A Review of Neoadjuvant Therapy and the Watch-and-Wait Protocol in Rectal Cancer: Current Evidence and Future Directions.

The treatment of rectal cancer underwent a significant change with the introduction of total mesorectal excision (TME), which substantially improved recurrence rates. However, TME is associated with complications such as fecal incontinence and poor bladder control, especially in tumors located near the anal verge. The watch-and-wait (WW) protocol has emerged as an alternative for patients achieving a clinical complete response (cCR) following neoadjuvant radiochemotherapy. This narrative review, developed according to the Scale for the Assessment of Narrative Review Articles guidelines, evaluates neoadjuvant treatments and the WW protocol for rectal cancer. Literature was sourced from the PubMed database using specific search terms related to neoadjuvant therapy and the WW protocol, resulting in 63 articles selected for discussion. Neoadjuvant treatment, including chemoradiation and short-course radiotherapy, is indicated for T3 and T4 rectal adenocarcinomas. Studies like the German Rectal Cancer Study Group and the PRODIGE 23 trial have shown the benefits of preoperative treatment, including improved disease-free survival and reduced local recurrence rates. However, challenges in adopting the WW protocol include the risk of local regrowth and distant metastasis. Immune checkpoint inhibitors have shown promise in mismatch repair-deficient patients, yet the data are insufficient to fully endorse WW for these cases. The WW protocol is viable for selected rectal cancer patients, with ongoing debates regarding criteria for inclusion. Key challenges include accurately identifying cCR and managing patients with near-complete responses. MRI and endoscopic evaluation are crucial for assessing treatment response, although achieving a pathological complete response remains uncertain. The WW strategy offers a potential organ-preserving approach in rectal cancer management but requires careful patient selection and comprehensive risk-benefit discussions. Further research is needed to refine criteria for inclusion and optimize treatment protocols, enhancing outcomes while minimizing invasive interventions.

Outcomes of Watch-and-Wait Versus Abdominoperineal Resection in Lower Rectal Adenocarcinoma Post Neoadjuvant Therapy: An Iraqi Cohort Study.

BACKGROUND: Rectal malignancy ranks among the most prevalent malignancies in humans. Neoadjuvant chemoradiotherapy (nCRT) is advocated as the standard treatment for locally advanced rectal cancer. In patients who achieve complete clinical response (cCR), successive surgical intervention may result in favorable immediate and long-lasting results; however, it may be associated with decreased quality of life. This study aims to evaluate the incidence of local recurrence in rectal adenocarcinoma between patients who underwent a watch-and-wait approach and those who underwent abdominoperineal resection following the achievement of a cCR after nCRT. METHODS: This is an analytic cohort study that included 68 patients and was conducted in Baghdad Teaching Hospital/Medical City, Baghdad. The data were collected from the 1st of April 2021 to the 1st of October 2023. All patients with stage II and III rectal adenocarcinoma who achieved cCR after receiving nCRT were included in the study. RESULTS: There was no statistically significant difference between the two study groups regarding non-regrowth disease-free survival (p-value = 0.708). Cox-regression multivariate analysis revealed that baseline T stage and serum carcinoembryonic antigen (CEA) were significantly associated with locoregional failure. CONCLUSION: The present study reveals that implementing the watch-and-wait strategy had the benefit of avoiding major surgery, stoma, and their complications without coming at the cost of reduced locoregional recurrence.

Time to lymphoma treatment within 24 months in 'watch and wait' follicular lymphoma is associated with inferior outcomes: A multicentre analysis.

Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

Barriers to Offering Organ Preservation for Rectal Cancer in a Predominantly Hispanic Safety Net Hospital.

BACKGROUND: Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) has shown promise in achieving pathologic complete response (pCR) and enabling organ preservation through watch-and-wait (WW) strategies. However, implementation of WW protocols in diverse patient populations and safety-net hospitals faces unique challenges. The objective of this study is to evaluate TNT outcomes and identify barriers to WW implementation in a predominantly Hispanic safety-net hospital in South Texas. METHODS: A retrospective review was conducted of 40 LARC patients treated with TNT at an academic tertiary referral center in South Texas between 2018 and 2023. Patient demographics, disease characteristics, and pCR rates were analyzed. A survey of multidisciplinary providers assessed perceived institutional and patient-related barriers to WW implementation. RESULTS: The cohort was 70% Hispanic, with a median age of 54 years. Most patients had advanced disease at diagnosis (57.5% T4, 65% N2). The pCR rate was 18.5% (5/27) among patients undergoing surgery. Re-review of MRIs for pCR patients revealed that 2/5 had minimal residual disease. The provider survey identified MRI quality variability, lack of dedicated treatment coordinators, and concerns about patient compliance and financial barriers as key obstacles to WW implementation. CONCLUSIONS: Despite advanced disease presentation in a predominantly Hispanic population, TNT achieved pCR rates comparable to international trials. Institutional and patient-level barriers to WW were identified, informing the development of a tailored WW protocol for this unique patient population.

The Role of Predictive and Prognostic MRI-Based Biomarkers in the Era of Total Neoadjuvant Treatment in Rectal Cancer.

The role of magnetic resonance imaging (MRI) in rectal cancer management has significantly increased over the last decade, in line with more personalized treatment approaches. Total neoadjuvant treatment (TNT) plays a pivotal role in the shift from traditional surgical approach to non-surgical approaches such as 'watch-and-wait'. MRI plays a central role in this evolving landscape, providing essential morphological and functional data that support clinical decision-making. Key MRI-based biomarkers, including circumferential resection margin (CRM), extramural venous invasion (EMVI), tumour deposits, diffusion-weighted imaging (DWI), and MRI tumour regression grade (mrTRG), have proven valuable for staging, response assessment, and patient prognosis. Functional imaging techniques, such as dynamic contrast-enhanced MRI (DCE-MRI), alongside emerging biomarkers derived from radiomics and artificial intelligence (AI) have the potential to transform rectal cancer management offering data that enhance T and N staging, histopathological characterization, prediction of treatment response, recurrence detection, and identification of genomic features. This review outlines validated morphological and functional MRI-derived biomarkers with both prognostic and predictive significance, while also exploring the potential of radiomics and artificial intelligence in rectal cancer management. Furthermore, we discuss the role of rectal MRI in the 'watch-and-wait' approach, highlighting important practical aspects in selecting patients for non-surgical management.

Locally advanced rectal cancer in a young adult affected with dyskeratosis congenita (Zinsser-Cole-Engman syndrome): a case report.

BACKGROUND: Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a progressive genetic disease with a triad of reticulate skin pigmentation, nail dystrophy, and leukoplakia. Approximately 8-10% of patients with DKC develop malignancies, and cases of colorectal cancer with DKC in young people have been reported previously. CASE PRESENTATION: A 25-year-old man with DKC since approximately 10 years of age developed fever and lower abdominal discomfort. Diagnostic imaging revealed locally advanced rectal cancer with lymph node metastasis, direct invasion of the prostate, and pelvic abscess due to tumor microperforation (cT4bN2M0 cStage IIIC). Biopsy showed well to moderately differentiated ductal adenocarcinoma. Genetic testing was negative for RAS and BRAF gene mutations, and microsatellite instability (MSI) testing was also negative. After sigmoid colostomy, the patient was treated with total neoadjuvant therapy (TNT) with systemic chemotherapy (six courses of FOLFOX + panitumumab) followed by chemoradiation therapy (50.4 Gy with capecitabine). After TNT, the primary tumor and metastatic lymph nodes shrank. According to the findings of colonoscopy and magnetic resonance image (MRI), we diagnosed near complete response (near-CR) and decided to follow the patient without surgery by every 3 months re-evaluation. However, 5 months after TNT, tumor regrowth was detected on colonoscopy and imaging, and the patient underwent total pelvic exenteration. He developed paralytic ileus as a postoperative complication, and was discharged on the 38th postoperative day. Pathological examination revealed a residual tumor with invasion of the periprostatic tissue. There was no metastasis in the pararectal and lateral pelvic lymph nodes, but one extramural non-contiguous cancerous extension (tumor deposit) was observed (ypT4bN1cM0 ypStage IIIC). The patient has been free of recurrence for one year after surgery. CONCLUSIONS: DKC often develops into various tumors in the digestive system at an early age; therefore, appropriate surveillance may be required. In addition, considering that cancers in patients with DKC occur at a young age, fertility preservation and survivorship are also important, and adequate explanations and care should be provided to patients before and after treatment.

The Rise of Patients Declining Rectal Cancer Surgery in the Era of Total Neoadjuvant Therapy.

BACKGROUND: The treatment landscape for rectal cancer is rapidly evolving, particularly with the increasing use of neoadjuvant therapies. Still, up to 50% of patients with stage II-III disease require surgical resection post-neoadjuvant therapy to achieve the best oncologic outcomes. Many patients, however, hope to avoid surgery. This study aimed to assess trends and factors associated with declining recommended oncologic resection after systemic therapy nationally and in our institution. PATIENTS AND METHODS: This is a retrospective analysis using the National Cancer Database from 2009 to 2021 and an institutional cohort at an academic center between 2009 and 2022 including adults with stage I-III rectal adenocarcinoma who underwent neoadjuvant therapy and were suitable for surgery. RESULTS: Of 96,997 patients nationally, the rate of declining surgery increased from 2.3% in 2009 to 6.3% in 2021, a trend mirrored in our institutional cohort of 365 patients (0% in 2009/2010 to approximately 6-12% in 2021/2022). Locally, patients who declined surgery had higher rates of tobacco use, temporary loss to follow-up during therapy, and a more robust, albeit incomplete, tumor response to neoadjuvant therapy compared with controls who underwent surgery. Despite a stoma being the most cited reason for declining surgery, 30.4% of patients who declined oncologic resection died with a stoma. CONCLUSIONS: Our findings underscore a notable trend of patients declining oncologic resections following neoadjuvant therapy for rectal cancer. By shedding light on the outcomes of patients who opt against surgery, we address a critical gap in the literature essential for informing patients about potential risks.

The predicting value of post neoadjuvant treatment magnetic resonance imaging: a meta-analysis.

INTRODUCTION: Neoadjuvant therapy has become standard of care for locally advanced rectal cancer patients. It is correlated with improved clinical and pathological outcomes, including significant tumor downstaging and organ preservation in certain patients. Magnetic resonance imaging (MRI), which has become the standard for pre-operative staging, is also used for clinical and pre-operative restaging following pre-operative treatment. In this meta-analysis, we aimed to evaluate the concordance between restaging MRI (following the completion of neoadjuvant therapy) and postoperative pathology result. METHODS: We conducted a meta-analysis following the PRISMA 2020 guidelines. Two independent reviewers searched PubMed and Google Scholar for studies reporting restaging MRI results compared to pathological outcomes. Outcomes included tumor and nodal staging, circumferential resection margin (CRM) and pathological complete response (pCR). RESULTS: Out of 25,000 studies found on the initial search; 33 studies were included. The studies were published between 2005 and 2023 and included 4100 patients (57.14% males). The median age was 62.45 years. The median interval between the conclusion of neoadjuvant treatment and the subsequent restaging MRI was 6 weeks (range 4.14-8.8 weeks). The pooled concordance rates between the restaging MRI and the pathological outcomes for ypT stage and ypN stage were 63.9% (54.5%-73.3%, I2 = 96.02%) and 60.9% (42.9%-78.9%, I2 = 98.96%), respectively. The pooled concordance for predicting pathological complete response was 70.4% (53.6%-87.1%, I2 = 98.21%). As for the circumferential resection margin (CRM), the pooled concordance was 78.2.% (71.6%-84.8%, I2 = 83.76%). CONCLUSIONS: Our findings suggest that the concordance rates between restaging MRI and pathological outcomes in rectal cancer patients following neoadjuvant therapy are limited. Caregivers should take these results into consideration when making clinical decisions about these patients. More data should be gathered about the predictive value of MRI after total neoadjuvant therapy as well as immunotherapy in rectal cancer patients.

Integrating surgical intervention and watch-and-wait approach in dMMR metastatic rectal cancer with pembrolizumab: a case report.

BACKGROUND: Treating rectal cancer presents challenges due to postoperative complications and reduced quality of life (QOL). Recent evidence supports the watch-and-wait (WW) approach for patients with a clinical complete response (cCR) following preoperative treatment. In this report, we discuss a case of metastatic rectal cancer with deficient mismatch repair (dMMR) treated successfully with pembrolizumab. CASE PRESENTATION: A 47-year-old male with dMMR rectal cancer and a single liver metastasis underwent treatment with pembrolizumab as neoadjuvant therapy. After 10 courses, the rectal lesion achieved cCR, prompting the selection of the WW approach. The liver metastasis showed significant shrinkage; however, the presence of a residual tumor was suspected, leading to a metastasectomy. A pathological complete response (pCR) was confirmed via histological examination. During a 24-month follow-up, there was no evidence of tumor regrowth, local recurrence, or distant metastasis. CONCLUSIONS: The WW strategy is increasingly accepted for patients achieving cCR after preoperative treatment. While pCR in dMMR rectal cancer patients treated with immune checkpoint inhibitors (ICIs) has been documented, accurately predicting pCR from imaging remains challenging. This case illustrates that integrating ICI therapy, surgical interventions, and the WW approach can effectively achieve both oncological safety and improved QOL in the treatment of dMMR metastatic rectal cancer.

Outcomes associated with total neoadjuvant therapy with non-operative intent for rectal adenocarcinoma.

Purpose/objectives: To evaluate rates of clinical complete response (cCR), surgery-free survival, permanent ostomy-free survival, and factors associated with these outcomes in patients treated with total neoadjuvant therapy (TNT) with intent for non-operative management of rectal adenocarcinoma. Methods: A retrospective review was conducted of patients treated with TNT for stage II-IV rectal adenocarcinoma (n=45) at our institution between 2013 - 2022 with curative intent. All patients received radiation with concurrent capecitabine and additional chemotherapy, either prior to or following chemoradiation (CRT), with intent for non-operative management. Response rates were determined based on post-treatment MRI and endoscopy. Kaplan-Meier method was utilized to estimate the 1- and 2-year surgery- and permanent ostomy-free survivals. Cox regression was used to evaluate associations between surgery- and permanent ostomy-free survivals and various factors of interest, including patient and tumor characteristics and clinical response. Chi-squared analysis compared rates of cCR and surgery by sequence of TNT modality and cell count ratios. Results: Of the 45 patients treated with TNT, most patients had low-lying rectal tumors with a median distance of 4.1 cm from the anal verge (range, 0.0 - 12.0). Overall, 64.4% (n=29) achieved cCR after TNT. 13 patients (28.9%) underwent surgical resection following TNT, 12 of whom had incomplete response and one who elected to undergo surgery after reaching cCR. At median follow up of 32.0 months (range, 7.1 - 86.1), 22.2% (n=10) of patients had a permanent colostomy, with only 2 of these completed for tumor regrowth after cCR. At one and two years, respectively, surgery-free survival was 77.3% and 66.2%, and permanent ostomy-free survival was 90.9% and 78.2%. Rates of cCR were higher in patients who received CRT first compared to those who received chemotherapy first (72.2% vs. 33.3%, p=0.029) and rates of surgery were also lower in patients who received CRT first compared to those who received chemotherapy first (19.4% vs. 66.7%, p=0.005). On Cox regression model, cCR on 6 month post-CRT endoscopy was associated with surgery-free survival (p=0.006) and permanent ostomy-free survival (p=0.033). Clinical response at earlier follow up points did not predict surgery- nor permanent ostomy-free survival. Conclusion: These results support evidence that TNT may be a non-surgical option for select patients with rectal adenocarcinoma who desire organ preservation. In this investigation at a single institution, the treatment response on 6-month post-CRT endoscopy was the best predictor of surgery- and permanent ostomy-free survival, which are outcomes that are important to patient quality of life. CRT followed by consolidation chemotherapy was associated with higher rates of cCR and lower rates of surgery compared to those treated with induction chemotherapy.

Journey through the Decades: The Evolution in Treatment and Shared Decision Making for Locally Advanced Rectal Cancer.

The management of locally advanced rectal cancer has undergone significant transformations over the decades and optimal treatment approaches continue to evolve. There have been numerous advances in surgery, chemotherapy, and radiation therapy from the first description of the abdominoperineal resection in 1908, timing of chemotherapy and radiation therapy in the late 20th and early 21st century, and most recently, the introduction of organ preservation or nonoperative management in 2004. Alongside these advancements, the concept of shared decision making in medicine has evolved, prompting a focus on patient-centered care. This evolution in practice has been fueled by a growing recognition of the importance of patient autonomy and the alignment of treatment options with patients' values and preferences. With the growing number of possible treatment options, variability in patient counseling exists, highlighting the need for a standardized approach to shared decision making in locally advanced rectal cancer. This narrative review will describe the evolution of treatment options of locally advanced rectal cancer as well as the concept of shared decision making and decision aids, and will introduce a decision aid for patients with locally advanced rectal cancer who have achieved a complete clinical response and are eligible for watch and wait.

The Norwegian Watch and Wait study: Norwait for rectal cancer. A report from a failed study-a word of caution.

The paucity of prospective data on the subject of Watch and Wait for rectal cancer prompted the implementation of Norwait, a population-based study including rectal cancer patients after neoadjuvant therapy. The aim of the study was to assess the accuracy of clinical complete response (cCR) and quantify the regrowth rates. Norwait was a prospective population-based observational study with ethical approval (2017/935) registered at clinicaltrials.com (NTC03402477). Residents of Norway with histologically proven rectal cancer located within 15 cm from anal verge were eligible following completion of radiotherapy or chemoradiation at seven hospitals. cCR was the disappearance of tumour and of any ulcer with/without the appearance of whitening of prior tumour site and telangiectasia evaluated at 12 weeks by digital rectal exam, and endoscopic imaging. The study aimed to include 100 cCR patients with regrowth rates as primary endpoint. The data are presented in crude form. Eighty-two patients were included in seven hospitals from 2018 to 2020 when the study was terminated. Fifty-one patients were included in six hospitals, whereas protocol violations were identified in one hospital, where thirty-one (rather than protocol-estimated 12) patients were enrolled. Amongst the 31 patients, there were only 2 with documented cCR. Of the latter 29, there were 16 with ulcer or persistent tumour, and 13 without any documentation of cCR. Of these, 23 underwent surgery with a delay up to 50 weeks. At median 54-month follow-up of 31 patients, there were 77% local regrowths (n = 23), 40% metachronous metastases (n = 12) and 23% deaths (n = 7). At median 54-month follow-up of 51 cCR patients, there were 53% local regrowths (n = 27), 14% metachronous metastases (n = 7) and 4% deaths (n = 2). Norwait admonishes a word of caution reaching beyond the inconclusive results of a population-based study jeopardised by serious violation to protocol and legislation for conducting safe research.

Evaluating complete response rates and predictors in total neoadjuvant therapy for rectal cancer.

BACKGROUND: There is a paradigm shift in the management of locally advanced rectal cancer (LARC) from conventional neoadjuvant treatment to total neoadjuvant therapy (TNT). Despite its growing acceptance, there are limited studies that have examined its effects on disease presentation. In addition, it is important to determine the factors that play a role in complete response (CR). Our previous data from 119 patients revealed that the CR rate was 37%, and low rectal tumors and the absence of extramural vascular invasion (EMVI) were predictors of CR. Unfortunately, there continues to be a lack of data, and reliable markers are still needed to consistently identify the best respondents. Therefore, this study aimed to determine the factors associated with CR. Moreover, this study hypothesized that both predictive factors and the CR ratio might evolve over time because of the growing patient population. METHODS: This retrospective study included patients who completed TNT for LARC at our tertiary care center between 2015 and 2022. The primary outcome was to determine the predictors of CR. The secondary outcomes were the 2-year disease-free survival (DFS) rate and overall survival (OS) rate. CR consists of patients who sustained clinical CR (cCR) for at least 12 months under watch and wait or had pathologic CR (pCR) after surgery. RESULTS: Of 339 patients with LARC, 208 (61.3%) successfully completed TNT. Among 208 patients, 57 (27.4%) achieved cCR, and 166 (80.0%) sustained cCR without tumor regrowth after 1 year. The remaining 151 patients (72.6%) underwent surgery, and 42 patients had pCR. The final CR rate was 42.3%. The median age of the patients was 56 years (IQR, 49-66). Moreover, 132 participants (63.5%) were male, whereas 76 participants (36.5%) were female. The median tumor size was 4.95 cm (IQR, 3.60-6.43), with most tumors in the low rectum (119 [57.2%]). Based on the MRI findings, the mesorectal facia (MRF) involvement rate was 25.0% (n = 52), and EMVI was observed in 43 patients (20.7%). Low rectal tumors, the absence of MRF involvement, and the absence of EMVI were predictors of CR. With a median follow-up of 24.7 months, 2-year DFS and OS were significantly higher among patients with CR than among patients with incomplete response (91.3% vs 71.0% [P < .01] and 98.8% vs 90.2% [P = .03], respectively). CONCLUSION: An increasing CR rate was observed in our updated dataset compared with that in our previous study. In addition to previously identified predictors, low tumor location, and the absence of EMVI, the absence of MRF involvement was determined as a predictor of CR. Our findings offer valuable insights into clinical practice and help clinicians set clear expectations when counseling patients.

Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

BACKGROUND: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. METHODS: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . DISCUSSION: Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Neoadjuvant treatment of rectal cancer: Where we are and where we are going.

Locally advanced rectal cancer requires a multidisciplinary approach based on total neoadjuvant treatment with radiotherapy (RT) and chemotherapy (ChT), followed by deferred surgery. Currently, alternatives to the standard total neoadjuvant therapy (TNT) are being explored, such as new ChT regimens or the introduction of immunotherapy. With standard TNT, up to a third of patients may achieve a complete pathological response (CPR), potentially avoiding surgery. However, as of now, we lack predictive markers of response that would allow us to define criteria for a conservative organ strategy. The presence of mutations, genes, or new imaging tests is helping to define these criteria. An example of this is the diffusion coefficient in the diffusion-weighted sequence of magnetic resonance imaging and the integration of this imaging technique into RT treatment. This allows for the monitoring of the evolution of this coefficient over successive RT sessions, helping to determine which patients will achieve CPR or those who may require intensification of neoadjuvant therapy.

Natural history of indolent-anti-synthetase syndrome-associated interstitial lung disease.

BACKGROUND: Anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) may occur without myositis. Although a recent Japanese guide proposed a watch-and-wait approach for chronic ASS-ILD without obvious progression, the natural history of this subgroup and the appropriateness of the watch-and-wait approach remain unclear. We aimed to describe the natural history of ASS-ILD, that is sufficiently indolent to be a candidate for the watch-and-wait approach. METHODS: Among consecutive patients with ASS-ILD, we retrospectively identified those without myositis, acute/subacute onset, and significant lung function impairment, which qualified them as indolent-ASS-ILD cases, and described their natural course. Additionally, we evaluated the risk factors for fibrosis progression on computed tomography (CT) using the Cox proportional hazards model. RESULTS: Among 80 patients with ASS-ILD, we identified 33 with indolent-ASS-ILD, all of whom were initially followed up with a watch-and-wait approach. Among 30 patients with sufficient follow-up data, 27 (90%) showed a stable course without treatment over 24 months. Subsequently, four patients experienced ≥10% relative forced vital capacity (FVC) decline without treatment during a median follow-up duration of 81 months. Seven patients showed fibrosis progression with >10% increase in the total lung area on CT. Higher levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) were associated with fibrosis progression on CT. CONCLUSION: Most patients with indolent-ASS-ILD did not experience ≥10% relative FVC decline over five years without treatment. However, fibrosis progression on CT, which seemed to precede significant FVC decline, occurred more frequently, especially in patients with higher KL-6 and SP-D levels.

Recent updates on treatment options for primary follicular lymphoma of the gastrointestinal tract.

BACKGROUND: Primary gastrointestinal follicular lymphoma is a subtype of follicular lymphoma that originates directly from the gastrointestinal tract. Pathologically, it exhibits substantial similarities with the secondary gastrointestinal involvement observed in nodal follicular lymphoma. However, primary gastrointestinal follicular lymphoma presents clinically distinct features, necessitating divergent considerations in treatment selection compared with nodal follicular lymphoma. AREAS COVERED: This narrative review focused on recent articles (2018-2023) regarding the long-term prognosis and treatment options for gastrointestinal follicular lymphoma. In addition, a brief overview of gastrointestinal follicular lymphomas is provided. EXPERT OPINION: Patients with primary gastrointestinal follicular lymphoma often present with a low tumor burden. Lymphoma lesions typically remain asymptomatic for several years or may undergo spontaneous regression without immediate treatment. Therefore, a 'watch and wait' approach is justified. Conversely, when large tumor masses are identified in the gastrointestinal tract, the potential for tumor bleeding or intestinal obstruction requires timely therapeutic interventions.

Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: A narrative review.

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.

Sequence of Contact X-ray Brachytherapy (CXB) and External Beam Radiation (EBRT) in organ-preserving treatment for small rectal cancer.

BACKGROUND AND PURPOSE: External Beam Radiotherapy (EBRT) followed by Contact X-ray Brachytherapy (CXB) and vice versa are viable alternatives to surgery for selected rectal cancer patients who have small tumours (≤3 cm). However, the optimal sequence of treatment needs to be established. We compared two approaches using Propensity Score (PS) matching and inverse probability treatment weighting (IPTW) analyses to investigate whether the sequence of treatment affected patient outcomes. MATERIALS AND METHODS: This retrospective analysis (2008-2019) included patients with rectal adenocarcinoma (cT1-3,N0-1,M0, grade 1-2, size ≤ 3 cm) who received both EBRT and CXB, irrespective of treatment sequence. PS matching and IPTW were conducted to balance covariate standardised mean differences between groups. Oncological outcomes and rate of post-treatment rectal bleeding were assessed. RESULTS: Following PS matching and IPTW analyses from 251 eligible patients; 103 starting with EBRT (median follow-up: 37 [IQR:18-56] months) and 148 with CXB (median follow-up: 32 [IQR:16-54] months, a significant improvement in 3-year overall survival (77% vs 85%, p = 0.02, [HR:0.58 (95% CI:0.37-0.91)]) and a higher risk of post-treatment rectal bleeding (grade 1 (26%) and grade 2 (6%)) were found in patients who started with CXB (p = 0.08). No significant differences were observed in local regrowth (18% vs 12%, p = 0.47), distant relapse (10% vs 6%, p = 0.53), 3-year organ preservation rates (70% vs 75%, p = 0.20, [HR:0.66 (95% CI: 0.35-1.26)]), or disease-free survival (78% vs 82%, p = 0.17, [HR: 0.47 (95% CI: 0.16-1.38)]) CONCLUSION: In patients with rectal cancer (≤3 cm), commencing with CXB rather than EBRT, was associated with improved overall survival, but had a higher risk of G1/2 rectal bleeding. No statistically significant differences were observed in other oncological outcomes.

Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use?

Total neoadjuvant therapy (TNT) is a novel strategy for rectal cancer that administers both (chemo)radiotherapy and systemic chemotherapy before surgery. TNT is expected to improve treatment compliance, tumor regression, organ preservation, and oncologic outcomes. Multiple TNT regimens are currently available with various combinations of the treatments including induction or consolidation chemotherapy, triplet or doublet chemotherapy, and long-course chemoradiotherapy or short-course radiotherapy. Evidence on TNT is rapidly evolving with new data on clinical trials, and no definitive consensus has been established on which regimens to use for improving outcomes. Clinicians need to understand the advantages and limitations of the available regimens for multidisciplinary decision making. This article reviews currently available evidence on TNT for rectal cancer. A decision making flow chart is provided for tailor-made use of TNT regimens based on tumor location and local and systemic risk.