Pathological Complete Regression Research Articles

Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.

Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts. Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.

Predictive and prognostic value of preoperative pan-immune-inflammation value in patients with locally advanced rectal cancer.

This study aimed to investigate the prognostic value of the pan-immune-inflammation value (PIV) in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision. We retrospectively collected and analyzed the clinicopathological data of 215 resected LARC patients. X-tile software was used to determine the optimal threshold value for PIV in predicting overall survival (OS). The predictive ability of PIV for pathological complete regression (pCR), OS, and disease-free survival (DFS) was evaluated and compared with other inflammation markers. Univariate and multivariate logistic regression analyses for pCR and Cox regression analyses for OS and DFS were conducted. Theoptimal threshold value for PIV was determined to be 454.7 based on the X-tile software. Patients were then categorized into low (≤ 454.7) and high (> 454.7) PIV groups comprising 153 and 62 patients, respectively. PIV demonstrated superior predictive ability for pCR, OS, and DFS compared to other inflammation markers. LARC patients with low PIV had significantly higher pCR (P = 0.029), OS (P = 0.002), and DFS (P = 0.001) rates compared to those with high PIV. Multivariate regression analysis identified PIVas an independent prognostic factor for pCR (odds ratio = 0.32; 95% confidence interval [CI], 0.10-0.80; P = 0.014), OS (hazard ratio = 3.08; 95% CI, 1.77-5.35; P = 0.001), and DFS (hazard ratio = 2.53; 95% CI, 1.58-4.06; P = 0.002). Thisstudy confirmed thatpreoperativePIVcould serve asa useful independent prognostic factor in LARC patients treated with nCRT.

Factors influencing pathological complete response and tumor regression in neoadjuvant radiotherapy and chemotherapy for high-risk breast cancer

BackgroundPathological complete response (pCR) is a well-established prognostic factor in breast cancer treated with neoadjuvant systemic therapy (naST). The determining factors of pCR are known to be intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage as well as type of systemic therapy. The addition of neoadjuvant radiotherapy (naRT) to this paradigm might improve response, freedom from disease, toxicity and cosmetic outcome compared to adjuvant radiotherapy. The factors for pCR and primary tumor regression when neoadjuvant radiation therapy is added to chemotherapy have not been thoroughly described.MethodsWe performed a retrospective analysis of 341 patients (cT1-cT4/cN0-N+) treated with naRT and naST between 1990 and 2003. Patients underwent naRT to the breast and mostly to the supra-/infraclavicular lymph nodes combined with an electron or brachytherapy boost. NaST was given either sequentially or simultaneously to naRT using different regimens. We used the univariate and multivariate regression analysis to estimate the effect of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) as well as complete primary tumor response (ypT0/Tis; bpCR) in our cohort. Receiver operating characteristic (ROC) analysis was performed to evaluate the interval between radiotherapy (RT) and resection (Rx) as well as radiotherapy dose.ResultsOut of 341 patients, pCR and pbCR were achieved in 31% and 39%, respectively. pCR rate was influenced by resection type, breast cancer subtype, primary tumor stage and interval from radiation to surgery in the multivariate analysis. Univariate analysis of bpCR showed age, resection type, breast cancer subtype, clinical tumor stage and grading as significant factors. Resection type, subtype and clinical tumor stage remained significant in multivariate analysis. Radiation dose to the tumor and interval from radiation to surgery were not significant factors for pCR. However, when treatment factors were added to the model, a longer interval from radiotherapy to resection was a significant predictor for pCR.ConclusionsThe factors associated with pCR following naST and naRT are similar to known factors after naST alone. Longer interval to surgery might to be associated with higher pCR rates. Dose escalation beyond 60 Gy did not result in higher response rates.

Determinants of pathological complete response and tumor regression in high-risk breast cancer treated with neoadjuvant radiotherapy and chemotherapy.

e12652 Background: Pathological complete response (pCR) is a recognized prognostic indicator in breast cancer patients undergoing neoadjuvant systemic therapy (naST). Known determinants of pCR include intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage, as well as the type of systemic therapy. Incorporating neoadjuvant radiotherapy (naRT) may enhance response rates, disease-free survival, toxicity profiles, and cosmetic outcomes compared to adjuvant radiotherapy. However, the factors influencing pCR and primary tumor regression with the addition of neoadjuvant radiotherapy to chemotherapy are not well-documented. Methods: A retrospective analysis was conducted on 341 patients (cT1-cT4/cN0-N+) who received naRT and neoadjuvant chemotherapy between 1990 and 2003. Treatment included naRT to the breast and, in most cases, to the supra-/infraclavicular lymph nodes, complemented by an electron or brachytherapy boost. NaST was administered either sequentially or concurrently with RT, utilizing various regimens. Univariate and multivariate regression analyses were employed to evaluate the impact of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) and complete primary tumor response (ypT0/Tis). Receiver operating characteristic (ROC) analysis assessed the interval between radiotherapy (RT) and surgical resection (Rx), as well as the radiotherapy dose. Results: Out of 341 analyzed patients, 31.1% achieved pCR. Multivariate analysis revealed that pCR rates were affected by the planned type of resection, breast cancer subtype, primary tumor stage, and the interval between radiation and surgery. The biologically effective dose to the tumor did not significantly impact pCR. Univariate analysis identified age, resection type, breast cancer subtype, clinical tumor stage, and grading as significant factors for primary tumor regression. In the multivariate analysis, resection type, subtype, and clinical tumor stage remained significant. Radiation dose to the tumor and the interval from radiation to surgery were not significant for pCR. However, a longer interval from radiotherapy to resection significantly predicted pCR when treatment factors were included in the model. Conclusions: The factors associated with pCR following combined neoadjuvant chemotherapy and radiotherapy are akin to those identified with neoadjuvant chemotherapy alone. A prolonged interval to surgery may be linked to higher pCR rates. Escalating the dose beyond 60 Gy did not lead to increased response rates.

Neoadjuvant Immunotherapy Effectiveness in Patients With Microsatellite Instability-High (MSI-H) Gastric Cancer.

Purpose This research work evaluates monotherapy with checkpoint inhibitors (CPI). as a neoadjuvant treatment for patients with Microsatellite Instability-High (MSI-H) locally advanced gastric cancer. Methods Here we present the results of the retrospective study from Napalkov Cancer Center over 4.5 years on patients with MSI-H locally advanced gastric cancer. A total of 566 patients were analyzed, 18 of whom were included in the research, focusing on clinical response rate, surgical pathology, 'watch and wait' strategy, and safety outcomes on an exploratory basis. Patients were assigned to four to eight neoadjuvant cycles of CPI, followed by surgery. Results The objective response to neoadjuvant CPI in patients with MSI-H gastric cancer was 77.8%. Complete response was achieved in five (27.8%) and partial response in nine (50%) patients, accordingly. Surgery was performed on 14 patients. Complete margin-free (R0) resection rates were 100%. Downstaging was observed in 12 out of 14 patients. Histopathologic complete response rates (pathologic complete response or Tumor Regression Grade-major response (TRG1)) were achieved in eight (57.1%) patients. No disease progression was detected with a median follow-up of 33.7 months (4.4-55.7 months). Clinically significant adverse events were not observed. Conclusion CPI in a neoadjuvant setting for patients with MSI-H locally advanced gastric cancer is highly effective and safe.

A case of pathological complete regression in combined modality treatment of resectable Her2/neu-positive gastric cancer

Background. Overexpression of Her2neu occurs in 15–20% of patients with gastric cancer and correlates with an unfavorable prognosis. Case report. We report a case of pathological complete regression of resectable gastric cancer with Her2/neu overexpression. The patient received combined modality treatment including 8 cycles of neoadjuvant chemotherapy with mFLOT + trastuzumab followed by R0 resection. The addition of targeted therapy did not have a negative impact on the perioperative period. Histolohical examination of the surgical specimen revealed pathological complete response (Mandart TGR1). Currently, the patient has been followed-up for 27 months without signs of disease relapse. Conclusion. Total neoadjuvant chemotherapy with mFLОТ+ trastuzumab for operable gastric cancer with Her2/neu overexpression allows us to hope for improved long-term treatment outcomes.

MRI-based parameters and clinical risk factors to predict lymph node metastasis in patients with ypT0 rectal cancer after neoadjuvant chemoradiotherapy.

The aim of this study was to assess the significant risk factors that predict lymph node metastasis in ypT0 patients with locally advanced rectal cancer following chemoradiotherapy (CRT). Additionally, the study aimed to identify high-risk groups who would not be suitable candidates for a rectal-preserving strategy, despite achieving a complete tumour response. Between 2013 and 2021, 226 ypT0 patients with stages II/III rectal cancer underwent CRT and radical surgery were enrolled. Two groups of patients were evaluated: those with lymph nodes metastasis and those without. The selection of variables for multivariable logistic regression was conducted through bivariate logistic regression analysis. Furthermore, the determination of optimal cutoff values for risk factors was achieved using ROC curve analysis. Nearly 8% (18/226) of patients with ypT0 had positive lymph nodes (LN) on final pathology. Four variables resulted as being independent factors of LN metastasis: pre-CRT tumour movability (OR = 8.618, P = 0.003), pre-CRT maximal LN size (OR = 28.474, P = 0.004), post-CRT tumour vertical length (OR = 1.492, P = 0.050), post-CRT anaemia (OR = 10.288, P = 0.001). The optimal cutoff point of pre-CRT maximal LN size and post-CRT tumour vertical length was 7.50 mm and 3.05 cm, respectively. The prevalence of lymph node metastasis remains at 8% among patients who achieve pathological complete regression of the primary tumour. In instances where patients are considered appropriate candidates for a rectal-preserving strategy after clinical complete remission, careful consideration should be given to the selection of this strategy if specific risk factors are present. These risk factors encompass a maximal LN size surpassing 7.50 mm prior to CRT, a fixed tumour prior to CRT, a tumour vertical length exceeding 3.05 cm after CRT, and the existence of anaemia subsequent to CRT.

Atezolizumab and trastuzumab plus chemotherapy in patients with HER2+ locally advanced resectable gastric cancer or adenocarcinoma of the gastroesophageal junction: A multicenter, randomized, open-label phase II study.

312 Background: Currently, there are no standard perioperative regimens for human epidermal growth factor receptor 2 positive (HER2+) gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. Furthermore, despite advances in neoadjuvant or perioperative chemotherapy, the efficacy of treatment for locally resectable advanced GC or GEJ cancer remains unsatisfactory. To address this need, we evaluated the effectiveness of adding atezolizumab (programmed death ligand-1 inhibitor) to treatment with trastuzumab (a HER2 antibody) + capecitabine and oxaliplatin (XELOX) compared with trastuzumab + XELOX in patients eligible for surgery with HER2+ locally advanced GC or adenocarcinoma of the GEJ. Methods: Patients aged 18–75 years were randomized 1:1 to atezolizumab + trastuzumab + XELOX (Arm A) or trastuzumab + XELOX (Arm B) and received the regimen for three neoadjuvant cycles (3 weeks per cycle) and five adjuvant cycles. Treatment administration was atezolizumab 1200 mg, trastuzumab 6 mg/kg, oxaliplatin 130 mg/m2 intravenously on Day 1, and capecitabine 1000 mg/m2 orally twice daily on Days 1–14 of each 3-week cycle. The primary endpoint was the pathological complete regression (pCR) rate. Secondary endpoints were the objective response rate (ORR) during neoadjuvant systemic therapy (NAST) and the R0 resection rate. Time-to-event endpoints are not reported because of immaturity. Efficacy endpoints were analyzed in the intention-to-treat population. The clinical cutoff date for the primary analysis was 12 March 2023. Results: Forty-two Asian patients who provided informed consent were screened and randomized to Arm A (n = 21) or Arm B (n = 21); all patients completed NAST. Most patients were male (92.9%), and the median (range) age was 61 (33–72) years in Arm A and 65 (49–72) years in Arm B. The pCR rate was 38.1% (8/21) in Arm A and 14.3% (3/21) in Arm B (treatment difference: 23.8% [90% confidence interval (CI), 1.3%–44.7%]). The pCR rate was significantly better in Arm A than in Arm B (P = 0.079 <0.1; lower limit of the 90% CI >0). Subgroup analysis showed that age <65 years, male sex, and intestinal Lauren classification were associated with a better pCR rate for the atezolizumab inclusive treatment arm (Arm A); however, these results require further confirmation in future studies. No significant difference was detected between the two arms in ORR during NAST or the R0 resection rate. Conclusions: The addition of atezolizumab to trastuzumab + XELOX therapy was effective in patients with HER2+ locally advanced resectable GC or adenocarcinoma of the GEJ. Clinical trial information: NCT04661150 .

Neoadjuvant radiochemotherapy with cisplatin/5-flourouracil or carboplatin/paclitaxel in patients with resectable cancer of the esophagus and the gastroesophageal junction — comparison of postoperative mortality and complications, toxicity, and pathological tumor response

PurposeIn 2012, the CROSS trial implemented a new neoadjuvant radiochemotherapy protocol for patients with locally advanced, resectable cancer of the esophagus prior to scheduled surgery. There are only limited studies comparing the CROSS protocol with a PF-based (cisplatin/5-fluorouracil) nRCT protocol.MethodsIn this retrospective, monocentric analysis, 134 patients suffering from esophageal cancer were included. Those patients received either PF-based nRCT (PF group) or nRCT according to the CROSS protocol (CROSS group) prior to elective en bloc esophagectomy. Perioperative mortality and morbidity, nRCT-related toxicity, and complete pathological regression were compared between both groups. Logistic regression analysis was performed in order to identify independent factors for pathological complete response (pCR).ResultsThirty-day/hospital mortality showed no significant differences between both groups. Postoperative complications ≥ grade 3 according to Clavien-Dindo classification were experienced in 58.8% (PF group) and 47.6% (CROSS group) (p = 0.2) respectively. nRCT-associated toxicity ≥ grade 3 was 30.8% (PF group) and 37.2% (CROSS group) (p = 0.6). There was no significant difference regarding the pCR rate between both groups (23.5% vs. 30.5%; p = 0.6). In multivariate analysis, SCC (OR 7.7; p < 0.01) and an initial grading of G1/G2 (OR 2.8; p = 0.03) were shown to be independent risk factors for higher rates of pCR.ConclusionWe conclude that both nRCT protocols are effective and safe. There were no significant differences regarding toxicity, pathological tumor response, and postoperative morbidity and mortality between both groups. Squamous cell carcinoma (SCC) and favorable preoperative tumor grading (G1 and G2) are independent predictors for higher pCR rate in multivariate analysis.

A Modified NAR Scoring Model Incorporating Immune Infiltration Characteristics to Better Predict Long-Term Survival Following Neoadjuvant Radiotherapy in Rectal Cancer.

(1) Background: The neoadjuvant rectal (NAR) score has been developed as a prognostic tool for survival in locally advanced rectal cancer (LARC). However, the NAR score only incorporates weighted cT, ypT, and ypN categories. This long-term follow-up study aims to modify a novel prognostic scoring model and identify a short-term endpoint for survival. (2) Methods: The prognostic factors for overall survival (OS) were explored through univariate and multivariate analyses. Based on Cox regression modeling, nomogram plots were constructed. Area under the curve (AUC) and concordance indices were used to evaluate the performance of the nomogram. Receiver operating characteristic (ROC) analysis was conducted to compare the efficiency of the nomogram with other prognostic factors. (3) Results: After a long-term follow-up, the 5-year OS was 67.1%. The mean NAR score was 20.4 ± 16.3. Multivariate analysis indicated that CD8+ T-cell, lymphovascular invasion, and the NAR score were independent predictors of OS. The modified NAR scoring model, incorporating immune infiltration characteristics, exhibited a high C-index of 0.739 for 5-year OS, significantly outperforming any individual factor. Moreover, the predictive value of the nomogram was superior to the AJCC stage and pathological complete regression at 3-year, 5-year, and 10-year time points, respectively. Over time, the model's predictions of long-term survival remained consistent and improved in accuracy. (4) Conclusions: The modified NAR scoring model, incorporating immune infiltration characteristics, demonstrates high accuracy and consistency in predicting OS.

Development and Validation of a Recurrence-Free Survival Prediction Model for Locally Advanced Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemoradiotherapy

BackgroundA recurrence-free survival (RFS) prediction model was developed and validated for patients with locally advanced esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy (NCRT) in combination with surgery.Patients and MethodsWe included 282 patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy (NCRT) combined with surgery, constructed three models incorporating pathological factors, investigated the discrimination and calibration of each model, and compared the clinical utility of each model using the net reclassification index (NRI) and the integrated discrimination index (IDI).ResultsMultivariable analysis showed that pathologic complete response (pCR) and lymph node tumor regression grading (LN–TRG) (p < 0.05) were independent prognostic factors for RFS. LASSO regression screened six correlates of LN-TRG, vascular invasion, nerve invasion, degree of differentiation, platelet grade, and a total diameter of residual cancer in lymph nodes to build model three, which was consistent in terms of efficacy in the training set and validation set. Kaplan–Meier (K–M) curves showed that all three models were able to distinguish well between high- and low-risk groups (p < 0.01). The NRI and IDI showed that the clinical utility of model 2 was slightly better than that of model 1 (p > 0.05), and model 3 was significantly better than that of model 2 (p < 0.05).ConclusionsClinical prediction models incorporating LN-TRG factors have high predictive efficacy, can help identify patients at high risk of recurrence after neoadjuvant therapy, and can be used as a supplement to the AJCC/TNM staging system while offering a scientific rationale for early postoperative intervention.

Serum Interleukin 6 Level is Associated With Overall Survival and Treatment Response in Gastric and Gastroesophageal Junction Cancer.

To identify novel prognostic and predictive biomarkers for gastric and gastroesophageal junction (G+GEJ) adenocarcinoma. There are few biomarkers to guide treatment for G+GEJ. The systemic inflammatory response of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. We queried the UT Southwestern gastric cancer biobank to identify consecutive patients diagnosed with G+GEJ from 2016 to 2022; these patients had pretreatment serum collected at diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately before surgical resection. An unbiased screen of 17 cytokines was measured in a discovery cohort. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. Findings were validated in additional patients. In patients who received neoadjuvant therapy, we assessed whether the change in interleukin 6 (IL-6) after therapy was associated with TRG. Sixty-seven patients were included in the discovery cohort, and IL-6 was the only pretreatment cytokine associated with OS; this was validated in 134 other patients (hazard ratio: 1.012 per 1pg/mL increase, 95% CI: 1.006-1.019, P = 0.0002). Patients in the top tercile of IL-6 level had worse median OS (10.6 months) compared with patients in the intermediate (17.4 months) and bottom tercile (35.8 months, P < 0.0001). Among patients who underwent neoadjuvant therapy (n = 50), an unchanged or decrease in IL-6 level from pretreatment to posttreatment, had a sensitivity and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 0-1). Pretreatment serum level of IL-6 is a promising prognostic biomarker for G+GEJ patients. Comparing pre and post-neoadjuvant IL-6 levels may predict pathologic response to neoadjuvant therapy.

A randomized, open-label, phase II/III efficacy and safety study of atezolizumab in combination with FLOT versus FLOT alone in patients with gastric cancer and adenocarcinoma of the oesophagogastric junction and high immune responsiveness: The IKF-S633/DANTE trial, a trial of AIO in collaboration with SAKK.

TPS4177 Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable esophagogastric adenocarcinoma (EGA). However, patient outcomes are still unsatisfactory. Immune checkpoint inhibitors combined with chemotherapy have proven activity in advanced Her2 negative EGA with PD-L1 expression (KEYNOTE-590, Checkmate-649). Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles and will be evaluated in this study in the perioperative treatment of potentially resectable EGA in combination with FLOT. As shown at ASCO 2022 for the phase II part of DANTE, adding atezolizumab to FLOT led to improved tumor downsizing and pCR (24% vs 15%). Of note, regression rates further improved with higher PD-L1 expression (33% vs 12% in tumors with CPS ≥10) or in MSI-high tumors (63% vs 27%). Prompted by these results, we decided to transition this trial from the initial phase II to a phase III design. Methods: This is a multinational, prospective, randomized, investigator-initiated, open label phase II/III trial. Patients (pts) with locally advanced, potentially resectable EGA (≥cT2 and/or N-positive) without distant metastases are enrolled. Based on the subgroup analyses of the phase II trial, we decided to limit the future enrollment to pts with high immune responsiveness, i.e. either of the following: MSI-high, PD-L1 CPS≥1, TMB ≥10/MB or EBV+. Eligibility status is centrally evaluated. Pts are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) plus 840 mg atezolizumab q2w followed by surgery and 4 additional cycles of FLOT/atezolizumab, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is event-free survival (EFS) as assessed by the Kaplan-Meier-Method. An estimated HR of 0.72 would correspond to a median EFS of 41.67 months for the experimental Arm A. This difference is considered clinically relevant. A total of 556 pts (318 events) will be randomized. As 177/295 pts with PD-L1 positive or MSI status were already enrolled into the phase II portion, additional 379 pts will be enrolled into phase III. Main secondary endpoints are rates of locally assessed pathological regression (complete and nearly complete pathological regression), OS, OS and EFS in the subgroup of pts with PD-L1 CPS ≥5 and ≥10 and pts with MSI, R0 resection, and safety. In addition, a prospective biomarker study including serial circulating tumor DNA analysis before and during treatment will be performed. Recruitment started 2018 and continues for phase III in 2023. Clinical trial information: NCT03421288 .

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

One-Week versus Two-Week Chemoradiotherapy Followed by Curative Surgery in Rectal Cancer: Long-Term Comparative Pooled Analysis of Two Prospective Multicenter Phase II Trials.

The optimal short-course chemotherapeutic regimen for rectal cancer has not been clearly defined until now. KROG 10-01 and KROG 11-02 prospective trials investigated the efficacy and safety of one- and two-week CRT, respectively. Patients eligible for KROG 10-01 and KROG 11-02 involved those with clinical T3-4N0-2M0 rectal cancers. They received preoperative CRT and total mesorectal excision. Patients in KROG 10-01 received radiation of 25 Gy in 5 fractions during one week with 5-fluorouracil/leucovorin. Patients in KROG 11-02 received radiation of 33 Gy in 10 fractions during two weeks with oral capecitabine. A total of 150 patients consisting of 70 patients from KROG 10-01 and 80 patients from KROG 11-02 were collectively analyzed. With a median follow-up time of 89.2 months, the 5-year overall survival (OS) rate was 86.5% in one-week CRT and 85.3% in two-week CRT (p=0.84). The 5-year recurrence-free survival (RFS) rate was 83.5% in one-week CRT and 77.1% in two-week CRT (p=0.45). One patient (1.4%) in one-week CRT and eleven patients (13.8%) in two-week CRT exhibited pathologic complete regression (ypT0N0M0) after radiotherapy (p=0.01). One-week CRT had significantly higher acute hematologic (12.8% vs. 3.8%, p=0.040) and non-hematologic (38.6% vs. 16.3%, p=0.002) toxicity than two-week CRT. Both one- and two-week schedules of CRT showed favorable survival outcomes after seven years of follow-up. But, two-week course achieved more increased tumor response and decreased acute toxicity than one-week course.

Serum IL-6 level to predict survival and treatment response in gastric and gastroesophageal junction cancer.

444 Background: There are few biomarkers to guide treatment for gastric and gastroesophageal junction adenocarcinoma (G+GEJ). The systemic inflammatory response, which is reflected by circulating serum cytokine levels, of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. Methods: A retrospective review of a prospectively maintained biobank was performed to identify patients diagnosed with G+GEJ from 2016-2022. Pre-treatment serum was collected at the time of diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately prior to surgical resection. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. In patients who received neoadjuvant therapy, we assessed whether the change in IL-6 (ΔIL-6) after therapy was associated with TRG. Results: We first measured the pre-treatment levels of 17 different cytokines in a 67-patient cohort to determine if certain circulating cytokines were prognostic for OS. In a multivariable analysis adjusted for clinical stage and the expression level of the other cytokines, the only circulating cytokine level that was independently associated with OS was IL-6 (HR: 1.06 per 1 pg/ml increase, 95% CI: 1.04-1.08). We then analyzed the serum IL-6 level in an additional 134 patients, resulting in a final cohort of 201 patients. Serum IL-6 level ranged from 0.3-196.7 pg/ml. In a multivariable analysis adjusted for age, sex, clinical stage, pathologic differentiation, Lauren classification, H. pylori status and neutrophil-to-lymphocyte ratio, IL-6 level was independently associated with OS (HR: 1.012 per 1 pg/ml increase, 95% CI: 1.006-1.019). Patients in the top tercile of pre-treatment IL-6 level had worse median OS (10.6 months) compared to patients in the intermediate (17.4 months) and bottom tercile (35.8 months, p &lt; 0.0001). Among patients who received neoadjuvant therapy (n = 50), ΔIL-6 ≤ 0 had a sensitivity of 80% and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 1). Conclusions: Pre-treatment serum level of IL-6 is a promising prognostic biomarker for patients with G+GEJ. ΔIL-6 may predict response to neoadjuvant therapy.

A phase 2 study of durvalumab plus DOS (docetaxel, oxaliplatin, S-1) neoadjuvant chemotherapy followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable locally advanced gastric cancer: An interim efficacy report.

408 Background: The phase 3 PRODIGY study showed that neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, was effective and tolerable in Asian patients with resectable locally advanced gastric cancer (LAGC). The current study aimed to evaluate the efficacy and safety of neoadjuvant durvalumab plus DOS, which was followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable LAGC. Methods: In this single-center, open-label, phase II study, patients with locally advanced gastric or gastroesophageal junction cancer (i.e., cT2/3N+ or cT4Nany) were enrolled. In patients with proficient mismatch repair protein (pMMR) tumors (main arm), 3 cycles of neoadjuvant durvalumab plus DOS were administered every 3 weeks, which was followed by surgery and adjuvant S-1 plus durvalumab administered every 6 weeks for 12 months. The primary endpoints were the rate of pathologic complete regression (pCR) and the safety. For an exploratory purpose, patients with deficient mismatch repair protein tumors (exploratory arm) were treated with 3 cycles of neoadjuvant durvalumab and tremelimumab every 4 weeks followed by surgery and adjuvant durvalumab administered every 4 weeks for 12 months. At this interim analysis, we report the results of patients with pMMR. Results: As of SEP 2022, 40 subjects with pMMR were enrolled and received ≥ 1 dose of neoadjuvant treatment. Thirty-five subjects completed 3 cycles of neoadjuvant treatment, and 31 received surgery as of the data cut-off. Among 31 patients who received surgery, a pCR was confirmed in 9 (29.0%), meeting the primary efficacy endpoint (8 pCR out of 40) early. Among those who received 3 cycles of neoadjuvant treatment, 3 (8.6%) experienced the predefined unacceptable severe toxicities during the neoadjuvant treatment: febrile neutropenia (n=2) and G4 neutropenia persisted for ≥ 7 days (n=1). Conclusions: The current study met its primary efficacy endpoint and is expected to meet the primary safety endpoint (&lt;20%). Neoadjuvant durvalumab plus DOS followed by surgery and adjuvant durvalumab plus S-1 chemotherapy deserves to be investigated in a phase 3 trial in Asian patients with LAGC. Clinical trial information: 04221555 .

One-week versus two-week chemoradiotherapy followed by curative surgery in rectal cancer: Long-term comparative pooled analysis of two prospective multicenter phase II trials.

96 Background: The optimal short-course chemotherapeutic regimen for rectal cancer has not been clearly defined until now. KROG 10-01 and KROG 11-02 prospective trials investigated the efficacy and safety of one- and two-week chemoradiotherapy (CRT), respectively. We compare and report long-term outcomes by pooling data from two prospective trials for one- and two-week schedules of preoperative CRT and curative surgery in rectal cancer. Methods: Patients eligible for KROG 10-01 and KROG 11-02 involved those with clinical T3-4N0-2M0 rectal cancers. They received preoperative CRT and total mesorectal excision. Patients in KROG 10-01 received radiation of 25 Gy in 5 fractions during one week with 5-fluorouracil/leucovorin. Patients in KROG 11-02 received radiation of 33 Gy in 10 fractions during two weeks with oral capecitabine. Results: A total of 150 patients consisting of 70 patients from KROG 10-01 and 80 patients from KROG 11-02 were collectively analyzed. With a median follow-up time of 89.2 months, the 5-year overall survival (OS) rate was 86.5% in one-week CRT and 85.3% in two-week CRT ( P = 0.84). The 5-year recurrence-free survival (RFS) rate was 83.5% in one-week CRT and 77.1% in two-week CRT ( P = 0.45). One patient (1.4%) in one-week CRT and eleven patients (13.8%) in two-week CRT exhibited pathologic complete regression (ypT0N0M0) after radiotherapy ( P = 0.01). Downstaging (ypT0-2N0M0) occurred in 20 patients (28.2%) in one-week CRT and 27 patients (33.8%) in two-week CRT ( P = 0.50 ). One-week CRT arm had significantly higher acute hematologic (12.8% vs. 3.8%, P = 0.040) and non-hematologic (38.6% vs. 16.3%, P = 0.002) toxicities than two-week CRT arm. Conclusions: Both one- and two-week schedules of CRT showed favorable survival outcomes after seven years of follow-up. But, two-week course achieved more increased tumor response and decreased acute toxicity rather than one-week course. Clinical trial information: KROG 10-01 is registered at ClinicalTrials.gov (number, NCT01129700 ) and KROG 11-02 is registered at ClinicalTrials.gov (number, NCT01431599 ).

Pancreatic ductal adenocarcinoma complete regression after preoperative chemotherapy: Surgical results in a small series

BackgroundPancreatic ductal adenocarcinoma (PDAC) becomes a systemic disease from an early stage. Complete surgical resection remains the only validated and potentially curative treatment; disappointingly only 20% of patients present with a resectable tumour. Although a complete pathological regression (pCR) after the preoperative chemotherapy could intuitively lead to better outcomes and prolonged survival some reports highlighted significant rates of recurrence. Cases PresentationWe describe three cases of pCR following preoperative chemotherapy for PDAC. The first two cases received neoadjuvant mFOLFIRINOX and PAX-G scheme for borderline resectable PDAC. Recurrence appeared 9 and 12 months after surgery. Although both patients started adjuvant therapy straight after the diagnosis of recurrence, the disease rapidly progressed and led them to death 12 and 15 months after surgery. The third case was characterized by germline BRCA2 mutation. The patient presented with PDAC of the body, intrapancreatic biliary stenosis and suspected peritoneal metastasis. One year later, after first and second-line chemotherapy, she underwent explorative laparoscopy and total spleno-pancreatectomy without evidence of viable tumour cells in the surgical specimen. At six months she is recurrence-free. ConclusionsVery few reports describe a complete pathological response following preoperative chemotherapy in pancreatic cancer. We observed three cases in the last three years with disappointing oncological results. Further investigations are needed to predict PDAC prognosis in pCR after chemotherapy.

Complete pathological response following neoadjuvant chemoradiotherapy in locally advanced colorectal carcinoma

Background: The prognosis of rectal cancer has improved with neoadjuvant treatment for locally advanced disease. Twenty percent of patients respond to treatment with complete pathological regression, which is clinically estimated with magnetic resonance imaging. Aim: describe the properties of the pathological complete response group of patients at our institution Materials and methods: All selected patients received LCCRT at the University Hospital for Tumors Sestre milosrdnice University Hospital Center, Zagreb, between January 2014 and December 2019 and were later surgically treated at the same facility. Results: We identified 23 patients with complete pathological responses, of which, despite surgery, seven progressed. We recorded a higher proportion of female patients in that group and younger age of onset. MRI preoperatively was not yet predictive of a complete pathological response. Conclusion: The proportion of patients with a complete pathological response is 16% in this cohort. All patients underwent surgery but did not receive consolidating therapy. About 30% progressed during the observed period.