Introduction

Colorectal cancer is a serious cause of mortality and morbidity and is the third most common type of cancer and the fourth leading cause of cancer-related deaths in both men and women.¹

The primary treatment for non-metastatic, localized colon cancer is surgery. While historically open surgery (OP) had been preferred, the first-ever laparoscopic resection of colorectal cancer was performed in 1991 by Jacobs et al.² Laparoscopic surgery has been popularized since 1991 and provides advantages over OP in terms of short-term outcomes, such as reduced postoperative pain, decreased blood loss, shorter hospital stay, earlier resumption of bowel function, early mobilization, and better cosmesis^3-7 without any compromise in long-term oncologic outcomes.^3,8-11 Due to these advantages, the laparoscopic approach is becoming more extensively used in treating colorectal cancer at all stages except T4.

No consensus has yet been reached on the optimal surgical approach in T4 colorectal tumors, and there is still an ongoing debate. Data in the literature that compare the results of open and laparoscopic resection of T4 tumors in depth are rare. According to the American Joint Committee on Cancer (AJCC),⁴ European Association of Endoscopic Surgery,¹² and National Comprehensive Cancer Network¹³ guidelines, laparoscopic treatment of T4 colorectal cancers is not recommended due to technical difficulties of en bloc resection, longer operative times, higher perioperative morbidity, and questionable oncologic outcomes.¹⁴ These guidelines recommend OP, which enables easier extensive en bloc resection and avoids suspicion of tumor seeding due to excessive manipulation used in the laparoscopic technique.

In recent years, there has been significant improvement in minimally invasive surgery (MIS) techniques and surgeons’ experience. Parallel to these advances, growing literature on this topic demonstrated that the laparoscopic technique is safe and feasible in locally advanced cancers,^15-18 and other research demonstrated good surgical and oncologic outcomes.^15,17,19,20 However, these studies have certain limitations: a low number of cases, retrospective design, and lack of long-term oncological results.^{15,16,18,21,22} Therefore, although these articles show promising results, they still provide insufficient evidence to support laparoscopic resections.

This study aims to retrospectively demonstrate our experience in the MIS of T4 colorectal cancer. Furthermore, we compare R0 resection rates, perioperative results, and short- and long-term oncologic outcomes between propensity score-matched MIS and OP groups with T4 tumors.

Materials and Methods

Patients who underwent elective MIS or OP in Koç University Hospital and VKF American Hospital between January 2014 and September 2021 were recorded and their data were prospectively gathered and retrospectively analyzed. This study was approved by Koç University Institutional Board of Review (approval code: 2020.491.IRB1.181, date: 04.03.2021) and was conducted in compliance with the 1964 Helsinki Declaration. All participants agreed to a written informed consent before their participation. All methods were carried out according to the institutional review board’s relevant guidelines and regulations. Each patient was also discussed in the multidisciplinary team consisting of general surgery, medical oncology, radiation oncology, gastroenterology, radiology, pathology, and nuclear medicine. This study included patients aged >18 years with a T4 tumor located between the cecum and rectosigmoid colon. Patients undergoing emergency surgery, patients presenting with perforated tumors, patients with metastatic disease or underlying inflammatory bowel disease, and familial adenomatous polyposis were excluded. Patient demographics, including age, gender, body mass index (BMI), and history of previous abdominal surgery, were recorded. The American Society of Anesthesiologists (ASA) Physical Status Classification, length of stay, biochemical results, complications (anastomotic leakage, wound dehiscence, bleeding, ileus), operative details (type and duration of surgery), pathology reports (tumor location and dimensions, lymph node status, tumor invasion depth, number of harvested lymph nodes, apical lymph node status, surgical margin status, AJCC stages, and distance between vascular tie and tumor epicenter/colon wall), intensive care unit stay, readmission, data related with follow-up visits, morbidity, and perioperative mortality status were recorded.

The patients’ routine preoperative evaluation included a complete physical examination, colonoscopy and biopsy, computerized tomography (CT) of the chest and abdomen, and positron emission tomography with 2-deoxy-2-(fluorine-18)fluoro-D-glucose integrated with CT if necessary. Surgical procedures were performed using oncological resection principles. The extent of the surgery was decided according to the tumor location and adjacent organ involvement, and an en bloc resection was preferred in the case of adjoining organ involvement. The conversion was defined as performing laparotomy during MIS due to factors such as bleeding, adhesions, and tumor perforation to achieve R0 resection and critical alterations in patients’ vital status (Figures 1, 2). En bloc resections, cholecystectomy, and stoma-creation were accepted as additional procedures. Patients with postoperative complications within 30 days of colectomy were graded using the Clavien-Dindo grading system.²³

At the joint discretion of the surgeon and the patient, a decision was made on whether the surgery would be performed with an MIS or an OP technique. MIS was offered regardless of the presence of a history of previous abdominal surgery. Whereas the MIS strategy included high ligation, mediolateral dissection, radical lymphadenectomy, and en bloc multi-visceral resection, the open approach consisted of vein and artery ligation, followed by lateral-to-medial dissection, radical lymphadenectomy, and an en bloc multi-visceral resection.

Patients meeting the criteria were split into two groups: the MIS group, consisting of patients who underwent laparoscopic or robotic surgery, and the OP group, consisting of patients who underwent OP. Patients who converted from MIS procedures to OP procedures were evaluated in the MIS group based on the intention-to-treat principle. Propensity score matching was performed to minimize the confounding factors and selection bias. Age, gender, ASA score, and pathological T-stage subgroup (pT4a or pT4b) were the variables included in the score matching. Nearest neighbor matching was performed in a 1:1 ratio, with the caliper width set at 0.2. Postoperative outcomes were assessed and compared between the two groups.

The patients’ oncological follow-up was carried out in accordance with the American Society of Clinical Oncology and American Society of Colon and Rectal Surgeons guidelines.^24,25 Follow-up visits were scheduled every 3 months for the first 2 years and then every 6 months for the next 2 years. A physical examination was performed, and tumor marker levels (CEA, Ca-125, Ca 19-9) were measured during every follow-up visit. An annual control colonoscopy and CT scan of the chest and abdomen to check for recurrent cancer in the lymph nodes, lungs, and liver were performed for the first 3 years after surgery. The frequency of follow-up visits and tests was adjusted according to the disease’s progression.

The primary outcomes were oncological, such as R0 resection rates, overall survival (OS), disease-free survival (DFS), short and long-term mortality, and morbidity.

Statistical Analysis

Statistical analysis of the results was carried out using SPSS version 21.0 (IBM, Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) or median (range) based on data distribution, whereas categorical variables were presented as absolute values and percentages. Student’s t-test and the Mann-Whitney U test were used to compare normally and non-normally distributed variables, respectively. Fisher’s exact test and the chi-squared test were used to analyze categorical variables. The Kaplan-Meier curve was utilized to evaluate OS, and survival differences between ages were compared using the log-rank method. Cox’s proportional hazards regression model was used for the combined effect of different parameters on survival. Statistical significance was defined by a p-value of <0.05.

Results

Between January 2014 and September 2021, 181 patients with colon cancer clinically staged as T4 were operated upon, and 51 patients were excluded because of distant metastasis. Thus, the total sample size was 130 before matching, and after matching, 49 patients were selected for each group (Chart 1). The patients were followed up for 75 months on average. The mean age, male proportion, and BMI of the patients were 65 (SD=16.8)/68 (SD=14.9), 59.2/57.1%, and 26.7 (SD=5.3)/22.7 (SD=5.2) for the MIS and OP groups, respectively (Table 1). The “T” stage based on histopathology of surgery specimen was T4a for 42 and 40 patients and T4b for the remaining 7 and 9 patients for the MIS and OP groups, respectively, and there was no significant difference in the pT and pN grades between the two surgical groups (p=0.59 and p=0.88, respectively) (Table 2). Seventy-nine (70.4%) of the patients were ASAI-II, and the remaining 29 (29.6%) were ASAIII-IV and were similar in both groups (p=0.83). Furthermore, there were no differences in tumor location or type of surgery (p=0.51 and p=0.27, respectively) (Tables 1, 3).

The median operation duration for the MIS group was significantly longer than for the OP group (167.65 and 132 minutes, respectively, p<0.01) (Table 3).

The conversion rate was 8.2% (Table 3). The main reasons for conversion were bleeding and technical difficulties.

The mean length of hospital stay and Clavien-Dindo scores of the patients were similar in both groups (p=0.28 and p=0.18). Nine patients in the MIS group and twelve patients in the OS group had additional surgery, and there was no significant difference (p=0.45). The postoperative surgical complication rate, reoperation rate, readmission, and mortality within 30 days were also similar between the two groups (p=0.16, p=0.28, p=0.39, p=1.0, respectively). Anastomotic leakage was observed in none of the patients in the MIS group and 3 patients in the OP group, and no statistically significant difference was found between the two groups (p=0.79) (Table 4).

Surgical margin positivity was not observed in the histopathological analysis of any surgically resected specimen in both groups. The number of harvested lymph nodes was >12 in both groups, which is the minimum required number for accurate staging, and the average numbers were 43.10 and 40.71 in the MIS and OP groups, respectively (p=0.17). Tumor size was higher in the OP group than in the MIS group, but the difference did not reach statistical significance (5.5 cm vs. 4.4 cm, respectively, p=0.08). There was no significant difference between the lymphovascular and perineural invasion rates (p=0.52 and p=0.7, respectively). Furthermore, the distance between the vascular tie and colon wall and between the vascular tie and tumor were similar in both groups (p=0.82 and p=0.33, respectively) (Table 2).

The overall 5-year survival rate was 85% in the MIS group and 88.5% in the OP group, and there was no significant difference (p=0.7) (Chart 2). Furthermore, the 5-year DFS rates were similar, at 62.5% for the MIS group and 70% for the OP group (p=0.33) (Chart 3). The local recurrence rate was comparable between the two groups (14.2% in the OP group vs. 31.1% in the MIS group, p=0.12).

Discussion

The surgical treatment of T4 colon cancer is challenging, regardless of whether the MIS or OP technique is deployed. Surgery for T4 colon cancer includes the en bloc resection of adjacent infiltrated structures. Surgeons with limited experience benefit from guidelines,²⁶ whereas more experienced colorectal surgeons have less trouble in decision-making during patient selection and changing the preoperative surgical strategy. Therefore, the practices of more experienced surgeons, such as those in this study, may deviate from the guideline-suggested paths. As a result, even though guidelines determine approximately similar clinical strategies, the approach can vary among different centers.

The crucial factor for conversion to OP is the degree of invasion into adjacent structures. Although there is no definitive written rule, its presence helps discriminate T4a tumor from T4b and is approached differently. Unfortunately, according to Feinberg et al.²⁷, the preoperative distinction between T3 and T4a tumors is complex, which makes the decision-making process of finding the optimal surgical strategy challenging.

Conversion to OP causes undesirable consequences. Conversion from MIS to OP methods offers several advantages, but it also carries the potential risk of conversion when opting for the laparoscopic method. Hence, we incorporated and examined these patients in the MIS group utilizing the intention-to-treat principle. Also, as stated by Klaver et al.²⁸, high conversion rates create a risk of disturbing outcomes in the case of intention-to-treat analysis, which was not the case in our sample. The conversion rate was 8.2%, which is in accordance with rates presented in the literature, which range from 7.6% to 18% (Liu et al.²⁹ 10.7%, Chan and Tan³⁰ 8.6%, Bretagnol and Leroy³¹ 18%, Kang et al.³² 7.6%, Kim et al.³³ 13.7%, COLOR Trial Group³⁴ 17%). Despite being in the normal range of the literature, the conversion rate is close to the lower border due to the high-level experience of our surgeons and surgical team and being a high-volume center. Preoperative preparation for conversion can be essential in the practice of MIS resection of T4 tumors. Informing operation room staff about possible conversion before the onset of surgery in cases with a higher risk of conversion is beneficial as it allows adequate surgical instrument preparation. In patients with a high risk of conversion, we routinely prepare to keep the surgical instruments for OP ready in the operating theatre during MIS, enabling prompt intervention in the case of an emergency.

Achieving high R0 resection rates is crucial in oncologic surgery, particularly for patients with T4 colorectal cancer, because R0 resection is considered one of the most critical factors affecting long-term survival.^35-38 In this study, the R0 resection rate was 100%, and the harvested lymph node number was ≥12, as suggested for appropriate staging in both the MIS and OP cases. These results are a measure of our surgical experience and our success in managing patients with colorectal cancer. Analyses of the intraoperative frozen section of all patients in our routine clinical practice are among the most critical factors in achieving a high R0 resection rate.

As a result of smaller incisions, laparoscopic surgery offers faster recovery and early mobilization, preventing complications of immobility, without any significant drawbacks. A shorter hospital stay is more comfortable for patients and may also decrease hospital-related complications. In this study, although the MIS group exhibited a shorter length of hospital stay compared with the OP group in patients with T4 colon tumors, the difference was not statistically significant after matching.

The distance from the vascular tie to the tumor epicenter is one of the parameters that can help to measure the quality of complete mesocolic excision.^39-44 This distance was found to be greater in the MIS group than in the OP group, without reaching statistical significance. This may indicate the quality of the MIS approach in reaching complete mesocolic excision, which is a crucial part of current oncologic colon surgery.

After MIS resection of T4 colon tumors, we found the 5-year OS and DFS rates to be 85% and 62.5%, respectively. This is in accordance with the data in the literature, where the 5-year OS and DFS rates range from 44.6% to 77.2% and 39.4% to 63.5%, respectively.^20,35,45,46 Our patients’ survival rates are close to the upper limits presented in the literature, which demonstrates the high quality of care in our center. According to our study, MIS has comparable long-term oncologic outcomes and does not increase morbidity and mortality. As pivotal elements in evaluating the oncological outcome, OS and DFS are essential parameters. Our results show that MIS offers 5-year OS and DFS rates that are comparable with OP.

Study Limitations

Our study has some limitations. First, it is conducted in a single institution. Second, it is a retrospective study, and there is a lack of randomization in the selection procedure because of its retrospective nature. When extracting messages, we focused on the applicability of the MIS to patients with T4 colon cancer.

Conclusion

This study demonstrated that if the tumor’s en bloc resection can be achieved, MIS should not be accepted as an absolute contraindication in T4 colon cancers, with its advantages of achieving oncologically acceptable results. The decision should be made individually based on patient characteristics and surgeons’ experience.

Ethics

Ethics Committee Approval: This study was approved by Koç University Institutional Board of Review (approval code: 2020.491.IRB1.181, date: 04.03.2021).

Informed Consent: All participants agreed to a written informed consent before their participation.

Authorship Contributions

Surgical and Medical Practices: İ.H.Ö., D.S.U., İ.F.A., S.Z., D.B., E.B., Concept: İ.H.Ö., E.B., E.Ö., A.R., D.B., E.B., Design: İ.H.Ö., E.B., E.Ö., A.R., D.B., E.B., Data Collection or Processing: S.N.K., A.D.K., S.S., M.Y., E.Ö., D.S.U., İ.F.A., S.Z., Analysis or Interpretation: İ.H.Ö., S.N.K., A.D.K., S.S., M.Y., E.B., E.Ö., D.S.U., İ.F.A., S.Z., A.R., Literature Search: İ.H.Ö., S.N.K., A.D.K., M.Y., Writing: İ.H.Ö., S.N.K., A.D.K., S.S., M.Y., E.B., E.Ö., D.S.U., İ.F.A., S.Z., A.R., D.B., E.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.