Abstract
Aim: To compare the mid-term oncological results between patients with low rectal cancer who underwent minimally invasive laparoscopic surgery (MILS) and those who underwent open surgery (OS). Patients and Methods: Overall, 262 matched patients who underwent primary resection for low rectal cancer between 2000 and 2019 were divided into MILS (n=131; n=107, conventional laparoscopic surgery; n=24, robotic surgery) and OS (n=131) groups. The short- and mid-term outcomes were compared. Results: Similar baseline characteristics were noted. The operative time was longer and blood loss was lesser in the MILS group; the conversion rate was 3.8%. The incidence of postoperative complications was similar. The 2-year cumulative incidence of local recurrence was noted to be much lower in the MILS group (1.9%) than in the OS group (8.4%). MILS had a significantly low hazard ratio (0.208, p=0.036). Conclusion: MILS has potential benefits in reducing local recurrence of low rectal cancer.
Surgical resection remains an essential treatment modality for rectal cancer. Precise dissection in the narrow pelvic field is technically demanding, and is responsible for negative technical outcomes, such as anastomotic leakage (1), urogenital dysfunction (2), and local recurrence (LR) (3). Among these, LR remains one of the most important outcomes following rectal cancer surgery.
Minimally invasive laparoscopic surgery (MILS), including conventional laparoscopic surgery (CLS) and robot-assisted laparoscopic surgery (RALS), has been widely accepted as a useful alternative to surgical resection in rectal cancer. Its elaborate tissue handling and the magnified view can result in better oncological outcomes, especially in the narrow field around the lower rectum.
However, a recent large-scale multicentre study comparing the oncological outcomes between MILS and open surgery (OS) failed to demonstrate a better local control rate for MILS (4-8). The possible explanations are that the merit of MILS may be maximized in the lower rectal area; however, the previous studies included not only low rectal cancer, but also upper and mid rectal cancer. In addition, previous studies reported a learning curve regarding the outcomes of MILS for rectal cancer (9, 10). Both of these large-scale studies included many surgeons from various institutes, which led to a high heterogeneity in the operative method and proficiency levels. A few other studies have shown good long-term outcomes for MILS; the common factor in these studies was that they all were single-institute or small-group studies (11-13).
In the present study, the mid-term oncological outcomes of rectal cancer were compared between MILS and OS. To confirm the potential merits of MILS, the participants included were only those with low rectal cancer, and the procedure was performed in a single study group using the same operative method for MILS.
Patients and Methods
Ethical approval. All procedures performed in the study were in accordance with the ethical standards of the institutional research committee (Yokohama City University Institutional Review Board approval no. 170700003) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The requirement for informed consent was waived owing to the retrospective nature of the study. The details of the study protocol were provided to patients through a notice board at participating hospitals and were also published on hospital websites.
Study design. Between January 2000 and December 2019, 1,038 patients underwent primary resection for rectal cancer at three group hospitals (Hospitals A, B, and C) related to our Department of Surgery (Yokohama City University). Among these, patients with upper-mid rectal cancer, stage 0 disease, stage I disease, stage IV disease, local resection, R2 resection, and multiple cancer resections (1,038, 344, 7, 210, 74, 7, 12, and 1, respectively) were excluded. Consequently, 383 patients with stage II-III low rectal cancer (the lower border of the tumour lying below the peritoneal reflection) were included in the propensity matching process. Finally, 262 matched patients were divided into two groups: MILS (n=131) and OS (n=131). The MILS group included 107 patients with CLS and 24 with RALS (Figure 1). The median follow-up period for the present study was 35 months.
Patient flow diagram. MILS: Minimally invasive laparoscopic surgery; OS: open surgery; CLS: conventional laparoscopic surgery; RALS: robot-assisted laparoscopic surgery; Neo CRT: neoadjuvant chemoradiotherapy; LLD: lateral lymph node dissection; adjuvant CTx: adjuvant chemotherapy.
Patients were staged using the tumour-node-metastasis staging system of the American Joint Committee on Cancer Cancer Staging Manual (14). This staging system considers lateral lymph node metastasis as distant metastasis; however, the present study considered it as regional metastasis. A positive circumferential resection margin (CRM) was defined as a pathologically positive radial margin, according to a previous study (15).
Technical qualification of surgeons. In 2004, the Japan Society for Endoscopic Surgery introduced an endoscopic surgical skill qualification system (JSESQS) (16). Qualified surgeons are certified as having reliable laparoscopic skills to maintain a stable outcome for laparoscopic surgery.
In the present study, six key surgeons performed or directly supervised the operation in CLS, and five of them were JSESQS-qualified. Among a total of 107 CLS operations, 100 operations were performed or directly supervised by JSESQS-qualified surgeons. For RALS, two surgeons directly performed or supervised the operation. In Japan, the Japan Society for Endoscopic Surgery recommends that all operators for robotic gastrointestinal surgery be JSESQS-qualified surgeons. Five key surgeons were included in the study for OS. There is no clear qualification system for surgeons for OS in Japan.
Operative procedure. The operative procedure of MILS was standardized in our hospital groups; the details of which have been described previously (17). For MILS, initial access to the abdomen was usually achieved via the umbilical port. Once pneumoperitoneum was established, four additional ports were placed. Vessel ligation with lymph node dissection was performed, followed by left-sided colon mobilization. In the mesorectal excision step, a standardized seven-step total mesorectal excision approach was established. For the RALS, the da Vinci Si or Xi surgical system was used. After rectal mobilization and transection, the pathological specimen was extracted via a 4- to 6-cm wide umbilical incision.
In the OS group, a midline laparotomy was the choice for access. Left colon mobilization was followed by main vessel ligation and bowel resection.
In both MILS and OS, reconstruction was performed using the double-stapling technique with a circular stapler.
Indications for MILS. CLS for rectal cancer was first adopted in 2003 and has been performed at all three hospitals. The indications for OS and CLS are not standardized at each hospital but vary depending on the discretion of the surgeon after considering tumour factors, patient preferences, and the experience of the surgeon. RALS was adopted at hospitals A and B in 2017 and has been the first-choice approach for rectal cancer since 2018.
Indications for lateral lymph node dissection and neoadjuvant chemoradiotherapy. According to the Japanese Society for Cancer of the Colon and Rectum guidelines for the treatment of colorectal cancer (18), lateral lymph node dissection is considered when the lower border of the tumour is located in the lower rectum and has invaded tissue beyond the muscularis propria (cT3-4).
The basic concept of our study group for neoadjuvant chemoradiation therapy (neo-CRT) was that neo-CRT was considered only when margin positivity was highly suspected based on preoperative imaging findings.
Postoperative complications. Postoperative complications were evaluated using the Clavien–Dindo classification system (19). In this study, grade 3-5 postoperative complications that occurred during hospitalization or within 30 days after surgery or both were recorded.
Outcome of interest. The primary outcome of interest was the cumulative rate of LR, and the secondary outcome was the postoperative complication rate.
Postoperative follow-up. Postoperative follow-up involved measurement of serum carcinoembryonic antigen levels (every 6 months), computed tomography scans (every 6 months), colonoscopies (every year), and routine outpatient visits. LR was defined as any recurrence in the pelvic field, such as presacral, anterior, anastomotic, lateral, and perineal field, detected during the follow-up.
Propensity score matching and statistical analyses. Propensity score matching was performed based on the baseline characteristics. Patients in the MILS group were matched in a 1:1 ratio to those in the OS group based on the following factors: age (75≥/<75 years), neo-CRT (yes/no), pT (1-3/4), pN (negative/positive), lateral lymph node dissection (yes/no), residual tumour (R0/R1), and adjuvant chemotherapy use (yes/no). The patient cohort before matching had a high discrepancy in terms of sex; therefore, sex was excluded as a matching factor to maintain a sufficient number of patients. The standardized difference for all matching factors was confirmed to be less than 0.25. The significance of the association between the study groups and clinicopathological parameters was assessed using Fisher’s exact test or t-tests. The hazard ratio (HR) of cumulative LR was calculated using the Fine–Gray analysis, using death as the competing risk event. Curves for relapse–free survival (RFS), measured from surgery, were constructed using the Kaplan–Meier method and compared using the log-rank test.
All statistical analyses were performed using EZR (20) (Jichi Medical University, Saitama, Japan) and R software (version 3.4.3). All p-values were two-sided, and a p-value of less than 0.05 was considered to indicate statistical significance.
Results
Patient characteristics. The baseline characteristics of the MILS and OS groups are presented in Table I. There were no significant differences between the two groups with regard to age, American Society of Anesthesiologists score, body mass index (BMI), pT, pN, and adjuvant chemotherapy. The proportion of women (45.0% vs. 71.0%, p<0.001) and the preoperative serum carcinoembryonic antigen level (3.2 vs. 4.2 ng/dl, p=0.049) were lower in the MILS group than in the OS group.
Patient characteristics (n = 262).
Short-term outcomes. Table II summarizes the short-term outcomes of patients. The operative time was longer (306 vs. 200 min, p<0.001) and blood loss was lesser (20 vs. 290 g, p<0.001) in the MILS group than in the OS group. The rate of lateral lymph node dissection tended to be higher in the MILS group than in the OS group (23.7% vs. 14.5%, p=0.083).
Short-term outcomes (n=262).
The incidence of postoperative complications (12.2% vs. 16.0%, p=0.478) and the types of complications were similar in both groups. A negative CRM was achieved in 97.7% of the patients in both groups. The length of the postoperative hospital stay was shorter in the MILS group than in the OS group (15 vs. 19 days, p<0.001).
Survival outcome. The cumulative incidence of LR according to groups is shown in Figure 2. The 2-year cumulative incidence of LR in the MILS and OS groups was 1.9% and 8.4%, respectively. The HR analysis for the LR showed a significantly low LR risk for MILS compared with OS (HR=0.208, 95% confidence interval=0.048-0.899; p=0.036) (Figure 2).
Cumulative local recurrence (LR). MILS: minimally invasive laparoscopic surgery; OS: open surgery; HR: hazard ratio; CI: confidence interval.
RFS analysis showed no significant difference in the 3-year RFS rate between the MILS and OS groups (78.6% vs. 72.4%, p=0.249) (Figure 3).
Relapse-free survival (RFS). MILS: Minimally invasive laparoscopic surgery; OS: open surgery.
Patterns of recurrence are shown in Table III. In the follow-up period, 19 and 36 patients had developed recurrence in the MILS and OS groups, respectively (p=0.015). The proportion of LR was lower in the MILS group than in the OS group (1.5% vs. 11.5%, p=0.002), while the other patterns were not significantly different.
Pattern of recurrence (n=262).
Discussion
In the present study, considering that the benefit of laparoscopic surgery can be maximized in the low rectal area, and that LR is correlated with the proficiency level of the surgeon, we compared MILS and OS in a single group sharing the same surgical procedures. The 2-year LR was significantly lower in the MILS group than in the OS group (1.9% vs. 8.4%).
In recent large-scale studies, the incidence of LR was 2-5% for the entire rectum (6, 8, 21) and 8-10% for the low rectum (15). Securing the CRM is a key strategy for preventing LR (3), and precise dissection under a magnified view in laparoscopic surgery (22, 23) is expected to contribute to better surgical outcomes. However, previous large-scale, multicentre studies have failed to demonstrate the superiority of laparoscopic surgery in terms of LR (6, 8, 15, 21).
The findings of a recent large-scale, multicentre studies on MILS for rectal cancer are summarized in Table IV. In the Color II trial (21, 24), patients with upper, mid, and low rectal cancer from 30 institutions who underwent CLS or OS were compared. The lower pelvic area was better visualised in CLS than in OS; however, LR occurred in approximately 5% of cases following CLS surgery, which was similar to that found in OS. There was no direct discussion of why CLS failed to lead to a better outcome.
Recent large-scale, multicentre studies regarding minimally invasive laparoscopic versus open surgery for rectal cancer.
Similarly, in the ALaCaRT (5, 6) and Z6051 (7, 8) trials, patients with upper, mid, and low rectal cancer from 24 and 35 institutions showed a 5% LR incidence following MILS and OS, respectively. In both trials, the authors expected that improved pelvic visualization with laparoscopy would lead to better pelvic dissections and oncological outcomes; however, they were unable to confirm the noninferiority of laparoscopic surgery to OS in terms of CRM, resulting in a similar LR rate. We presume that one of the reasons for this result was surgeon heterogeneity.
In the COREAN (25, 26) trial, surgeons from three participating institutes were qualified through a videotape-based reviewing system that assessed the surgeon’s oncological technique, including quality of total mesorectal excision. In addition, a surgeon was able to join the study after a fellowship training program for learning the standardized procedure. Because this study had a noninferiority design, the authors did not mention the superiority of the MILS approach; however, this homogeneous surgeon quality may have contributed to the relatively low LR rate (3%) after MILS for mid and low rectal cancer.
The level of a surgeon’s proficiency in laparoscopic surgery is difficult to measure objectively; however, it is reflected to a certain extent by the conversion rate (27). Additionally, low rectal cancer (28) and high BMI (29) are risk factors for conversion. The conversion rate in the present study was relatively low for low rectal cancer, compared to previous reports (Table IV). The same surgical procedure in the single-study group and Asian patients with BMI lower than that of Western patients may have contributed to the low conversion rate in the present study.
In terms of the morbidity rate, the present study showed that, under MILS, postoperative complications developed in 12.2% of patients, which is in line with the observations of recent reports (5, 7, 15, 24, 30).
In the present study, the MILS group had an anastomotic leakage rate of 5%. It is difficult to compare this to other studies due to the differences in inclusion and grading criteria; however, the 5% anastomotic leakage rate for low rectal cancer seems satisfactory.
The limitations of this study should be considered when interpreting the results. Firstly, there may have been a selection bias when considering patients who underwent MILS and OS. Propensity score matching was performed to eliminate selection bias as far as possible and to balance the cohort. However, due to the reasons mentioned previously, sex and the preoperative carcinoembryonic antigen level remained significantly different between the two groups. The number of patients who underwent lateral lymph node dissection tended to be higher in the MILS group than in the OS group (23.7% vs. 14.5%, p=0.083), which may have contributed to the better local control rate for the MILS group. Secondly, the follow-up period was insufficient for some patients to determine the 2-year local control rate.
In conclusion, this study is the first to demonstrate the potential benefits of clear, magnified visualization in MILS in terms of local control in patients with low rectal cancer treated by the same surgical technique. Further investigation is warranted to confirm the merits of MILS.
Footnotes
Authors’ Contributions
All Authors contributed to the study conception and design. Data collection was performed by Masakatsu Numata, Hiroshi Tamagawa, Keisuke Kazama, Yosuke Atsumi, Kenta Iguchi, Sho Sawazaki, Toru Aoyama, Sumito Sato, Nobuhiro Sugano, Teni Godai, Akio Higuchi, Hiroyuki Saeki, Takanobu Yamada, Takashi Oshima, Manabu Shiozawa, Norio Yukawa, and Yasushi Rino. The statistical analysis was performed by Yusuke Saigusa. The first draft of the article was written by Masakatsu Numata, and all Authors commented on previous versions of the article. All Authors read and approved the final article.
Conflicts of Ιnterest
The Authors declare that they have no conflicts of interest related to this study.
- Received March 10, 2021.
- Revision received April 2, 2021.
- Accepted April 8, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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