Abstract
Background/Aim: Thanks to the promising benefits obtained in terms of quality of life, there has been growing interest in organ-sparing approaches after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer, mainly represented by transanal local excision and watch-and-wait. The main mandatory criterion is complete lymph nodal response (pN0). However, considering the reduced specificity of current radiological means in identifying one-to-one correspondence between clinical and pathological staging, the problem of underestimating lymph nodal involvement remains unsolved. The aim of this study was to identify the true percentage of patients eligible for conservative surgery and possible predictive factors. Patients and Methods: Data for 59 patients with rectal cancer treated with nCRT followed by total mesorectal excision were analyzed. Patients with metastatic tumors and tumors treated with up-front surgery were excluded. Our primary endpoint was the pathological lymph nodal response rate after neoadjuvant chemoradiotherapy. The secondary endpoint was to identify predictive factors for lymph nodal response. Results: The percentage of patients with pN0 was 62.71%, while in 37.28%, an organ-sparing approach would have not been oncologically correct. Parameters associated with pN0 were lower tumor size (T0-T2) (p=0.013) and lower grading (<G3) (p=0.06). Parameters associated with poorer disease-free survival were pN+ (p=0.019), higher lymph node ratio (p=0.001), and higher stage (p=0.038). Conclusion: Organ-sparing approaches may be a promising option in patients with extraperitoneal rectal cancerthat respond to nCRT. Nevertheless, it is essential to consider the limit of lymph node metastases to ensure oncological safety and, especially in cases with advanced tumors, total mesorectal excision should be the approach of choice.
- Rectal cancer
- organ-sparing surgery
- lymph node metastasis
- watch and wait
- neoadjuvant chemoradiotherapy
- complete pathological response
- clinical complete response
Colorectal cancer is the third most common cancer worldwide, the second largest cause of death related to cancer, and the main cause of death from gastrointestinal cancer. The mortality is 4-10/100, 000 population per year (1). To date, the only curative treatment consists of surgery combined with chemo/radiotherapy based on tumor stage. Surgical management depends on patient and tumor factors, with the aim of optimizing function and survival with the lowest risk of recurrence. Total mesorectal excision (TME) is the gold standard for rectal cancer with the aim of removing the tissue next to the rectum, also called the mesorectum, that contains lymph nodes and blood vessels. However, after TME, functional disorders are very frequent, leading to significant changes in quality of life, including various degrees of bowel dysfunction that is identified as low anterior resection syndrome (2). The transanal approach for TME, described firstly in 2010, seems to improve clinical and oncological outcomes in some cases, although in regard to functional outcomes, no significant differences were reported and there is no consensus in literature (3, 4). For this reason, the transanal local excision (TLE) approach for localized rectal cancer has been developed. This technique is only appropriate for selected T1N0 early-stage cancers. Small (<3 cm), well- to moderately differentiated tumors that are within 8 cm from the anal verge and limited to <30% of the rectal circumference, and for which there is no evidence of nodal involvement (5). However, there is no lymphadenectomy with local excision. Thus, the substantial reduction in morbidity with local excision must be balanced against the possible risks of positive resection margins, loco regional recurrence, and lower overall survival than an abdominal resection with TME (6). Transanal minimally invasive surgery allows an important saving of organ, since it removes only damaged tissues, leaving intact the rest. The promising results of neoadjuvant therapy regarding the response rate has allowed a greater uptake of the organ-sparing surgical approach, however, standardized criteria of inclusion are necessary to increase accuracy (7). To ensure oncological radicality with a minimally invasive approach, correct restaging after neoadjuvant therapy is mandatory. However, current methods do not ensure one-to-one correspondence between clinical and pathological staging (8, 9). An important predictor of survival after neoadjuvant therapy is the nodal status, which has to be considered to choose the correct surgical approach and, in the case of lateral pelvic lymph nodal involvement, a selective lateral dissection can be performed (10). Although a decrease in size implies a treatment response within a node, the ability of magnetic resonance imaging (MRI) to depict small amounts of residual tumor within nodes is limited, particularly if one is relying only on size criteria. This condition affects the surgical approach to the mesorectum.
Fluorodeoxyglucose positron-emission tomography/MRI is a useful imaging modality for response evaluation because it reports the metabolic activity of the region of interest, in fact it can distinguish cancer residues from scarred tissues and fibrosis, nevertheless, the same limits remain even after nCRT. Indeed, some authors report it that the accuracy of positron-emission tomography–MRI is higher than MRI alone both for ypT (92% vs. 89%, respectively) and ypN (92% vs. 86%, respectively) staging (11). Therefore, there is a lack of tools for accurately selecting patients to be referred for parenchymal-sparing surgery. Therefore, the aim of our study was to analyze the true rate of pathological complete lymph node response of patients undergoing radical surgery to assess patients who are most eligible for conservative surgery.
Patients and Methods
Population selection. We performed a retrospective observational study selecting patients with locally advanced adenocarcinoma of the rectum undergoing neoadjuvant therapy and anterior rectal resection with TME at the General Surgery Department at Sant’ Andrea Hospital from 2012 to 2019. Inclusion criteria included patients with rectal adenocarcinoma reported from pathological examination with age ≥18 years. Exclusion criteria were total intraperitoneal rectal adenocarcinoma, local rectal adenocarcinoma treated with upfront surgery or transanal surgery, not undergoing neoadjuvant therapy, age <18 years and metastatic rectal cancer. From 204 patients, 145 were excluded because they did not meet the inclusion criteria. Finally, 59 patients were selected for the analysis. The eighth edition of the TNM staging system was used for classification (12).
Radiotherapy. At our Center of Radiotherapy at Sant’ Andrea Hospital in Rome, 59 patients with locally advanced rectal cancer were submitted to neoadjuvant RT before surgery from November 2012 to October 2019, with or without concomitant chemotherapy depending on the course of RT (13). The median patient age was 68 years (range=42-87 years). A total of 38 patients were treated with long-course CRT. All of these underwent intensity-modulated RT and received 45 Gy in 1.8-Gy daily fractions to the pelvis, with a boost to the tumor and positive lymph nodes in the form of simultaneous integrated boost of 55 Gy in 2.2-Gy daily fractions or concomitant boost of 10 Gy in 1-Gy biweekly fractions. Concurrent chemotherapy with oral capecitabine was administered, 825 mg/m2 twice per day, 5 days per week (14). In four patients, chemotherapy was interrupted due to gastrointestinal acute toxicity. The remaining 21 patients were treated with short-course intensity-modulated RT and received 25 Gy in 5-Gy daily fractions to the pelvis, without concurrent chemotherapy.
Both groups of patients examined received irradiation of the pelvis, which includes lymph node stations highly at risk of local recurrence. Pelvic subsites are chosen according to the major lymphatic drainage pathways of the rectum and based on the stage and the level of the primary lesion. Mesorectal, internal iliac and presacral lymph nodes should always be included. Obturator lymph nodes are included in the tumors below the peritoneal reflection. The external iliac nodal region must be included in the case of anterior organ involvement (cT4). Inguinal lymph nodes can be included in cases with infiltration of the anal canal below the dentate line or in cases of infiltration of the lower third of the vagina (15, 16).
Acute toxicity (from the end of RT to the following 6 months) was assessed and described according to the Common Terminology Criteria for Adverse Events (version 5.0) (17) and relative to gastrointestinal, genitourinary, and hematological aspects.
Statistical methods. Nominal continuous variables are expressed as averages with range (min to max), categorical variables are expressed in units and percentages. Descriptive statistics were used to summarize information relevant to the study. Associations between categorical variables were estimated using logistic regression and the univariate Cox regression model. A multivariate logistic regression was developed using stepwise regression (forward selection, with enter and remove limits of p=0.10 and p=0.15, respectively), to identify independent predictors of outcomes. Disease-free survival (DFS) was estimated by the Kaplan–Meier product-limit method from the date of surgical resection until death whether from cancer or other causes. Significance was accepted at p<0.05. The licensed statistical programs SPSS (version 21.0; IBM, Armonk, NY, USA) and MedCalc (version 14.2.1; MedCalc software, Ostend, Belgium) were used for all analyses.
Results
From February 2013 to September 2019, 59 patients underwent surgery for rectal cancer at Sant’ Andrea Hospital of La Sapienza University of Rome. In the examined population, 22 patients were females (37.3%) and 37 males (62.7%) with a mean age of 65.49 years (range=41-87 years) and a total of 32 patients had American Society of Anesthesiologists score ≤2. Twenty-seven patients had a tumor with a distance from the anal verge of between 0-5 cm and 32 patients of between 5-10 cm (Table I).
General features of study patients.
Neoadjuvant treatment was performed in all cases: short-course RT in 21 (35.5%) and long-course CRT in 38 (64.4%). Acute gastrointestinal toxicity of grade 1 was registered in 21 patients (35%), grade 2 in 27 patients (45%) and grade 3-4 in four patients (7%). Acute genitourinary toxicity of grade 1 was recorded in 21 patients (36%) and grade 2 in 12 patients (20%). Acute hematological toxicity of grade 1 and grade 2 occurred in five patients (8%), respectively. Overall, anterior rectal resection was performed in 46 patients and abdominoperineal excision in 13, both in association with TME. A stoma was created in 53 of them, of which 39 were ileostomies and 14 colostomies. Moreover, in 11 cases, the operation was associated with multiple abdominal resections (hysterectomy and bilateral oophorectomy, omentectomy, cholecystectomy). The median operative time was 242 minutes (120-430 min), and the predominant surgical approach was an open one (72.9%). The complication rate was 20% (12 patients). Specifically, 25% of these were grade I, 58% were grade II and 16% were grade III according to the Clavien–Dindo Classification. Canalization was a median of 2 (range=1-5) days for gas and 3 (range=1-5) days for stool (Table II).
Intraoperative and perioperative details of the study population.
An average of 19 lymph nodes were removed (range=3-50). A complete response (N0) was observed in 61% (36 cases), while 39% (23 cases) were N+. In patients who underwent short-course RT the mean number of harvested lymph nodes was 26 (range=14-50) with a mean of four positive lymph nodes (range 0-28); in patients who underwent long-course RT, a mean of 15 (range=3-47) lymph nodes were harvested, with a mean of one lymph node being positive (range=0-9). Several parameters were examined, and a close relationship was observed between lymph node response and some factors such as smaller tumor size (p=0.013) and lower grade (p=0.062) (Table III).
Analysis of factors associated with lymph nodal response.
The mean DFS was 36 (range=0-112) months and was significantly related to the presence of lymph node metastases (p=0.019) (Figure 1) and stage of disease (p=0.038). However, grading and type of RT did not show significant correlation with DFS (Table IV).
Kaplan-Meier curves of disease-free survival according to lymph nodal staging (pN).
Predictive factors for disease free survival (DFS).
Discussion
In patients with locally advanced rectal cancer, the role of nCRT in local control has been widely discussed (18-23). Thanks to the promising results obtained in terms of quality of life, i.e., lower stoma rate and morbidity (24, 25), there has been growing interest in organ-sparing approaches after nCRT, mainly represented by TLE and watch-and-wait.
The watch-and-wait approach, after being described by Habr-Gama et al. in 2004 (26), has also recently appeared in international guidelines as a therapeutic option to consider in selected patients. European Society for Medical Oncology guidelines (1) allow consideration of the possibility of watch-and-wait only in patients who reach a clinical complete response (cCR) after CRT or short-course RT, definable as the absence of a palpable tumor on digital rectal examination associated with a negative proctoscopy (except for a flat scar, telangiectasia or whitening of the mucosa). A negative scar biopsy and a no suspicious lymph nodes in MRI or endorectal ultrasound are considered optional criteria. Zhang et al. (27) in a metanalysis conducted in 2022, described better results of a watch-and-wait approach compared with radical surgery in terms of permanent colostomy rate and 2-and 3-year overall survival (but the significant heterogeneity of the studies and the fact that salvage surgery was conducted in the watch-and-wait group whenever necessary should be considered). However, the between-group difference did not reach statistical significance in terms of cancer-related-death, DFS and 5-years overall survival. As regards to local recurrence, a significantly higher rate was found in the watch-and-wait group (odds ratio=11.09), relatively lower than that described by Dossa et al. (28) in 2017 (10.5% vs. 15.7%), probably due to advances in nCRT results.
Regarding TLE, the GRECCAR 2 trial (29) failed to show superiority of local excision over TME in terms of oncological safety. In terms of morbidity and side-effects, as expected, the lowest rate was observed in the TLE group, followed by those in the primary TME group and, interestingly, patients who underwent TLE plus completion TME had the highest rate of morbidity and side-effects (Clavien–Dindo III-V: 12% vs. 22% vs. 46%; definitive colostomy: 4% vs. 9% vs. 25%; sexual dysfunction: 13% vs. 17% vs. 41%).
Van Oostendorp et al. (30) in 2020 showed that in high-risk pT1 cancer, the risk of local recurrence using TLE to be comparable to that with TME, but in pT2 tumors, TLE was less effective than TME (14.7% vs. 4% of local recurrence), probably also due to the higher probability of leaving undetected lymph node metastases [considering that the positive lymph node rates after nCRT in patients with ypT0, ypT1, ypT2 and ypT3-4 were estimated at 5%, 8%, 26% and 55%, respectively (31)].
Therefore, solid data about oncological safety of these conservative approaches is lacking and TME remains the standard of care, even in patients who reach cCR to CRT. The main issue is the partial overlap between cCR and pathological complete response (pCR), defined as no residual tumor cells or lymphatic involvement in the resected specimen (ypT0N0M0) after nCRT. According to this study, it seems mandatory to refine indications for organ-sparing approaches in patients with locally advanced rectal cancer to ensure oncological radicality.
The role of T-stage in predicting CRT response is becoming clear: Smith et al. in a retrospective observational study showed that mucosal cCR was statistically associated with ypT0 status (p<0.0001) (although it is worth noting that 27% of patients with mucosal cCR still had residual disease) (32). The systematic review published in 2018 by Chadi et al. showed cT stage to be a factor predictive of local regrowth in patients selected for a watch-and-wait approach (33).
On the contrary, the role of mesorectal lymph node metastasis remains nebulous and less investigated. Considering the rate of false-positives [e.g. radiation-induced fibrosis mistaken for lymph node metastasis: in the PRODIGE trial, among 38 patients with ypCR, only 11 had shown cCR (34)] and false-negatives (due to imperfect sensitivity of current staging techniques, especially for mesorectal lymph nodes), according to this research group, it is mandatory to identify predictive factors of true lymph node response after CRT before considering the possibility of an organ-sparing approach to minimalize the risk of suspicious mesorectal lymph nodes.
Among our patients, in fact, only 61% (n=36) had a complete lymph node response (ypN0) after CRT. It should also be considered that 41.67% (n=15) of these patients had pT3 stage and therefore would not have been candidates for a conservative approach in any case; while 38.89% (n=14) of cases were pT1-2, eligible for TLE, and only 19.44% (n=7) were patients who reached cCR (pT0N0M0) and therefore eligible for a watch-and-wait approach. As to be expected, lower T-stage was significantly associated with better lymph node response (p=0.013). Other factors possibly implicated were the tumor distance from the distal edge of resection and younger age at diagnosis. Association with tumor grading was not found to be significant (p=0.062), but it seems likely that this result was affected by the high rate of unspecified grading in postoperative histology (45.8%).
Therefore, indication for conservative therapy seems to include a modest percentage of patients and, even among these, oncological radicality can be challenging to achieve. Therefore, it is essential to carry out a close and standardized follow-up. National Comprehensive Cancer Network guidelines suggest surveillance with digital rectal examination and proctoscopy every 3-4 months for 2 years, then every 6 months for a total of 5 years. MRI is recommended every 6 months for at least 3 years (5).
Finally, according to this study, an organ-sparing approach may be considered as an attempt to avoid radical surgery with poor long-term functional outcome in two categories of patients: i) Elderly patients unfit for surgery, and ii) young patients with very low rectal cancer in order to postpone highly destructive surgery. However, it should not be forgotten that delayed TME after TLE has been shown to result in a higher rate of abdominal perineal resections compared to first-line TME (35).
This study has several limitations. Firstly, its retrospective nature and smallness of study sample, which exposes the study to high risk of bias, even though it should be mentioned that patients were highly selected, and every decision was made by the same multidisciplinary team. It should also be noted that in 52.5% (n=31) of patients, the number of lymph nodes harvested was <18; however, it must be taken into account that a higher number of harvested lymph nodes might only increase the nodal involvement rate, supporting the hypothesis that a careful evaluation of the effective response rate after nCRT is mandatory before considering any conservative treatment. In the future, we hope that, based on these preliminary results, a multicentric randomized study will be performed to clarify the role of lymph node metastasis in organ-sparing surgery in local advanced rectal cancer, also considering that there are currently no means to assess lymph node involvement with 100% accuracy even in pre-nCRT staging.
In the future, it will be essential to investigate factors predictive of pathological complete CRT response to refine indications for organ-sparing approaches. To follow this path, molecular medicine could be useful: normalization of serum carcinoembryonic antigen levels <5 ng/ml, for example, is already considered a factor predictive of overlap between cCR and pCR (36), and fluorescence endoscopy targeting epithelial cell adhesion molecule has shown encouraging results (37). Furthermore, radiomic features derived from MRI have been studied to predict tumor regression grade in patients with locally advanced rectal cancer before undergoing nCRT and showed promising results, suggesting possible application to lymph nodal response (38).
To ensure oncological radicality for transanal local excision and to reduce technical difficulties and the surgical burden of radical surgery (preventing life-threatening complications such as anastomotic leakage), robotic surgery, improved by indocyanine green fluorescence might be an interesting frontier (39, 40). Finally, regarding the study of lymphatic involvement, in 2014, Arezzo et al. (41) described a transrectal sentinel lymph node biopsy during TME, which seems attractive and worthy of further studies.
Conclusion
In patients with good response to nCRT for locally advanced rectal cancer, an organ-sparing approach may be a promising option. Despite that, it remains essential to consider the limit of lymph node metastasis to ensure oncological safety. Our preliminary results have shown that in patients with advanced tumors that seem to respond completely, the approach of choice should, in any case, be the traditional one, with TME; on the contrary, in initial stages with cCR to nCRT, the conservative approach might prove to be curative, also guaranteeing a better quality of life.
Footnotes
Authors’ Contributions
Conceptualization: Edoardo Maria Muttillo and Alice La Franca; methodology: Isabella Sperduti; software: Isabella Sperduti and Alice La Franca; validation: Edoardo Maria Muttillo, Isabella Madaffari and Fanny Massimi; formal analysis: Isabella Sperduti and Alice Ceccacci; investigation: Ilaria Angelicone; resources: Flavia de Giacomo; data curation: Alice La Franca; original draft preparation: Edoardo Maria Muttillo, Alice La Franca, Isabella Madaffari, Fanny Massimi and Giuseppe Longo; review and editing: Alice La Franca and Edoardo Maria Muttillo; visualization: Edoardo Maria Muttillo; supervision: Genoveffa Balducci, Paolo Mercantini and Mattia Falchetto Osti; project administration: Genoveffa Balducci, Paolo Mercantini and Mattia Falchetto Osti. All Authors read and agreed to the published version of the article.
Conflicts of Interest
The Authors declare no competing interests.
- Received March 15, 2023.
- Revision received April 2, 2023.
- Accepted April 5, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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