TYPE Opinion PUBLISHED 14 October 2022 DOI 10.3389/fonc.2022.994720 Low anterior resection OPEN ACCESS syndrome: An unavoidable price EDITED BY Ian Daniels FRCS, Royal Devon and Exeter Hospital, to pay to preserve the rectum? United Kingdom REVIEWED BY Franco Marinello 1*, Gianluca Pellino 1,2 and Eloy Espı́n-Basany 1 Audrius Dulskas, National Cancer Institute 1 Colorectal Surgery Unit – Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, (Lithuania), Lithuania Barcelona, Spain, 2 Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy *CORRESPONDENCE Franco Marinello franco.marinello@vallhebron.cat SPECIALTY SECTION This article was submitted to Gastrointestinal Cancers: KEYWORDS Colorectal Cancer, a section of the journal LARS – low anterior resektion syndrome, rectal cancer, complication, sacral Frontiers in Oncology neuromodulation, rectal surgery RECEIVED 15 July 2022 ACCEPTED 23 August 2022 PUBLISHED 14 October 2022 CITATION Marinello F, Pellino G and Espı´n-Basany E (2022) Low anterior resection syndrome: An unavoidable price to pay to preserve the rectum? Introduction Front. Oncol. 12:994720. doi: 10.3389/fonc.2022.994720 Rectal cancer surgery has radically evolved over the past 30 years. Multimodal COPYRIGHT treatment together with consistent use of total mesorectal excision (TME) has improved © 2022 Marinello, Pellino and the oncological outcomes (1–3) and led to increased rates of anal sphincters preservation. Espı´n-Basany. This is an open-access article distributed under the terms of In turn, this has resulted in higher incidence of functional disorders, including LARS the Creative Commons Attribution (Low Anterior Resection Syndrome), which are often difficult to manage. License (CC BY). The use, distribution or reproduction in other forums is The etiology of LARS is multifactorial, but the loss of the rectum is considered as the permitted, provided the original ultimate explanation. Other mechanisms which can explain LARS are a direct lesion of the author(s) and the copyright owner(s) anal sphincters, damage of the nerves involved in the defecation with anal-rectal inhibitory are credited and that the original publication in this journal is cited, in reflex annulment, decrease of the distensibility and denervation of colonic plasty, and use of accordance with accepted academic preoperative radiotherapy which might reduce the elasticity of the tissues (4, 5). Also, practice. No use, distribution or reproduction is permitted which does patients who had had a diverting ileostomy are at twice-fold risk of LARS (6). not comply with these terms. LARS includes a wide constellation of symptoms such as fecal incontinence, urgency, stool clustering and fragmentation. Many patients also complain of urinary and sexual dysfunction (7, 8). Nevertheless, the main affection of patients who suffer LARS is a high level of unproductive fecal stool incidents which can be reported to as clustering and fragmentation, fecal urgency or a mixed pattern. Dysfunction translates into impairment of patients’ daily activities that end up in “toilet-dependence” and deterioration of their quality of life, even in the long-term (9, 10). These concerns have motivated the development of a new LARS Patient-Reported Outcome Measure tool that includes symptoms and consequences (11). Frontiers in Oncology 01 frontiersin.org Marinello et al. 10.3389/fonc.2022.994720 Preventing or minimizing the impact patients, the good results of high fiber intake in reducing the odds of fecal incontinence in the general population (15), or the of LARS use of anti-diarrheal agents such as loperamide if necessary, can also apply to LARS. The authors also recommend and instruct Since LARS is multifactorial, it is almost impossible to avoid patients – at an early stage after reconstruction – to achieve a it in many patients. The authors strongly recommend having a self-management control, changing their dietary or medication detailed preoperative discussion of potential bowel, urinary and habits according to their symptoms. sexual disorders after resection, and to capture it in the Pelvic floor rehabilitation is aimed to restore muscular respective informed consents. This is especially relevant in strength and enhance pelvic floor contractions to ensure a better those cases who require an ultra-low anastomosis to ensure defecation coordination, and it has shown positive outcomes (16). transit restauration, resulting in a high risk of LARS Also, biofeedback and balloon rectal distension can improve (neo) development. The authors believe that proper information to rectal capacity, maximum anal resting and squeeze pressure (17). patients might tip the balance to an abdominoperineal resection. Percutaneous tibial nerve stimulation (PTNS) can reduce urgency In order to prevent the surge of functional disorders, episodes in LARS patients compared to sham stimulation (18). A surgeons have tried different sorts of reconstructions such as recent pilot study investigating the role of acupuncture in LARS colonic j-pouch, side-to-end colorectal anastomosis, or also showed positive results in a small series of patients (19) The coloplasty. However, neorectal reservoirs have only showed authors believe that a comprehensive rehabilitation program, better outcomes regarding stool fragmentation in the first 18 including combined pelvic floor physiotherapy, biofeedback and months with no further benefit beyond this point (12). PTNS, can be useful in some patients affected by LARS. However, In order to minimize LARS, surgeons must raise awareness treatment adherence is key to maintain better outcomes and many before and immediately after rectal resection to identify bowel of these patients who have suffered from prolonged visits to the disorders and start treatment timely, since many of the hospital and different treatments might not adhere. symptoms are underreported. Concerning this aspect, the The use of transanal irrigation (TAI) has gained popularity in BOREAL program for patients following TME resection has the non-conservative management of LARS, with very promising recently been published (13). This path consists of a series of results. This technique provides a mechanical flush of the colon stepwise measures determined after several postoperative with warm water to remove feces with defecation-free days. The assessments of LARS and continence scores over a 12-month good results of TAI in patients with spinal cord injuries have been period. Patients are escalated to different treatments based on replicated in patients with LARS in terms of compliance, bowel routine check-ups at 3, 6, 9 and 12 months, starting from function and quality of life, with significant reduction of in the antidiarrheal medication, and progressing to laxative bulking number of daily movements (7 to 1) and in median LARS score agents, pelvic floor physiotherapy, transanal irrigations, and (35 to 12) with a short follow-up of 6 months (20, 21). It has also sacral neuromodulation. The results showed that the majority been reported that early institution of TAI (after one month of of patients improved with the baseline treatment, with under colorectal reconstruction or ileostomy closure) showed better 15% of progression from conservative measures to further results compared with patients on supportive therapy only. actions at 12 months with an overall compliance of 72.9% (9). However, time availability for defecation is a vital requisite for This study suggested that LARS might need a comprehensive successful results after TAI, which can rise to 45 minutes per and routine evaluation in order to adjust/escalate treatment. session at 3 months (22). This required evacuation time, Symptoms might ameliorate throughout the first year of combined with the fact that TAI may stop providing benefits if reconstruction (14), but the authors of the current overview suspended, represent the “Achilles heel” of the technique. At the consider that some of this improvement might just be patient author’s Institution, patients are strongly encouraged to try TAI if adaptation to their new bowel movements, justifying the need conservative treatment fails, especially those who mainly for an early action. complain about clustering and fragmentation. In some cases, the introduction of total neoadjuvant therapy Sacral neuromodulation (SNM) has also been proposed to (TNT) with consolidation radiotherapy, associated to local palliate symptoms associated with rectal resection after the excision or a “watch and wait” regime, might reduce the optimal results reported in the treatment of fecal incontinence recommendation for rectal resection and potential LARS. (23). According to a recent systematic review, including 114 patients, the overall success rate was 83.30% (24). Despite these promising results, the retrospective nature of the studies Available treatments for LARS included in this review, the lack of control group, and the small numbers of patients included in each study, generated As any other functional disorder, conservative management high heterogeneity and made it difficult to draw definitive should be introduced as a first step. Even though there is little conclusions. A randomized, cross-over, multicentric trial to evidence that dietary modifications are effective for LARS assess the efficacy of SNM in major LARS (SANLARS Trial Frontiers in Oncology 02 frontiersin.org Marinello et al. 10.3389/fonc.2022.994720 NCT03598231) has recently been terminated, and the data are schemes, some patients could avoid systematic preoperative currently being analyzed and could provide useful information radiotherapy with the potential of diminishing LARS. For for the use of this technique. The mechanism of action for example, the use of selective consolidation radiotherapy based which SNM might work in LARS is still unclear, especially on tumor response after induction neoadjuvant chemotherapy because there is no (or almost none) rectum. In a recent study (PROSPECT trial – Clinicaltrials.gov NCT01515787) might be on colonic motility, a significant reduction in the sigmoid beneficial in postoperative bowel function. The introduction of cyclic motor pattern has been observed in patients with immunotherapy in locally advanced rectal cancer, which targets LARS compared to healthy adults (25). This pattern, which specific gene changes might also allow to use radiotherapy more may act as a brake helping to control normal bowel continence, selectively, thereby improving bowel function. can be initiated by SNM (26, 27). SNM is a two-stage procedure Also, accurate rectal anatomy definition at MRI scans can consisting of a test phase with a lead and a subsequent contribute to a better indication to preoperative radiotherapy implantation of a generator in those patients in whom a (31). Since the use of preoperative radiotherapy is one of the good clinical response is observed. The authors have main factors to perform a protective stoma, its selective use experienced that even though the lead implantation can be might reduce the rate of diverting stomas after TME. On the technically demanding due to the fibrosis in the sacral tissues other hand, some patients with non-locally advanced rectal induced by radiotherapy and surgical changes, it is safe in this cancers might be offered an organ-sparing approach after population of patients. Since SNM is a surgical technique, it has preoperative chemoradiation. Further research might be been settled in a higher step in the treatment ladder of LARS needed to assess the role of transanal surgery platforms and (13, 28, 29). The authors would suggest, however, that since it is techniques on subsequent faecal function after minimally minimally invasive and performed under an ambulatory basis, invasive removal of transanal lesions (32). it could be offered to patients who prefer it to TAI. However, The systematic high ligation of the inferior mesenteric artery since LARS presents with two broad patterns (fecal (IMA) might be responsible of the onset of autonomic incontinence, clustering, or a combined syndrome), the best dysfunction which might translate in longer colonic transit candidates that might benefit from SNM or TAI, have not been below the sigmoid colon, decreased propagated colonic clearly identified yet. Besides, one must not forget that LARS contractions and increased spastic minor contractions (33). might involve extra-intestinal symptoms such as urinary Since the oncological outcomes are similar comparing low or incontinence and sexual dysfunction. Since SNM is a high IMA ligation (34), some patients might benefit from low multidimensional approach to pelvic disorders, it might be ligation, even though the real risk of developing LARS with high- useful to palliate other non-intestinal symptoms in LARS, even ligation remains unclear and in some patients is mandatory to though further research should be done in this direction. allow a tension-free colo-anal anastomosis. Lastly, patients can be offered a definitive stoma. It is has Additional aspects to consider in terms of LARS research been reported that around 6% may end up with a permanent include optimization of body composition and general health ostomy due to LARS (30), even though this figure might not status of patients, as well as the volume of operating surgeons and match patients’ real feelings and might be underestimated. Since hospitals on subsequent LARS development. Obese patients have many LARS patients had lived with an ileostomy after rectal been reported to be at increased risk of complications following resection, many express the desire to go back to the “non-toilet- surgery for malignant gastrointestinal diseases (35), and morbidly dependent” status that stomas provide. The authors tend to wait obese patients have higher risk of LARS (36). A higher proportion for at least one or two years and offer a colostomy after failure of of elderly patients with rectal cancer is being offered restorative TAI and/or SNM. surgical procedures, but frailty is frequent if proper assessment tools are utilized (37). It is therefore of outmost importance to adequately assess and prepare patients ahead of surgery, and to Discussion: Considerations to start identify those who might be better suited for a colostomy, in order focusing and future directions to further reduce the risk of LARS and subsequent complications. Lastly, consistent data have been suggested that rectal cancer Acknowledgment of LARS has risen in the last decade, but treatment performed in referral centers is associated with reduced surgeons need to keep focusing on trying to prevent, ameliorate anastomotic leaks and complications (38, 39). Future studies or palliate it. Besides the importance of performing an accurate should address if hospital and/or surgeon caseload can influence and adequate technique of proctectomy and reconstruction, the subsequent risk of LARS. additional factors, e.g., avoiding the over-use preoperative There is increasing awareness among colorectal surgeons radiotherapy, associated with higher risk of LARS after TME about functional outcomes after rectal resection, and many (10), are important. With new neoadjuvant chemotherapy patients have started to seek out for help. Fortunately, there Frontiers in Oncology 03 frontiersin.org Marinello et al. 10.3389/fonc.2022.994720 are different therapies to palliate LARS, but a comprehensive should be included in the assessment of patients after management algorithm with strong recommendations cannot be rectal surgery. provided, due to the lack of high-quality data. Therefore, it is Functional impairment is an almost constant finding after imperative to set patients’ expectations for any therapy and TME surgery. An improvement in information to patients, establish a shared decision making with them. The current developing evidence to better recommend therapies, and algorithm for LARS is pyramid-shaped, ranging from tailoring treatments is mandatory if we thrive for a patient- conservative measures to definitive stoma. Obviously, non- driven management of rectal surgery with a seal of excellence for invasive treatment must always be prioritized, but patients both oncological and functional outcomes. should be offered the opportunity to contribute to an interactive flow among other options such as TAI, SNM, or in those refractive cases, end-colostomy rather than having to go through all the steps. Treatment for LARS needs to be adapted to Author contributions each individual case. For example, some patients with fecal All authors listed have made a substantial, direct, and incontinence predominant pattern or who do not want to intellectual contribution to the work and approved it spend time for TAI might be better candidates for SNM, while for publication. others with clustering would be better suited for TAI. An interesting future direction is to individualize treatments based on the assessment of concomitant urinary and sexual disfunction after rectal resection, along with bowel dysfunction. Conflict of interest Another field to develop is prehabilitation which could have an important role in preparing patients to colorectal The authors declare that the research was conducted in the reconstruction. Studies are being performed (PRELARS – absence of any commercial or financial relationships that could Clinicaltrials.gov NCT04612569, CONTICARE – be construed as a potential conflict of interest. Clinicaltrials.gov NCT03876561) which will explore this field. Regarding patients’ expectation, there is a need to highlight the lack of consensus regarding outcomes measures. LARS score is an excellent tool to screen patients with LARS, but it might not Publisher’s note be useful to appreciate outcomes after treatment implantation. 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