Peritoneal metastatic colorectal cancer (pmCRC) is common and has been considered as the terminal stage. The theory of "seed and soil" and "oligometastasis" are the acknowledged hypotheses of pathogenesis of pmCRC. In recent years, the molecular mechanism related to pmCRC has been deeply researched. We realize that the formation of peritoneal metastasis, from detachment of cells from primary tumor to mesothelial adhesion and invasion, depends on the interplay of multiple molecules. Various components of tumor microenvironment also work as regulators in this process. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been widely used in clinical practice as an established treatment for pmCRC. Besides systemic chemotherapy, targeted and immunotherapeutic drugs are also increasingly used to improve prognosis. This article reviews the molecular mechanisms and treatment strategies related to pmCRC.
Humans ; Colorectal Neoplasms/pathology* ; Combined Modality Therapy ; Peritoneal Neoplasms/secondary* ; Hyperthermia, Induced ; Colonic Neoplasms/therapy* ; Rectal Neoplasms/therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Prognosis ; Cytoreduction Surgical Procedures ; Survival Rate ; Tumor Microenvironment

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged

Objective: To methodically assess the clinical effectiveness and safety of robot-assisted total rectal mesenteric resection (RTME), laparoscopic-assisted total rectal mesenteric resection (laTME), and transanal total rectal mesenteric resection (taTME). Methods: A computer search was conducted on PubMed, Embase, Cochrane Library, and Ovid databases to identify English-language reports published between January 2017 and January 2022 that compared the clinical efficacy of the three surgical procedures of RTME, laTME, and taTME. The quality of the studies was evaluated using the NOS and JADAD scales for retrospective cohort studies and randomized controlled trials, respectively. Direct meta-analysis and reticulated meta-analysis were performed using Review Manager software and R software, respectively. Results: Twenty-nine publications comprising 8,339 patients with rectal cancer were ultimately included. The direct meta-analysis indicated that the length of hospital stay was longer after RTME than after taTME, whereas according to the reticulated meta-analysis the length of hospital stay was shorter after taTME than after laTME (MD=-0.86, 95%CI: -1.70 to -0.096, P=0.036). Moreover, the incidence of anastomotic leak was lower after taTME than after RTME (OR=0.60, 95%CI: 0.39 to 0.91, P=0.018). The incidence of intestinal obstruction was also lower after taTME than after RTME (OR=0.55, 95%CI: 0.31 to 0.94, P=0.037). All of these differences were statistically significant (all P<0.05). There were no statistically significant differences between the three surgical procedures regarding the number of lymph nodes cleared, length of the inferior rectal margin, or rate of positive circumferential margins (all P>0.05). An inconsistency test using nodal analysis revealed no statistically significant differences between the results of direct and indirect comparisons of the six outcome indicators (all P>0.05). Furthermore, we detected no significant overall inconsistency between direct and indirect evidence. Conclusion: taTME has advantages over RTME and laTME, in terms of radical and surgical short-term outcomes in patients with rectal cancer.
Humans ; Robotics ; Robotic Surgical Procedures/adverse effects* ; Network Meta-Analysis ; Retrospective Studies ; Postoperative Complications/etiology* ; Transanal Endoscopic Surgery/methods* ; Rectum/surgery* ; Rectal Neoplasms/pathology* ; Laparoscopy/methods* ; Treatment Outcome

Intersphincteric resection (ISR) is the ultimate sphincter-preserving surgical technique for low rectal cancer. To promote the standardized implementation of ISR, this review discusses the important issues regarding the clinical application of ISR with reference to the latest Chinese expert consensus on ISR. In terms of ISR-related pelvic anatomy of the rectum/anal canal, hiatal ligament is not identical with the anococcygeal ligament. At the level where the rectourethralis muscle continuously extends to the posteroinferior area of the membranous urethra from the rectum, the neurovascular bundle is identified between the posterior edge of rectourethralis muscle and the anterior edge of the longitudinal muscle of the rectum. This knowledge is crucial to detect the anterior dissection plane during ISR at the levator hiatus level. The indication criteria for ISR included: (1) stage I early low rectal cancer; (2) stage II-III low rectal cancer undergoing neoadjuvant treatment, and supra-anal tumors and juxta-anal tumors of stage ycT3NxM0, or intra-anal tumors of stage ycT2NxM0. However, signet ring cell carcinoma, mucinous adenocarcinoma and undifferentiated carcinoma should be contraindicated to ISR. For locally advanced low rectal cancer (especially anteriorly located tumor), neoadjuvant treatment should be carried out in a standardized manner. However, it should be recognized that neoadjuvant chemoradiotherapy was a risk factor for poor anal function after ISR. For surgical approaches for ISR, including transanal, transabdominal, and transanal transabdominal approaches, the choice should be based on oncological safety and functional consequences. While ensuring the negative margin, maximal preservation of rectal walls and anal canal contributs to better postoperative anorectal function. Careful attention must be paid to complications regarding ISR, with special focus on the anastomotic complications. The incidence of low anterior resection syndrome (LARS) was higher than 40%. However, this issue is often neglected by clinicians. Thus, management and rehabilitation strategies for LARS with longer follow-ups were required.
Humans ; Rectal Neoplasms/pathology* ; Postoperative Complications ; Laparoscopy/methods* ; Anal Canal/pathology* ; Anus Neoplasms/pathology* ; Anus Diseases/surgery* ; Low Anterior Resection Syndrome ; Carcinoma, Signet Ring Cell/pathology* ; Treatment Outcome

Objective: To compare the long-term outcomes of intersphincteric (trans-internal and external) sphincter resection (ISR) and abdominoperineal proctocolectomy (APR) for low-grade rectal cancer. Methods: We used a meta-analytic approach to compare these procedures . Published reports comparing ISR and APR for low rectal cancer in Pubmed, Medline, EMBASE and Cochrane, China Knowledge Network (CNKI), China Biomedical Literature Database, and Vipers databases between January 2005 and January 2023 were searched and those meeting the eligibility criteria were selected for extraction of data for analysis. Inclusion criteria were as follows: (1) all reports comparing ISR and APR for low rectal cancer before January 2023; and (2) prospective randomized controlled studies or well-designed cohort studies. Exclusion criteria were as follows: (1) full text not available; (2) duplicate publications, missing primary outcome indicators, and unknown data; and (3) invalid statistical analysis. Results: Sixteen studies with 2498 patients were included in this study. Compared with the APR group, patients in the ISR group were relatively younger (weighted mean difference [WMD]=-1.82, 95%CI=-2.94 to -0.70, P=0.01), had tumors farther from the anal verge (WMD=0.43, 95%CI=0.18 to 0.67, P<0.01), and lower pathological T-stage (T3-4 stage: OR=0.54, 95%CI=0.36 to 0.81, P<0.01). In contrast, there were no statistically significant differences between the two groups in gender (P=0.78), body mass index (P=0.77), or pathological N stage (P=0.09). Compared with the APR group, patients in the ISR group had a lower rate of postoperative complications (OR=0.77, 95%CI=0.60 to 0.99, P=0.04), shorter hospital stay (WMD=-4.30, 95%CI=-7.07 to -1.53, P<0.01), higher 5-year overall survival (HR=0.54, 95%CI=0.33 to 0.88, P=0.01), and higher 5-year disease-free survival (HR=0.65, 95%CI=0.47 to 0.90, P<0.01). Five-year locoregional failure (HR=0.66, 95%CI=0.40 to 1.10, P=0.11) and time to surgery (WMD=-9.71, 95%CI=-41.89 to 22.47, P=0.55) did not differ significantly between the two groups. Conclusion: ISR is a safe and effective alternative to APR for early-stage low-grade rectal cancer.
Humans ; Prospective Studies ; Rectal Neoplasms/pathology* ; Rectum/surgery* ; Proctectomy ; Anal Canal/pathology* ; Treatment Outcome

Because the classification system of radical surgery for rectal cancer has not been established, it is impossible to select the appropriate surgical method according to the clinical stage of the tumor. In this paper, we explained the theory of " four fasciae and three spaces " of pelvic membrane anatomy and then combined this theory with the membrane anatomical basis of Querleu-Morrow classification for radical cervical cancer resection. Based on this theory and the membrane anatomy of Querleu-Morrow classification of radical cervical cancer resection, we proposed a new classification system of radical rectal cancer surgery based on membrane anatomy according to the lateral lymph node dissection range of the rectum. This system classifies the surgery into four types (ABCD) and defines corresponding subtypes based on whether the autonomic nerve was preserved. Among them, type A surgery is total mesorectal excision (TME) with urogenital fascia preservation, type B surgery is classical TME, type C surgery is extended TME, and type D surgery is lateral extended resection. This classification system unifies the anatomical terminology of the pelvic membrane, validates the feasibility of using the " four fasciae and three fascial spaces " theory to classify rectal cancer surgery, and lays the theoretical foundation for the future development of a unified and standardized classification of radical pelvic tumor surgery.
Female ; Humans ; Uterine Cervical Neoplasms ; Rectal Neoplasms/pathology* ; Rectum/anatomy & histology* ; Pelvis/innervation* ; Proctectomy

After the implementation of neoadjuvant chemoradiotherapy and total mesorectal excision, lateral local recurrence becomes the major type of local recurrence after surgery in rectal cancer. Most lateral recurrence develops from enlarged lateral lymph nodes on an initial imaging study. Evidence is accumulating to support the combined use of neoadjuvant chemoradiotherapy and lateral lymph node dissection. The accuracy of diagnosing lateral lymph node metastasis remains poor. The size of lateral lymph nodes is still the most commonly used variable with the most consistent accuracy and the cut-off value ranging from 5 to 8 mm on short axis. The morphological features, differentiation of the primary tumor, circumferential margin, extramural venous invasion, and response to chemoradiotherapy are among other risk factors to predict lateral lymph node metastasis. Planning multiple disciplinary treatment strategies for patients with suspected nodes must consider both the risk of local recurrence and distant metastasis. Total neoadjuvant chemoradiotherapy is the most promising regimen for patients with a high risk of recurrence. Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy seemingly improves the local control of positive lateral nodes. However, its impact on the safety of surgery in patients with no response to the treatment or regrowth of lateral nodes remains unclear. For patients with smaller nodes below the cut-off value or shrunken nodes after treatment, a close follow-up strategy must be performed to detect the recurrence early and perform a salvage surgery. For patients with stratified lateral lymph node metastasis risks, plans containing different multiple disciplinary treatments must be carefully designed for long-term survival and better quality of life.
Humans ; Lymphatic Metastasis/pathology* ; Quality of Life ; Neoplasm Staging ; Retrospective Studies ; Lymph Nodes/pathology* ; Rectal Neoplasms/surgery* ; Lymph Node Excision/methods* ; Neoadjuvant Therapy/methods* ; Neoplasm Recurrence, Local/surgery*

Objective: To investigate the factors influencing tumor-specific survival of early-onset locally advanced rectal cancer. Methods: All-age patients with primary locally advanced rectal cancer from the Surveillance, Epidemiology, and End Results (SEER) database (2010 to 2019) were included in this study. Early- and late-onset locally advanced rectal cancer was defined according to age of 50 years at diagnosis. Early-onset locally advanced rectal cancer was divided into five age groups for subgroup analyses. Age, sex, tumor-specific survival time and survival status of patients at diagnosis, pathological grade, TNM stage, perineural invasion, tumor deposits, tumor size, pretreatment CEA , radiotherapy, chemotherapy, and number of lymph node dissections were included. Progression-free survival (PFS) was analyzed and compared between patients with early- and late-onset rectal cancer. Results: A total of 5,048 patients with locally advanced rectal cancer were included in the study (aged 27-70 years): 1,290 (25.55%) patients with early-onset rectal cancer and 3,758 (74.45%) patients with late-onset rectal cancer. Patients with early-onset rectal cancer had a higher rate of perineural invasion (P<0.001), more positive lymph nodes dissected (P<0.001), higher positive lymph node ratios (P<0.001), and a higher proportion receiving preoperative radiotherapy (P=0.002). Patients with early-onset rectal cancer had slightly better short-term survival than those with late-onset rectal cancer (median (IQR ): 54 (33-83) vs 50 (31-79) months, χ²=5.192, P=0.023). Multivariate Cox regression for all patients with locally advanced rectal cancer showed that age (P=0.008), grade of tumor differentiation (P=0.002), pretreatment CEA (P=0.008), perineural invasion (P=0.021), positive number (P=0.004) and positive ratio (P=0.001) of dissected lymph nodes, and sequence of surgery and radiotherapy (P=0.005) influenced PFS. This suggests that the Cox regression results for all patients may not be applicable to patients with early-onset cancer. Cox analysis showed tumor differentiation grade (patients with low differentiation had a higher risk of death, P=0.027), TNM stage (stage III patients had a higher risk of death, P=0.025), T stage (higher risk of death in stage T4, P<0.001), pretreatment CEA (P=0.002), perineural invasion (P<0.001), tumor deposits (P=0.005), number of dissected lymph nodes (patients with removal of 12-20 lymph nodes had a lower risk of death, P<0.001), and positive number of dissected lymph nodes (P<0.001) were independent factors influencing PFS of patients with early-onset locally advanced rectal cancer. Conclusion: Patients with early-onset locally advanced rectal cancer were more likely to have adverse prognostic factors, but an adequate number of lymph node dissections (12-20) resulted in better survival outcomes.
Humans ; Prognosis ; Retrospective Studies ; Neoplasm Staging ; Extranodal Extension/pathology* ; Survival Analysis ; Rectal Neoplasms/surgery* ; Lymph Nodes/pathology*

The treatment of locally advanced rectal cancer (LARC) or locally recurrent rectal cancer (LRRC) has been a difficulty and challenge in the field of advanced rectal cancer, while pelvic exenteration (PE), as an important way to potentially achieve radical treatment of LARC and LRRC, has been shown to significantly improve the long-term prognosis of patients. The implementation of PE surgery requires precise assessment of the extent of invasion of LARC or LRRC and adequate preoperative preparation through multidisciplinary consultation before surgery. The lateral pelvis involves numerous tissues, blood vessels, and nerves, and resection is most difficult, and the ureteral and Marcille triangle approaches are recommended; while the supine transabdominal approach combined with intraoperative change to the prone jacket position facilitates adequate exposure of the surgical field and enables precise overall resection of the bony pelvis and pelvic floor muscle groups invaded by the tumor. Empty pelvic syndrome has always been an major problem to be solved during PE. The application of extracellular matrix biological mesh to reconstruct pelvic floor defects and isolate the abdominopelvic cavity is expected to reduce postoperative pelvic floor related complications. Reconstruction of the urinary system and important vessels after PE is essential, and the selection of appropriate reconstruction methods helps to improve the patient's postoperative quality of life, while more new methods are also being continuously explored.
Humans ; Pelvic Exenteration/adverse effects* ; Quality of Life ; Neoplasm Recurrence, Local/surgery* ; Pelvis/pathology* ; Postoperative Complications/etiology* ; Rectal Neoplasms/pathology* ; Retrospective Studies ; Treatment Outcome

Objective: To investigate the value of reconstruction of pelvic floor with biological products to prevent and treat empty pelvic syndrome after pelvic exenteration (PE) for locally advanced or recurrent rectal cancer. Methods: This was a descriptive study of data of 56 patients with locally advanced or locally recurrent rectal cancer without or with limited extra-pelvic metastases who had undergone PE and pelvic floor reconstruction using basement membrane biologic products to separate the abdominal and pelvic cavities in the Department of Anorectal Surgery of the Second Affiliated Hospital of Naval Military Medical University from November 2021 to May 2022. The extent of surgery was divided into two categories: mainly inside the pelvis (41 patients) and including pelvic wall resection (15 patients). In all procedures, basement membrane biologic products were used to reconstruct the pelvic floor and separate the abdominal and pelvic cavities. The procedures included a transperitoneal approach, in which biologic products were used to cover the retroperitoneal defect and the pelvic entrance from the Treitz ligament to the sacral promontory and sutured to the lateral peritoneum, the peritoneal margin of the retained organs in the anterior pelvis, or the pubic arch and pubic symphysis; and a sacrococcygeal approach in which biologic products were used to reconstruct the defect in the pelvic muscle-sacral plane. Variables assessed included patients' baseline information (including sex, age, history of preoperative radiotherapy, recurrence or primary, and extra-pelvic metastases), surgery-related variables (including extent of organ resection, operative time, intraoperative bleeding, and tissue restoration), post-operative recovery (time to recovery of bowel function and time to recovery from empty pelvic syndrome), complications, and findings on follow-up. Postoperative complications were graded using the Clavien-Dindo classification. Results: The median age of the 41 patients whose surgery was mainly inside the pelvis was 57 (31-82) years. The patients comprised 25 men and 16 women. Of these 41 patients, 23 had locally advanced disease and 18 had locally recurrent disease; 32 had a history of chemotherapy/immunotherapy/targeted therapy and 24 of radiation therapy. Among these patients, the median operative time, median intraoperative bleeding, median time to recovery of bowel function, and median time to resolution of empty pelvic syndrome were 440 (240-1020) minutes, 650 (200-4000) ml, 3 (1-9) days, and 14 (5-105) days, respectively. As for postoperative complications, 37 patients had Clavien-Dindo < grade III and four had ≥ grade III complications. One patient died of multiple organ failure 7 days after surgery, two underwent second surgeries because of massive bleeding from their pelvic floor wounds, and one was successfully resuscitated from respiratory failure. In contrast, the median age of the 15 patients whose procedure included combined pelvic and pelvic wall resection was 61 (43-76) years, they comprised eight men and seven women, four had locally advanced disease and 11 had locally recurrent disease. All had a history of chemotherapy/ immunotherapy and 13 had a history of radiation therapy. The median operative time, median intraoperative bleeding, median time to recovery of bowel function, and median time to relief of empty pelvic syndrome were 600 (360-960) minutes, 1600 (400-4000) ml, 3 (2-7) days, and 68 (7-120) days, respectively, in this subgroup of patients. Twelve of these patients had Clavien-Dindo < grade III and three had ≥ grade III postoperative complications. Follow-up was until 31 October 2022 or death; the median follow-up time was 9 (5-12) months. One patient in this group died 3 months after surgery because of rapid tumor progression. The remaining 54 patients have survived to date and no local recurrences have been detected at the surgical site. Conclusion: The use of basement membrane biologic products for pelvic floor reconstruction and separation of the abdominal and pelvic cavities during PE for locally advanced or recurrent rectal cancer is safe, effective, and feasible. It improves the perioperative safety of PE and warrants more implementation.
Male ; Humans ; Female ; Middle Aged ; Aged ; Aged, 80 and over ; Pelvic Exenteration ; Biological Products/therapeutic use* ; Pelvic Floor/pathology* ; Neoplasm Recurrence, Local/surgery* ; Rectal Neoplasms/surgery* ; Postoperative Complications/prevention & control* ; Retrospective Studies ; Treatment Outcome