Can compartment-based complete mesocolic excision improve outcomes in patients with right colon cancer with metastatic D3 nodes?

I am pleased to provide an editorial comment on the article titled, “Are Metastatic Central Lymph Nodes (D3 volume) in right-sided Colon Cancer a Sign of Systemic Disease? A sub-group Analysis of an Ongoing Multicenter Trial” by Banipal et al. (1) published in the Annals of Surgery. This paper represents a subgroup analysis from an ongoing multicenter trial in which computed tomography (CT) angiography is utilized to personalize the D3 dissection [based on the arterial and venous anatomy of superior mesenteric artery (SMA)/superior mesenteric vein (SMV)] for each patient to ensure complete removal of all lymphatic tissue comprising the D3 nodal basin which recruited 623 patients. The study being commented on represents a subgroup analysis of patients with positive D3 nodes (42 patients). The authors then stratify these patients with positive D3 nodes into 2 groups based on presence (13 patients) or absence (29 patients) of residual disease. Residual disease was defined as either incomplete resection (R1/R2 resection), tumor deemed inoperable at time of surgery or patients who developed early recurrence (within 3 months of surgery if no chemotherapy was administered or within 6 months of surgery if chemotherapy was administered). The authors aimed to assess long-term outcomes in patients with positive D3 nodes and also assess the impact of learning curve on survival by dividing the study into time periods to demonstrate.

The role of D3 dissection and the concept of central vascular ligation has gained a lot of attention since the description of complete mesocolic excision-central vascular ligation (CME-CVL) by Hohenberger (2) in 2009 and is claimed to improve outcomes in node positive right colon cancer in many retrospective series (3,4). This interest in increasing the radicality of resection in colon cancers is in stark contrast to other malignancies where the new paradigm of ‘less is more’ with regards to surgery as evidenced by the watch and wait approach in rectal cancer surgery and replacing axillary dissection with sentinel node biopsy in breast cancer. Detractors of D3 dissection procedure claim that survival benefits can largely be explained by stage migration achieved by the more extensive lymph node clearance. The four randomized controlled trials (RCTs) evaluating the benefit of the CME-CVL procedure have only published short-term outcomes to date (5-8) and until long-term survival data from these trials is available the question regarding the actual benefit of D3 dissection remains unanswered. Furthermore, the definition of what constitutes a D3 dissection is highly variable in literature (2,9-11) ranging from the ambiguous ‘central vascular ligation’ to dissection along right border of SMV to the much more radical definition involving dissection along the left border of the SMA. A cadaveric study by Spasojevic et al. (12) demonstrated the variability of lymphatic anatomy based on the arterial anatomy of the SMA branches and authors chose to utilize a personalized “D3 volume” based on preoperative CT angiography to achieve a standardized and reproducible template. This extended D3 volume dissection involving dissecting not only to the left of the SMA but also posterior to both the SMA and SMV is more radical than what most centers practice. The central issues surrounding D3 dissection are the low incidence of positive D3 nodes [3–5% in literature (7,8)] and the potential for significant morbidity including life-threatening vascular complications. The authors report a 6.7% incidence of positive D3 nodes in this study and 90-day mortality of 4.8% with a high incidence of anastomotic leak (11.9%), intraoperative bleeding (13.8%) and Clavien-Dindo III complications (16.7%). The median hospital stay of 10.7 days is also significantly higher than what would be expected from a routine right hemicolectomy, with an American College of Surgeons National Surgical Quality Improvement Project (NSQIP) analysis of 26,072 right colon resections by Squires et al. showing that most patients are discharged by postoperative day (POD) 5 and only 34% stay in the hospital for more than 5 days (13). The unreliability of imaging in detecting involved central nodes (in the present study only 50% of pathologically involved D3 nodes were seen on preoperative CT) would necessitate a D3 dissection to be done for all colon cancer patients with advanced tumours (node positive or T3/T4 tumours). The reproducibility of authors proposed D3 ‘extended mesenteric excision’ with dissection both anterior and posterior to the SMA and SMV by every colorectal surgeon without undue morbidity is questionable. A routine D3 dissection is technically demanding and extending this dissection posterior to the SMA would be even more demanding, especially in obese individuals [there no BMI data in this paper by Banipal et al. (1)].

While the authors aim to assess the long-term outcomes, the limited number of patients (13 and 29 in the residual disease positive and negative groups respectively) limits the results to hypothesis generating at best. The lack of information on the median follow-up period also limits the conclusions that can be drawn from their results. That being said, the impressive long-term outcomes in the residual disease negative group [residual disease negative 5-year overall survival (OS) and disease-free survival (DFS) 72.9% and 73.1% respectively as compared to residual disease positive 5-year OS and DFS 7.7% and 0% respectively] do lend credence to the hypothesis that if a complete resection can be obtained, patients with D3 nodal disease can expect long-term survival comparable to patients without metastatic D3 nodes. While this impressive outcome does promote optimism regarding the benefit of D3 dissection, it should be noted that the authors strict definition of what includes residual disease, such as patient recurring within 3 months of surgery (or 6 months if chemotherapy was delivered) effectively excludes patients with very aggressive tumour biology (who recur early) from the residual disease negative arm, and thus may exaggerate the differences in outcomes between patients with and without residual disease after surgery. Excluding patients with peritoneal or liver disease at the time of surgery from the survival analysis would probably give a more accurate insight idea about the benefit of the D3 extended mesenterectomy.

A study by Kang et al. looking at the prognostic impact of inferior mesenteric artery nodes in left colon/rectal cancer patients demonstrated that N2 nodal disease is predictive for apical node positivity and that positive apical nodes are associated with higher rates of systemic recurrence and resulted in a reduction of 5-year survival from 69.4% to 31.9% (14). It would be interesting to know if the same is true for right sided cancers and it would be a good idea to compare the results of patients with and without D3 node involvement when publishing the final results of this multicentric study.

D3 dissection is a technically demanding procedure and even more so if done via a minimally invasive approach. The fact that 73.8% of procedures were done via an open approach is testament to the difficulty in performing complex dissections along major vascular structures, something also seen in other studies evaluating CME-CLV with 88.4% of patients in the RESECTAT study having an open surgery (15). Studies have shown that D3 dissection is safe and can have comparable short-term outcomes when performed by experienced surgeons (6). The results reported support this claim with significant improvements in the OS and DFS progressively along different time points in the study (5-year OS increasing from 20% in the 2011–2013 period to 60% during 2017–2019 period, P<0.05) though some of these improvements could possibly be attributed to improvements in systemic therapy over the past 2 decades. The importance of this fact cannot be overstated: however impressive the results of D3 dissection may appear on the surface, there are unforgiving complications associated with this procedure and there is a definite learning curve. Standardization and referral to high-volume centers to ensure that these resections are performed by experienced surgeons is key to good outcomes, but given the poor sensitivity in identifying patients with D3 disease preoperatively, is it feasible to refer all patients with advanced tumours to specialized centers? The recent interest in neoadjuvant therapy in colon cancer after the publication of the FOxTROT (16) and impressive results with immunotherapy in microsatellite unstable tumours (17,18) may change the landscape of colon cancer surgery, obviating the need for such radical and technically demanding procedures.

The limitations of this study are mainly related to the small sample size of 42 patients and the author’s definition used for defining residual disease (which is not the standard definition). Data regarding the quality of life of the patients who underwent this “personalized D3 extended mesenterectomy” would also throw some light on the true morbidity of this procedure as it would be expected that disruption of the autonomic nerves around the SMA would result in some worsening of bowel function.

In conclusion, this paper by Banipal et al. (1) provides interesting insight into personalized D3 lymphadenectomy utilizing preoperative CT angiography. Although limited by the small number of positive apical node patients, and a novel concept of minimal residual disease (which is not standard), it does show that long-term survival is achievable with complete resections. The authors also demonstrate the significant learning curve associated with the procedure showing significant improvements in survival at progressive time points in the study.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-59/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-59/coif). The authors have no conflicts of interest to declare.

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