Circumferential Rectal Cancer Is a Risk Factor for Stricture Formation and Restaging Uncertainties Following Neoadjuvant Therapy.

Total neoadjuvant therapy in the treatment of stage II and III rectal cancer involves the administration of either induction or consolidation chemotherapy with chemoradiation before surgery. Total neoadjuvant therapy is associated with an increased complete response rate, which is defined as the proportion of patients who either had a pathological complete response after surgery or sustained a clinical complete response for at least 1 year under surveillance. To identify the predictors of complete response to total neoadjuvant therapy and compare different diagnostic tools in predicting complete response. Retrospective cohort study. A single tertiary care center. Patients with stage II and III rectal cancer who were diagnosed between January 2015 and December 2021. Total neoadjuvant therapy. Complete response rate, predictors of complete response, sensitivity and specificity of sigmoidoscopy, and MRI in predicting complete response. One hundred nineteen patients (mean age 56 [±11.3] years, 47 [39.5%] women, 100 [84%] stage III rectal cancer) were included. The median tumor size was 5.1 (4-6.5) cm, and 63 (52.9%) were low rectal tumors. Twenty-one patients (17.6%) had extramural vascular invasion and 62 (52.1%) had elevated CEA at baseline. One hundred eight patients (90.8%) received consolidation chemotherapy. After total neoadjuvant therapy, 88 of 119 patients (73.9%) underwent surgery, of whom 20 (22.7%) had pathological complete response. Thirty-one patients (26.1%) underwent watch-and-wait, of whom 24 (77.4%) had sustained clinical complete response. Overall, the complete response rate was 37%. Low rectal tumors (OR 1.5 [95% CI, 1.03-2.4], p = 0.04) and absence of extramural vascular invasion (OR 2.2 [95% CI, 1.1-5.6], p = 0.01) were predictors of complete response. In predicting complete response, sigmoidoscopy was more sensitive (76.0% vs 62.5%) and specific (72.5% vs 69.2%) than MRI. The specificity further increased when 2 techniques were combined (82.5%). Retrospective study. The complete response rate after total neoadjuvant therapy was 37%. Low rectal tumors and the absence of extramural vascular invasion were predictors of complete response. Sigmoidoscopy was better in predicting incomplete response, whereas combination (MRI and sigmoidoscopy) was better in predicting complete response. See Video Abstract. ANTECEDENTES:La terapia neoadyuvante total en el tratamiento del cáncer de recto en estadios II-III implica la administración de quimioterapia de inducción o de consolidación con quimio radiación antes de la cirugía. La terapia neoadyuvante total se asocia con una mayor tasa de respuesta completa, que se define como la proporción de pacientes que tuvieron una respuesta patológica completa después de la cirugía o una respuesta clínica completa sostenida al menos durante un año bajo vigilancia.OBJETIVO:Identificar los predictores de respuesta completa a la terapia neoadyuvante total y comparar diferentes herramientas de diagnóstico para predecir la respuesta completa.DISEÑO:Estudio de cohorte retrospectivo.LUGARES:Un único centro de atención terciaria.PACIENTES:Pacientes con cáncer de recto en estadio II-III diagnosticados entre enero de 2015 y diciembre de 2021.INTERVENCIÓN(S):Terapia neoadyuvante total.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de respuesta completa, predictores de respuesta completa, sensibilidad y especificidad de la sigmoidoscopia y la resonancia magnética para predecir la respuesta completa.RESULTADOS:Se incluyeron 119 pacientes [edad media 56 (±11,3) años, 47 (39,5%) mujeres, 100 (84%) cáncer de recto en estadio III]. La mediana del tamaño tumoral fue de 5,1 (4-6,5) cm, 63 (52,9%) fueron tumores rectales bajos. Veintiún (17,6%) pacientes tenían invasión vascular extramural (EMVI), 62 (52,1%) tenían CEA elevado al inicio del estudio. Ciento ocho (90,8%) pacientes recibieron quimioterapia de consolidación. Después de la TNT, 88 (73,9%) de 119 pacientes fueron intervenidos quirúrgicamente, de los cuales 20 (22,7%) tuvieron respuesta patológica completa. Treinta y un (26,1%) pacientes fueron sometidos a observación y espera, de los cuales 24 (77,4%) tuvieron una respuesta clínica completa sostenida. La tasa de respuesta completa general fue del 37%. Los tumores rectales bajos [OR 1,5 (IC 95% 1,03-2,4), p = 0,04] y la ausencia de EMVI [OR 2,2 (IC 95% 1,1-5,6), p = 0,01] fueron predictores de respuesta completa. Para predecir la respuesta completa, la sigmoidoscopia fue más sensible (76,0 % frente a 62,5 %) y específica (72,5 % frente a 69,2 %) que la resonancia magnética. La especificidad aumentó aún más cuando se combinaron dos técnicas (82,5%).LIMITACIONES:Estudio retrospectivo.CONCLUSIONES:La tasa de respuesta completa después de la terapia neoadyuvante total fue del 37%. Los tumores rectales bajos y la ausencia de EMVI fueron predictores de respuesta completa. La sigmoidoscopia fue mejor para predecir la respuesta incompleta, mientras que la combinación (MRI y sigmoidoscopia) fue mejor para predecir la respuesta completa. (Traducción-Dr Osvaldo Gauto ).

3519 Background: The most common therapy for locally advanced (T3/4 or N+) rectal cancer (LARC) consists of preoperative chemoradiotherapy (chemoRT) followed by surgery and adjuvant chemotherapy. Recently, use of total neoadjuvant therapy (TNT) with preoperative chemotherapy in addition to chemoRT prior to resection has been accepted as an alternative. Methods: Of 811 consecutive patients (pts) who presented with LARC at our cancer center in 2009-2015, 320 received chemoRT with planned adjuvant chemotherapy, and 308 received TNT (induction FOLFOX/CAPOX chemotherapy followed by chemoRT). Treatment and outcome data for those two cohorts were compared. Results: Pts in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort (p < 0·005 and p < 0·001, respectively). The complete response (CR) rate, which includes pathological CR (pCR) and clinical CR (cCR) at 6 months post-treatment, was 21% in the chemoRT with planned adjuvant chemotherapy cohort and 36% in the TNT cohort. The median follow-up was 40 months in the chemoRT with planned adjuvant chemotherapy cohort and 23 months in the TNT cohort. Fewer distant recurrences were seen in patients who had T downstaging (p < 0·001), N downstaging (p < 0·005), a cCR (p = 0·005), or a pCR (p < 0·005). There was no statistically significant difference in distant-recurrence-free survival between the two cohorts. Conclusions: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines for rectal cancer treatment, which categorizes TNT as a viable treatment strategy that facilitates superior compliance and delivery of systemic therapy. Given its high CR rate, TNT may be beneficial as part of a nonoperative treatment strategy aimed at organ preservation.

In the management of locally advanced rectal cancer, organ preservation after total neoadjuvant therapy requires complete clinical response and close surveillance. Patients with near-complete response or tumor regrowth during watch and wait are recommended to undergo total mesorectal excision. Selective use of local resection procedures, such as endoscopic submucosal dissection, may expand organ preservation in these patients. To assess the feasibility, safety, and outcomes of endoscopic submucosal dissection for patients with near-complete response or tumor regrowth after total neoadjuvant therapy. Retrospective cohort study. Single tertiary care center. Patients with locally advanced rectal cancer treated with total neoadjuvant therapy between 2015 and 2024 and who underwent endoscopic submucosal dissection for near-complete response or tumor regrowth during active surveillance. Endoscopic submucosal dissection for near-complete response and tumor regrowth during watch and wait. Organ preservation and regrowth rates after endoscopic submucosal dissection. Twenty patients were included (40% women, mean age 59.1 ± 13.1 years). Although 10 patients underwent endoscopic submucosal dissection for near-complete response with endoluminal lesions after total neoadjuvant therapy completion, 10 underwent endoscopic submucosal dissection due to tumor regrowth during watch and wait. The median time for tumor regrowth was 12.5 months. Pathologic examination of specimens showed no invasive cancer in 14 patients (70%). Total mesorectal excision was performed in 5 patients in whom invasive adenocarcinoma was found on endoscopic submucosal dissection. The 1 remaining patient refused proctectomy. One patient with dysplasia, after an additional watch-and-wait period after endoscopic submucosal dissection, underwent total mesorectal excision to address a second regrowth. Fourteen patients, including the one who refused surgery, have been closely monitored to date, with no evidence of disease for a mean of 27.7 months. Retrospective design and small sample size. Selective use of endoscopic submucosal dissection can be feasible and safe for organ preservation in highly selected patients with locally advanced rectal cancer after total neoadjuvant therapy. Larger prospective trials with longer follow-up are needed to validate its value. See Video Abstract. ANTECEDENTES:En el tratamiento del cáncer rectal localmente avanzado, la preservación del órgano tras una terapia neoadyuvante total requiere una respuesta clínica completa y una vigilancia estrecha. Se recomienda a los pacientes con respuesta casi completa o recidiva tumoral durante el periodo de observación y espera someterse a una disección mesorrectal total. El uso selectivo de procedimientos de resección local, como la disección endoscópica submucosa, puede ampliar la preservación del órgano en estos pacientes.OBJETIVO:Evaluar la viabilidad, la seguridad y los resultados de la disección endoscópica submucosa en pacientes con respuesta casi completa o recidiva tumoral tras una terapia neoadyuvante total.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO:Centro único de atención terciaria.PACIENTES:Pacientes con cáncer rectal localmente avanzado tratados con terapia neoadyuvante total entre 2015 y 2024, que se sometieron a disección endoscópica submucosa por respuesta casi completa o recidiva tumoral durante la vigilancia activa.INTERVENCIONES:Disección endoscópica submucosa para la respuesta casi completa y el recidiva tumoral durante la vigilancia activa.PRINCIPALES MEDIDAS DE RESULTADO:Tasas de preservación de órganos y recidiva tras la disección endoscópica submucosa.RESULTADOS:Se incluyeron 20 pacientes (40 % mujeres, edad media 59,1 ± 13,1 años). Mientras que 10 pacientes se sometieron a disección endoscópica submucosa para obtener una respuesta casi completa con lesiones endoluminales tras completar la terapia neoadyuvante total, 10 se sometieron a disección endoscópica submucosa debido al recidiva tumoral durante la vigilancia activa. La mediana del tiempo de recidiva tumoral fue de 12,5 meses. El examen patológico de las muestras no reveló cáncer invasivo en 14 pacientes (70 %). Se realizó una disección mesorrectal total en cinco pacientes debido al adenocarcinoma invasivo encontrado en la disección endoscópica submucosa. El otro paciente rechazó la proctectomía. Un paciente con displasia, tras un periodo adicional de espera y observación después de la disección endoscópica submucosa, se sometió a una extirpación mesorrectal total debido a un segundo recidiva. Catorce pacientes, incluido el que rechazó la cirugía, han sido objeto de un seguimiento estrecho hasta la fecha, sin evidencia de enfermedad durante una media de 27,7 meses.LIMITACIONES:Diseño retrospectivo y tamaño reducido de la muestra.CONCLUSIÓN:El uso selectivo de la disección endoscópica submucosa puede ser viable y seguro para la preservación de órganos en pacientes altamente seleccionados con cáncer rectal localmente avanzado tras terapia neoadyuvante total. Se necesitan ensayos prospectivos más amplios con un seguimiento más prolongado para validar su valor. (AI-generated translation).

Recent studies have associated total neoadjuvant therapy (TNT) with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates in patients with locally advanced rectal cancer (LARC). However, real-world experience with TNT in the management of LARC remains limited. This study aimed to evaluate the efficacy and safety outcomes of TNT for LARC in Western Australia. Patients with LARC (cT2-4 and/or cN1-2) who underwent induction chemotherapy followed by neoadjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy followed by consolidation chemotherapy, followed by surgery were recruited from two hospitals in Western Australia. Efficacy outcomes assessed included clinical response (complete, partial, no response), and pathologic complete response (pCR) rate, R0 resection rate, and R1 resection rate were evaluated. Those patients who achieved clinical complete response following TNT were given the option of active surveillance. The safety and tolerability of TNT were assessed. 32 patients with LARC were treated with TNT. In total, 17 patients (53%) received chemoradiotherapy followed by consolidation chemotherapy and 15 patients (47%) received induction chemotherapy followed by chemoradiotherapy. Nine (28%) of the patients with LARC treated with TNT had a complete clinical response, twenty-one (66%) patients had a partial clinical response, and two (6%) patients had no response to TNT. Of the 32 patients, 27 (84%) underwent surgery. There was a 100% R0 resection rate. The pCR rate was 15%. pCR, clinical response, and the R0 resection rate were similar between the two TNT regimens. TNT was well tolerated, with the majority of patients (88%) completing the chemotherapy course with grade 1 and 2 adverse effects. In conclusion, TNT emerges as a promising approach for the management of LARC. However, further research is warranted to refine the optimal TNT protocols, determine its long-term outcomes, and identify patient populations who would benefit the most from this innovative therapeutic strategy.

Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

284 Background: Total neoadjuvant therapy (TNT) has dramatically shifted the paradigm in the treatment of locally advanced rectal cancer (LARC), prolonging survival with high rates of pathologic complete response (pCR) and introducing non-operative management (NOM). However, no predictive biomarkers of TNT efficacy, the regrowth of NOM, or prognosis have been developed. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker used to detect molecular residual disease (MRD) and predict recurrence in colon cancer after curative resection. The effectiveness of ctDNA MRD status as a predictive biomarker for TNT was evaluated in the Phase II TNT study, ENSEMBLE-2 (jRCTs071210143), conducted in Japan. Methods: Patients with LARC undergoing TNT were enrolled in ENSEMBLE-2. Protocol treatment was defined as total mesorectal excision (TME) following long course chemoradiotherapy (LCCRT: 50.4Gy, capecitabine) plus four cycles of CAPOX. NOM was allowed if a clinical complete response (cCR) was achieved in the evaluation after TNT. ctDNA MRD was measured by Signatera (Natera, Inc.) at the following time points: baseline, after LCCRT, after TNT, post operative 4w, 12w, 24, 36 and 48w in the GALAXY trial (UMIN000039205). Results: A total of 28 patients were enrolled in the study. Treatment was discontinued at the patient's request in one case. After completing TNT, TME and NOM were performed in 21 (77.8%) and 6 (21.4%) patients, respectively. ctDNA positivity rates were 96.4. % (27/28) at baseline, 14.8% (4/27) after LCCRT, and 34.6 % (9/26) after TNT. Post-LCCRT ctDNA status was not significantly associated with cCR + near CR (nCR) vs. incomplete clinical response (iCR), pCR vs. non-pCR (p=0.065 and p=0.539, respectively). In contrast, ctDNA status after TNT was significantly associated with cCR + nCR vs. iCR (p=0.028), as well as pCR vs. non-pCR (p=0.038). Conclusions: Our study indicates that post TNT ctDNA status may be a predictive biomarker for TNT response in LARC patients. ctDNA negativity upon completion of neoadjuvant treatment may indicate a favorable response. Clinical trial information: jRCTs071210143 . Correlation with ctDNA, clinical response, treatment after TNT and pathological response. After LCCRT p value After TNT p value Clinical ResponsecCR + nCR vs. iCR (ctDNA -/+) cCR + nCR 18 / 1 0.065 cCR + nCR 15 / 4 0.028 iCR 5 / 3 iCR 2 / 5 Treatment after TNTNOM vs. TME (ctDNA -/+) TME 17 / 3 0.438 TME 11 / 9 0.063 NOM 6 / 0 NOM 6 / 0 Pathological response after TMEpCR vs. non pCR (ctDNA -/+) pCR 5 / 0 0.539 pCR 5 / 0 0.038 non pCR 12 / 3 non pCR 6 / 9 Fisher's exact test was used to statistically examine the correlation between ctDNA MRD status and the factors at each timing.

Simple SummaryModern rectal cancer treatment in the form of total neoadjuvant therapy (TNT) offers additional opportunities for organ preservation and consideration for a watch-and-wait (WW) surveillance only approach. Preoperative predictors of pCR after TNT can guide the ideal selection criteria for WW in the current era. An exhaustive literature review found predictors for pCR to include the following: (1) biochemical factors; (2) clinical factors; (3) patient demographics; and (4) treatment sequence for TNT. Additional data from long-term trials using TNT is critical to better inform those considering watch-and-wait approaches following a clinical complete response.The modern rectal cancer treatment paradigm offers additional opportunities for organ preservation, most notably via total neoadjuvant therapy (TNT) and consideration for a watch-and-wait (WW) surveillance-only approach. A major barrier to widespread implementation of a WW approach to rectal cancer is the potential discordance between a clinical complete response (cCR) and a pathologic complete response (pCR). In the pre-TNT era, the identification of predictors of pCR after neoadjuvant therapy had been previously studied. However, the last meta-analysis to assess the summative evidence on this important treatment decision point predates the acceptance and dissemination of TNT strategies. The purpose of this systematic review was to assess preoperative predictors of pCR after TNT to guide the ideal selection criteria for WW in the current era. An exhaustive literature review was performed and the electronic databases Embase, Ovid, MEDLINE, PubMed, and Cochrane were comprehensively searched up to 27 June 2023. Search terms and their combinations included “rectal neoplasms”, “total neoadjuvant therapy”, and “pathologic complete response”. Only studies in English were included. Randomized clinical trials or prospective/retrospective cohort studies of patients with clinical stage 2 or 3 rectal adenocarcinoma who underwent at least 8 weeks of neoadjuvant chemotherapy in addition to chemoradiotherapy with pCR as a measured study outcome were included. In this systematic review, nine studies were reviewed for characteristics positively or negatively associated with pCR or tumor response after TNT. The results were qualitatively grouped into four categories: (1) biochemical factors; (2) clinical factors; (3) patient demographics; and (4) treatment sequence for TNT. The heterogeneity of studies precluded meta-analysis. The level of evidence was low to very low. There is minimal data to support any clinicopathologic factors that either have a negative or positive relationship to pCR and tumor response after TNT. Additional data from long-term trials using TNT is critical to better inform those considering WW approaches following a cCR.

4145 Background: Despite increased utilization of neoadjuvant therapy for pancreatic cancer (PC), a substantial proportion of patients never receive adjuvant therapy. We examined if total neoadjuvant therapy (TNT) would facilitate delivery of all prescribed (≥6 months) non-surgical therapy (NST: chemotherapy ± radiation) to improve oncologic outcomes. Methods: Patients receiving neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ±radiation followed by pancreatectomy at 7 centers were reviewed. Patients receiving TNT (≥6 months NST pre-resection) were compared to those receiving < 6 months ( < TNT). Primary outcomes were major (complete/near-complete) pathologic response (MPR) and overall survival (OS). Results: Of 504 patients, 105 (21%) were selected for TNT. TNT and < TNT patients had similar performance status and rates of borderline resectable/locally advanced disease (82% vs. 80%). TNT patients were significantly more likely to receive ≥6 months NST (100% vs. 31%; p < 0.001) vs. < TNT. While selection of chemotherapy regimen (FOLFIRINOX or gemcitabine/nab-paclitaxel) did not differ between TNT and < TNT cohorts, TNT patients were more likely to receive neoadjuvant radiation (44% vs. 25%, p < 0.001). Rates of vascular resection, postoperative complications, and mortality were similar between groups. TNT was associated with decreased rates of lymphovascular/perineural invasion (p = 0.002) and nodal positivity (p = 0.001), and increased rates of MPR (41% vs. 23%; p = 0.001) and pathologic complete response (13% vs. 6%; p = 0.02). TNT was associated with improved OS compared with < TNT (median 38 vs. 30 months; p = 0.039). Both MPR (median 38 [MPR] vs. 28 [limited response] months; p = 0.002) and ≥6 months NST (TNT or peri-operative) (median 38 [≥6m] vs. 26 [ < 6m] months; p = 0.001) were associated with improved OS. Addition of radiation was not associated with MPR or OS. Conclusions: The TNT approach allows more patients with localized PC to receive ≥6 months NST and is associated with improved rates of MPR and OS. TNT should be considered for all patients with operable PC when possible.

In rectal cancer patients with a clinical complete response managed nonoperatively, local regrowth occurs in up to 35%. Although prior studies suggest a higher metastatic risk after regrowth, most data are derived from conventional chemoradiotherapy cohorts. The risk in a total neoadjuvant therapy setting remains unclear. To assess whether local regrowth after clinical complete response in patients treated with total neoadjuvant therapy increases the risk of distant metastasis, and to evaluate if the risk could be reduced by upfront surgery performed after total neoadjuvant therapy. Retrospective cohort study. Single tertiary care center. Patients with locally advanced rectal cancer treated with total neoadjuvant therapy between 2018 and 2024 who achieved a clinical complete response, were managed nonoperatively, developed local regrowth, and subsequently underwent salvage total mesorectal excision, compared with those who underwent upfront total mesorectal excision after total neoadjuvant therapy, with final pathology demonstrating a near-complete response. Total neoadjuvant therapy followed by either watch & wait and salvage total mesorectal excision or upfront total mesorectal excision. The primary outcome was distant metastasis. Secondary outcomes included distant metastasis-free survival and independent predictors of distant spread. Seventy-four patients were included (median age: 58 years [IQR, 51-67]; 58% male): 32 with local regrowth managed by salvage total mesorectal excision and 42 with upfront total mesorectal excision. The distant metastasis-free survival was comparable between groups, and local regrowth was not independently associated with distant metastasis (OR, 0.99; 95% CI, 0.25-4.00). ypT3-4 stage was independently associated with increased risk of distant metastasis (OR, 5.8; 95% CI, 1.3-25.3), while complete mesorectal excision was protective (OR, 0.08; 95% CI, 0.01-0.59). Retrospective design, small sample size, and limited follow-up. Patients treated with total neoadjuvant therapy who developed local regrowth and underwent salvage total mesorectal excision achieved distant metastasis rates comparable to those who underwent upfront surgery after total neoadjuvant therapy and demonstrated a pathologic near-complete response. High-quality salvage surgery and close surveillance are essential for optimizing oncologic outcomes. See Video Abstract.

41 Background: The treatment of localized rectal adenocarcinomas with Total Neoadjuvant Therapy (TNT) has become the national standard. Data on the efficacy of TNT in a predominantly rural community oncology setting is limited. Methods: This ongoing retrospective analysis included 94 patients with proficient MMR Stage II or III rectal adenocarcinoma treated with traditional neoadjuvant treatment of chemoradiation followed by surgical resection +/- adjuvant chemotherapy, or Consolidation (chemoradiation upfront) TNT versus Induction (chemotherapy upfront) TNT followed by surgical resection, diagnosed between 2017 and 2022 and treated at the Avera Cancer Institute in Sioux Falls, South Dakota. The primary objectives were to compare the pathologic response and treatment completion rates in patients with rectal cancer treated with TNT to patients treated with traditional neoadjuvant treatment. The secondary objective was to compare the pathologic response rate for TNT at different tumor locations. Results: Of 94 patients assessed, 54 patients received traditional neoadjuvant treatment and 40 patients received TNT. For patients treated with traditional neoadjuvant treatment, 43% (n=23) completed all recommended treatment, with 63% (n=34) achieving a partial response (PR) and 19% (n=10) a complete pathologic response (CR). For patients treated with TNT, 93% (n=37) completed all recommended treatment, and 68% (n=27) achieved a PR and 15% (n=6) achieved a CR. For patients that received Consolidation TNT (n=21), 66% (n=12) achieved a PR and 21% (n=4) achieved a CR. For patients that received Induction TNT (n=19), 68% (n=13) achieved a PR and 11% (n=2) achieved a CR. For patients with high tumor location (n=4) treated with TNT, 50% (n=2) achieved a PR and one patient achieved a CR (25%). For patients with mid tumor location (n=18) treated with TNT, 67% (n=12) achieved a PR and 22% (n=4) achieved a CR. For patients with low tumor location (n=18) treated with TNT, 72% (n=13) achieved a PR and one patient (6%) achieved a CR. Conclusions: The treatment of rectal adenocarcinoma with TNT in the rural community cancer center setting is achievable with a higher completion rate compared to traditional neoadjuvant treatment. Our results also show a trend toward a higher complete pathologic response rate in Consolidation compared to Induction approach and in high/mid rectal tumors compared to low rectal tumors. Future work will be conducted to assess for any differences in recurrence and survival.

e15582 Background: Despite the widespread application of standard chemoradiotherapy (CRT) followed by total mesorectal excision with adjuvant chemotherapy, the mortality reduction for locally advanced rectal cancer (LARC) has slowed in recent years. Total neoadjuvant therapy (TNT) is a novel therapeutic strategy in LARC which incorporates both systemic chemotherapy and neoadjuvant CRT prior to surgery. Recent studies have associated TNT with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates. However, real-world experience with TNT in the management of LARC remains limited. Methods: Records from patents with LARC who underwent TNT at two oncology centres in Western Australia since 2018 were screened. Patient demographics, diagnostic workup, treatment regimens, surgical, pathological reports, post-operative surveillance scans and adverse effects’ documentation were reviewed. TNT regimens included neoadjuvant chemotherapy (NAC) with oxaliplatin in combination with either 5-FU (FOLFOX) or capecitabine (CAPOX) with chemoradiation given prior or after NAC, which is then followed by surgery. Patients who had radiological complete response (rCR) were given the option of “watch and wait (W&W)” instead of proceeding to surgery. Outcomes assessed included radiological complete response (rCR), pathological complete response (pCR) rate, proportion of patients with progressive disease, type of surgery, rate of R0 resection, proportion of patients who completed planned cycles of chemotherapy and radiotherapy and treatment-related adverse effects. Results: 29 patients with LARC have thus far have completed TNT followed by surgery. The mean age was 59 years (range 34-84), 58% and 42% of patients were male and female respectively. 11 (38%), 16 (55%) and 2 (7%) patients were ECOG 0, 1 and 2 respectively. The majority of patients were stage 3 (90%), with the remaining 3 patients at stage 1, 2 and 4 at time of presentation. 3 (10%) and 7 (24%) patients had pCR and rCR respectively, of which 4 opted for W&W approach. Treatment was well-tolerated with 86% and 96% of patients completing the planned total course of chemotherapy and radiotherapy respectively although dose reductions and/or delay were required for many. Common adverse effects included neuropathy, neutropenia, anaemia and fatigue, most of which were grade 1. Of the 22 patients who underwent surgery, 19 (82%) and 4 (18%) patients had R0 resection and R1 resection respectively. Majority of the patients who underwent surgery had an anterior resection with temporary loop ileostomy (64%) while the remaining had an abdominoperineal resection (36%). After a median follow up time of 27 months, 10 (34%) patients had progressive disease. Conclusions: TNT is a well-tolerated, effective and promising strategy for the management of LARC. Further data is needed to determine the standard TNT protocol.

71 Background: Total neoadjuvant therapy (TNT) has dramatically shifted the treatment paradigm for locally advanced rectal cancer (LARC), prolonging survival with high rates of pathologic complete response (pCR) and introducing opportunities for nonoperative management (NOM). However, there is a need for robust predictive biomarkers of TNT efficacy, local cancer regrowth in NOM, and overall prognosis. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker used to detect molecular residual disease (MRD) and predict recurrence in colorectal cancer after curative resection. The effectiveness of ctDNA MRD status specifically as a predictive biomarker for TNT was evaluated in the Phase II TNT study, ENSEMBLE-1 (jRCTs051200113), conducted in Japan. Methods: Patients with LARC undergoing TNT were enrolled in ENSEMBLE-1. Protocol treatment was defined as short-course radiotherapy (SCRT: 25Gy) followed by six cycles of CAPOX and total mesorectal excision (TME). NOM was allowed if a clinical complete response (cCR) was achieved after TNT. ctDNA was measured by SignateraTM (Natera, Inc.) at the following time points: baseline (pre-treatment), after SCRT, after 4 cycles of CAPOX, before TME, and post operatively at 4w, 12w, 24, 36 and 48w in the GALAXY trial (UMIN000039205). Results: A total of 30 patients were enrolled in the study. After completing TNT, TME and NOM were performed in 20 and 7 patients, respectively. ctDNA was measured in 26 patients (TME: 19 patients, NOM: 7 patients). ctDNA was detected in 100% (25/25) at baseline, 81% (21/26) after SCRT, 31% (8/26) after 4 cycles of CAPOX, and 45% (9/20) after TNT. The attached table shows the results of statistical analyses of the correlation between ctDNA status, clinical response, TME or NOM, and pathologic complete response (pCR). It was found that ctDNA status after SCRT and after 4 cycles of CAPOX was associated with cCR or non cCR (p=0.007 and p=0.007, respectively). Additionally, ctDNA status after TNT was associated with pCR or non pCR (p=0.029). Conclusions: Our study demonstrates that ctDNA-based MRD may predict TNT response in LARC patients. Negative ctDNA during treatment correlates with favorable responses and may be an aid in NOM decision making. Clinical trial information: jRCTs051200113 . [Table: see text]

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

Total neoadjuvant therapy for pancreatic adenocarcinoma increases probability for a complete pathologic response

Patterns of Care for Patients With Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy at Predominately Academic Centers between 2016-2020: An NCDB Analysis