study, the median time for the development of local recurrence was 30 months. Interestingly, none of the patients who were converted to open resection developed local tumour recurrence. In this respect, the long-term data of the COLOR-II, a large prospective, randomized, multicenter trial, will be of great interest [15].
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In 2008, we have published our results on conversion from laparoscopic to open rectal resection in patients with rectal cancer [16]. We could demonstrate that the conversion rate is based on a learning curve and correlated with an increased morbidity compared with patients operated completely laparoscopically (61.2 % vs. 36.8 %, p = 0.025). This finding is concurrent with the results of a recent multicenter study confirming that conversion of laparoscopic to open resection is associated with a significantly higher rate of intra- and postoperative complications [17]. In addition, patients converted to open resection had significantly longer operation time (p = 0.001) and required more blood transfusions (p = 0.001) than nonconverted patients. In all our patients, conversion to open surgery was due to technical but not oncological (e.g., perforation of the tumour, insufficient distance to the tumour) reasons. Nevertheless, we could detect a significant difference between converted and nonconverted patients regarding overall (p = 0.003) and disease-free survival (p = 0.004). Several studies had demonstrated a significant association between postoperative morbidity and overall and disease-free survival rate in patients undergoing colorectal cancer surgery [18–20], probably due to a profound immunosuppression and a catabolic state caused by septic complications [21]. Thus, we believe, an increased postoperative morbidity rate in converted patients might be the reason for the impaired longterm outcome. This suggestion was confirmed by the Cox regression analysis. Our data are consistent with the results published in the CLASICC trial showing a statistically inferior overall survival rate in patients who had to be converted to open surgery [3, 10]. In the CLASICC trial, the negative effect of conversion was also related to technical events. Contrary to it, in a German multicenter study, which included 237 patients with laparoscopic rectal resection, no difference between converted and nonconverted patients was reported with respect to overall and disease-free survival after 5 years [22]. This analysis demonstrates the long-term results of one of the biggest series after laparoscopic rectal resection due to rectal carcinoma. Our data confirm previous reports that oncological criteria established in open rectal surgery can be preserved in laparoscopic surgery. Although surgery was performed by several surgeons, we could show that using a standardised technique, laparoscopic rectal resection can reveal similar longterm results compared to the open procedure.
Conclusions Our study demonstrates that surgery for rectal cancer can reveal good long-term outcome using the laparoscopic
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approach. However, because this is a technically challenging procedure, we recommend that laparoscopic resection of the rectum should be performed in centers with sufficient expertise and standardized procedures in laparoscopic surgery. Acknowledgments The authors thank Richard John Heald for critical reading of the manuscript.
11.
12.
Disclosures Drs. Agha, Benseler, Hornung, Gerken, Iesalnieks, Fu¨rst, Anthuber, Jauch and Schlitt have no conflict of interest or financial ties to disclose.
13.
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