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26 Who Needs aLoop Ileostomy After Low Anterior Resection forRectal Cancer?
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on 78 patients undergoing LAR for rectal tumors 4–12cm from the anal verge at a single hospital in India, who were randomized to ileostomy vs. no ileostomy. The authors focused on stoma-related outcomes, but unfortunately did not include infor­mation on use of neoadjuvant or adjuvant radiation therapy. Data revealed a lower leak rate in the diverted group (6% vs. 11%). Ileostomy predisposed patients to electrolyte imbalance in the postoperative period, as well as a signicant overall stomal complication rate of 25.4%. The authors also found stoma closure to be associated with an overall complication rate of 67.7%.
More recent studies have examined the effects of wholesale policy changes on AL and diverting stoma formation. Blok et al. compared outcomes of patients undergoing LAR for low to mid rectal tumors at a single Dutch university hospital in an era of “highly selective diversion” vs. historical controls who underwent “rou­tine diversion” [26]. The data are heterogeneous, as selection of diversion was left up to the surgeon, who selected for lower risk patients (e.g., higher tumors, no neo­adjuvant long course radiation, healthy patient) to leave undiverted. The authors also incorporated a new practice pattern, transanal total mesorectal excision (TaTME), during the course of the data collection, which may confound results. They reported that stoma-related readmission and reoperation rate (including rever­sal) were signicantly lower in their study group than in their control group (17% and 17%; vs. 84% and 86%; p<0.001), and total hospital stay within 1year was median 5 vs. 11days, p<0.001. AL rate was higher in the historical control group (20% vs. 8%), which also more frequently underwent long course chemoradiation (50% vs. 25%, p=0.016). The ndings do suggest that, when looking at the big picture of policy (mandatory vs. selective diversion), allowing surgeons to utilize diversion selectively might have signicant benets for patients.
Taken together, these data overall demonstrate that fecal diversion offers a clear benet in LAR in lowering anastomotic leak rate and need for reoperation. While early retrospective studies arrived at varying conclusions, prospective randomized trials have all demonstrated a clear benet to fecal diversion. Therefore, at this point, it is clear that at a population level, fecal diversion should be the default operation in combination with LAR.However, what these studies fail to address is which patients are at decreased risk of anastomotic leak and therefore could avoid defunctioning stoma placement.
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Who Is at Highest Risk forDeveloping aLeak?
Patient factors associated with poor wound healing increase the risk of developing an anastomotic leak. Patients who are malnourished, on steroids, and obese, are at higher risk for developing an anastomotic leak [27]. Early retrospective analyses found specic rectal cancer factors associated with increased risk of AL: distance from anal verge was found to have the strongest association with leak rate (OR=5.4–6 for anastomosis 5cm from anal verge) [28, 29]. Further operative fac­tors related to anastomotic leak included male gender (OR=2.36), and intraopera­tive blood loss (OR=1.05) [29]. Predictive risk score calculators may be useful in
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assessing patient and cancer-related factors. The REAL (REctal Anastomotic Leak) score was proposed by a collaborative study group based on meta-analysis of stud­ies including 9735 patients, and utilizes 12 preoperative factors (interval from neo­adjuvant therapy to surgery, short course radiotherapy, TNM staging, anastomotic distance from anal verge, patient age, gender, smoking status, BMI, diabetes, ASA grade, prior abdominal surgery, and hemoglobin) to calculate a patient’s risk of AL [30].
Intraoperative assessment of the anastomosis may play an important role in reducing the leak rate and in deciding on the need for proximal diversion. Common methods of evaluating a colorectal anastomosis include air leak testing, saline leak, methylene blue leak tests and endoscopic assessment. Two randomized trials have evaluated the validity of performing an intraoperative leak test and have found that the risk of leak in those tested was signicantly lower than the untested controls (5.8% versus 16%, p<0.05) [31, 32]. Therefore, intraoperative leak testing should be performed and patients found to have concerning ndings on exam should undergo repair, revision, and possibly fecal diversion.
A 2014 meta-analysis by Qin etal. included seven randomized controlled trials evaluating the role of preoperative radiotherapy as a risk factor for AL after LAR [33]. In the pooled studies, 1660 patients were included in the preoperative radio­therapy group and 1715 patients were included in the control group. In this analysis, rates of anastomotic leak were not increased in the preoperative radiotherapy group (OR=1.02; CI 0.80, 1.30; p=0.88). This analysis, however, is limited by the use of clinically detected anastomotic leaks in the individual trials making up the analysis, which may underreport anastomotic leaks that would be clinically signicant if no defunctioning stoma were in place. Because it is not possible to directly measure the rate of clinically signicant leaks in the presence of a defunctioning stoma, making strong recommendations in patients who received preoperative radiotherapy remains difcult. Short course chemoradiotherapy (delivery of neoadjuvant therapy over the course of 5days vs. 25 fractions) has gained in popularity. The most direct compari­son of relevant outcomes, a randomized controlled trial in which patients with T3 rectal adenocarcinoma within 12cm of the anal verge were randomized to short course radiotherapy vs. long course chemoradiotherapy, demonstrated no signi­cant difference in AL rate [34].
A new and growing body of evidence also points to the role gut microbiome in AL.A study by Shogan etal. in 2015 was one of the rst to demonstrate the contri­bution of specic bacteria in development of AL [35]. This group noted that matrix metalloproteinase enzymes produced by Enterococcus faecalis were responsible for tissue degradation at the anastomosis in rats and found the same strains in anasto­motic samples of patients undergoing colon resections. While research in this area is still ongoing, a substantial and growing body of literature suggests that environ­mental factors, including diet, antibiotics, bowel prep, and physiological stress from surgery, alter the microbiome to cause AL or worsened oncologic outcomes after colorectal surgery [36]. Upcoming microbiome sequencing technology may thus inform decisions about AL risk and diversion.
26 Who Needs aLoop Ileostomy After Low Anterior Resection forRectal Cancer?
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What Type ofDiverting Ostomy Should WeUse?
When considering fecal diversion, the two common options are loop ileostomy and loop colostomy. Four randomized trials have compared these two options to each other, with two studies favoring the use of loop colostomy [37, 38] and two favoring loop ileostomy [39, 40]. A 2007 Cochrane review found ve randomized studies involving 334 patients: 168 undergoing loop Ileostomy and 166 undergoing loop colostomy [41]. There was a large and signicant difference in stomal prolapse rates, with a rate of 2% in the ileostomy group vs. 19% in the colostomy group (p<0.01); however, there were no other differences noted. Given the large differ­ence in rates of prolapse, current recommendations are to create a loop ileostomy when possible.
Are There Benefits toEarly Ileostomy Closure?
Most surgeons close a diverting ileostomy at 2–3months after the initial LAR.Under traditional models of neoadjuvant chemoradiation and possible adjuvant chemo­therapy, this occasionally caused considerable delay in closure, as patients might need to undergo uninterrupted adjuvant chemotherapy. Conversely, patients who developed stoma-related complications might be prevented from undergoing needed adjuvant therapy. There was thus signicant interest in the possibility of early clo­sure of diverting ileostomy, within 2weeks of LAR.One multicenter randomized controlled trial from Denmark and Sweden addressed this question, nding that the mean number of complications up to 12months of follow up after LAR was actually signicantly lower in the early closure group vs. the control group undergoing ileos­tomy closure at 12weeks (1.2 vs. 2.9, p<0.0001) [42]. Cost analysis from this same trial demonstrated a mean cost savings of $3608in favor of early closure [43]. Given the known functional impacts of delayed ileostomy closure including impaired bowel function, delaying ileostomy closure no longer than 6months is recommended [44]. Total neoadjuvant therapy, in which both chemoradiotherapy and consolidation chemotherapy are delivered up-front before surgery, may help prevent prolonged interval to ileostomy closure after LAR.
Personal View oftheData
While proximal diversion is not without risks, the consequences of an anastomotic leak are signicant enough that the benets usually outweigh the risks. Therefore, proximal fecal diversion following anterior resection for rectal cancer should be considered standard practice in most patients. Some patients may be at low risk for developing an anastomotic leak, and consideration of patient factors such as age, sex, weight and smoking status, tumor factors, and intraoperative factors; as well as utilization of a risk calculator, may help determine those patients who are candi­dates for non-diversion. After creation, all colorectal anastomoses should be tested
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for the presence of an anastomotic leak. A positive test may necessitate a revision of the anastomosis and/or repair followed by proximal fecal diversion.
References
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3. Rahbari NN, Weitz J, Hohenberger W, etal. Denition and grading of anastomotic leakage fol­lowing anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer. Surgery. 2010;147:339–51.
4. Kulu Y, Ulrich A, Bruckner T, Contin P, Welsch T, Rahbari NN, Büchler MW, Weitz J.Validation of the international study Group of Rectal Cancer denition and severity grading of anastomotic leakage. Surgery. 2013;153:753–61.
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13. Sun R, Dai Z, Zhang Y, Lu J, Zhang Y, Xiao Y.The incidence and risk factors of low anterior resection syndrome (LARS) after sphincter-preserving surgery of rectal cancer: a systematic review and meta-analysis. Support Care Cancer. 2021;29:7249–58.
14. Keane C, Sharma P, Yuan L, Bissett I, O’Grady G.Impact of temporary ileostomy on long­term quality of life and bowel function: a systematic review and meta-analysis. ANZ J Surg. 2020;90:687–92.
15. Gadan S, Floodeen H, Lindgren R, Matthiessen P. Does a Defunctioning stoma impair ano­rectal function after low anterior resection of the rectum for cancer? A 12-year follow-up of a randomized multicenter trial. Dis Colon Rectum. 2017;60:800–6.
16. Chow A, Tilney HS, Paraskeva P, Jeyarajah S, Zacharakis E, Purkayastha S.The morbidity surrounding reversal of defunctioning ileostomies: a systematic review of 48 studies including 6,107 cases. Int J Color Dis. 2009;24:711–23.
17. Alves A, Panis Y, Lelong B, Dousset B, Benoist S, Vicaut E.Randomized clinical trial of early versus delayed temporary stoma closure after proctectomy. Br J Surg. 2008;95:693–8.
18. Jørgensen JB, Erichsen R, Pedersen BG, Laurberg S, Iversen LH.Stoma reversal after intended restorative rectal cancer resection in Denmark: nationwide population-based study. BJS Open. 2020;4:1162–71.
26 Who Needs aLoop Ileostomy After Low Anterior Resection forRectal Cancer?
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19. Graffner H, Fredlund P, Olsson S-Å, Oscarson J, Petersson B-G. Protective colostomy in low anterior resection of the rectum using the EEA stapling instrument. Dis Colon Rectum. 1983;26:87–90.
20. Pakkastie TE, Ovaska JT, Pekkala ES, Luukkonen PE, Järvinen HJ.A randomised study of colostomies in low colorectal anastomoses. Eur J Surg. 1997;163:929–33.
21. Matthiessen P, Hallböök O, Rutegård J, Simert G, Sjödahl R. Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer. Ann Surg. 2007;246:207–14.
22. Chude GG, Rayate NV, Patris V, Koshariya M, Jagad R, Kawamoto J, Lygidakis NJ.Defunctioning loop ileostomy with low anterior resection for distal rectal cancer: should we make an ileostomy as a routine procedure? A prospective randomized study. Hepato­Gastroenterology. 2008;55:1562–7.
23. Ulrich AB, Seiler C, Rahbari N, Weitz J, Büchler MW.Diverting stoma after low anterior resection. Dis Colon Rectum. 2009;52:412–8.
24. Montedori A, Cirocchi R, Farinella E, Sciannameo F, Abraha I.Covering ileo- or colostomy in anterior resection for rectal carcinoma. Cochrane Database Syst Rev. 2010; https://doi.
org/10.1002/14651858.CD006878.pub2.
25. Thoker M, Wani I, Parray FQ, Khan N, Mir SA, Thoker P.Role of diversion ileostomy in low rectal cancer: a randomized controlled trial. Int J Surg. 2014;12:945–51.
26. Blok RD, Stam R, Westerduin E, Borstlap WAA, Hompes R, Bemelman WA, Tanis PJ.Impact of an institutional change from routine to highly selective diversion of a low anastomosis after TME for rectal cancer. Eur J Surg Oncol. 2018;44:1220–5.
27. Hüser N, Michalski CW, Erkan M, Schuster T, Rosenberg R, Kleeff J, Friess H.Systematic review and meta-analysis of the role of Defunctioning stoma in low rectal cancer surgery. Ann Surg. 2008;248:52–60.
28. Bertelsen CA, Andreasen AH, Jørgensen T, Harling H. Anastomotic leakage after anterior resection for rectal cancer: risk factors. Color Dis. 2010;12:37–43.
29. Rullier E, Laurent C, Garrelon JL, Michel P, Saric J, Parneix M.Risk factors for anastomotic leakage after resection of rectal cancer. Br J Surg. 2003;85:355–8.
30. Arezzo A, Migliore M, Chiaro P, etal. The REAL (REctal anastomotic leak) score for predic­tion of anastomotic leak after rectal cancer surgery. Tech Coloproctol. 2019;23:649–63.
31. Beard JD, Nicholson ML, Sayers RD, Lloyd D, Everson NW. Intraoperative air testing of colorectal anastomoses: a prospective, randomized trial. Br J Surg. 2005;77:1095–7.
32. Ivanov D, Cvijanovic R, Gvozdenovic L.Intraoperative air testing of colorectal anastomoses. Srp Arh Celok Lek. 2011;139:333–8.
33. Qin C, Ren X, Xu K, Chen Z, He Y, Song X.Does preoperative radio(chemo)therapy increase anastomotic leakage in rectal cancer surgery? A meta-analysis of randomized controlled trials. Gastroenterol Res Pract. 2014;2014:1–7.
34. Ansari N, Solomon MJ, Fisher RJ, et al. Acute adverse events and postoperative compli­cations in a randomized trial of preoperative short-course radiotherapy versus long-course Chemoradiotherapy for T3 adenocarcinoma of the rectum. Ann Surg. 2017;265:882–8.
35. Shogan BD, Belogortseva N, Luong PM, et al. Collagen degradation and MMP9 activa­tion by enterococcus faecalis contribute to intestinal anastomotic leak. Sci Transl Med. 2015;7:286ra68.
36. Gaines S, Shao C, Hyman N, Alverdy JC.Gut microbiome inuences on anastomotic leak and recurrence rates following colorectal cancer surgery. Br J Surg. 2018;105:e131–41.
37. Gooszen AW, Geelkerken RH, Hermans J, Lagaay MB, Gooszen HG.Temporary decompres­sion after colorectal surgery: randomized comparison of loop ileostomy and loop colostomy. Br J Surg. 2003;85:76–9.
38. Law WL, Chu KW, Choi HK.Randomized clinical trial comparing loop ileostomy and loop transverse colostomy for faecal diversion following total mesorectal excision. Br J Surg. 2002;89:704–8.
39. Khoury GA, Lewis MC, Meleagros L, Lewis AA.Colostomy or ileostomy after colorectal anastomosis?: a randomised trial. Ann R Coll Surg Engl. 1987;69:5–7.
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40. Williams NS, Nasmyth DG, Jones D, Smith AH. De-functioning stomas: a prospec­tive controlled trial comparing loop ileostomy with loop transverse colostomy. Br J Surg. 2005;73:566–70.
41. Güenaga KF, Lustosa SA, Saad SS, Saconato H, Matos D. Ileostomy or colostomy for temporary decompression of colorectal anastomosis. Cochrane Database Syst Rev. 2007;2010:CD004647. https://doi.org/10.1002/14651858.CD004647.pub2.
42. Danielsen AK, Park J, Jansen JE, Bock D, Skullman S, Wedin A, Marinez AC, Haglind E, Angenete E, Rosenberg J.Early closure of a temporary ileostomy in patients with rectal can­cer: a multicenter randomized controlled trial. Ann Surg. 2017;265:284–90.
43. Park J, Angenete E, Bock D, etal. Cost analysis in a randomized trial of early closure of a tem­porary ileostomy after rectal resection for cancer (EASY trial). Surg Endosc. 2020;34:69–76.
44. Vogel I, Reeves N, Tanis PJ, Bemelman WA, Torkington J, Hompes R, Cornish JA.Impact of a defunctioning ileostomy and time to stoma closure on bowel function after low ante­rior resection for rectal cancer: a systematic review and meta-analysis. Tech Coloproctol. 2021;25:751–60.
L. Cunningham and E. Huang
Reoperative Surgery forLocally
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Recurrent Rectal Cancer
NicholasP.McKenna andRobertR.Cima
Introduction
Locoregional rectal cancer recurrence rates have decreased from as high as 30% to less than 10% since the widespread adoption of total mesorectal excision along with administration of neoadjuvant or adjuvant chemoradiotherapy [14]. Locoregional recurrences treated with chemoradiation alone have poor outcomes, with a median survival of only 12 to 24months [57]. However, the combination of preoperative chemoradiation or re-irradiation, an R0 resection, and intraoperative radiation ther­apy (IORT) when indicated can signicantly improve outcomes. Patients with locoregional recurrences undergoing this multimodal treatment approach have 5-year survival between 37% and 57% [7, 8].
Reoperative surgery for locally recurrent rectal cancer is associated with major morbidity rates ranging from 15% to 68% and mortality rates of up to 10% [9]. Therefore, patient selection is critical to ensure that only patients with a reasonable chance for an R0 resection undergo such an extensive operation. Additional impor­tant considerations are ensuring the patient is optimized from a nutritional stand­point, is not smoking, the resection of local recurrence is technically feasible, and that any metastatic disease is controlled or controllable. The latter two factors inu­ence whether the operation is curative or palliative. Optimally, the patient’s case is reviewed by a multidisciplinary team to ensure that appropriate preoperative ther­apy is provided. Given the complexity of these cases, care should provided at a tertiary referral center with the resources and experience to perform an R0 multiv­isceral resection as well as manage potentially signicant postoperative complica­tions [10].
27
N. P. McKenna · R. R. Cima (*) Mayo Clinic, Division of Colon and Rectal Surgery, Rochester, MN, USA e-mail: McKenna.Nicholas@mayo.edu; cima.robert@mayo.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 K. Umanskiy, N. Hyman (eds.), Difcult Decisions in Colorectal Surgery, Difcult Decisions in Surgery: An Evidence-Based Approach,
https://doi.org/10.1007/978-3-031-42303-1_27
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Table 27.1 PICO question search strategy for the chapter
Patients Patients with recurrent rectal cancer Surgery Palliative treatment
Intervention Comparator
Non-treatment
N. P. McKenna and R. R. Cima
Outcomes Survival
Cure Morbidity Quality of life
Search Strategy
PubMed was utilized to conduct a review of the English literature on recurrent rectal cancer. Search terms used included “recurrent rectal cancer,” “locally recurrent rec­tal cancer,” and “intraoperative radiation therapy.” Original studies were used where possible and supplemented by meta-analyses. Reference lists in systematic reviews were used to identify additional manuscripts. Manuscripts published between 1986 and 2022 were assessed with a focus on the last 10years (Table27.1).
Results
Diagnosis
Data on diagnosis of locoregional recurrence of rectal cancer is heterogeneous, with some studies describing over 65% of patients diagnosed due to symptoms [7, 11], while others describe the majority of recurrences diagnosed based on routine sur­veillance imaging and carcinoembryonic antigen (CEA) levels [12]. All patients with a conrmed recurrence require a full staging workup, including cross-sectional imaging, a colonoscopy, and a CEA level. Cross-sectional imaging should include CT scan of the chest, abdomen, and pelvis, as well as a pelvic MRI. Chest and abdominal imaging are useful for the detection of distant recurrence, while CT and MRI of the pelvis dene the anatomic relationships of the locoregional recurrence. MRI is particularly useful since it allows better soft-tissue resolution and can distin­guish recurrent rectal cancer from presacral scar [13]. Tissue diagnosis via colonos­copy if a luminal recurrence or via CT-guided biopsy is important before committing to an operation. If biopsies are non-diagnostic, PET CT is also often helpful to dis­tinguish brosis from recurrence. It may also detect distant metastatic disease missed by CT scan.
Classification Systems andOutcomes
Once a recurrence is diagnosed, there are numerous classication systems to describe the recurrence pattern without clear superiority of one system [14]. The Memorial Sloan Kettering system is based on anatomical compartments (axial, anterior, posterior, or pelvic sidewall). Axial recurrences can be anastomotic (patients status post low anterior resection), perineal (patients status post
27 Reoperative Surgery forLocally Recurrent Rectal Cancer
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abdominoperineal resection), or local recurrence after transanal or transsphincteric excision. Anterior recurrences involve the urogenital structures while posterior recurrences involve the sacrum and/or coccyx. Lateral recurrences involve the pel­vic sidewall bones, musculature, or sidewall structures [15]. In studies that have used the Memorial Sloan Kettering system to evaluate surgical outcomes, R0 resec­tions were more common for axial recurrences compared all other compartments [1517]. Iliac vessel involvement was also specically associated with decreased R0 resections rates [15]. Yamada etal. proposed a system based on the pattern of pelvic invasion– localized type, sacral invasive type, and lateral invasive type [18]. Like the Memorial Sloan Kettering system axial compartment recurrence type, sur­vival was best with the local invasive type [1820]. The Mayo Clinic system uses sites of xation [from 0 sites of xation (F0) to 3–4 sites of xation (F3)] and symp­toms [no symptoms or pain (S0) to symptomatic and painful (S2)] to classify recur­rence [21]. Survival has been shown to decrease with both increasing sites of xation and increasing symptoms and pain [8, 2123]. Additional classication systems exist and are largely based on the pattern of pelvic invasion [23, 24]. The common theme amongst all recurrence classication systems is that axial or local recurrences and therefore less points of xation are associated with either improved rates of R0 resection, survival, or both. No comparisons between the classication systems exist to determine whether one is more prognostic than others.
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Treatment andOncologic Outcomes
Since an R0 resection is the most consistent favorable factor for survival, it is criti­cally important to maximize the chances of this. Multimodal therapy with a combi­nation of chemotherapy, chemoradiotherapy, and surgery have shown the best outcomes compared to surgery alone or radiotherapy alone [2527]. Specic treat­ment received and the sequence of treatment depends on several factors related to the extent of the local recurrence and prior treatment received.
The patients who are radiation naïve, should receive a full course of chemoradia­tion following the same protocols used for locally advanced rectal cancer with 50 to
50.4Gy in 25–28 fractions with radiosensitizing chemotherapy [28]. Patients who previously received radiation can typically receive up to 30.4–39Gy in additional radiation with acceptable toxicity [2931]. Re-irradiation may be better tolerated moving forward with increased use of intensity-modulated radiation therapy [32], which allows precise dose delivery [33]. Hyperfractionated radiotherapy may also reduce the late toxicity of reirradiation [34].
Receipt of radiation or re-irradiation is essential as pooled data from the Mayo Clinic, Rochester and the Catharina Hospital, Eindhoven showed lower rates of R0 resections in patients who never received either radiation or re-irradiation (25.9%) versus those who received full course (50.2%) or re-irradiation (43.0%) in the larg­est series to date (n=565) [25]. Additionally, neoadjuvant chemoradiation and re­irradiation are associated with improved 3-year overall survival (full course 49.3%, re-irradiation 47.6%, no radiation 25.0%) and 3-year local control (full course
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69.0%, re-irradiation 48.9%, no radiation 37.6%) compared to patients who were not re-irradiated [35]. Lastly, in a recent systematic review of studies from 1999 to 2021, the highest proportion of R0 resections were observed in patients treated with neoadjuvant chemoradiotherapy compared to neoadjuvant radiotherapy or adjuvant chemoradiotherapy [36].
Recently, Catharina Hospital, Eindhoven published their results of adding induc­tion chemotherapy to the treatment regimen for recurrent rectal cancer with the goal of improved downsizing the local recurrence and increasing pathologic complete response rates. The regimen consists of either 3cycles of CAPOX (capecitabine and oxaliplatin) or 4 cycles of FOLFOX (leucovorin, 5-uorouraicl, oxaliplatin) fol­lowed by radiation or re-irradiation as described above. If on restaging imaging a patient had a good response to chemotherapy, consolidation chemotherapy is con­sidered during the interval between radiation and surgery.
With this regimen, they achieved a 17% completely pathologic response [37, 38]. This is better than reported complete pathologic response rates of 8%–12% with radiotherapy alone [3941]. Mayo Clinic employs a similar protocol with 4cycles of FOLFOX followed by re-staging imaging with PET-CT and musculoskeletal pro­tocol MRI followed by radiation or re-irradiation [42].
With respect to long-term outcomes, patients in the Catharine Hospital experi­ence with a complete pathologic response had a 3-year overall survival of 92%. Since all patients with a complete response have an R0 resection, by denition, the authors also studied patients with a good response to neoadjuvant therapy and R0 resection. These patients did better than patients with a poor response and R0 resec­tion in both overall survival and local disease-free interval. Interestingly, patients with a poor response but an R0 resection had outcomes similar to patients without an R0 resection for both local-recurrence free survival and metastasis-free survival. Toxicity from chemotherapy was acceptable with 10% of patients experiencing grade 3–4 toxicity and no grade 5 events.
No other institutions have reported outcomes of induction chemotherapy for locally recurrent chemotherapy yet, but the results from Catharina Hospital are promising. They also are in line with the increasing utilization of total neoadjuvant therapy for primary locally advanced rectal cancer [43], which is addressed in a separate chapter. Randomized controlled trials comparing neoadjuvant chemother­apy followed by pelvic re-irradiation versus neoadjuvant chemotherapy alone (GRECCAR 15) and neoadjuvant chemotherapy followed by pelvic re-irradiation versus neoadjuvant chemoradiotherapy (PelvEx II) are currently recruiting patients with recurrent rectal cancer [44, 45]. Therefore, higher-level evidence on preopera­tive therapy for recurrent rectal cancer may be available in the future.
Intraoperative radiation therapy can be added after surgical resection to over­come the dose tolerance of normal tissue to external beam radiation and re­irradiation. Outcomes with the use of IORT are generally favorable in terms of local control and survival without a concomitant increase in morbidity [25, 4650]. At the Mayo Clinic and Catharina Hospital, IORT is delivered via a dedicated linear accel­erator in the operating room [25, 51]. The IORT dose is determined intraoperatively based on frozen section pathologic margins and the radiation dose the patient received preoperatively. For patients who received 45–54Gy preoperatively, IORT