Is the Postoperative Inflammatory Response Decreased in Robotic Compared with Laparoscopic Anterior Resection for Rectal Cancer?

Abstract

Aim:

To investigate postoperative inflammatory response as assessed by C-reactive protein (CRP) levels in patients undergoing anterior resection (AR) for rectal cancer by minimally invasive surgery (MIS).

Method:

All patients diagnosed with rectal cancer between 2011 and 2021 undergoing AR by MIS without conversion at one university hospital were included. Open surgery was not included. Patient data were obtained from the Swedish Colorectal Cancer registry and from local patient charts, including CRP levels preoperatively and postoperative day (POD) 1–5.

Results:

A total of 123 patients were identified with rectal cancer, of which the proportion of laparoscopic surgery (LAP) was 31% (n = 38) and robotic assisted rectal cancer surgery (ROBOT) 69% (n = 85). The proportion of women was 37%, median age 69, median body mass index 26, 25% had ASA class ≥3, 27% had neoadjuvant radiotherapy, 12% had neoadjuvant radiotherapy combined with chemotherapy, and 59% had a planned defunctioning stoma. No complications were noted in 44.7% of LAP and in 51.8% of ROBOT. Complications defined as Clavien–Dindo grade ≥IIIb were 10.5% in LAP and 9.4% in ROBOT. Hospital stay was a median 9.5 days in LAP and 10 in ROBOT. The median CRP values in LAP and ROBOT preoperatively were 3 and 4 (P = .845), on POD 1: 100 and 110 (P = .865); POD 2: 218 and 145 (P = .159); POD 3: 181 and 141 (P = .097); POD 4: 128 and 95 (P = .502), and on POD 5: 73 and 71 (P = .785), respectively.

Conclusion:

Postoperative inflammatory response as assessed by postoperative CRP values was not statistically different between LAP and ROBOT. CRP levels on POD 2–4 were numerically lower in ROBOT. The clinical relevance of this finding warrants further investigation.

Keywords

robotic surgery laparoscopy anterior resection rectal cancer inflammatory response CRP

Introduction

Approximately 700,000 individuals are diagnosed with rectal cancer worldwide, whereof 2200 patients annually in Sweden. Radiotherapy alone or various combinations of radio- and chemotherapy may be given as neoadjuvant therapy in selected cases depending on clinical cancer stage. A proportion of patients with neoadjuvant treatment obtain a complete clinical response following such treatment and may be offered inclusion in organ-sparing treatment strategies, often coined as watch and wait. Nevertheless, to this date, resection surgery is still the cornerstone of curative rectal cancer treatment.

Laparoscopic surgery (LAP) for rectal cancer surgery was introduced in the 1990s and was later followed by international randomized controlled trials (RCT) such as the COLOR II and the COREAN trials.^1,2 The results of these RCTs are well known and demonstrated short-term advantages for LAP as compared with open surgery, such as less intraoperative blood loss, less pain, shorter time to enteral feeding, and shorter hospital stay.

Robotic assisted rectal cancer surgery (ROBOT) was introduced after the turn of the millennium but gained more general use in the 2010s. The first multicentric RCT comparing LAP and ROBOT, the ROLLAR trial, comprising 450 patients, did not demonstrate any significant differences regarding the primary endpoint conversion rate nor secondary outcomes.^3,4 Recently a Chinese RCT, the REAL trial, comprising more than 1200 patients, demonstrated lower local and distant recurrence rates for ROBOT as compared with LAP, but no difference in overall survival nor in ano-rectal and uro-genital functional results.^5,6

The protein coined CRP was discovered in the 1930s and is a pentameric protein that responds to local or systemic inflammation by an increased production in the liver and a subsequent increase in serum level. CRP is usually measured in milligram per liter (mg/L), and levels tend to increase due to factors such as infection and surgical trauma. In clinical surgical practice, assessment of CRP can be a helpful tool in the postoperative phase, as it gives an indication of the inflammatory response, and if postoperatively more elevated than expected, may aid in detecting postoperative complications, including anastomotic leakage. In recent years a limited number of publications have compared LAP and ROBOT regarding the postoperative inflammatory response, most often by assessing early post-operative CRP levels.^7–15

The aim of the present investigation was to assess whether the inflammatory response, as measured by serum CRP levels, may differ in LAP as compared with ROBOT following anterior resection (AR) for rectal cancer. The primary hypothesis was that CRP levels may be lower in AR performed by ROBOT as compared to LAP.

Method

The primary research question was to assess the impact of LAP as compared with ROBOT on postoperative inflammatory response as measured by serum CRP values preoperatively and on postoperative day (POD) 1–5. The study population included all patients diagnosed with rectal cancer between January 1, 2011, and December 31, 2021, who underwent AR for rectal cancer by LAP or ROBOT at the Department of Surgery, Örebro University Hospital, Örebro, Sweden. Abdomino-perineal resection and Hartmann’s procedure were not included in the analysis. Moreover, it was deemed reasonable to exclude all converted operations since they may mimic open surgery. Other exclusion criteria included patients who underwent local procedures such as open transanal excision, endoscopic microsurgery, or endoscopic excision. Four experienced colorectal surgeons were in charge of all procedures, and they all performed both LAP and ROBOT (Fig. 1).

Patient data were obtained from the Swedish Colorectal Cancer Registry (SCRCR) and from local patient files. The SCRCR is a nationwide registry in which registration is mandatory, and nearly all (>99%) adenocarcinomas of the rectum diagnosed in Sweden since 1995 have been included. The definition of rectal cancer in the SCRCR is a tumor with the lower edge at a maximal distance from the anal verge of 15 cm as measured with a rigid sigmoideoscope. Tumors with a histology other than adenocarcinoma are not registered. The registry has been validated on several occasions, most recently by Arnarsson et al in 2024.^16,17

The Clavien–Dindo classification is a system utilized to grade surgical complications based on degree of severity, ranging from grade 1 to 5. Data regarding the Clavien–Dindo classification outcome was obtained from the SCRCR, in which grade 2–5 are recorded, while grade 1 is not recorded.^18,19

Results are presented as counts and percentages for categorical variables and median values together with interquartile range or mean values with standard deviation for continuous variables. For comparing CRP values the Mann–Whitney U test was used. For statistical calculations the SPSS version 29.0 (SPSS, Chicago, Illinois, USA) was used.

Ethical approval was obtained from the National Ethical Committee (DNR: 2023-00232-01). Approval for using registry data was obtained from the steering committee of the SCRCR. Consent was waived, as the study is an observational study using prospectively recorded registry data.

Results

Patient demography

A total of 123 patients were identified who underwent AR of the rectum for adenocarcinoma by MIS without conversion between 2011 and 2021 at the Surgical Department, Örebro University Hospital, Örebro, Sweden.

The distribution of surgical modality was LAP 30.9% (n = 38) and ROBOT 69.1% (n = 85). Age, sex distribution, body mass index, clinical TNM stage, and tumor height were similar between groups. The proportion of ASA class 3 was higher in ROBOT as compared with LAP (Table 1).

Table 1.

Demographic Data in Patients Undergoing Curative Minimally Invasive Non-Converted Anterior Resection for Rectal Cancer at the Department of Surgery, Örebro University Hospital, Sweden. Mann–Whitney U Test If Otherwise Not Stated.

Variable	LAP (n = 38)	ROBOT (n = 85)	P value
Age, median (Q1;Q3)	68 (60;73)	69 (63;73)	P = .550
Females^b	17 (44.7%)	28 (32.9%)	P = .201
BMI, median (Q1;Q3)	25.8 (23.5;27.7)	26.3 (23.8;29.4)	P = .216
ASA score^a
1–2	35 (92.1%)	61 (71.7%)
≥3	3 (7.9%)	24 (28.3%)	P = .017
Tumor height, cm	11 (9;13)	11 (8;13)	P = .348
Clinical UICC cancer stage^b
I	4 (10.5%)	5 (5.9%)
II	11 (28.9%)	34 (40.0%)
III	20 (52.6%)	43 (50.6%)
IV	3 (7.9%)	3 (3.5%)	P = .441
Clinical tumor stage^a
cT1-3	38 (94.4%)	81 (95.2%)
cT4	2 (5.6%)	4 (4.8%)	P = .504
Neoadjuvant therapy
None	22 (57.9%)	53 (62.4%)
Radiotherapy only^b	12 (31.6%)	21 (24.7%)
Radio- and chemotherapy^a	4 (10.5%)	11 (12.9%)	P = .714

Radio- and chemotherapy.

Chi square test.

Surgical outcomes

The median duration of surgery was 272 minutes in LAP and 230 minutes in ROBOT. The median intraoperative blood loss was 100 mLs in LAP and 50 mLs in ROBOT. Complications graded as Clavien–Dindo ≥ 3 occurred in 10.5% in LAP and in 9.4% in ROBOT. The rate of symptomatic anastomotic leakage was 10.5% in LAP and 8.2% in ROBOT, while the rate of reoperation was 5.3% in LAP and 11.8% in ROBOT. The median length of hospital stay was similar, a median of 9.5 in LAP and 10 days in ROBOT, and the rate of readmission within 30 days was similar between groups (Table 2).

Table 2.

Intraoperative and Postoperative Details in Patients Undergoing Curative Minimally Invasive Non-Converted Anterior Resection for Rectal Cancer at the Department of Surgery, Örebro University Hospital, Sweden. Mann–Whitney U Test If Not Otherwise Stated.

Variable	LAP (n = 38)	ROBOT (n = 85)	P value
Duration of surgery, minutes, median (Q1;Q3)	272 (193;368)	230 (180;279)	P = .051
Bleeding, mLs, median (Q1;Q3)	100 (25;200)	50 (25;100)	P < .001
Defunctioning stoma^a	52.6% (20/38)	61.2% (52/85)	P = .374
Intensive care unit^c	1 (2.6%)	2 (2.4%)	P = 1.0
Anastomotic leakage within 30 days^c	4 (10.5%)	7 (8.2%)	P = .681
Reoperation within 30 days^c	2 (5.3%)	10 (11.8%)	P = .262
No complication^b	17 (44.7%)	44 (51.8%)	P = .471
Claven Dindo grade ≥3b^c	4 (10.5%)	8 (9.4%)	P = .847
Hospital stay, median (Q1;Q3)	9.5 (7;15)	10 (7;13)	P = .632
Readmission within 30 days^c	5 (13.2%)	8 (9.4%)	P = .532
90-day mortality^c	0	1 (1.2%)	P = 1.0

Defunctioning stoma at index surgery.

Chi square test.

Fisher′s exact test.

Outcome of CRP

The median CRP values in LAP and ROBOT preoperatively were 3 and 4 (P = .845), on POD 1: 100 and 110 (P = .865); POD 2: 218 and 145 (P = .159); POD 3: 181 and 141 (P = .097); POD 4: 128 and 95 (P = .502), and on POD 5: 73 and 71 (P = .785), respectively. Postoperative CRP values were numerically lower in ROBOT on POD 2–4, but these differences did not reach statistical significance (Table 3; Fig. 2).

Table 3.

Serum Levels of CRP Preoperatively and on Postoperative Day (POD) 1–5 Following Anterior Resection for Rectal Cancer by Non-Converted Laparoscopic or Robotically Assisted Surgery at the Department of Surgery, Örebro University Hospital, Sweden. Median Values with Interquartile Range (Q1;Q3). Mann–Whitney U Test.

Variable	LAP (n = 38)	ROBOT (n = 85)	P value
Preop, median (Q1;Q3)	3 (1;11)	4 (1;14)	P = .845
POD l, median (Q1;Q3)	100 (28;260)	110 (90;161)	P = .865
POD 2, median (Q1;Q3)	218 (88;279)	145 (86;237)	P = .159
POD 3, median (Q1;Q3)	181 (111;241)	141 (79;201)	P = .097
POD 4, median (Q1;Q3)	128 (83;193)	95 (67;182)	P = .502
POD 5, median (Q1;Q3)	73 (52;114)	71 (45;162)	P = .785

Discussion

In the present study with an explorative, hypothesis-generating approach, a cohort of consecutive minimally invasive non-converted ARs for rectal cancer were assessed with regard to postoperative CRP values on POD 1–5, comparing LAP and ROBOT, and no statistically significant differences were found.

The study hypothesis proposed by the authors stating that the inflammatory response may be lower in ROBOT was based on the assumption that the intraabdominal pressure in general can be kept at a lower level in ROBOT compared with LAP, which in turn may decrease the surgical trauma. However, in view of the present findings, this study hypothesis could not be confirmed. Moreover, length of hospital stay, which could be viewed as a proxy for the impact of postoperative trauma and subsequent inflammatory response, was comparable with a median of 9.5 and 10 days in LAP and ROBOT, respectively.

Nevertheless, CRP was numerically lower in ROBOT on POD 2–4, and these findings suggest that ROBOT may induce a decreased postoperative systemic inflammatory response as compared with LAP.²⁰ Moreover, these differences in CRP may theoretically be true although not statistically significant in the present setting due to a limited cohort size with insufficient statistical power and a subsequent type II error.

Numerous previous studies have assessed the postoperative stress response in open surgery as compared with LAP and have demonstrated a lower degree of stress response in LAP. Other studies have compared open surgery to ROBOT and found a lower inflammatory response in ROBOT. Only a few studies have in fact compared ROBOT and LAP, or these two in combination with OPEN, in abdominal rectal cancer surgery.^21,22

The ROLLAR trial, a multicentric RCT comprising 450 patients, did not demonstrate any significant differences regarding the primary endpoint conversion rate, nor regarding any secondary outcomes.²³ In a single-center RCT by Feng et al., with nearly 350 abdomino-perineal resections, and in a multicenter RCT comprising nearly 1200 patients with mid- and low-rectal cancer, the REAL trial, patients were randomized to LAP or ROBOT. These two RCTs demonstrated less intraoperative bleeding, lower rates of conversion, postoperative complications, readmission, as well as shorter hospital stay, in ROBOT.^14,24 A systematic review and meta-analysis by Safiejko et al. comprising more than 19,000 patients from 41 studies, found shorter operation time, lower conversion rate and shorter hospital stay in ROBOT.²⁵

However, none of these publications assessed inflammatory response. In one retrospective study by Widder et al., comprising patients undergoing left-sided hemicolectomy, LAP, as compared with ROBOT, had increased CRP levels as reported exclusively on POD 1, 3, and 5. In a retrospective study by Cuk et al.,¹² CRP values for POD 1–7 were increased in LAP as compared with ROBOT in a study population in which one-third of the patients had undergone rectal resection and the remaining patients colon resection. In a recent retrospective study by Ingham et al., LAP and ROBOT were compared with regard to CRP values on POD 1–4 in patients undergoing left-sided colon or rectal resection, and ROBOT was found to have lower CRP values on POD 1–3.²⁶

To the knowledge of the authors, there is no publication to date assessing postoperative CRP daily in the early postoperative period in patients undergoing exclusively AR of the rectum, and furthermore, to obtain a maximally standardized cohort, with converted procedures excluded.

Although speculative, it could be presumed that the intra-abdominal pressure can be held at a lower level in ROBOT, inducing less tension in the abdominal wall and subsequently a less negative impact in general on the microcirculation. However, the specific effects of potential differences in intra-abdominal pressures in ROBOT as compared with LAP are not well-studied. The effects of lower intra-abdominal pressure were in fact the explanation suggested by Celerier et al. in their RCT comparing low (7 mm Hg) and standard (12 mm Hg) intra-abdominal pressure in 120 patients undergoing laparoscopic right-sided hemicolectomy. In this RCT the primary endpoint was hospital stay, which turned out to be 1 day shorter, a median of 3 versus 4 days, in the low-pressure arm compared with the standard arm, a statistically significant difference.^20,23

The present study has some limitations. Firstly, registry data from the SCRCR as well as from patient charts were prospectively collected but retrospectively analyzed, with the risk of potential residual confounding, which cannot be completely ruled out. Second, although patient files were scrutinized, in retrospect it is not always possible to identify the exact reason for choosing LAP or ROBOT. Third, the present cohort is of limited size, which impacts on statistical power with a subsequent potential risk of statistical type II error. Lastly, the fact that this is a single-center cohort, and spans over a relatively long time period, may also, to some extent, impact on the generalizability of the results

The following strengths of the present study can be noted. First, a cohort of consecutive patients undergoing non-converted standardized total mesorectal excision AR for cancer were operated by a limited number of surgeons who performed both LAP and ROBOT. Second, the high completeness of the data set retrieved from the SCRCR. Third, local patient charts were scrutinized and provided data on CRP, as laboratory data in general are not available in surgical registries.

Conclusion

The present explorative study did not find any statistically significant difference in inflammatory response as assessed by CRP on POD 1–5. In ROBOT, CRP values were numerically lower on POD 2–4, but the clinical relevance of this finding remains unclear and warrants further investigation in multicentric settings.

Ethics Approval and Consent to Participate

Ethics approval was obtained from the national Ethical Committee (DNR: 2023-00232-01). Consent was waived, as the study is an observational study using prospectively recorded registry data. The study adhered to the Declaration of Helsinki.

Availability of Data and Materials

The datasets generated and analzsed during the current study were obtained from the Swedish Colorectal Cancer Registry (SCRCR) and from local patient files under license of the current study. Data are available from the corresponding author with permission of the SCRCR.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported financ

References

van der Pas

, Haglind

, Cuesta

, et al.; COlorectal cancer Laparoscopic or Open Resection II (COLOR II) Study Group. Laparoscopic versus open surgery for rectal cancer (COLOR II): Short-term outcomes of a randomised, phase 3 trial. Lancet Oncol, 2013; 14(3):210–218.

Kang

S-B

, Park

, Jeong

S-Y

, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Short-term outcomes of an open-label randomised controlled trial. Lancet Oncol, 2010; 11(7):637–645.

Bonjer

, Deijen

, Abis

, et al.; COLOR II Study Group. A randomized trial of laparoscopic versus open surgery for rectal cancer. N Engl J Med, 2015; 372(14):1324–1332.

Jeong

S-Y

, Park

, Nam

, et al. Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Survival outcomes of an open-label, non-inferiority, randomised controlled trial. Lancet Oncol, 2014; 15(7):767–774.

Lujan

, Valero

, Biondo

, et al. Laparoscopic versus open surgery for rectal cancer: Results of a prospective multicentre analysis of 4,970 patients. Surg Endosc, 2013; 27(1):295–302.

Dehlaghi Jadid

, Cao

, Petersson

, et al. Long term oncological outcomes for laparoscopic versus open surgery for rectal cancer—A population-based nationwide noninferiority study. Colorectal Dis, 2022; 24(11):1308–1317.

Matthiessen

, Henriksson

, Hallbook

, et al. Increase of serum C-reactive protein is an early indicator of subsequent symptomatic anastomotic leakage after anterior resection. Colorectal Dis, 2008; 10(1):75–80.

Chow

, Tilney

, Paraskeva

, et al. The morbidity surrounding reversal of defunctioning ileostomies: A systematic review of 48 studies including 6,107 cases. Int J Colorectal Dis, 2009; 24(6):711–723.

Yamaguchi

, Kinugasa

, Shiomi

, et al. Robotic-assisted vs. conventional laparoscopic surgery for rectal cancer: Short-term outcomes at a single center. Surg Today, 2016; 46(8):957–962.

10.

Asklid

, Gerjy

, Hjern

, et al. Robotic vs laparoscopic rectal tumour surgery: A cohort study. Colorectal Dis, 2019; 21(2):191–199.

11.

Crippa

, Grass

, Dozois

, et al. Robotic surgery for rectal cancer provides advantageous outcomes over laparoscopic approach: Results from a large retrospective cohort. Ann Surg, 2021; 274(6):e1218–e1222.

12.

Cuk

, Simonsen

, Komljen

, et al. Improved perioperative outcomes and reduced inflammatory stress response in malignant robot-assisted colorectal resections: A retrospective cohort study of 298 patients. World J Surg Oncol, 2021; 19(1):155.

13.

, Yuan

, Li

, et al. Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Short-term outcomes of a multicenter randomized controlled trial. JCO, 2022; 40(4_suppl):14.

14.

Feng

, Tang

, Zhang

, et al. Robotic versus laparoscopic abdominoperineal resections for low rectal cancer: A single-center randomized controlled trial. J Surg Oncol, 2022; 126(8):1481–1493.

15.

RCC. Swedish Regional Cancer Center (RCC) website. Available from: https://statistik.incanet.se/kolorektal/rektum/

16.

Moberger

, Sköldberg

, Birgisson

. Evaluation of the Swedish colorectal cancer registry: An overview of completeness, timeliness, comparability and validity. Acta Oncol, 2018; 57(12):1611–1621.

17.

Arnarson

, Moberger

, Skoldberg

, et al. A validation of the Swedish colorectal cancer register - With focus on histopathology, complications and recurrences. Clin Epidemiol, 2024; 16:525–532.

18.

Dindo

, Demartines

, Clavien

. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg, 2004; 240(2):205–213.

19.

SCRCR. Swedish Colorectal Cancer Registry (SCRCR). Available from: https://scrcr.se/

20.

Celarier

, Monziols

, Célérier

, et al. Low-pressure versus standard pressure laparoscopic colorectal surgery (PAROS trial): A phase III randomized controlled trial. Br J Surg, 2021; 108(8):998–1005.

21.

Shibata

, Ishihara

, Tada

, et al. Surgical stress response after colorectal resection: A comparison of robotic, laparoscopic, and open surgery. Tech Coloproctol, 2015; 19(5):275–280.

22.

Widder

, Kelm

, Reibetanz

, et al. Robotic-assisted versus laparoscopic left hemicolectomy-postoperative inflammation status, short-term outcome and cost effectiveness. Int J Environ Res Public Health, 2022; 19(17):10606.

23.

Jayne

, Pigazzi

, Marshall

, et al. Effect of robotic-assisted vs conventional laparoscopic surgery on risk of conversion to open laparotomy among patients undergoing resection for rectal cancer: The ROLARR randomized clinical trial. JAMA, 2017; 318(16):1569–1580.

24.

Feng

, Yuan

, Li

, et al.; REAL Study Group. Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Short-term outcomes of a multicentre randomised controlled trial. Lancet Gastroenterol Hepatol, 2022; 7(11):991–1004.

25.

Safiejko

, Tarkowski

, Koselak

, et al. Robotic-assisted vs. standard laparoscopic surgery for rectal cancer resection: A systematic review and meta-analysis of 19,731 patients. Cancers (Basel), 2021; 14(1):180.

26.

Ingham

, Kong

, Wong

T-N

, et al. Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: A cohort study. Surg Endosc, 2024; 38(5):2577–2592.