Clinical and Translational Oncology (2022) 24:646–657 https://doi.org/10.1007/s12094-022-02816-9 CLINICAL GUIDES IN ONCOLOGY SEOM‑GEMCAD‑TTD clinical guidelines for localized rectal cancer (2021) Jaume Capdevila1 · Ma Auxiliadora Gómez2 · Mónica Guillot3 · David Páez4 · Carles Pericay5 · Maria José Safont6 · Noelia Tarazona7,8 · Ruth Vera9 · Joana Vidal10 · Javier Sastre11 Accepted: 22 February 2022 / Published online: 18 March 2022 © The Author(s) 2022 Abstract The management of localized rectal cancer requires a multidisciplinary approach to optimize outcomes, reduce morbidity and prevent under or overtreatments. While early stages may obtain benefit of local resections without any additional thera- pies, locally advanced rectal cancer becomes a challenge defining the better sequential strategy of surgery, radiotherapy and chemotherapy. The latest results of international phase III studies have positioned the total neoadjuvant therapy as a potential new standard of care in high risk rectal cancers, however, the best schedule is still not well defined. Keywords Rectal cancer · Total neoadjuvant therapy · Guideline 2 * Jaume Capdevila Department of Medical Oncology, Hospital Universitario jacapdevila@vhebron.net Reina Sofía. IMIBIC. CIBERONC, Córdoba, Spain 3 Ma Auxiliadora Gómez Department of Medical Oncology, Hospital Universitario magespanya@hotmail.com Son Espases, Palma de Mallorca, Spain 4 Mónica Guillot Department of Medical Oncology, Hospital de la Santa Creu monicam.guillot@ssib.es i Sant Pau. U705. CIBERER, Barcelona, Spain 5 David Páez Department of Medical Oncology, Hospital Universitari dpaez@santpau.cat Mútua de Terrassa, Terrassa, Spain 6 Carles Pericay Department of Medical Oncology, Consorcio Hospital cpericay@gmail.com General Universitario de Valencia, Universidad de Valencia. CIBERONC, Valencia, Spain Maria José Safont 7 mjsafont@yahoo.es Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain Noelia Tarazona 8 noetalla@incliva.es Instituto de Salud Carlos III, CIBERONC, Madrid, Spain 9 Ruth Vera Department of Medical Oncology, Hospital Universitario de ruth.vera.garcia@cfnavarra.es Navarra; Navarrabiomed, IDISNA, Pamplona, Spain 10 Joana Vidal Department of Medical Oncology, Hospital del Mar-IMIM, jvidal@parcdesalutmar.cat CIBERONC, Barcelona, Spain 11 Javier Sastre Department of Medical Oncology, Hospital Universitario jsastrev@salud.madrid.org Clínico San Carlos, Madrid, Spain 1 Department of Medical Oncology, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain 13 Vol:.(1234567890) Clinical and Translational Oncology (2022) 24:646–657 647 Introduction Diagnosis and staging In Spain, colorectal cancer (CRC) is the most common type Most frequent warning signs for RC are rectal bleeding, of cancer in both genders and the second cause of all cancer tenesmus, and the change in bowel habit. 95% of cases are deaths. The incidence of CRC in 2021 has been estimated in adenocarcinoma. 43,581 new cases. Of them, 14,209 have been cases of rectal RC is defined as a tumour from the anal verge to cancer (8720 in men and 5489 women) [1]. Median age at 12–15 cm measured by rigid sigmoidoscopy or magnetic the time of diagnosis is about 70 years. Global incidence resonance imaging (MRI). According to the location is sub- of CRC is increasing mainly due to left-sided cancers in divided as low (up to 5 cm), middle (> 5 to 10 cm) and high general and rectal cancer (RC) in particular. (> 10 to 15 cm). Risk factors include age, diet (red or processed meat), All patients must be discussed by a multidisciplinary alcohol and tobacco, overweight, physical inactivity, type team after diagnosis to individualize treatment. II diabetes, inflammatory bowel disease (ulcerative colitis After a suspicion, diagnostic procedures should include a and Crohn`s) and family history of adenomas or CRC. The complete anamnesis with family and personal history, physi- majority of cases of RC are sporadic. Hereditary component cal examination including digital rectal examination, perfor- (lynch syndrome or familial adenomatous polyposis) is less mance status, laboratory tests (complete blood count, liver frequent than in colon cancer. and renal function, and serum level of carcinoembryonic The most common molecular pathway of RC develop- antigen) [3]. ment is chromosomal instability while approximately 13% Total colonoscopy/rectoscopy with biopsy is mandatory are caused by a deficient mismatch repair. to confirm the diagnosis [3]. Virtual colonoscopy is an alter- The introduction screening programs (faecal occult blood native if full colonoscopy is not feasible to rule out con- test) have played roles to detect asymptomatic early stage comitant colon tumors; in case where complete colonoscopy and reducing mortality of CRC. cannot be carried out before surgery, it should be performed 3–6 months after surgery. Thoraco-abdominopelvic computed tomography (CT) scan with intravenous contrast administration is the pre- Methodology ferred study for evaluating the presence of distant metastases [3]. When a CT scan cannot be performed, chest X-ray and For developing this clinical guideline authors have reviewed abdominal MRI should be considered. and discussed most relevant literature published about RC. Endorectal ultrasound (EUS) is recommended for evalu- All the recommendations included in this guideline have had ating tumour depth in early stages (cT1–T2) [4]. the consensus of all the authors and have been graded using Rectal high-resolution MRI is the most accepted modality “The Infectious Diseases Society of America-US Public for preoperative local staging, determining the depth trans- Health Service Grading System” [2] (Table 1). mural tumour invasion, the status of the circumferential Table 1  Levels of evidence and grades of recommendation Levels of evidence I. Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well- conducted randomized trials without heterogeneity II. Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III. Prospective cohort studies IV. Retrospective cohort studies or case–control studies V. Studies without control group, case reports, expert opinions Grades of recommendation A. Strong evidence for efficacy with a substantial clinical benefit, strongly recommended B. Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended C. Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs), optional D. Moderate evidence against efficacy or for adverse outcome, generally not recommended E. Strong evidence against efficacy or for adverse outcome, never recommended 13 648 Clinical and Translational Oncology (2022) 24:646–657 resection margin (CRM), the extramural venous invasion preoperative chemoradiotherapy (CRT) could be evaluated. (EMVI), the height from the anorectal junction, the invasion If we treat these patients without neo(adjuvant) treatment, other structures, the sphincter complex and the presence of the risk of local recurrence is unacceptable, being around suspicious regional nodes (has less sensitivity and specificity 30–50% [12]. to evaluate lymph nodes). The current evidence supporting TEM with perioperative MRI is recommended to plan surgical approach after neo- CRT in cT2N0 RC comes from single series, prospective adjuvant therapy in RC. CRM involvement is an independent single arm phase II studies and meta-analyses, suggesting prognostic factor for overall survival, local recurrence and an acceptable local control (local recurrence (LR) between disease-free survival. The presence of EMVI is associated 4 and 7%) and no differences in distant metastases compared with poor prognosis of local recurrence and disease-free with TME [13–15]. Randomized clinical trials are currently survival. ongoing to assess this strategy in early stage RC [16]. Positron emission tomography (PET) is not recommended routinely for staging localized RC [4]. The 8th edition of the TNM staging system for rectal can- Preoperative management of intermediate cer should be used for clinical and histopathological staging risk rectal cancer [5]. T1 tumours have to be classified according to Haggitt and Kudo-Kikuchi stages depending on polyp morphology TME surgery should be also proposed for those patients [6, 7]. diagnosed with cT3 tumors without clear involvement of After surgery, histopathological analysis of the sample mesorectal fascia due to the high risk of recurrence and the should include: grade, quality of mesorectum, margins high risk of mesorectal lymph node involvement [17]. (proximal, distal and circumferential), depth of penetration Overall, intermediate risk patients (cT3 with very low, (T), lymph, vascular and nerve invasion, number of regional levators clear, MRF clear or cT1-3 in mid or high rectum, lymph nodes (N), extranodal tumour deposits and response cN1 (not extranodal), no EMVI) benefit from preoperative to neoadjuvant treatment. treatment including either short-course radiotherapy (SCRT) Recommendations: or CRT based on fluoropyrimidines followed by high-quality 1. Multidisciplinary team is mandatory for individualized TME. CRT usually consists of 28–30 fractions of 1.8 Gy treatment (III, A). with concurrent with fluorouracil-based chemotherapy fol- 2. Rectal MRI is the standard method for evaluating lowed by surgery after an interval of ≥ 6 weeks, while SCRT locally advanced rectal cancer. Endorectal ultrasound could implies the delivery of 5 fractions of 5 Gy followed by sur- be useful in early stage rectal cancers (III, A). gery either 1 or up to 8 weeks later [18–20]. Both therapeu- tic approaches are equivalent in terms of survival, toxicity and clinical outcomes [21]. Therefore, CRT and SCRT are Management of resectable localized disease considered interchangeable, with a preference for the former when substantial tumour downsizing is needed to achieve Radical resection of early stage RC (cT1/T2N0M0) should clear resection margins or allow sphincter-sparing surgery guarantee cure in these patients. Meta-analysis has shown [22, 23]. Adding oxaliplatin or targeted drugs to fluoropyri- that total mesorectal excision (TME) is equivalent to new midines in the neoadjuvant setting does not improve clinical local resection techniques (especially in cT1N0), but pro- outcomes and thus are not recommended [24–26]. vides greater morbidity (sexual and urinary dysfunction) and the greater presence of a definitive stoma in distal tumors [8]. Preoperative management of high‑risk rectal cancer Studies and meta-analysis have placed transanal endo- scopic microsurgery (TEM) as a technique of choice in High-risk of recurrence rate RC defined by MRI includes cT1N0 rectal tumors [9], when they meet low-risk crite- the presence of extramural vascular invasion (EMVI), cir- ria[10] (low tumour grade, absence of lymphovascular and cumferential resection margin (CRM) threat or involvement, perineural invasion, and correct margin resection). Other- existence of enlarged lateral lymph nodes, tumour location wise, TME should continue to be the treatment of choice in the lower third of the rectum and the high-risk TNM clas- for cT1, due to the high risk of local recurrence, although sification factors. distant recurrence presents similar values between the two The subdivision of category T3 rectal cancer into two surgical techniques [11, 12]. subgroups of extramural spread ≤ 5 mm or more than 5 mm Stage cT2N0M0 RC should be treated upfront with TME resulted in significant different survival and local recurrence without perioperative treatments. However, if these tumors rates [27]. In a Norwegian study, the estimated rates of LR meet low-risk criteria, treatment with TEM associated with increased dramatically twofold with N stage from N0 to N2 13 Clinical and Translational Oncology (2022) 24:646–657 649 and there was a fourfold increase in the rates of metastases continuous infusion of 5FU with regard to 5-year OS (75.7% from N0 to N2 [28]. vs 66.6%; p = 0.0004) [41]. The presence of EMVI is associated with poorer 3 years Likewise, preoperative CPC CRT achieved similar rates relapse-free survival (RFS) and a 3.7 times higher relative of pCR, sphincter-sparing surgery, and surgical downstaging risk of developing metachronous metastases within 1 year compared with continuous infusion of 5FU in the NSABP of diagnosis [29, 30]. CRM is a powerful predictor of devel- R-04 trial, which in a 2 × 2 design included 1608 patients opment of local recurrence, distant metastases and survival with stage II or III RC. In this trial, the addition of oxalipl- [31]. In the context of lateral nodal spread, LR rates can be atin did not improve locoregional events, pCR, DFS, OS or as high as 35% [32]. Low tumour height is related to pelvic surgical outcomes while toxicity was increased significantly recurrence, worse 5-year overall survival (OS) and disease- [42, 43]. free survival (DFS) rates [33, 34]. Similar results were seen when the addition of oxaliplatin These risk factors, as well as obesity or gender, which to 5FU/RT or CPC/RT was evaluated in the STAR-01[24] may influence the quality of surgery, should be taken into and ACCORD 12/0405-Prodige 2[44] trials respectively. In account when deciding on preoperative treatment. the most recent trial published addressing this question, the PETACC 6 trial, preoperative oxaliplatin plus CPC-based CRT again impairs tolerability and does not improve effi- Treatment selection cacy [45]. In contrast, higher rates of pCR were seen in the oxalipl- Preoperative chemoradiotherapy or short‑course atin plus 5FU/RT arm in the CAO/ARO/AIO-04 trial (17% radiotherapy vs 13%; p = 0.038) [25]. The DFS at 3 years was 75.9% (95% CI, 72.4–79.5) in the oxaliplatin group versus 71.2% A number of randomized trials have evaluated the effec- (95% CI 67·6–74·9) in the control group (hazard ratio [HR] tiveness of the addition of chemotherapy to preoperative 0.79, 95% CI 0.64–0.98; p = 0.03). Recently, results from radiotherapy [35, 36]. Putative benefits of this therapeutic the Chinese FOWARC phase III randomized trial found that strategy include local radio-sensitization which may in turn oxaliplatin plus 5FU CRT although improved the pCR, no reduce tumour volume, increase rates of pCR and facilitate significant differences in 3-year DFS were detected [46]. a sphincter-sparing procedure. Other randomized trials have also investigated the addi- Results from the German Rectal Cancer Study Group tion of targeted therapies to preoperative CRT for localized (the CAO/ARO/AIO-94 trial) demonstrated a benefit of rectal cancer. However, further evidence is needed for a clear preoperative CRT compared with postoperative treatment. recommendation to add other agents to fluoropyrimidine- Preoperative therapy was initially associated with signifi- based CRT and how to integrate them within the total neo- cant improvements in LR (6% vs 13%; p = 0.006), sphinc- adjuvant therapy (TNT) approach. ter-sparing surgery (39% vs 19%; p = 0.004) and treatment The so called preoperative short-course radiotherapy related toxicity (27% vs 40%; p = 0.001) [37]. Long-term (SCRT), 25 Gy over 5 days followed by immediate TME follow-up confirmed the improvement in the 10-year cumu- has demonstrated decreased rate of local recurrences com- lative LR (7.1% vs 10.1%; p = 0.048), although OS, DFS pared to surgery alone[18]. No differences in rate of local and the occurrence of distant metastases was similar in the recurrence or survival have been found when comparing two groups [19]. The EORTC2291 and FFCD9203 trials both strategies, though a higher tumour downstaging were corroborated the local control benefit of preoperative CRT observed in favour of CRT [21, 40]. SCRT could be con- versus long-course RT alone but with no differences in sur- sidered an alternative to CRT in intermediate-risk RC, and vival [38, 39]. in high-risk RC for patients not suitable to receive a more Preoperative CRT was then compared to SCRT in two intensive regimen due to comorbidity, age or poor perfor- randomized trials. In the Polish trial, CRT compared to mance status. SCRT demonstrated a higher pCR rate (16.1% vs 0.7%) and a lower positive circumferential resection margin rate (12.9% Total neoadjuvant therapy vs 4.4%)[40]. Similarly, a higher pCR was achieved with CRT (15% vs 1%) in the Trans-Tasman trial[21]. However, in Preoperative chemotherapy (CT) may be associated with bet- both trials, there were no differences in LR rates or survival ter treatment compliance, may allow full systemic doses of outcomes between the two preoperative treatments. CT to be delivered and an early micrometastases treatment. With respect to the type of CT administered concurrently A recent meta-analysis shows that addition of preoperative with RT, a phase III randomized trial compared capecitabine CT to standard neoadjuvant chemoradiotherapy results in (CPC)- or 5-fluorouracil (5FU) -based CRT either pre- or a higher pCR rate [47]. The optimal sequence of CRT/RT postoperatively demonstrated that CPC was non-inferior to and CT is not well defined. The CAO/ARO/AIO-12 trial 13 650 Clinical and Translational Oncology (2022) 24:646–657 suggested a higher complete response rate after consolida- a benefit in PFS or OS, although they suffer from many chal- tion CT than after induction CT [48]. Data from OPRA trial lenges (old 5FU-based schedules, poor patient accrual and report a higher organ preservation rate in the consolidation low compliance) [61–64]. A meta-analysis of these studies CT arm [49]. also failed to demonstrate a significant benefit [65]. Only 2 Three randomized trials have shown benefit of total subsequent studies evaluating the addition of oxaliplatin to neoadjuvant therapy (TNT) when comparing with stand- adjuvant fluoropyrimidine therapy have demonstrated a mod- ard treatment of CRT regarding 3-years DFS (induction est increase in PFS. The German phase III study CAO/ARO/ mFOLFIRINOX followed of CRT vs CRT) [50], cumulative AIO-04 examines the addition of oxaliplatin to both neoadju- probability of disease-related treatment failure (SCRT fol- vant and adjuvant therapy [25]. The long-term results of the lowed of consolidation CAPOX/FOLFOX vs CRT) [51] and randomized phase II ADORE study demonstrated a significant 3-years OS rate (SCRT followed of consolidation CAPOX/ PFS benefit, although the OS benefit is limited to patients with FOLFOX vs CRT) [52]. Inclusion criteria for these phase ypN2 and minimally regressed tumours [66]. III trials were slightly different and increases the complex- It is also unclear whether the benefit of adjuvant CT depends ity of patient selection. The French study included stage II- on the response to previous CRT. Postoperative pathological stag- III RC, the international RAPIDO trial recruited patients ing (ypTNM) may predict a high risk of subsequent local and with high-risk RC defined y MRI bas cT4a or cT4b, EMVI, distant recurrence, but there is no automatic benefit from the use cN2, involved mesorectal fascia, or enlarged lateral lymph of adjuvant CT. A pooled analysis of 3313 patients observed that nodes, and finally the Polish study randomized patients with those with a pCR after CRT may not benefit from adjuvant CT, primary or locally recurrent RC involving adjacent organs whereas patients with residual tumour had superior outcomes (cT4) or a palpably fixed cT3. when this treatment was administered although the test for inter- On the basis of these results, in front of a high-risk RC, a action did not reach statistical significance [67]. TNT scheme might be considered in the setting of a multi- disciplinary discussion and a case by case decision (Table 2). Adjuvant chemoradiotherapy Nevertheless, although results of TNT seem favourable, some issues must be clarified in future trials: Neoadjuvant treatment (CRT or SCRT) has better outcomes than postoperative CRT with concomitant fluoropyrimidine- – Chemotherapy regimen to add to neoadjuvant radiother- based chemotherapy after immediate radical TME, so adjuvant apy CRT is no longer recommended as a standard of care[37]. – Type of radiotherapy: SCRT vs CRT​ Only in those scenarios that are included in the below recom- – Induction CT (before radiotherapy) vs consolidation CT mendations, adjuvant CRT may play a role. (after radiotherapy) Recommendations: – Subgroup of patients who benefit from TNT 1. It is reasonable to consider adjuvant CT after preopera- – Selective radiotherapy tive CRT in patients with high-risk yp stage II and III (II, C). In – Non-operative management the absence of more solid results, the decision to use adjuvant CT (fluoropyrimidines alone or in combination with oxalipl- Recommendations: atin) should be evaluated considering the risk of relapse and potential toxicity. This option should be assessed on a person- 1. Preoperative SCRT or continuous intravenous infusions alized basis with each patient. For patients who are frail, with of 5FU or oral capecitabine during CRT are recom- significant comorbidities, or with life expectancy of less than mended for patients with stage II or III rectal cancer [I, 5 years, CT should be omitted. A] 2. Adjuvant CRT could be used in patients with unexpected 2. The addition of oxaliplatin or to preoperative CRT is not adverse histopathological features after primary surgery as posi- recommended [I, D] tive CRM, pT4b, incomplete mesorectal resection, pN2 extracap- sular spread close to MRF or extranodal deposits or in other cases with high-risk of LR if preoperative RT was not given. Postoperative management of intermediate and high‑risk rectal cancer Non‑operative management of localized Adjuvant chemotherapy rectal cancer The evidence on the role of adjuvant CT in RC is limited. The pCR and cure rates have increased in the last years in The vast majority of studies evaluating the use of adjuvant CT patients with RC thanks to the improvement of neoadju- after preoperative CRT and total TME failed to demonstrate vant treatment strategies and TME. However, long-term 13 Clinical and Translational Oncology (2022) 24:646–657 651 Table 2  Main randomized trials of TNT Study N Eligibility Treatment strategy Primary end- Primary out- pCR DFS point come Marechal et al. [53] 57 cT2-T4/N + mFOLFOX × 2 ypT0-1 N0 32% vs. 34%* 25% vs. 28%* NR -CRT-TME vs. CRT-TME GCR 3 [54, 55] 108 ≥ cT3, N + , CAPOX × 4 -CRT- pCR 14% vs. 13%* NR 62% vs. 64%* EMVI + TME MRF + or distal vs. CRT—TME— CAPOX × 4 WAIT [56] 49 cT3-T4 or N + CRT—5FU × 3 pCR 16% vs. 25%* NR NR -TME vs. CRT—TME KCSG CO 14–03 [57] 110 cT3-T4 CRT— ypT0-2 N0 36% vs. 21% 14% vs. 6%* NR CAPOX × 2— TME vs. CRT -TME POLISH II [52, 58] 515 Fixed cT3 or cT4 SCRT- FOL- R0 resection 77% vs. 71%* 16% vs. 12%* 43% vs. 41%* FOX4 × 3 -TME vs. CRT (FOL- FOX) -TME KIR [59] 180 cT2/3 and N + FOLFOX × 6— Chemo compli- 80% vs. 53% 31% vs28%* 72% vs. 68%* EMVI + , or HDRBT ance MRF + HDRBT vs. HDRBT STELLAR 599 Distal or middle SCRT— 3-year DFS 64% vs. 62.3% 22.5% vs. 12.6% 64% vs. 62.3% SPS:refid::bib60(60) third CAPOXX4— T3-T4 and/or N + TME ± CAPOX X2 vs CRT -TME ± CAPOX X6 RAPIDO [51] 912 cT4a or cT4b, SCRT -CAPOX × 6 3-year disease- 23.7% vs 30.4% 28% vs. 14% 23.7% vs 30.4% EMVI, cN2, / FOLFOX4 × 9 related treat- MRF + or -TME ment failure enlarged vs. LCRT -TME lateral lymph -CAPOX × 8 / nodes FOLFOX4 × 12 PRODIGE 23 [50] 461 cT3-T4 mFOL- 3-year DFS 76% vs. 69% 28% vs. 12% 76% vs. 69% FIRINOX × 12— CRT—TME -mFOLFOX × 6/ Cape × 4 vs. CRT –TME— mFOLFOX6 × 12/ Cape × 8 DFS disease-free survival, pCR pathological complete response, CRT​ chemoradiotherapy, EMVI extramural venous invasion, MRF mesorectal fascia, HDRBT high-dose rate endorectal brachytherapy, NR not reported *Non-statistically significant functional sequelae including sexual and urinary dysfunc- management or watch-and-wait (W&W)) has been proposed tion has been reported in more of half of patients with a as an alternative to rectal surgery with the benefits of a proc- permanent colostomy [68, 69]. In addition, 40% of patients tectomy sparing approach. with bowel continuity preservation describes a significant New international consensus criteria describe cCR as (a) reduction in their quality of life (QoL) due to altered bowel the absence of any palpable tumour at digital rectal exami- function in the frequency, consistency, unpredictability or nation (DRE) and rectoscopy (except a small residual ery- faecal incontinence [70–72]. For those patients achieving a thematous ulcer or scar) and (b) a substantial downsizing complete clinical response (cCR) after a preoperative treat- in the MRI with no observable residual tumour or residual ment, a close surveillance strategy (so called, non-operative fibrosis only and no suspicious lymph nodes. Endoscopic 13 652 Clinical and Translational Oncology (2022) 24:646–657 biopsy is only recommended when DRE and MRI are not Local relapse conclusive [73]. Habr-Gama pioneered the W&W strategy more than The incidence of LR has decreased significantly with 20 years ago in a prospective unicentric study for patients the advances in multimodality treatment, but almost with a cCR after CRT with 5-FU, Leucovorin plus 50,4 Gy 4–10% of rectal cancer patients will develop LR disease radiotherapy[74]. Authors demonstrated the safety of this which prognosis is poor with a median survival about approach with LR treated with savage surgery and no 1–2 years. MRI is the optimal imaging modality for the negative impact on RFS or OS. Currently, this treatment assessment but there is no standard classification system paradigm is of growing interest worldwide. The evidence of LR and treatment is very heterogeneous between cent- from non-randomized studies in highly-specialized centers ers [84]. Because up to 74% of patients will present LR [75–77], as well as systematic reviews and meta-analysis with synchronous distant metastatic disease, all patient [78, 79] show that avoiding surgery in patients with a cCR with suspected LR should undergo a full clinical stag- is safe keeping the surgery for those patients with tumour ing evaluation. Treatment remains a major concern and regrowth during follow-up. Recently, a large international it has to be discussed by a specialized multidisciplinary multicenter registry (the International Watch & Wait Data- team taken into consideration prior therapy, the local base) included more than 1000 patients with RC from 15 extent of the recurrence, and whether distant metastases countries [80] that received neoadjuvant treatment and are present or not. were managed by W&W strategy. At a median follow-up of Recommendation: 3.3 years, the 2-year cumulative incidence of local regrowth was 25.2% (95% CI 22.2–28.5%). Distant metastases were – Surgery diagnosed in 8% of patients and 5-year OS was 85% (95% CI 80.9–87.7%). Discordantly, a retrospective case series   Surgery can be performed in a small number analysis from Memorial Sloan Kettering Cancer center of cases (<20% in the best series). A complete resec- group showed that patients who avoid surgery after a cCR tion (R0 with negative margins) is the most important had worse survival and a higher incidence of distant metas- prognostic factor and whenever possible, an attempt tases compared to patients who underwent to surgery after should be made to remove the tumour and affected neoadjuvant treatment [81]. Again, this data comes from a organs [III, C]. When radical resection is achieved, retrospective non-randomized observational study including 3-year DFS is approximately 57% and 3-year OS elderly patients and high prevalence of low rectal tumors. between 48 and 65% [85]. Currently, prospective clinical trials are ongoing to inter- – Combined modality therapy rogate the organ preservation strategy according to clinical response after TNT [82]. For most cases of LR, we suggest combined modality Till now, no evidence from randomized trials is avail- therapy rather than surgery alone. The specific approach able to confirm both the long-term oncological outcomes depends on the previous treatment: and the superiority of organ preservation in terms of QoL. For previously irradiated patients, LR is habitually not Currently, a recommendation for non-operative management easily resectable and reirradiation combined or not with after neoadjuvant treatment cannot formally be proposed and chemotherapy could be an option. Re-irradiation is feasible the W&W strategy may be reserved for prospective clinical in selected patients and may permit surgical salvage and trials and individually selected patients after a multidiscipli- long-time survival [IV, C]. New techniques as intensity- nary evaluation of response. modulated RT (IMRT), proton beam irradiation or ste- reotactic body radiation therapy (SBRT) could be used in selected centres and have shown a low rate of acute toxic- Management of unresectable rectal cancer ity (10–20%), good symptomatic relief (82–100%) and an acceptable incidence of late complications with median sur- A RC involving adjacent non-resectable structures such as vivals about 40-60 months. When surgical option or re-irra- the proximal sacrum, pelvic sidewall, pelvic floor, prostate, diate is not possible, systemic palliative CT may be used to or base of the urinary bladder or palpably fixed is considered downstage the tumour, but efficacy is limited [V, C] [86, 87]. not optimal for a complete and curative resection. One rand- For previously unirradiated patients, management should omized trial comparing RT versus CRT showed favourable be similar to that of newly diagnosed tumors, with neoadju- results in favour of CRT [83]. Data from Polish trial, which vant therapy prior to surgery [III, A]. In centres with experi- includes palpably fixed rectal tumours, showed a benefit in ence, intraoperative radiotherapy could also be considered 3-years OS in patients treated with SCRT and consolidation [88]. oxaliplatin based CT [52]. 13 Clinical and Translational Oncology (2022) 24:646–657 653 Fig. 1  Recommendations for the management of rectal cancer For patients not candidate for potentially curative mul- • Clinical assessment and CEA determination every timodality therapy, symptom relief can often be achieved 3–6 months for the first 2 years, and then every 6 months through a diverting colostomy, endoscopic laser ablation, for a total of 5 years [V, D] stent placement or palliative radiotherapy [V, C]. • Annual computed tomography (CT) of the chest, abdo- men, and pelvis for 5 years [V, B] Follow up • Colonoscopy is recommended at approximately 1 year following resection (or at approximately 3–6 months About 25–40% of patients who present stage II or III of rec- post-resection if not performed preoperatively due to tal cancer will develop recurrence. It is well reported than an obstructing lesion). Repeat colonoscopy is typically more than 90% of recurrences occur in the first 5 years after recommended at 3 years, and then every 5 years there- surgery and most of them within the first 3 years. Addi- after, unless follow-up colonoscopy indicates advanced tionally, approximately 7% of patients will present with adenoma (villous polyp, polyp > 1 cm, or high-grade dys- metachronous colon tumors. plasia), in which case colonoscopy should be repeated in Surveillance programs are generally based on physical 1 year [I, A]. examination, CEA evaluation, imaging and endoscopy, but • For patients with rectal cancer treated with transanal the best follow-up strategy is not established (specific tests local excision only or those who have undergone low and inter-test interval). The most recent Cochrane analysis anterior resection and who have not received pelvic radi- comparing less versus intensive follow-up, found that sal- ation therapy (RT), we suggest flexible proctosigmoidos- vage surgery with curative intent was more frequent with copy every 6 months for 3–5 years. intensive surveillance but this did not appear to translate into a survival advantage. Nevertheless, in line with most expert We do not recommend for routine surveillance: faecal groups and published guidelines, we recommend intensive occult blood testing, liver function tests, complete blood postoperative surveillance for most patients with resected count, chest radiograph, positron emission tomography stage II or III rectal cancer who would be considered candi- (PET) scans or ctDNA assays (Fig. 1). dates for curative-intent surgery. We also suggest not practic- Surveillance should be guided by presumed risk of recur- ing any post-treatment surveillance for asymptomatic stage rence and functional status of the patient. Patients at higher I rectal cancer except of interval colonoscopy. Besides, the risk should be considered for more frequent testing. Addition- surveillance strategy for resected stage IV disease should be ally, if the patient is not a surgical candidate or a candidate for individualized [22, 89]. systemic therapy because of severe comorbid conditions or Recommendation: advanced age, surveillance tests should not be performed [90]. 13 654 Clinical and Translational Oncology (2022) 24:646–657 Declarations T1N0M0 rectal adenocarcinoma: a systematic review and meta- analysis. Dis Colon Rectum. 2015;58(1):122–40. 9. Lu JY, Lin GL, Qiu HZ, Xiao Y, Wu B, Zhou JL. Comparison of Conflict of interest MJSA reports Advisory Board, Speaker and Other transanal endoscopic microsurgery and total mesorectal excision from Amgen, Merck, Sanofi, Servier and Pierre Fabre. JCC reports in the Treatment of T1 Rectal Cancer: A Meta-Analysis. PLoS Advisory Board, Speaker and Grant from Bayer, Eisai, Ipsen, Adacap One. 2015;10(10):e0141427. and Amgen; Advisory Board and Speaker from Novarti, Pfizer, Ex- 10. Gunderson LL, Sargent DJ, Tepper JE, Wolmark N, O’Connell elisis, Sanofi, Lilly, Huchmed and ITM and Advisory Board from MJ, Begovic M, et al. Impact of T and N stage and treatment on Merck Sereno. JVB reports Advisory Board and Speaker from Merck survival and relapse in adjuvant rectal cancer: a pooled analysis. Serono, BMS and Novartis and Speaker from Sanofi, MSD and Pierre J Clin Oncol. 2004;22(10):1785–96. Fabre. DPLB reports Honoraria from Amgen, Sanofi, Novartis; Con- 11. Sajid MS, Farag S, Leung P, Sains P, Miles WF, Baig MK. Sys- sulting Advisory Role from Amgen, Ipsen, Servier; Research Funding tematic review and meta-analysis of published trials comparing from Merck and Travel Accommodation Expenses from Amgen, Mer- the effectiveness of transanal endoscopic microsurgery and radical ck, Roche, Lilly, Servier, Sanofi and Ipsen. MGM, RVG, CPP, NTL, resection in the management of early rectal cancer. Colorectal Dis. JSV and MAGE have nothing to disclose. 2014;16(1):2–14. 12. Junginger T, Goenner U, Hitzler M, Trinh TT, Heintz A, Wol- Ethical approval This article does not contain any studies with human lschlaeger D, et al. Long-term oncologic outcome after transanal participants or animals performed by any of the authors. endoscopic microsurgery for rectal carcinoma. Dis Colon Rectum. 2016;59(1):8–15. Informed consent For this type of study formal consent is not required. 13. Borstlap WA, Coeymans TJ, Tanis PJ, Marijnen CA, Cunning- ham C, Bemelman WA, et al. Meta-analysis of oncological Open Access This article is licensed under a Creative Commons Attri- outcomes after local excision of pT1-2 rectal cancer requiring bution 4.0 International License, which permits use, sharing, adapta- adjuvant (chemo)radiotherapy or completion surgery. Br J Surg. tion, distribution and reproduction in any medium or format, as long 2016;103(9):1105–16. as you give appropriate credit to the original author(s) and the source, 14. Pericay C, Serra-Aracil X, Ocana-Rojas J, Mora-Lopez L, Dotor provide a link to the Creative Commons licence, and indicate if changes E, Casalots A, et al. Further evidence for preoperative chemora- were made. The images or other third party material in this article are diotherapy and transanal endoscopic surgery (TEM) in T2–3s, N0, included in the article's Creative Commons licence, unless indicated M0 rectal cancer. Clin Transl Oncol. 2016;18(7):666–71. otherwise in a credit line to the material. If material is not included in 15. 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