Surgical resection is the cornerstone of rectal cancer treatment. Following neoadjuvant chemoradiotherapy (nCRT), many patients undergo surgery. Another group of patients may not undergo surgery for various reasons, regardless of nCRT response. This study investigates the differences in clinical characteristics and long-term oncological outcomes of operated and non-operated elderly rectal cancer patients.

This multicentre observational retrospective cohort analysis included 296 elderly patients (169 surgery, 127 non-surgical) treated at three tertiary cancer centres in Turkey between January 2010 and April 2024. Clinicopathologic features and survival outcomes were compared between groups.

Patients in the surgery group were younger (p < 0.000) and had better performance scores (p < 0.000). There were no differences in initial clinical (c) T stages or cM stages; however, cN2 patients were more prevalent in the surgical group and cN1 patients were more prevalent in the non-surgical group (p = 0.010). No differences in radiotherapy treatment schedules were observed among the groups. The surgical group received more concurrent (p = 0.046) and adjuvant (p < 0.000) chemotherapy. Patient refusal (63.8%) was the most common reason among non-surgical patients. The surgery group showed better overall survival (OS) (median, 99 vs. 33 months) (p < 0.000), local recurrence-free survival (LRFS) (97.8% vs. 65.8% at 3 years, p < 0.000), and distant metastasis-free survival (DMFS) (80.3% vs. 73.3% at 3 years, p = 0.022).

This study shows that elderly rectal cancer patients without surgery had poor survival and tumour control. Surgical resection in rectal cancer is very important and should be strongly recommended for all medically suitable elderly patients.

As patients with rectal cancer with clinical complete response (cCR) after neoadjuvant therapy may be safely spared Total Mesorectal Excision (TME), strategies to maximize cCR are needed.

We conducted a single-arm phase II study to determine whether dose-escalated short-course radiotherapy (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by eight cycles of FOLFOXIRI increased cCR rates among adult patients with > T2N0M0 or low T2N0 rectal cancer.

Between 2020 and 2023, we enrolled 37 patients, of whom 27 (73 %) had at least one high-risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin, positive lateral node). At primary endpoint assessment, nine (24 %) patients had cCR on both endoscopy and MRI, and pursued organ preservation (OP). Fourteen (38 %) patients had cCR only on endoscopy, nine of whom pursued OP. Of the 18 patients who pursued OP, nine had local regrowth at two years from radiotherapy start, with two-year TME-free survival of 26 %. Baseline factors significantly associated with not achieving OP included age < 50 years and T4 disease. At mid-treatment restaging, patients who achieved OP were significantly less likely to have persistent node positivity, EMVI, and endoscopically visible tumor. Grade 3+ adverse events at least possibly attributed to chemotherapy and radiotherapy occured in 51% and 43% of patients, respectively.

Short-course radiotherapy with a boost followed by FOLFIXIRI results in OP in one-quarter of patients with high-risk rectal cancer, with poorer response among younger patients and T4 disease. Mid-treatment response may help guide timely decision-making regarding treatment.

Organ preservation has become an attractive alternative to surgery (total mesorectal excision [TME]) among patients with rectal cancer after neoadjuvant therapy who achieve a clinical complete response (cCR). Nearly 30% of these patients will develop local regrowth (LR). Although salvage resection is frequently feasible, there may be an increased risk for development of subsequent distant metastases (DM). The aim of this study is to compare the risk of DM between patients with LR after Watch and Wait (WW) and patients with near-complete pathologic response (nPCR) managed by TME at the time of reassessment of response.

Data from patients enrolled in the International Watch & Wait Database (IWWD) with cCR managed by WW and subsequent LR were compared with patients managed by TME (with ≤10% cancer cells-nPCR) from the Spanish Rectal Cancer Project (VIKINGO project). The primary end point was DM-free survival at 3 years from decision to WW or TME. The secondary end point was possible risk factors associated with DM.

Five hundred and eight patients with LR were compared with 893 patients with near-complete response after TME. Overall, DM rate was significantly higher among LRs (22.8% v 10.2%; P ≤ .001). Independent risk factors for DM included LR (v TME at reassessment; P = .001), ypT3-4 status (P = .016), and ypN+ status (P = .001) at the time of surgery. 3-year DM-free survival was significantly worse for patients with LR (75% v 87%; P = .001). When stratified for pathologic stage, patients with LR did significantly worse through all stages (P ≤ .009).

Patients with LR appear to have a higher risk for subsequent DM development than patients with nPCR managed by TME at restaging irrespective of final pathology. Leaving the primary undetectable tumor in situ until development of LR may result in worse oncologic outcomes.

BackgroundNonoperative management in patients with rectal cancer with complete response to radiation therapy and chemotherapy is of increasing interest. Most of the data on nonoperative management have centered around patients treated with long-course chemoradiotherapy. The ability of short-course radiation-based treatment courses to achieve durable complete responses with sustained organ preservation is less defined. This study updates our institution's long-term experience with nonoperative management following upfront short-course radiation therapy and sequential/consolidation chemotherapy.MethodsWe retrospectively reviewed patients with nonmetastatic rectal cancer treated with sequential short-course radiation therapy and chemotherapy who reached complete response and were subsequently followed with nonoperative management. We report on disease control outcomes, including rates of regrowth and results of salvage surgery. We investigated characteristics associated with local tumor regrowth.ResultsOur study included 52 patients. The 2-year freedom from local regrowth for the entire cohort was 75%. Notably, patients with high-risk disease characteristics at diagnosis exhibited a trend toward a higher rate of local tumor regrowth. No patient with sustained clinical complete response developed metastatic disease. Of the twelve patients undergoing surgical salvage for regrowth of disease, ten were resected with complete/near-complete total mesorectal surgical specimens with negative margins.ConclusionsThe optimal approach to achieving sustained organ preservation through the use of radiation therapy and chemotherapy is not well defined. Our findings show the viability of neoadjuvant therapy incorporating short-course radiation therapy to achieve durable complete responses.

Radical treatment of rectal cancer has evolved quite significantly over the last few decades with the development of optimal local disease staging with magnetic resonance (MR), refined surgical techniques including total mesorectal excision (TME) with or without sphincter-preservation, and multimodality treatment with the use of chemotherapy and radiation. While oncological outcomes have shown some significant improvements in terms of local disease control and distant metastases rates, complication rates and functional sequelae remain quite significant for patients undergoing TME surgery. In this setting, organ-preserving alternatives, including transanal local excision (TAE) and Watch and Wait (WW), have become increasingly attractive to patients in an attempt to avoid major surgery (TME) as an alternative treatment strategy with no oncological compromise. In the present narrative review, the fundamentals of selection and outcomes of patients undergoing WW will be covered to provide updated information for colorectal surgeons and surgical oncologists interested in this treatment alternative in clinical practice.

Organ preservation through a watch-and-wait (W&W) strategy has become a viable option for select rectal cancer patients with clinical complete responses (cCR) to total neoadjuvant therapy (TNT). This approach limits the morbidity associated with multimodal treatment. However, the optimal treatment strategy and predictors of treatment response are still unresolved. Rectal cancer incidence is rising, particularly in developing countries, and the disease is a major public health concern in Chile. Prior to the no operation after short-course radiotherapy followed by consolidation chemotherapy in locally advanced rectal cancer (NOAHS-ARC) trial, TNT-based treatments and W&W programs had not been implemented in Chile.

This single-arm, multicenter, phase II prospective trial, conducted in Santiago, Chile, will enroll patients with stage II/III rectal adenocarcinoma. Treatment involves induction short-course radiotherapy (25 Gy in 5 fractions) followed by consolidation chemotherapy (FOLFOX × 9 or CAPOX × 6 cycles). The response will be assessed 4-8 weeks after chemotherapy completion. Patients achieving cCR will be offered W&W, while those with incomplete responses will undergo total mesorectal excision. The primary endpoint is the rate of complete tumor response, combining pathologic complete responses (pCR) and sustained cCR (> 1 year), compared to a matched cohort treated with neoadjuvant chemoradiation alone. The trial aims to recruit 48 patients, assuming a combined pCR/sustained cCR rate of 12%. Quality of life measures will be assessed, and a biorepository of tissue and plasma samples will be established for future research, alongside serial endoscopic and MRI images.

NOAHS-ARC seeks to advance organ preservation strategies in rectal cancer while pioneering TNT and W&W protocols in Chile. The study will also focus on functional outcomes and provide valuable data for improving patient care both locally and globally.

ClinicalTrials.gov identifier NCT04864067. Registered on April 28, 2021.

With the results of several recently published clinical trials, this guideline focused update provides evidence-based recommendations for the indications and dose-fractionation regimens for neoadjuvant radiation therapy (RT), optimal sequencing of RT and systemic therapy in the context of total neoadjuvant therapy (TNT), and considerations for selective omission of RT and surgery for rectal cancer.

The American Society for Radiation Oncology convened a multidisciplinary task force to update 3 key questions that focused on the role of RT for patients with operable rectal cancer. The key questions addressed (1) indications for neoadjuvant RT, (2) selection of neoadjuvant regimens, and (3) indications for consideration of a nonoperative management (NOM) or local excision approach after definitive/preoperative chemoradiation. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for quality of evidence grading and strength of recommendation.

For patients with stage II-III rectal cancer, neoadjuvant RT was strongly recommended; however, among patients deemed at lower risk of locoregional recurrence, consideration of omission of neoadjuvant RT was conditionally recommended in favor of neoadjuvant chemotherapy with a favorable treatment response or upfront surgery. For patients with T3-T4 and node-positive rectal cancer undergoing neoadjuvant RT, a TNT approach was strongly recommended. Among patients with higher risk of locoregional recurrence, TNT with chemotherapy before or after long-course chemoradiation was strongly recommended, whereas TNT with short-course RT followed by chemotherapy was conditionally recommended. For patients with rectal cancer for whom NOM is a priority, concurrent chemoradiation followed by consolidation chemotherapy was strongly recommended. Selection of RT dose-fractionation regimen, sequencing of therapies, and consideration of NOM should be determined by multidisciplinary consensus and based on disease extent, disease location, patient preferences, and quality of life considerations.

The task force proposed recommendations to inform best clinical practices on the use of RT for rectal cancer with strong emphasis on multidisciplinary care. Future studies should focus on further addressing optimal treatment regimens to allow for more personalized recommendations based on individual risk stratification and patient priorities regarding quality of life.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with rising incidence due to aging populations and obesity-related factors. This review explores the evolving molecular and FIGO classifications of EC, highlighting their significance in diagnosis, prognosis, and personalized treatment strategies. Molecular subtyping based on The Cancer Genome Atlas (TCGA) classification offers a more precise understanding of EC, dividing it into POLE ultramutated, microsatellite instability-high (MSI-H), copy-number low (CNL), and copy-number high (CNH) subtypes. Each subgroup has distinct genetic, histological, and prognostic characteristics. Recent updates to the FIGO staging system incorporate molecular features, allowing for more tailored treatment approaches. Advances in immunotherapy, targeted therapies, and novel therapeutic combinations have reshaped clinical management. This review emphasizes the integration of molecular diagnostics into routine practice, outlining challenges and future perspectives in managing EC for improved patient outcomes.

At the end of the past century, the introduction of Total Mesorectal Excision (TME), preceded by either short-course radiotherapy (SCRT) or chemoradiation (CRT), established the new standard of care for locally advanced rectal cancer (LARC). Recently, significant advancements were achieved for both dMMR/MSI and pMMR/MSS LARC patients. For the 2-3% of dMMR/MSI LARCs, ablative immunotherapy emerged as a curative approach, offering the possibility of avoiding chemotherapy (CT), radiotherapy, and surgery altogether. In pMMR/MSS LARCs, the intensification of preoperative treatments with Total Neoadjuvant Treatment (TNT) afforded three outcomes: (a) a reduction of distant metastases, positively impacting on survival endpoints, (b) a significant increase of complete clinical response (cCR) rate, paving the way for non-operative management (NOM), and (c) the selective omission of radiotherapy following induction CT. The choice of the most appropriate therapeutic strategy can only be made through the shared decision-making process between physician and patient based on risk stratification and patient preferences.

For patients with rectal cancer, the standard approach of chemotherapy, radiation therapy, and surgery (trimodality therapy) is associated with significant long-term toxicity and/or colostomy for most patients. Patient options focused on quality of life (QOL) have dramatically improved, but there remains limited guidance regarding comparative effectiveness. This systematic review and associated guidelines evaluate how various treatment strategies compare to each other in terms of oncologic outcomes and QOL. Cochrane and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology were used to search for prospective and retrospective trials and meta-analyses of adequate quality within the Ovid Medline database between January 1, 2012, and June 15, 2023. These studies informed the expert panel, which rated the appropriateness of various treatments in 6 clinical scenarios through a well-established consensus methodology (modified Delphi). The search process yielded 197 articles that advised voting. Increasing data have shown that nonoperative management (NOM) and primary surgery result in QOL benefits noted over trimodality therapy without detriment to oncologic outcomes. For patients with rectal cancer for whom total mesorectal excision would result in permanent colostomy or inadequate bowel continence, NOM was strongly recommended as usually appropriate. Restaging with tumor response assessment approximately 8 to 12 weeks after completion of radiation therapy/chemoradiation therapy was deemed a necessary component of NOM. The panel recommended active surveillance in the setting of a near-complete or complete response. In the setting of NOM, 54 to 56 Gy in 27 to 31 fractions concurrent with chemotherapy and followed by consolidation chemotherapy was recommended. The panel strongly recommends primary surgery as usually appropriate for a T3N0 high rectal tumor for which low anterior resection and adequate bowel function is possible, with adjuvant chemotherapy considered if N+. Recent data support NOM and primary surgery as important options that should be offered to eligible patients. Considering the complexity of multidisciplinary management, patients should be discussed in a multidisciplinary setting, and therapy should be tailored to individual patient goals/values.

Potential differences in organ preservation between total neoadjuvant therapy (TNT) regimens integrating long-course chemoradiotherapy (LCCRT) and short-course radiotherapy (SCRT) in rectal cancer remain undefined.

This natural experiment arose from a policy change in response to the COVID-19 pandemic during which our institution switched from uniformly treating patients with LCCRT to mandating that all patients be treated with SCRT. Our study includes 323 locally advanced rectal adenocarcinoma patients treated with LCCRT-based or SCRT-based TNT from January 2018 to January 2021. Patients who achieved clinical complete response were offered organ preservation with watch-and-wait (WW) management. The primary outcome was 2-year organ preservation. Additional outcomes included local regrowth, distant recurrence, disease-free survival (DFS), and overall survival (OS).

Patient and tumor characteristics were similar between LCCRT (n = 247) and SCRT (n = 76) cohorts. Median follow-up was 31 months. Similar clinical complete response rates were observed following LCCRT and SCRT (44.5% versus 43.4%). Two-year organ preservation was 40% [95% confidence interval (CI) 34% to 46%] and 31% (95% CI 22% to 44%) among all patients treated with LCCRT and SCRT, respectively. In patients managed with WW, LCCRT resulted in higher 2-year organ preservation (89% LCCRT, 95% CI 83% to 95% versus 70% SCRT, 95% CI 55% to 90%; P = 0.005) and lower 2-year local regrowth (19% LCCRT, 95% CI 11% to 26% versus 36% SCRT, 95% CI 16% to 52%; P = 0.072) compared with SCRT. The 2-year distant recurrence (10% versus 6%), DFS (90% versus 90%), and OS (99% versus 100%) were similar between WW patients treated with LCCRT and SCRT, respectively.

While WW eligibility was similar between cohorts, WW patients treated with LCCRT had higher 2-year organ preservation and lower local regrowth than those treated with SCRT, yet similar DFS and OS. These data support induction LCCRT followed by consolidation chemotherapy as the preferred TNT regimen for patients with locally advanced rectal cancer pursuing organ preservation.

Overall survival benefit of total neoadjuvant treatment (TNT) remains unconfirmed. Thus, in our opinion, the main rationale for using TNT is a planned watch-and-wait (w&w) strategy to improve patients' long-term quality of life through organ preservation. The OPRA randomized trial, which examined a planned w&w strategy using TNT, showed a higher organ preservation rate but also a higher regrowth rate compared to studies on the opportunistic w&w strategy. Higher rates of complete clinical response with TNT did not improve disease-free survival compared to historical controls. Therefore, the gain in organ-sparing capability might not be balanced by the increased oncological risk. The ultimate local failure rate in the intention-to-treat analysis of the OPRA trial was 13% for induction chemotherapy and 16% for consolidation chemotherapy, which seems higher than expected compared to 8% in a meta-analysis of w&w studies or 12% after TNT and surgery in the PRODIGE-23 and RAPIDO trials, which enrolled patients with more advanced cancers than the OPRA trial. Other studies also suggest worse local control when surgery is delayed for radio-chemoresistant cancers. Our review questions the safety of the planned w&w strategy using TNT in unselected patients. To reduce the oncological risk while maintaining high organ preservation rates, we suggest that the planned w&w strategy using TNT requires a two-tier patient selection process: before treatment and after tumor response assessment at the midpoint of consolidation chemotherapy. These robust selections should identify patients who are unlikely to achieve organ preservation with TNT and would be better managed by preoperative chemoradiotherapy (without consolidation chemotherapy) and surgery, or by discontinuing consolidation chemotherapy and proceeding directly to surgery.

Rectal cancer is a highly prevalent malignancy with an increasing number of treatment strategies and sequencing. Short-course radiotherapy (SCRT) combined with chemotherapy has shown to be a feasible treatment option for non-metastatic disease within the total neoadjuvant therapy paradigm. In contrast to conventionally fractionated chemoradiation, SCRT carries less logistical burden and reduces time off systemic therapy, which is particularly beneficial for patients with metastatic disease. We present a case of a 42-year-old male with metastatic rectal cancer who received SCRT using CT-based adaptive radiation, delivering 25 Gy to the pelvis with a simultaneous integrated boost of 30 Gy to the rectal tumor over five treatments. CT-based adaptive radiation was effective and well-tolerated and offers a pathway towards isotoxic radiotherapy dose escalation for patients considered to be inoperable. This case demonstrates the integration of adaptive SCRT as a promising strategy for rectal cancer.

In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors.

We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME.

The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ2=9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05).

RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value.

As watch and wait has become an attractive management alternative among patients with rectal cancer who achieve a clinical complete response to neoadjuvant chemoradiation, the focus of organ preservation has now shifted toward the use of this approach in patients with early rectal cancer. These patients would otherwise be treated without the use of neoadjuvant therapy for oncological reasons. The sole purpose of any neoadjuvant treatment here would be the achievement of a complete clinical response in an attempt to avoid total mesorectal excision. This has become particularly interesting after the incorporation of total neoadjuvant therapy regimens. These regimens have resulted in significantly higher rates of complete tumor regression and therefore become an interesting alternative among early rectal cancer patients where organ preservation is desired. The present review provides an overview of the currently available evidence and the preliminary experience with this rather controversial approach.

Though resection has been the mainstay of treatment for nonmetastatic rectal cancer over the past century, radiation has become an increasingly integral component of care for locally advanced disease. Today, two predominant radiotherapy approaches-hyperfractionated chemoradiotherapy and "short-course" radiation-are widely utilized to reduce local recurrence and, in some cases, cure disease. Both have been incorporated into total neoadjuvant therapy (TNT) regimens and achieved excellent local control and superior complete response rates compared to chemoradiation alone. Additionally, initial results of "watch and wait" protocols utilizing either radiation modality have been promising. Yet, differences do exist; though short course is cheaper and more convenient for patients, recently published data may show superior complete response and local recurrence rates with chemoradiation. Ultimately, direct comparisons of short-course radiotherapy against chemoradiation within the TNT framework are needed to identify optimal radiation regimens in the treatment of locally advanced rectal cancer.

The treatment paradigm for rectal cancer has been shifting toward de-escalated approaches to preserve patient quality of life. Historically, the standard treatment in the United States for locally advanced rectal cancer has standardly comprised preoperative chemoradiotherapy coupled with total mesorectal excision. Recent data challenge this "one-size-fits-all" strategy, supporting the possibility of omitting surgery for certain patients who achieve a clinical complete response to neoadjuvant therapy. Consequently, patients and their physicians must navigate diverse neoadjuvant options, often in the context of pursuing organ preservation. Total neoadjuvant therapy, involving the administration of all chemotherapy and radiation before total mesorectal excision, is associated with the highest rates of clinical complete response. However, questions persist regarding the optimal sequencing of radiation and chemotherapy and the choice between short-course and long-course radiation. Additionally, meticulous response assessment and surveillance are critical for selecting patients for nonoperative management without compromising the excellent cure rates associated with trimodality therapy. As nonoperative management becomes increasingly recognized as a standard-of-care treatment option for patients with rectal cancer, ongoing research in patient selection and monitoring as well as patient-reported outcomes is critical to guide personalized rectal cancer management within a patient-centered framework.

Locally advanced rectal cancer has historically been treated with multimodal therapy consisting of radiation therapy, chemotherapy, and total mesorectal excision. However, recent prospective trials and registry studies have demonstrated similar disease outcomes with nonoperative management for patients who experience an excellent clinical response to radiation and chemotherapy. This article reviews data regarding nonoperative management for rectal cancer, and highlights current challenges and limitations in a point-counterpoint format, in the context of two clinical cases.

Watch-and-wait has emerged as a new strategy for the management of rectal cancer when a complete clinical response is achieved after neoadjuvant therapy. In an attempt to standardize this new clinical approach, initiated by the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), and with the participation of the Spanish Association of Coloproctology (AECP), the Spanish Society of Pathology (SEAP), the Spanish Society of Gastrointestinal Endoscopy (SEED), the Spanish Society of Radiation Oncology (SEOR), and the Spanish Society of Medical Radiology (SERAM), we present herein a consensus on a watch-and-wait approach for the management of rectal cancer. We have focused on patient selection, the treatment schemes evaluated, the optimal timing for evaluating the clinical complete response, the oncologic outcomes after the implementation of this strategy, and a protocol for surveillance of these patients.

This study assessed quality of life (QoL) and clinical outcomes in rectal cancer patients treated with magnetic resonance (MR) guided short-course radiation therapy (SCRT) on a 1.5 Tesla (T) MR-Linac during the first 12 months after treatment.

Rectal cancer patients treated with 25 Gy SCRT in five fractions with curative intent in the Netherlands (2019-2022) were identified in MOMENTUM (NCT04075305). Toxicity (CTCAE v5) and QoL (EORTC QLQ-C30 and -CR29) was primarily analyzed in patients without metastatic disease (M0) and no other therapies after SCRT. Patients who underwent tumor resection were censored from surgery. A generalized linear mixed-model was used to investigate clinically meaningful (≥10) and significant (P < 0.05) QoL changes. Clinical and pathological complete response (cCR and pCR) rates were calculated in patients in whom response was documented.

A total of 172 patients were included, of whom 112 patients were primarily analyzed. Acute and late radiation-induced high-grade toxicity were reported in one patient, respectively. CCR was observed in 8/64 patients (13 %), 14/37 patients (38 %) and 13/16 patients (91 %) at three, six and twelve months; pCR was observed in 3/69 (4 %) patients. After 12 months, diarrhea (mean difference [MD] -17.4 [95 % confidence interval [CI] -31.2 to -3.7]), blood and mucus in stool (MD -31.1 [95 % CI -46.4 to -15.8]), and anxiety (MD -22.4 [95 % CI -34.0 to -10.9]) were improved.

High-field MR-guided SCRT for the treatment of patients with rectal cancer is associated with improved disease-related symptom management and functioning one year after treatment.

cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes, extramural vascular invasion (EMVI) and mesorectal fascia threatening (MRF+) have been utilized as exclusion criteria in several studies on the watch-and-wait (w&w) strategy. Here, our aim was to validate these criteria through a post hoc analysis of two pooled prospective studies on w&w following routine radio(chemo)therapy.

A review of baseline magnetic resonance imaging was performed in a subgroup of 223 patients treated at a single institution. Of these, 17.9 % started w&w, 12.6 % achieved clinical complete response (cCR) and 9.0 % sustained cCR during median follow-up of 54 months.

The multivariable logistic analysis showed that the proportion of circumferential bowel involvement and EMVI significantly influenced the chance of sustained cCR; odds ratios were 0.063 (95 % confidence interval [CI] 0.008-0.489, p = 0.008), and 0.109 (95 % CI 0.014-0.850, p = 0.034), respectively. Sustained cCR was observed in none of the 57 patients with 90 %-100 % circumferential bowel involvement and in only one of the 89 patients with EMVI. In contrast, cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes or MRF+ were not independently associated with sustained cCR. Among the subgroups of patients with these features but without (near-)circular tumour or EMVI+, sustained cCR was observed in 12 %-25 % of patients.

Sustained cCR after routine preoperative radio(chemo)therapy is unlikely in patients with (near-)circular tumour or EMVI, whereas patients with cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes and MRF+ should not be denied w&w.

Management of lateral pelvic lymph nodes in locally advanced rectal cancer is controversial, with limited data indicating the optimal approach. In addition, no data exist regarding the treatment of lateral nodes in the setting of short-course radiation and nonoperative intent.

To evaluate a novel approach incorporating simultaneous integrated boost to suspicious lateral nodes.

A retrospective study.

This study was conducted at a large tertiary referral center.

Patients treated with radiation therapy and consolidation chemotherapy were included. All primary tumors underwent biopsy confirmation and disease staging with pelvic MRI.

Primary tumors were biopsy proven and staged with pelvic MRI. A subset of lateral pelvic lymph node patients received a simultaneous integrated boost of 35 Gy in 5 fractions. Then, chemotherapy was administered, with the majority receiving modified folinic acid, fluorouracil, and oxaliplatin. Clinical partial response required total mesorectal excision.

Patterns of failure and survival analyses by subgroup were assessed. Outcomes based on receipt of radiation were compared across node status.

Between January 2017 and January 2022, 155 patients were treated with short-course chemotherapy, with 121 included in the final analysis. Forty-nine percent of patients underwent nonoperative management. The median follow-up was 36 months and the median age was 58 years. Thirty-eight patients (26%) had positive lateral pelvic lymph nodes. Comparing lateral node status, progression-free survival was significantly worse for patients with positive disease ( p < 0.001), with a trend for worse overall survival. Receipt of nodal boost in patients with lateral nodes resulted in meaningful locoregional control. Nodal boost did not contribute to additional acute or late GI toxicity.

Limitations include retrospective nature and lack of lateral node pathology; however, a thorough radiographic review was performed.

Lateral node-positive rectal cancer is correlated with worse oncologic outcomes and higher locoregional failure. Boost to clinically positive lateral nodes is a safe approach in the setting of short course radiation and in those receiving nonoperative intent. See Video Abstract.

ANTECEDENTES:El manejo de los ganglios linfáticos pélvicos laterales en el cáncer de recto localmente avanzado es controvertido, con datos limitados que indiquen el abordaje óptimo. Además, no existen datos sobre el tratamiento de los ganglios linfáticos laterales en el contexto de la radiación de curso corto y la intención no operatoria.OBJETIVO:Evaluamos un enfoque novedoso que incorpora sobreimpresión integrada simultánea (SIB) a los linfonodos laterales sospechosos.DISEÑO:Este fue un estudio retrospectivo.ESCENARIO:Este estudio se realizó en un gran centro de referencia terciario.PACIENTES:Se incluyeron pacientes tratados con radiación y quimioterapia de consolidación. Todos los tumores primarios se confirmaron mediante biopsia y la enfermedad se estadificó con resonancia magnética pélvica.INTERVENCIONES:Los tumores primarios se confirmaron mediante biopsia y se estadificaron con RM pélvica. Un subconjunto de pacientes con linfonodos pélvicos laterales (LPLN) recibió SIB a 35 Gy en 5 fracciones. Luego, se administró quimioterapia y la mayoría recibió mFOLFOX. La respuesta clínica parcial requirió la escisión total del mesorrecto.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron los patrones de fracaso y los análisis de supervivencia por subgrupo. Los resultados basados en el esquema de radiación se compararon según el estado de los ganglios.RESULTADOS:Entre enero de 2017 y enero de 2022, 155 pacientes fueron tratados con ciclo corto y quimioterapia con 121 incluidos en el análisis final. El 49% se sometió a manejo no operatorio. La mediana de seguimiento fue de 36 meses y la mediana de edad fue de 58 años. 38 pacientes (26%) tuvieron LPLN positivos. Comparando el estado de los ganglios laterales, la supervivencia libre de progresión fue significativamente peor para los pacientes con LPLN positiva ( p < 0,001) con una tendencia a una peor supervivencia global. La recepción de refuerzo nodal en pacientes con nodos laterales dio como resultado un control locorregional significativo. La sobreimpresión ganglionar no contribuyó a la toxicidad GI aguda o tardía adicional.LIMITACIONES:Las limitaciones incluyeron la naturaleza retrospectiva y la falta de patología de los ganglios linfáticos laterales; sin embargo, se realizó una revisión radiográfica exhaustiva.CONCLUSIONES:El cáncer de recto con ganglio lateral positivo se correlaciona con peores resultados oncológicos y mayor fracaso locorregional. La sobreimpresión a los ganglios laterales clínicamente positivos es un enfoque seguro en el contexto de un curso corto y en aquellos que siguen un manejo no operatorio. (Traducción-Dr. Felipe Bellolio ).

A novel O-ring gantry can deliver stereotactic body radiation therapy (SBRT) with artificial intelligence-facilitated, CT-guided online plan adaptation. It gates mobile targets by optically monitoring skin surface motion. However, this gating solution has not been clinically validated. We conducted a trial to evaluate the feasibility of optical skin surface-guided gating for patients with mobile upper abdominal or lower thoracic malignancies treated with SBRT on this platform (NCT05030454).

Ten patients who were prescribed SBRT to a thoracic or abdominal target and were capable of breath-hold for at least 17 s enrolled. They received SBRT in five fractions with breath-hold technique and optical skin surface motion monitored-gating with a ± 2 mm tolerance. Online plan adaptation was left to the discretion of the daily treating physician. The primary endpoint was defined as successful completion of > 75 % of attempted fractions. Exploratory endpoints included local control and acute grade ≥ 3 toxicity rates after three months. For adapted fractions the contouring, planning, quality assurance, and treatment delivery times were recorded.

Forty-seven of 51 SBRT fractions (92 %) were successfully gated at breath-hold by optical skin surface motion monitoring. The tumor centroid position during breath-hold varied by a mean of approximately 2 mm. Sixty-three percent of fractions were adapted online with a median total treatment time of 78.5 min. After three months no local recurrences or acute grade ≥ 3 toxicities were observed.

SBRT treatment to mobile targets with surface-monitored gating on a novel O-ring gantry was prospectively validated.

Non-operative management of patients with locally advanced rectal cancer (LARC) is emerging as a popular approach for patients that have no evidence of disease following neoadjuvant therapy. However, high rates of local recurrence or distant metastases have highlighted the urgent need for robust biomarker strategies to aid clinical management of these patients.

This review summarizes recent advances in the utility of cell-free (cf) and circulating tumor (ct) DNA as potential biomarkers to help guide individualized non-operative management strategies for LARC patients receiving neoadjuvant therapy.

Liquid biopsies and the detection of cfDNA/ctDNA is an emerging technology with the potential to provide a non-invasive approach to monitor disease response and improve the identification of patients with LARC that would best benefit from non-operative management.

Substantial work is still needed before cfDNA/ctDNA monitoring can be widely adopted in the clinical setting. Studies reviewed herein highlight several areas of opportunity for improving the effectiveness and utility of cfDNA/ctDNA for managing patients with LARC.

Current management of locally advanced rectal cancer achieves high cure rates, distant metastatic spread being the main cause of patients' death. Total neoadjuvant therapy (TNT) employs (chemo)radiotherapy and combined chemotherapy prior to surgery to improve the treatment outcomes. TNT has been shown to reduce significantly distant metastases, increase disease-free survival by 5 - 10% in 3 years, and finally also overall survival (≈ 5% in 7 years). It proved to double the rate of pathologic complete responses, making it an attractive strategy for non-operative management to avoid permanent colostomy in patients with distal tumors. In addition, it endorses adherence to the therapy due to better tolerance and, potentially, shortens its overall duration. A number of questions related to TNT remain currently unresolved including the indications, preferred radiotherapy and chemotherapy regimens, their sequence, timing of surgery, and role of adjuvant therapy. A stratified approach may be the optimal way to go.

Short-course radiation therapy and consolidation chemotherapy with nonoperative intent has emerged as a novel treatment paradigm for patients with rectal cancer, but there are no data on the predictors of clinical complete response.

Evaluate the predictors of clinical complete response and survival.

Retrospective cohort.

National Cancer Institute-designated cancer center.

Patients with stage I to III rectal adenocarcinoma treated between January 2018 and May 2019 (n = 86).

Short-course radiation therapy followed by consolidation chemotherapy.

Logistic regression was performed to assess for predictors of clinical complete response. The end points included local regrowth-free survival, regional control, distant metastasis-free survival, and overall survival.

A positive (+) circumferential resection margin by MRI at diagnosis was a significant predictor of nonclinical complete response (OR: 4.1, p = 0.009) when adjusting for CEA level and primary tumor size. Compared to patients with a negative (-) pathologic circumferential resection margin, patients with a positive (+) pathologic circumferential resection margin had inferior local regrowth-free survival (29% vs 87%, p < 0.001), regional control (57% vs 94%, p < 0.001), distant metastasis-free survival (43% vs 95%, p < 0.001), and overall survival (86% vs 95%, p < 0.001) at 2 years. However, the (+) and (-) circumferential resection margin by MRI subgroups in patients who had a clinical complete response both had similar regional control, distant metastasis-free survival, and overall survival of more than 90% at 2 years.

Retrospective design, modest sample size, short follow-up, and the heterogeneity of treatments.

Circumferential resection margin involvement by MRI at diagnosis is a strong predictor of nonclinical complete response. However, patients who achieve a clinical complete response after short-course radiation therapy and consolidation chemotherapy with nonoperative intent have excellent clinical outcomes regardless of the initial circumferential resection margin status. See Video Abstract at http://links.lww.com/DCR/C190 .

ANTECEDENTES:La radioterapia de corta duración y la quimioterapia de consolidación en el manejo conservador, han surgido como un nuevo paradigma de tratamiento, para los pacientes con cáncer de recto, lastimosamente no hay datos definitivos sobre los predictores de una respuesta clínica completa.OBJETIVO:Evaluar los predictores de respuesta clínica completa y de la sobrevida.DISEÑO:Estudio retrospectivo de cohortes.AJUSTES:Centro oncológico designado por el NCI.PACIENTES:Adenocarcinomas de recto estadio I-III tratados entre 01/2018 y 05/2019 (n = 86).INTERVENCIONES:Radioterapia de corta duración seguida de quimioterapia de consolidación.PRINCIPALES MEDIDAS DE RESULTADO:Se realizó una regresión logística para evaluar los predictores de respuesta clínica completa. Los criterios de valoración incluyeron la sobrevida libre de recidiva local, el control regional, la sobrevida libre de metástasis a distancia y la sobrevida general.RESULTADOS:Un margen de resección circunferencial positivo (+) evaluado por imagenes de resonancia magnética nuclear en el momento del diagnóstico fue un predictor no clínico muy significativo de respuesta completa (razón de probabilidades/ OR: 4,1, p = 0,009) al ajustar el nivel de antígeno carcinoembrionario y el tamaño del tumor primario. Comparando con los pacientes que presetaban un margen de resección circunferencial patológico negativo (-), los pacientes con un margen de resección circunferencial patológico positivo (+) tuvieron una sobrevida libre de recidiva local (29% frente a 87%, p < 0,001), un control regional (57% frente a 94%, p < 0,001), una sobrevida libre de metástasis a distancia (43% frente a 95%, p < 0,001) y una sobrevida global (86% frente a 95%, p < 0,001) inferior en 2 años de seguimiento. Sin embargo, los subgrupos de margen de resección circunferencial (+) y (-) evaluados por imágenes de resonancia magnética nuclear en pacientes que tuvieron una respuesta clínica completa tuvieron un control regional similar, una sobrevida libre de metástasis a distancia y una sobrevida general >90% en 2 años de seguimiento.LIMITACIONES:Diseño retrospectivo, tamaño modesto de la muestra, seguimiento corto y heterogeneidad de tratamientos.CONCLUSIONES:La afectación del margen de resección circunferencial evaluado por resonancia magnética nuclear al momento del diagnóstico es un fuerte factor predictivo no clínico de respuesta completa. Sin embargo, los pacientes que logran una respuesta clínica completa después de un curso corto de radioterapia y quimioterapia de consolidación como manejo conservador tienen excelentes resultados clínicos independientemente del estado del margen de resección circunferencial inicial. Consulte Video Resumen en http://links.lww.com/DCR/C190 . (Traducción-Dr. Xavier Delgadillo ).

Neoadjuvant chemoradiation(nCRT) has been considered the preferred initial treatment strategy for distal rectal cancer. Advantages of this approach include improved local control after radical surgery but also the opportunity for organ preserving strategies (Watch and Wait-WW). Consolidation chemotherapy(cCT) regimens using fluoropyrimidine-based with or without oxalipatin following nCRT have demonstrated to increase complete response and organ preservation rates among these patients. However, the benefit of adding oxaliplatin to cCT compared to fluoropirimidine alone regimens in terms of primary tumor response remains unclear. Since oxalipatin-treatment may be associated with considerable toxicity, it becomes imperative to understand the benefit of its incorporation into standard cCT regimens in terms of primary tumor response. The aim of the present trial is to compare the outcomes of 2 different cCT regimens following nCRT (fluoropyrimidine-alone versus fluoropyrimidine + oxaliplatin) for patients with distal rectal cancer.

In this multi-centre study, patients with magnetic resonance-defined distal rectal tumors will be randomized on a 1:1 ratio to receive long-course chemoradiation (54 Gy) followed by cCT with fluoropyrimidine alone versus fluoropyrimidine + oxaliplatin. Magnetic resonance(MR) will be analyzed centrally prior to patient inclusion and randomization. mrT2-3N0-1 tumor located no more than 1 cm above the anorectal ring determined by sagittal views on MR will be eligible for the study. Tumor response will be assessed after 12 weeks from radiotherapy(RT) completion. Patients with clinical complete response (clinical, endoscopic and radiological) may be enrolled in an organ-preservation program(WW). The primary endpoint of this trial is decision to organ-preservation surveillance (WW) at 18 weeks from RT completion. Secondary endpoints are 3-year surgery-free survival, TME-free survival, distant metastases-free survival, local regrowth-free survival and colostomy-free survival.

Long-course nCRT with cCT is associated with improved complete response rates and may be a very attractive alternative to increase the chances for organ-preservation strategies. Fluoropyrimidine-based cCT with or without oxaliplatin has never been investigated in the setting of a randomized trial to compare clinical response rates and the possibility of organ-preservation. The outcomes of this study may significantly impact clinical practice of patients with distal rectal cancer interested in organ-preservation.

www.

gov NCT05000697; registered on August 11^th, 2021.

Short-course radiotherapy (SCRT) of 25 Gy in five daily fractions is a recommended strategy in the neoadjuvant setting for resectable locally advanced rectal cancer (LARC), as well as in cases of metastatic disease for local control. There is scarce information regarding the use of SCRT for patients who have received nonoperative management.

To describe the characteristics of patients who received treatment with SCRT for LARC and metastatic rectal cancer, toxicity, and the approach after radiation treatment.

This is a retrospective analysis of all patients who underwent SCRT for rectal cancer at the Alexander Fleming Institute from March 2014 to June 2022.

In total, 44 patients were treated with SCRT. The majority were male (29, 66%), with a median age of 59 years (interquartile range 46-73). Most patients had stage IV disease (26, 59.1%), followed by LARC (18, 40.9%). Most lesions were located in the middle rectum (30, 68%). The majority of LARC patients underwent SCRT followed by consolidation chemotherapy (ChT) (16/18, 89%), while most patients with metastatic disease underwent SCRT followed by consolidation ChT (14/26, 53.8%). A clinical complete response (cCR) was documented in 8/44, 18.2% of patients. Most patients with LARC and cCR were managed by a watch and wait approach (5/18, 27.7%). Local recurrence was observed in LARC cases (2/18, 11.1%). Patients who underwent SCRT following consolidation ChT were more likely to have adverse events (AEs) than those undergoing induction ChT following SCRT (11/30, 36.7% versus 3/12, 25%, p = 0.02).

In a subgroup of patients diagnosed with LARC and treated with SCRT followed by ChT, surgical treatment could be omitted after they achieved a cCR. Local recurrence was similar to that reported in a previous study. SCRT is a reasonable option for local disease control in stage IV disease, yielding low toxicity rates. Therefore, decisions must be made by a multidisciplinary team. Prospective studies are necessary to reach further conclusions.

Total neoadjuvant therapy (TNT) has emerged as the preferred approach for locally advanced rectal cancer (LARC), defined as T3/4 or any T with N+ disease. Our objective was to (1) determine the proportion of patients with LARC receiving TNT over time, (2) determine the most common method in which TNT is being delivered, and (3) determine what factors are associated with a greater likelihood of receiving TNT in the United States. Retrospective data was obtained from the National Cancer Database (NCDB) for patients diagnosed with rectal cancer between 2016 and 2020. Patients were excluded if they had M1 disease, T1-2 N0 disease, incomplete staging information, nonadenocarcinoma histology, received RT to a nonrectum site, or received a nondefinitive RT dose. Data were analyzed using linear regression, χ2 test, and binary logistic regression. Of the 26,375 patients included, most patients were treated at an academic facility (94.6%). Five thousand three (19.0%) patients received TNT, and 21,372 (81.0%) patients did not receive TNT. The proportion of patients receiving TNT increased significantly over time, from 6.1% in 2016 to 34.6% in 2020 (slope = 7.36, 95% CI 4.58-10.15, R2 = 0.96, P = .040). The most common TNT regimen was multiagent chemotherapy followed by long-course chemoradiation (73.2% of cases from 2016-2020). There was a significant increase in utilization of short-course RT as part of TNT from 2.8% in 2016 to 13.7% in 2020 (slope = 2.74, 95% CI 0.37-5.11, R2 = 0.82, P = .035). Factors associated with a lower likelihood of TNT usage included age >65, female gender, Black race, and T3 N0 disease. TNT use in the United States has increased significantly from 2016-2020, with approximately 34.6% of patients with LARC receiving TNT in 2020. The observed trend appears to be in line with the recent National Comprehensive Cancer Network guidelines recommending TNT as the preferred approach.

The administration of neoadjuvant chemoradiotherapy (nCRT) followed by total mesorrectal excision (TME) and selective use of adjuvant chemotherapy can still be considered the standard of care in locally advanced rectal cancer (LARC). However, avoiding sequelae of TME and entering a narrow follow-up program of watch and wait (W&W), in select cases that achieve a comparable clinical complete response (cCR) to nCRT, is now very attractive to both patients and clinicians. Many advances based on well-designed studies and long-term data coming from big multicenter cohorts have drawn some important conclusions and warnings regarding this strategy. In order to safely implement W&W, it is important consider proper selection of cases, best treatment options, surveillance strategy and the attitudes towards near complete responses or even tumor regrowth. The present review offers a comprehensive overview of W&W strategy from its origins to the most current literature, from a practical point of view focused on daily clinical practice, without losing sight of the most important future prospects in this area.

We analyzed the effectiveness, safety, and mid-term oncological outcomes of short-course radiotherapy (SCRT) and oxaliplatin-based consolidation chemotherapy in patients with locally advanced rectal cancer (LARC).

We retrospectively evaluated 64 patients with LARC who underwent SCRT and tegafox (tegafur-uracil/leucovorin plus oxaliplatin) or mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) consolidation chemotherapy before surgery between January 2015 and December 2020. Tumor response, patient compliance, toxicity, surgical outcomes, overall survival (OS), and disease-free survival (DFS) were analyzed.

Sixty-four patients with a mean age of 58.67 years (44 males) were included; 48 (75%) had tumors within 5 cm of the anal verge. Additionally, 93.8% of the patients underwent at least 2 months of chemotherapy, and three required dose reduction. Grade III toxicity occurred in 2 patients, and 10 had a clinical complete response and opted for non-operative management. One patient experienced tumor progression and underwent further treatment without surgery. Among the 53 patients who underwent surgery, 51 (96.2%) had sphincter preservation, 3 had Clavien-Dindo grade III complications, and no mortality occurred. The complete response rate for the entire cohort was 23.4%. Moreover, 47 patients (74.6%) had a neoadjuvant rectal score of < 16 after treatment. After a median follow-up time of 32.01 months, 6 (9.3%) had local recurrence, and 17 (26.6%) had distant metastasis. The 3-year OS, DFS and stoma-free rates were 89.5%, 65.5%, and 78.1% respectively.

SCRT followed by oxaliplatin-based consolidation chemotherapy is safe and effective for tumor downstaging in LARC, further improving the sphincter preservation rate.

The current preferred standard of care management for patients with locally advanced rectal cancer is total neoadjuvant therapy, in which all chemotherapy and radiotherapy is delivered before surgery. Within this approach, developed in response to persistently high distant failure rates despite excellent local control with preoperative chemoradiotherapy, there remains questions regarding the optimal radiotherapy regimen (short course vs long course) and sequencing of chemotherapy (induction vs consolidation).

Over the last two decades, the standard treatment for locally advanced rectal cancer (LARC) has been neoadjuvant chemoradiotherapy plus total mesorectal excision followed by adjuvant chemotherapy. Total neoadjuvant treatment (TNT) and immunotherapy are two major issues in the treatment of LARC. In the two latest phase III randomized controlled trials (RAPIDO and PRODIGE23), the TNT approach achieved higher rates of pathologic complete response and distant metastasis-free survival than conventional chemoradiotherapy. Phase I/II clinical trials have reported promising response rates to neoadjuvant (chemo)-radiotherapy combined with immunotherapy. Accordingly, the treatment paradigm for LARC is shifting toward methods that increase the oncologic outcomes and organ preservation rate. However, despite the progress of these combined modality treatment strategies for LARC, the radiotherapy details in clinical trials have not changed significantly. To guide future radiotherapy for LARC with clinical and radiobiological evidence, this study reviewed recent neoadjuvant clinical trials evaluating TNT and immunotherapy from a radiation oncologist's perspective.

Nonoperative management (NOM) is increasingly utilized for rectal cancer patients with a clinical complete response (cCR) following total neoadjuvant therapy (TNT). The objective of this pilot study was to determine whether FDG-PET/MRI alters clinical response assessments among stage I-III rectal cancer patients undergoing TNT followed by NOM, relative to MRI alone. This prospective study included 14 subjects with new rectal cancer diagnoses. Imaging consisted of FDG-PET/MRI for initial staging, post-TNT restaging, and surveillance during NOM. Two independent readers assessed treatment response on MRI followed by FDG-PET/MRI. Inter-reader differences were resolved by consensus review. The reference standard for post-TNT restaging consisted of surgical pathology or clinical follow-up. 7/14 subjects completed post-TNT restaging FDG-PET/MRIs. 5/7 subjects had evidence of residual disease and underwent total mesorectal excision; 2/7 subjects had initial cCR with no evidence of disease after 12 months of NOM. FDG-PET/MRI assessments of cCR status at post-TNT restaging had an accuracy of 100%, compared with 71% for MRI alone, as FDG-PET detected residual tumor in 2 more subjects. Inter-reader agreement for cCR status on FDG-PET/MRI was moderate (kappa, 0.56). FDG-PET provided added value in 82% (9/11) of restaging/surveillance scans. Our preliminary data indicate that FDG-PET/MRI can detect more residual disease after TNT than MRI alone, with the FDG-PET component providing added value in most restaging/surveillance scans.