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Is there a role for salvage endoscopic submucosal dissection after chemoradiation for locally advanced rectal cancer?

      Abbreviations:

      EAC (esophageal adenocarcinoma), ESD (endoscopic submucosal dissection), LARC (locally advanced rectal adenocarcinoma), nCRT (neoadjuvant chemoradiotherapy)
      For decades, surgical resection has been the cornerstone for the treatment of locally advanced rectal adenocarcinoma (LARC). Recently, this paradigm has been questioned, with an organ-preserving watch-and-wait approach. After neoadjuvant chemoradiotherapy (nCRT), patients with complete clinical response are surveyed closely, and incomplete responders undergo total mesorectal excision. Given the operative morbidity and mortality associated with total mesorectal excision, this watch-and-wait approach is attractive for those who want to try to avoid surgery. After receiving nCRT, some patients may still have adenomatous polypoid tissue left behind because this tissue may be less sensitive to nCRT.
      • Shia J.
      • Guillem J.G.
      • Moore H.G.
      • et al.
      Patterns of morphologic alteration in residual rectal carcinoma following preoperative chemoradiation and their association with long-term outcome.
      This polypoid tissue can lead to concern that residual tumor remains and poses a risk for disease recurrence. Transanal full-thickness local excision of residual mucosal abnormalities after nCRT has been performed to exclude residual disease and confirm complete pathologic response. The concern about full-thickness local excision is that postoperative adverse events of wound dehiscence, fistula formation, and severe rectal pain may result in prolonged hospital stay or a need for fecal diversion.
      • Perez R.O.
      • São Julião G.P.
      Local excision—better than all (TME) or nothing (watch and wait) in complete clinical response following neoadjuvant chemoradiation for rectal cancer?.
      Endoscopic submucosal dissection (ESD) is less invasive and requires a shorter hospital stay than transanal surgery.
      • Kiriyama S.
      • Saito Y.
      • Matsuda T.
      • et al.
      Comparing endoscopic submucosal dissection with transanal resection for non-invasive rectal tumor: a retrospective study.
      Salvage ESD for local failure after CRT has been described for esophageal squamous cell cancer.
      • Ego M.
      • Abe S.
      • Nakatani Y.
      • et al.
      Long-term outcomes of patients with recurrent squamous cell carcinoma of the esophagus undergoing salvage endoscopic resection after definitive chemoradiotherapy.
      However, the technical feasibility and role of salvage ESD in LARC after nCRT have not been previously explored.
      In this issue of Gastrointestinal Endoscopy, Leung et al
      • Leung G.
      • Nishimura M.
      • Hingorani N.
      • et al.
      Technical feasibility of salvage endoscopic submucosal dissection after chemoradiation for locally advanced rectal adenocarcinoma.
      present their findings of salvage ESD of LARC after nCRT for diagnostic and therapeutic purposes. Patients who were eligible for salvage ESD were carefully selected after multidisciplinary discussion with a focus on lesions that showed clinical response after nCRT, but with a soft polyp seen on endoscopic examination. Clinical response was defined as an unremarkable rectal examination with no evidence of invasive disease or lymph nodes on rectal magnetic resonance imaging and no metastatic disease on a computerized tomography scan. A total of 12 patients who underwent salvage ESD after nCRT were identified. They were compared with 27 patients who underwent standard ESD for rectal tumors without nCRT.
      The outcomes evaluated in the study were technical feasibility, defined by en bloc and R0 resection rates, and adverse event rate, defined by bleeding and perforation within 30 days of the procedure. The 2 groups had similar demographics (age [P = .66], comorbidities [P = .32], American Society of Anesthesiologists class [P = .20]). The standard ESD group had a trend toward a larger median lesion size (35 mm) than those in the salvage ESD group (25 mm). The lesion characteristics were similar between both groups. with most lesions as 0-Is or 0-IIa (P = .14). All salvage ESD lesions were scarred down compared with 9 (33.3%) scarred lesions in the standard ESD group (P < .01). The 2 groups had similar procedure times (P = .74), and there was a trend for more submucosal injection fluid to be used in traditional ESD (49 mL) than in salvage ESD (25 mL).
      Both groups had comparable high en bloc (92.7% and 91.7%) and R0 (66.7% and 75%) resection rates. Adverse event rates were also comparable (P = .50) between both groups, with no bleeding or perforation noted in the salvage ESD group. Two patients in the traditional ESD group had delayed bleeding that was managed endoscopically. In the salvage ESD group, 75% (9) of the lesions were benign hyperplastic or adenomatous polyps, and 16.7% (2) went on to surgery when pathologic examination showed margin-positive resection of adenocarcinoma demonstrating incomplete pathologic response to nCRT.
      The authors should be congratulated on this novel comparative study, definitely a challenging task given the lack of evidence on this topic and the rarity of cases requiring careful multidisciplinary selection. The authors were able to demonstrate that salvage ESD after nCRT is technically feasible, with high en-bloc resection rates and no major adverse events. These outcomes were comparable with those of traditional rectal ESD without nCRT.
      Whereas the outcomes were comparable between the groups, this should not lull us into thinking that salvage ESD is not more technically challenging than standard rectal ESD. All salvage ESD lesions (100%) were scarred with fibrosis, and although the groups had similar procedure times, this was despite a trend toward larger lesions in the standard ESD group (35 mm vs 25 mm). Specific techniques were used to address the fibrosis encountered in salvage ESD. The pocket creation method was used to overcome the inadequate submucosal lift.
      • Sakamoto H.
      • Hayashi Y.
      • Miura Y.
      • et al.
      Pocket-creation method facilitates endoscopic submucosal dissection of colorectal laterally spreading tumors, non-granular type.
      A tapered distal attachment was used to access the narrow submucosal space, and clip line traction was used to lift the lesion away from the muscularis propria to help protect against perforation during dissection. In addition, the single endoscopist who performed these procedures had >20 years of experience in performing ESD. Further multicenter data are needed to support these results. In our limited experience (3 cases) of salvage ESD after nCRT for LARC, we found the resections challenging, but technical success without adverse events was achieved in all cases, lending support to the findings of this study.
      The study has shown the technical feasibility of salvage ESD after nCRT for LARC. The initial results are promising: salvage ESD was able to differentiate which polypoid lesions were benign and could avoid surgery and those with residual cancer that required surgery. A question that remains is this: Does all residual cancer reside in the polypoid lesion? A previous study showed that tumor scatter or fragmented response to nCRT for LARC may occur, with the presence of cancer cells outside of the visible lesion.
      • Hayden D.M.
      • Jakate S.
      • Pinzon M.C.
      • et al.
      Tumor scatter after neoadjuvant therapy for rectal cancer: are we dealing with an invisible margin?.
      Could this lead to the absence of residual cancer in the resected polypoid specimens while leaving behind microscopic foci of cancer cells elsewhere? Longer-term data are needed to see whether this approach ultimately affects patients’ outcomes and could be incorporated into the watch-and-wait approach for LARC after nCRT.
      The authors should also be congratulated on incorporating ESD within the multidisciplinary approach of LARC. Advances in therapeutic endoscopy are allowing us to endoscopically treat more GI cancers, creating a field of endo-oncology. For this field to grow, it is important that we become more incorporated into tumor boards and become part of the multidisciplinary approach to cancer. This study also brings up an interesting concept—that adenomatous or precancerous lesions may be less sensitive to CRT—and raises the question whether other tumors could benefit from a similar approach. After definitive CRT for esophageal adenocarcinoma (EAC), endoscopic evaluation and treatment of residual Barrett’s neoplasia are not commonly performed. In our experience, some of the recurrences that we have seen after definitive CRT of EAC arise from metachronous lesions rather than from the primary tumor, raising this question: Should we also consider surveying and treating Barrett’s neoplasia after definitive CRT of EAC?
      Salvage ESD after nCRT of LARC should not be done in isolation but should be part of a multidisciplinary approach with tumor board guidance, similarly to how LARC is usually managed. It also should be noted that the watch-and-wait approach is not standard of care and is currently under evaluation and recommended only in highly selected patients with complete clinical response in a protocolized setting.
      • You Y.N.
      • Hardiman K.M.
      • Bafford A.
      • et al.
      The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of rectal cancer.
      It's undoubtedly exciting that salvage ESD may play a role in the watch-and-wait approach after nCRT for LARC, and further longer-term studies are needed to support this approach.

      Disclosure

      Dr Bhatt is a consultant for Boston Scientific, Olympus, Lumendi, and Medtronic and the recipient of royalties from Medtronic. The other author disclosed no financial relationships.

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