Distal margin distance in radical resection of locally advanced rectal cancer after neoadjuvant therapy

Abstract

Colorectal cancer has a high incidence and mortality rate in China, with the majority of cases being middle and low rectal cancer. Surgical intervention is currently the main treatment modality for locally advanced rectal cancer, with the common goal of improving oncological outcomes while preserving function. The controversy regarding the circumferential resection margin distance in rectal cancer surgery has been resolved. With the promotion of neoadjuvant therapy concepts and advancements in technology, treatment strategies have become more diverse. Following tumor downstaging, there is an increasing trend towards extending the safe distance of distal rectal margin. This provides more opportunities for patients with low rectal cancer to preserve their anal function. However, there is currently no consensus on the specific distance of distal resection margin.

In China, colorectal cancer ranks second in incidence and fourth in mortality. The incidence of rectal cancer is approximately twice that of colon cancer (1.5−2.0:1.0), with approximately 70% of cases being mid- to low-grade rectal cancer (1). Most rectal cancers in China are diagnosed at an advanced stage. Currently, total mesorectal excision (TME) is a standardized surgical procedure for locally advanced rectal cancer (2). With continuous improvements in the treatment of rectal cancer, it is important to not only enhance the oncological efficacy of radical treatments but also reduce the incidence of complications such as sexual and urinary dysfunctions and, wherever possible, to preserve anal function, thereby improving patient quality of life. This is particularly challenging for patients with low rectal cancer because avoiding a permanent abdominal stoma has been a difficult aspect of rectal cancer treatment. In sphincter-preserving surgeries, accurately controlling the safe distal margin (DM) distance from the tumor is critical.

Controversy and current status of DM in rectal cancer surgery

In rectal cancer surgery, the concept of margins broadly encompasses DM, proximal margin (PM), and circumferential resection margin (CRM) (2). A CRM greater than 1 mm is internationally accepted as a safe circumferential margin (3), a standard that has achieved consensus among scholars both domestically and abroad. However, the determination of a safe DM remains controversial (4-7). For colon cancer resection, based on the findings of Hohenberger and colleagues (8), a safe DM of at least 5 cm is recommended. The Miles operation has been adopted for locally advanced low rectal cancer in some medical centers around the world (below the peritoneal reflection) to ensure “reliable” radicality and sufficient DM to prevent recurrence. This approach often results in a permanent stoma, which is a deterrent for both physicians and patients.

Peking University People’s Hospital has conducted extensive research on sphincter-preserving surgery for low rectal cancer (9-12). We included clinical data from 309 patients who were diagnosed with low rectal cancer (with the lower edge of the tumor 3−6 cm from the anal margin) and who underwent radical surgery between January 1998 and December 2010. Patients were divided into two groups: the Dixon procedure group, with 158 patients, and the Miles procedure group, with 151 patients. The analysis indicated that the local recurrence rates and overall prognoses of the two groups were comparable (9). To date, there is no unified standard for the surgical DM in rectal cancer patients. Currently, most scholars in China believe that a minimum of 2 cm of DM should be ensured during low rectal cancer sphincter-preserving surgeries.

Impact of neoadjuvant therapy on DM in rectal cancer surgery

A considerable body of clinicopathological research suggests that rectal cancer infiltrates distally into the bowel wall to a lesser extent than colon cancer, with only approximately 2% of rectal cancer patients demonstrating infiltration beyond 2 cm distal to the bowel wall (13). This implies that approximately 98% of rectal cancer patients may not require resection with more than 2 cm of DM, potentially preserving more of the bowel and increasing the chances of sphincter preservation while maintaining oncological safe margins. The “2 cm” standard was established prior to the widespread adoption of neoadjuvant therapy (14). The current phase of incorporating neoadjuvant therapy into the overall treatment for rectal cancer has proven to be highly effective, with treated lesions demonstrating varying degrees of macroscopic shrinkage and pathological clearance, thereby increasing the distance between the distal end of the tumor and the anus (15).

The macroscopic DM is defined as the distance between the visible lesion or scar tissue and the distal tissue, while the microscopic DM is the distance between the furthest tumor cells and the distal tissue. Pathological studies (16-18) have shown that a DM less than 2 cm in diameter can still be considered safe following neoadjuvant therapy and radical rectal cancer surgery. To minimize errors between tumor and margin distances in routine pathological slices, Mezhir and colleagues (18) studied 103 surgical specimens from patients who underwent neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Pathological analysis of the entire specimen was performed with 5 mm continuous thick sections, and the distance of tumor tissue infiltration was examined distally. All specimens had negative distal margins, with 80% of the procedures being sphincter-preserving surgery. The median distance of distal tumor cell infiltration was 1 cm, with a 5-year disease-free survival rate of 86% and only one case of local recurrence. A meta-analysis (19) showed that for middle and low rectal cancer patients, a DM ≤1 or >1 cm had no significant impact on overall survival (OS), and a DM≤1 cm did not significantly affect the local recurrence rate in patients who received neoadjuvant therapy. However, for those who undergo surgery alone, a DM≤1 cm may increase the risk of local recurrence. Thus, these variables should be considered when selecting surgical patients with a DM≤1 cm. Özer (16) and Smith (17) also reported similar outcomes by observing that the distal infiltration distance of rectal cancer lesions in pathological sections after neoadjuvant therapy did not exceed 1 cm, which is related to the tumor stage.

Owing to the adoption of personalized medicine, there are concerns about the resection of previously tumor-filled areas that have regressed or clinically resolved after neoadjuvant therapy. Studies (20) have indicated that 37% of patients may have microscopic intramural lateral spread that is not visible to the naked eye; thus, reliable intraoperative assessment of negative resection margins may not be feasible. However, such intramural lateral spread did not have a significant impact on oncological outcomes in the present study, which may also be due to the limited number of patients included. Overall, neoadjuvant therapy effectively suppresses local tumor infiltration and lesion proliferation, reduces tumor size, and extends the effective DM for rectal cancer, enabling more patients with low rectal cancer to transit from resection with sphincter preservation to anus conservation.

Influence and controversy of neoadjuvant radiotherapy on surgical DM in rectal cancer surgery

Neoadjuvant chemoradiotherapy is currently the standard treatment for locally advanced rectal cancer (21), with studies indicating that neoadjuvant radiotherapy contributed to tumor downstaging, decreased local recurrence rates, and improved OS (22). Concurrently, radiotherapy can cause pelvic organ edema and rectal wall stiffening, which increases the difficulty of sphincter-preserving surgery for low rectal cancer, and radiation-induced damage does not dissipate in the short term but instead may worsen over time (23). Since the introduction of the Miles operation, the sphincter preservation rate for patients with low rectal cancer has increased from 30%−40% to 70%−75% (24,25) due to factors such as the implementation of neoadjuvant chemoradiotherapy, the advancement of laparoscopic techniques, and the development of rectal stapling devices. However, it is unclear whether neoadjuvant radiotherapy can increase the sphincter preservation rate for patients with low rectal cancer (25-27). The author believes that although neoadjuvant chemoradiotherapy can reduce the incidence of tumor downstaging, the edema and stiffening of the rectal wall resulting from postradiation damage directly lead to poorer tissue flexibility and extensibility, increasing the difficulty of excision during surgery and complicating the precise control of the desired DM. This may result in patients who could theoretically undergo sphincter-preserving surgery but ultimately have to undergo the Miles operation. The primary benefit of radiotherapy is the alleviation or suppression of the local pathological activity of rectal tumor tissues (28). With economic development and improvements in the public’s living standards, enhanced physical fitness allows for the tolerance of more intensive systemic comprehensive treatment. Therefore, to reduce the toxicity of radiotherapy while ensuring that local control rates and OS are not compromised, scholars both domestically and internationally have proposed single neoadjuvant chemotherapy (29,30) and single neoadjuvant immunotherapy (31), with significant clinical benefits observed. The UK’s GRECCAR-14 study (32) included patients with mid-to-low locally advanced rectal cancer (CRM≤2 mm, T3 with vascular invasion) who were receiving neoadjuvant induction intensified therapy (mFOLFIRINOX ×6). Patients who achieved a good response (>60% tumor reduction) were randomized into two groups: the control group (underwent surgery) and the experimental group (continued with standard chemoradiotherapy regimen following intensified induction therapy before surgery). This study aimed to determine whether patients who respond well to early neoadjuvant chemotherapy could be considered for personalized treatment plans to avoid radiotherapy toxicity or to directly avoid radical surgical resection to achieve clinical complete response, thus realizing the optimal toxicity-efficacy ratio. The authors await the final results. Unfortunately, the study did not include DM as an indicator in the analysis.

Remediation after positive margins following neoadjuvant therapy

Following neoadjuvant therapy, tumors may regress to various degrees, increasing the amount of tissues available for a safe margin. However, a small number of cancer cells may remain within the fibrotic tissue of the original lesion after shrinkage induced by neoadjuvant therapy (33). When sphincter-preserving surgery is performed for ultra-low rectal cancer, postoperative pathology can reveal a DM of less than 1 mm (R1), with R1 resection indicating a poor prognosis (34). Tilly et al. (34) compared the outcomes of patients with low rectal cancer who underwent unplanned R1 resection after neoadjuvant therapy to those with R0 resections. The R1 resection group had a worse prognosis, but the proportion of purely local recurrences was less than 1%, and no significant difference in local recurrence rates between the two groups was observed. This suggests that poorer tumor prognosis and aggressive biological behavior are related and that remedial measures following R1 resection should focus on systemic therapy. Denost et al. (35) reached similar conclusions. Some centers consider intraoperative radiotherapy as an adjunctive treatment for potential R1 or confirmed R1 resections to minimize the possibility of local recurrence as much as possible (36).

There is no consensus on the positive management of distal resection margins for radical rectal cancer after neoadjuvant therapy (37). In some medical centers, salvage surgery is recommended if the DM=0 mm, and if the patient refuses to undergo salvage surgery, postoperative adjuvant chemoradiotherapy is recommended after discussion amongst the members of the multidisciplinary treatment (MDT), such as DM (0−1 mm), and in some medical centers, R1 patients with T1/T2, a good degree of differentiation and no nerve or vascular invasion, postoperative adjuvant therapy is not recommended due to low systemic invasiveness, and salvage surgery is preferred.

Dilemma of precise DM in context of neoadjuvant therapy

In the context of neoadjuvant therapy for rectal cancer surgery, there is a trend toward a reduction in the safe DM, but the specific margin distance remains undefined. Most studies on the DM in locally advanced rectal cancer surgery are retrospective and not high-quality prospective clinical research. The main way to determine the surgical margin of rectal cancer patients is through preoperative imaging, colonoscopy and magnetic resonance imaging. During the procedure, the surgeon’s experience is combined with digital rectal examination and surgical methods. Postoperative pathological examination, including negative pathology, tumor budding and some molecular pathological indicators, should be confirmed.

Current clinical challenges include predicting the intraoperative DM based on preoperative indicators and accurately detecting the safe DM during surgery. In the majority of research, DM measurements are based on formalin-fixed pathological samples. The length measured before the specimen was detached, after resection, and after fixation tended to decrease successively. The degree of shrinkage after fixation varies among different tumor regression grades after neoadjuvant therapy (38); thus, the actual length of the resected tumor should be greater than the final pathological length (39). The extent of tumor spread to distal tissues is related to the tumor location, stage, molecular subtype, and other factors (40). The most common clinical method for determining the presence of residual tumor is intraoperative digital palpation. However, lesions that remain after neoadjuvant therapy can have a heterogeneous and unpredictable dispersion pattern (41), increasing the likelihood of positive margins with this method. Considering the varying degrees of tumor regression after neoadjuvant therapy, it is difficult to precisely control the optimal margin distance intraoperatively. Banu et al. (42) suggested endoscopic marking of the distal edge of the tumor with permanent ink prior to neoadjuvant therapy to obtain a safe distal margin distance. Georvasili et al. (43) utilized an intraoperative flow cytometer to analyze the rectal tumor and margin tissues and evaluated the status of the tumor edge within a total operation time of 10 min. This provides an auxiliary means to preserve more distal rectal tissues during surgery, but it has not yet been widely applied in clinical practice. The premise of precise treatment requires accurate preoperative imaging staging, which currently overestimates the postoperative pathological stage in some patients (44). Collaboration with other disciplines, such as radiology, endoscopy, oncology, and radiation therapy (MDT), employing magnifying endoscopy, high-quality preoperative endoscopic biopsy, and intraoperative margin frozen section examination can compensate for deviations in preoperative examinations to some extent (45). In the era of big data, artificial intelligence, and precision medicine (46), stratified selection of different types of patients for individualized treatment is a trend, shifting from past empirical treatment to precise DM planned treatment.

Conclusions and perspective

Neoadjuvant therapy combined with TME is currently the standard treatment protocol for locally advanced rectal cancer. However, the specific extent of DM remains controversial, especially for patients with low rectal cancer, where the ability to preserve the anus intraoperatively is directly determined by the extent of DM resection. Neoadjuvant therapy effectively downstages the tumor, reducing the incidence of micrometastases around the tumor and creating a safe surgical margin and a viable tissue resection plane. This decreases the difficulty of the operation, increases the rate of sphincter preservation, and simultaneously reduces local recurrence rate and improves long-term survival. With the diversification and iteration of neoadjuvant treatment modalities, the development of MDT, and the advent of high-tech products such as naked-eye 3D and ultrahigh-definition 4K laparoscopic systems, da Vinci robotic systems, and tumor molecular typing tests, there is now a theoretical basis and technical assurance for preserving more distal rectal tissue during radical surgery for low rectal cancer. Along with advancements in treatment philosophies, the future of rectal cancer treatment is evolving towards diversification and precision individualization. While ensuring a safe surgical margin, this approach also considers the preservation of the patient’s rectoanal organ function, aiming to enhance the patient’s quality of life.