Pathologic Tumor Response Research Articles

Pathologic tumour response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

Pathologic tumour response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma

To evaluate the differences in pathologic complete response (pCR) rates, TRG score, pathologic T stage and the pattern of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant immunochemotherapy (NICT) prior to esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC). A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy at three cancer centers from January 2017 to December 2022 were enrolled. Among the included patients, 382 patients were treated with NCR, 172 with NCRT, and 148 with NICT. Inverse probability of treatment weighting (IPTW) was performed to control potential confounding factors. Pathological response of primary tumor was evaluated using the Chirieac modified tumor regression grade (TRG) system. The complete regression of primary lesion and nodal metastases were considered pCR. Lymph node classification system used the 8th edition of AJCC. Specimens were assessed for pattern of lymphatic spread. After adjusting for baseline characteristics, the R0 resection rate did not significantly differ between the patients receiving NCT or NCRT or NICT (99.48% vs.100% vs.98.65%, P = 0.273). Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P<0.05). The pCR rate was 7.07% in the NCT group, 30.23% in the NCRT group, and 22.30% in the NICT group. Compared to the other two groups, the TRG score (P<0.05) and pathologic T stage (P<0.05) in the NCT group were significantly higher. In the NCT group, 9.97% had ypT0 disease, compared with 35.76% in the NCRT group and 25.68% in the NICT group. And in the NCT group, 9.71% had TRG1 disease, compared with 32.76% in the NCRT group and 25% in the NICT group. Compared with NICT, NCRT can significantly reduce the rate of LNM in station 1R (0 vs 3.38%, P<0.05) and 2R (1.15% vs 6.76%, P<0.05). Subgroup analysis according to the tumor location distribution showed that in upper thoracic cases, there was no statistical difference in LNM rates among stations no matter whether patients received NCT or NCRT or NICT. NICT group had higher LNM rates in station 2R (9.1%) in middle thoracic cases (P<0.05) and in station 18 (7.5%) (P<0.05) in lower thoracic cases, compared with the NCRT group and NCT group. NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. No matter whether patients received NCT or NCRT or NICT, multiple level and skip node metastases are common, and adequate lymphadenectomy should be achieved to ensure the complete removal of metastatic lymph nodes.

Correlation between Lymph Node Regression Grading and Tumor Regression Grading after Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

This study aimed to determine the relationship between tumor regression grading (TRG) and lymph node regression grading (LRG) after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). The study was a retrospective analysis of the clinical data of LARC patients who underwent preoperative nCRT at one institution. A total of 101 rectal cancer patients who received nCRT and underwent total rectal mesenteric excision (TME) were included. Pathologists independently assessed the pathological response of the primary tumor and lymph nodes (LN) to nCRT using TRG and LRG, respectively. The highest LRG score for each patient was defined as LRGmax, and LRGsum was the overall tumor burden of all LNs in the specimen. The study included 101 LARC patients who underwent nCRT and TME. The patient population consisted of 65 males and 36 females with an average age of 54.86 years (range 20-81 years), of which 68 were aged 60 years or younger and 33 were older than 60. The radiotherapy treatment plan consisted of 1.8-2Gy per dose, administered 5 times per week for a total dose of 45-50.4Gy, along with oral capecitabine chemotherapy (825 mg/m2, bid) on the day of radiation therapy. The chemotherapy treatment plan included XELOX, mFOLFOX6, and FOLFOX4. The cTNM stage of the tumor before surgery was cT2 in 2 cases, cT3 in 63 cases, and cT4 in 36 cases. Eight cases were cN0 and 93 were cN+. After surgery, the ypTNM stage was T0 in 19 cases, T1 in 4 cases, T2 in 27 cases, T3 in 45 cases, and T4 in 6 cases. The N stage was N0 in 76 cases, N1 in 20 cases, and N2 in 5 cases. TRG was 0 in 17 cases (16.8%), 1 in 15 cases (14.9%), 2 in 61 cases (60.4%), and 3 in 8 cases (7.9%). LRGmax scores were 0 in 66 cases (65.3%), 1 in 17 cases (16.8%), 2 in 5 cases (5.0%), 3 in 3 cases (3.0%), 4 in 5 cases (5.0%), and 5 in 5 cases (5.0%). LRGsum scores were ≤3 in 85 cases (84.2%), 4-9 in 11 cases (10.9%), and ≥10 in 5 cases (5.0%). Correlation analysis showed that LRGmax was significantly correlated with TRG, ypT, and ypN (P = 0.038, P = 0.015, P < 0.01), with correlation coefficients of 0.184, 0.212, and 0.626, respectively. There was no significant correlation between LRGmax and cT and cN+. Similarly, LRGsum was significantly correlated with TRG, ypT, and ypN (P = 0.022, P = 0.002, P < 0.01) with correlation coefficients of 0.212, 0.276, and 0.707, respectively. There was no significant correlation between LRGsum and cT and cN. The results of our study indicate a significant correlation between LRG and TRG (P = 0.022). Additionally, LRG was found to be positively correlated with the ypT and ypN stages of the primary tumor and lymph nodes post-surgery, with correlation coefficients of 0.276 and 0.707, respectively (P = 0.002 and P<0.01). No significant correlations were observed between LRG and cT and cN+ stages. Our findings demonstrate a significant association between LRG and TRG, as well as a positive correlation between LRG and the ypT and ypN stages of the primary tumor and lymph nodes following surgery.

Sarcopenia as a Predictor of Neoadjuvant Therapy-Related Toxicity in Esophageal Squamous Cell Carcinoma Patients

Sarcopenia, characterized by loss of muscle mass, plays a critical role in patients with esophageal squamous cell cancer (ESCC). Preoperative chemoradiotherapy and immunotherapy in ESCC patients has been reported to improve survival. Therefore, we sought to evaluate the predictive value of preoperative sarcopenia for toxicity and pathological tumor response to neoadjuvant therapy (NAT) in ESCC patients. A retrospective analysis was performed using a prospectively collected patient cohort of an academic cancer center diagnosed with cT2-4N0-3M0 ESCC between 2019-2022 and treated with neoadjuvant chemoradiotherapy ± pembrolizumab. Sarcopenia was assessed by skeletal muscle index at the third lumbar vertebra in computed tomography scans before NAT (men: 43cm²/m² for body mass index (BMI) < 25kg/m², 53cm²/m² for BMI≥25 kg/m²; women: 41cm²/m²). Logistic regression was performed to assess the association between sarcopenia and preoperative therapy-related toxicity and tumor response. The study included 59 locally advanced ESCC patients (53 male and 6 female), 48 (81.4%) in the non-sarcopenia group, and 11 (18.6%) in the sarcopenia group. Mean age at diagnosis was 62±8 years. Mean BMI at diagnosis was 22.13±2.85 kg/m². 19 patients (32.2%) were stage ⅢA, 25 patients (42.4%) were ⅢB, 15 patients (25.4%) were ⅣA. No significant differences were found between both groups regarding sex, age, BMI, and clinical stage. Acute grade ≥3 toxicity occurred significantly more frequently in the sarcopenia group (54.5% vs. 22.9%, p = 0.045), which mainly included leukopenia, neutropenia, anemia and thrombocytopenia. The discontinuation of NAT owing to toxicity occurred in 8 patients (13.5%), which was significantly associated with sarcopenia (p = 0.003). All patients proceeded to surgery and 33 patients (55.9%) had a pathological complete response (pCR). Univariate analysis revealed no significant association between sarcopenia and pCR (p = 0.071). Among patients with locally advanced EC, sarcopenia is not a predictor of poor NAT response, but it is strongly associated with discontinuation of NAT due to toxicity.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Abstract PO-078: Tissue-resident memory CD8+ T cells correlate with anti-PD-1 response in head and neck cancer and expand upon cDC1 activation in tumor-draining lymph nodes to overcome PD-1 resistance

Abstract Introduction: Tumor infiltrating tissue-resident memory CD8+ T (TRM) cells correlate with immunotherapy response against several solid tumor types. Recent data from neoadjuvant immunotherapy studies highlight CD8+ TRM cells as early responders in head and neck squamous carcinoma (HNSCC). Here, we defined anti-tumor CD8+ TRM cell representation in neoadjuvant anti-PD1 clinical trial HNSCC tumors and examined their development in anti-PD1 responsive and resistant HNSCC mouse models. Methods: CD8+ CD103+ TRM cells were quantified using CODEX (CO-detection by inDEXing) in tumor tissue microarray cores from 28 HNSCC patients treated with neoadjuvant anti-PD1 on a previously reported clinical trial (NCT02296684). Anti-PD1 sensitive MOC1 and isogenic anti-PD1 resistant MOC1-esc1 cells were engineered to express ovalbumin derived SIINFEKL peptide (OVA). OVA-specific CD8+ TRM induction and activation from endogenous T cells and following OT-1 adoptive transfer was evaluated in orthotopic (buccal) MOC1/MOC1esc1-OVA tumor bearing mice by ELISA and flow cytometry employing SIINFEKL-H2Kbdextramers. In vitro OVA-directed T cell activity was evaluated using co-culture of OT-1 T cells and MOC1/MOC1OVA/MOC1esc1OVA cells, OVA peptide, or IL-2. OT-1 CD8+ T cells were transferred into MOC1OVA or MOC1-esc1OVA-bearing mice and the dynamics of TRM development were evaluated using flow cytometry. Conventional Dendritic cells 1 (cDC1s) from tumor-draining lymph nodes (TDLNs) were cocultured with OT-1 cells and evaluated for antigen-specific TRM development. Results: CD8+ CD103+ TRM cells were more frequent in baseline tumors that developed pathological tumor response following neoadjuvant pembrolizumab compared to baseline nonresponding tumors (p=0.011). In mouse orthotopic models, MOC1-esc1OVA cells maintained in vivo PD-1 resistance despite eliciting SIINFEKL dextramer+ antigen-specific T cells in the tumors that expanded in response to PD-1 blockade. Further characterization of these tumor antigen specific T cells showed that compared to MOC1OVA, MOC1-esc1OVA had reduced CD69 and CD103 expression (MOC1OVA, Average 17.55% (14.1-19.4%); MOC1-esc1OVA, Average 11.84% (9.42-15.8%); p=0.025) and reduced response to SIINFEKL restimulation (MOC1OVA, Average 1093.3 pg/mL (860.6-1240.9 pg/mL); MOC1-esc1OVA, Average 533.3 pg/mL (254.5-749.0 pg/mL); p=0.006). A time course analysis in vivo showed that OVA-specific TRM cells were generated in TDLN and migrated into tumor. Compared to MOC1-OVA, MOC1-esc1OVA TDLN cDC1s had reduced CD40 expression and fewer TRM cells. Anti-CD40 blocking monoclonal antibodies reduced OVA-specific TRM cells in MOC1OVA while CD40 agonist antibodies increased antitumor TRMs and reduced PD1-resistant tumor growth compared to the control IgG groups. Conclusion: These findings highlight TRM CD8_+ T cells as a correlate of PD-1 blockade response in HNSCC patient tissues and mouse models and delineate cDC1 CD40 function in the TDLN as critical for effective antitumor TRM development. Citation Format: Michihisa Kono, Shin Saito, Geoff Ivison, Ayano Kondo, Aaron Mayer, Jonathan D. Schoenfeld, Ann Marie Egloff, Ravindra Uppaluri. Tissue-resident memory CD8+ T cells correlate with anti-PD-1 response in head and neck cancer and expand upon cDC1 activation in tumor-draining lymph nodes to overcome PD-1 resistance [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-078.

Safety and efficacy of P2Et extract from Caesalpinia spinosa in breast cancer patients: study protocol for a randomized double blind phase II clinical trial (CS003-BC)

BackgroundChemotherapy in breast cancer is effective but can generate significant toxicity and lead to tumor resistance. Joint treatment with standardized plant extracts can be an alternative to improve the response and allow an effective activation of the antitumor immune response that favors recovery in the short and long term. The P2Et extract of Caesalpinia spinosa presents antitumor activity in cells and animal models of breast cancer, improves the tumor microenvironment, and induces activation of the specific immune response against the tumor and is synergistic when used together with anthracyclines, which makes it a good candidate for evaluation in patients.MethodsConducted at a single center, this phase II study is a randomized, double-blind, placebo-controlled trial aimed at assessing the safety and efficacy of P2Et extract in patients diagnosed with stage II and III breast cancer, who are eligible for neoadjuvant treatment. The study aims to determine the safety profile at the previously established optimal biological dose from phase I trial while investigating various efficacy outcomes. These outcomes include improvements in quality of life, immunomodulation, metabolic profile, microbiome, as well as clinical indicators such as tumor reduction, disease-free survival, and pathological response, assessed at different stages of the treatment regimen.DiscussionTreatment with the P2Et extract in breast cancer patients is hypothesized to enhance overall well-being, positively influencing their quality of life, while also triggering an antitumor immune response and enhancing immune infiltration. These combined effects have the potential to contribute to improved long-term survival outcomes for patients receiving the phytomedicine alongside neoadjuvant chemotherapy treatment.Trial registrationThis trial was registered in the US National Library of Medicine with identifier NCT05007444. First Registered August 16th, 2021. Last Updated: August 9th, 2022.

Value of mammographic microcalcifications and MRI-enhanced lesions in the evaluation of residual disease after neoadjuvant therapy for breast cancer.

Microcalcifications persist even if a patient with breast cancer achieves pathologic complete response (pCR) as confirmed by surgery after neoadjuvant treatment (NAT). In practice, surgeons tend to remove all the microcalcifications. This study aimed to explore the correlation between changes in the extent of microcalcification after NAT and pathological tumor response and compare the accuracy of mammography (MG) and magnetic resonance imaging (MRI) in predicting the size of residual tumors. This was a retrospective study which included a consecutive series of patients in Guangdong Provincial People's Hospital. Between January 2010 and January 2020, 127 patients with breast cancer and Breast Imaging Reporting and Data System (BI-RADS) 4-5 microcalcifications were included in this study. The maximum diameter of the microcalcifications on MG and lesion enhancement on MRI pre- and post-NAT were measured. The correlations between the changes in residual microcalcifications on MG and pCR were analyzed. Intraclass correlation coefficients (ICCs) were computed between the extent of the residual microcalcifications, residual enhancement, and residual tumor size. There were no statistically significant differences in the changes in microcalcifications after NAT according to the RECIST criteria on MRI (P=0.09) and Miller-Payne grade (P=0.14). MRI showed a higher agreement than did residual microcalcifications on MG in predicting residual tumor size (ICC: 0.771 vs. 0.097). MRI is more accurate for evaluating residual tumor size in breast cancer. In our study, the extent of microcalcifications on MG after NAT had nearly no correlation with the pathological size of the residual tumor. Therefore, residual tumors with microcalcifications may not necessarily be a contraindication to breast-conserving surgery.

Enhancing Prediction for Tumor Pathologic Response to Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Cancer by Dynamic Parameters from Clinical Assessments.

To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

183. NEOADJUVANT CAMRELIZUMAB PLUS CHEMOTHERAPY (NICE) VERSUS CROSS REGIMENS IN OESOPHAGEAL SQUAMOUS CELL CARCINOMA, A PROPENSITY-SCORE MATCHED ANALYSIS

Abstract Background The CROSS regimen represents standard neoadjuvant management for oesophageal squamous cell carcinoma (ESCC) for the last decade, while the utility of Camrelizumab plus chemotherapy (NICE) is increasingly gaining attention. In the absence of published Randomized Controlled Trials, there remains a paucity of robust information on comparison of these two modalities. This study aims to compare the treatment response and short-term outcomes of NICE followed by oesophagectomy with that after CROSS-induced chemoradiotherapy, in treatment for ESCC. Methods A total of 234 patients staged as clinical II-IV, 117 in each arm, was enrolled in this study after propensity-score match. The primary outcomes were tumor response and survival. Secondary outcomes were toxicity and postoperative complications. Pathological response of tumor was evaluated by Chirieac tumor regression grade (TRG) and major pathological response (MPR) as well as responders were defined as TRG1–2 N0. Complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria and severity per Clavien-Dindo. Survival was evaluated by Kaplan–Meier method using Breslow test, and freedom from recurrence with the competing risk of death estimated per Fine-Gray method. Results After matching, R0 resection (93.2% vs 94.9%, P = 0.784), pCR (ypT0N0) (25.6% vs 30.8%, P = 0.468), MPR (46.2% vs 47.0%, P = 0.896) rates and TRG1/2 grades (P = 0.331) were comparable between CROSS and NICE regimens. However, NICE was associated with more lymph nodes yield (P &amp;lt; 0.001) and higher risk of anastomotic leak (type2/3) (P = 0.030)(Fig. 1A-C). The 1-year overall survival was 86.6% and 93.5% for CROSS and NICE (P = 0.088) with comparable recurrence risk (21% vs 21%, P = 0.520) (Fig. 1D/E). Patients with pCR or responders showed similar K-M curves, but in nonresponder subgroup analysis, NICE regimen demonstrated superior survival benefit than CROSS (P = 0.035) (Fig. 1F-H). Conclusion In this matched study, NICE is safe and feasible for ESCC with comparable perioperative outcomes compared to CROSS. Moreover, NICE regimen shows superior survival benefit in nonresponder group than CROSS, suggesting its more powerful systemic treatment effects. However, Prospective RCT studies are needed to further verify these findings.

462. MAJOR PATHOLOGIC RESPONSE IN ESOPHAGEAL ADENOCARCINOMA: SHOULD WE ADOPT A NEW PARADIGM IN DEFINING RESPONSE TO TREATMENTS?

Abstract Background Incidence of adenocarcinoma (ADC) of the esophagus is arising in Western countries and it is still burdened by a significant mortality. A complete primary tumor regression after neoadjuvant treatment is associated with improved long-term survival, however this favorable response is rarely achieved. The primary endpoint of this study was to determine whether the survival benefit associated with a complete tumor regression could be achieved also with a major, albeit subtotal, tumor response. Methods We evaluated all consecutive patients who underwent esophagectomy for cancer at 2 high-volume centers. Inclusion criteria were histologically confirmed ADC involving the thoracic esophagus or Siewert I and II cancers, treated by neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) and surgery. Pathological tumor response was quantified using the Mandard score. Kaplan-Maier plots were used to estimate overall survival (OS) according to the TRG. Results Overall, 424 patients were recruited in the study period, 236 received CT and 188 CRT. The median follow-up time was 55 months. TRG 1 and 2 showed comparable OS curves both in the CT group (p = 0.76) and in the CRT group (p = 0.82) (Figure 1). TRG 1–2 were associated with a significantly improved OS compared to TRG 3–5 after CT (p = 0.004) and CRT (p = 0.0003). The trend was confirmed in the whole cohort, with TRG 1 and 2 patients showing comparable 5-years OS proportions (70% vs. 65%, p = 0.52) and a significantly improved survival compared to TRG 3–5 (p &amp;lt; 0.0001). Conclusion Tumor regression after neoadjuvant treatment is significantly associated with long term survival irrespective of the adopted regimen. The long-term survival was comparable between TRG 1 and TRG 2 patients after CT and CRT and in the overall population. This finding allowed us to define the criterion of major tumor response, which includes both TRG 1 and 2 patients, potentially creating a homogeneous and larger subgroup of subjects to be evaluated in future clinical trials.

463. THE IMPACT OF PATHOLOGICAL TUMOR RESPONSE FOLLOWING NEOADJUVANT CHEMOTHERAPY AND CHEMORADIOTHERAPY FOR ESOPHAGEAL ADENOCARCINOMA. A RETROSPECTIVE MULTICENTER COHORT STUDY

Abstract Background Two multimodal strategies are available for the treatment of esophageal cancer: neoadjuvant chemotherapy (CT) and chemoradiotherapy (CTRT). The higher rate of pathological complete response (pCR) after CTRT is an argument to support this treatment. However, previous studies have failed to demonstrate a survival benefit of CTRT for adenocarcinoma (ADC) and the correlation between pathological tumor response (pTR) and survival is unclear. Methods This multicenter retrospective cohort study included data from 2 high-volume centers. Only patients with ADC who underwent CT or CTRT and surgery between 2012 and 2019 were included. The correlation between pTR and survival after both treatments was evaluated using Kaplan–Meier analysis. The 5-year overall (OS) and disease-free survivals (DFS) of patients showing pCR after the 2 treatments were compared. pTR was assessed using the Mandard tumor regression grade (TRG). Results Overall, 424 patients were included, 236 received CT and 188 CTRT. The incidence of pCR was 12.7% in the CT group and 26.1% after CTRT (p = 0.0005). At 5-years the OS rate after CT was 85.6% for TRG1 patients, 75.5% for TRG2, 57% for TRG3 and 42% for TRG4–5 (p = 0.004). After CTRT it was 72.8% for TRG1, 60.8% for TRG2, 39% for TRG3 and 27% for TRG4–5 (p = 0.0003) (figure 1). The OS of patients with pCR was not significantly different after CT and CTRT (p = 0.65). The 5-years DFS of pCR patients was higher in the CT group (86% vs. 70%, p = 0.05). Conclusion Despite a lower rate of pCR, both OS and, especially, DFS of pCR patients were improved after CT compared to CTRT. TRG showed to be significantly associated with survival in both treatment groups. The effectiveness of long-term disease control after CT and CTRT should be further analyzed in ADC.

430. MAPPING OF LYMPH NODE METASTASIS FROM ESCC AFTER NEOADJUVANT TREATMENT: A PROSPECTIVE ANALYSIS FROM A HIGH-VOLUME INSTITUTION IN CHINA

Abstract Objective The aim of the study was to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Methods Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. Two-field lymphadenectomy was routinely performed and an extensive three-field lymphadenectomy was performed if cervical lymph nodes metastasis were suspected. Lymph node stations according to AJCC 8 were separately investigated. Percentage of patients with lymph node metastases was defined as number of patients with metastatic lymph nodes/number of patients with lymph node dissection of this station. Data is also separately analyzed according to pathological response of the primary tumor, pretreatment tumor length and tumor location. Results Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled (Table 1–1). Lymph node metastases were found in 215 patients (34.5%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587) and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length &amp;gt; 4 cm and non-PCR of primary tumor, the metastatic rate of right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively (Table 1–2). For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most frequently seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285) and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252) (Table 1–3). Conclusion The study accurately identified the distribution of lymph node metastases from ESCC after neoadjuvant treatment, which may contribute to guide the optimal extent of lymphadenectomy in the surgical treatment of ESCC patients after neoadjuvant treatment.

Pathologic tumor response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

Neoadjuvant therapy (NAT) + surgical resection for pancreatic cancer (PC) has gained consensus in recent years. Pathological response (PR) is generally assessed according to the College of American Pathologists grading system, ranging from 0 (complete response) to 3 (no response). The aim of our study is to evaluate the PR in a series of resections for PC after NAT and its prognostic implication. 112 patients undergone NAT and resection for PC between 2011 and 2020 were retrospectively evaluated. PR was 0/1, 2 and 3 in 18 (15%), 79 (61%) and 29 (24%) cases, respectively. Chemotherapy regimens different from FOLFIRINOX and gemcitabine + nab-paclitaxel (OR 11.61 (2.53-53.36), p = 0.002) and lymphovascular invasion (OR 11.28 (1.89-67.23), p = 0.008) were associated to PR-3. Median follow-up was 25.8 (3.6-130.5) months. For PR-0/1, PR-2 and PR-3, median DFS was 45.8, 11.5, 4.6months (p < 0.0001), respectively, while median OS was not reached, 27.1 and 17.5months (p = 0.0006), respectively. At univariate analysis, PR-0/1 was significantly associated to better DFS and OS (HR 0.33 (0.17-0.67), p = 0.002; HR 0.20 (0.07-0.54), p = 0.002, respectively). At multivariate analysis, pancreaticoduodenectomy (HR 0.50 (0.30-0.84), p = 0.009), LNR (HR 27.14 (1.21-608.9), p = 0.038) and lymphovascular invasion (HR 1.99 (1.06-3.76), p = 0.033) were independently associated to DFS; pre-treatment CA 19.9 value (HR 1.00 (1.00-1.00), p = 0.025), post-treatment resectability status (HR 0.51 (0.28-0.95), p = 0.035), pancreaticoduodenectomy (HR 0.56 (0.32-0.99), p = 0.050), severe morbidity (2.99 (1.22-7.55), p = 0.017), LNR (HR 56.8 (2.08-1548.3), p = 0.017), lymphovascular invasion (HR 2.18 (1.08-4.37), p = 0.029) were independently associated to OS. PR did not reach statistical significance at multivariate analysis. A favorable PR is observed only in a limited number of cases. The prognostic role of PR, despite being promising, remains unclear and further multicentric studies are needed.

Validated Pretreatment Prediction Models for Response to Neoadjuvant Therapy in Patients with Rectal Cancer: A Systematic Review and Critical Appraisal.

Pretreatment response prediction is crucial to select those patients with rectal cancer who will benefit from organ preservation strategies following (intensified) neoadjuvant therapy and to avoid unnecessary toxicity in those who will not. The combination of individual predictors in multivariable prediction models might improve predictive accuracy. The aim of this systematic review was to summarize and critically appraise validated pretreatment prediction models (other than radiomics-based models or image-based deep learning models) for response to neoadjuvant therapy in patients with rectal cancer and provide evidence-based recommendations for future research. MEDLINE via Ovid, Embase.com, and Scopus were searched for eligible studies published up to November 2022. A total of 5006 studies were screened and 16 were included for data extraction and risk of bias assessment using Prediction model Risk Of Bias Assessment Tool (PROBAST). All selected models were unique and grouped into five predictor categories: clinical, combined, genetics, metabolites, and pathology. Studies generally included patients with intermediate or advanced tumor stages who were treated with neoadjuvant chemoradiotherapy. Evaluated outcomes were pathological complete response and pathological tumor response. All studies were considered to have a high risk of bias and none of the models were externally validated in an independent study. Discriminative performances, estimated with the area under the curve (AUC), ranged per predictor category from 0.60 to 0.70 (clinical), 0.78 to 0.81 (combined), 0.66 to 0.91 (genetics), 0.54 to 0.80 (metabolites), and 0.71 to 0.91 (pathology). Model calibration outcomes were reported in five studies. Two collagen feature-based models showed the best predictive performance (AUCs 0.83-0.91 and good calibration). In conclusion, some pretreatment models for response prediction in rectal cancer show encouraging predictive potential but, given the high risk of bias in these studies, their value should be evaluated in future, well-designed studies.

Comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks: study protocol for a prospective, non-inferior, randomized control trial (COPEC trial)

BackgroundFor patients with low- and intermediate-risk stage II/III rectal cancer, current studies have reached a consensus that preoperative radiotherapy may be dispensed with, and neoadjuvant chemotherapy (NCT) alone might achieve an accepted local control. Our previous phase II study has evidenced that the morphological response of NCT could be better judged at a relatively early stage. Low- and intermediate-risk stage II/III rectal cancer patients could achieve a high rate of tumor shrinkage and downgrade after only 4 cycles of NCT and obvious tumor morphological changes could be observed after 2 cycles of NCT. However, there is still a lack of more detailed stratification and evidence for pathological criteria. The aim of the present study (comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks, COPEC trial) is to determine the pathological tumor regression grade (pTRG) rate of 2 or 4 cycles of NCT in low- and intermediate-risk stage II/III rectal cancer and verify the feasibility of early identification of chemotherapy-insensitive population.Methods/designThis is a multicenter, prospective, non-inferior, randomized controlled trial (RCT) initiated by West China Hospital of Sichuan University and designed to be conducted in fourteen hospitals around China. Eligible patients will be centrally randomized into 2 or 4 cycles of CAPOX in a 1:1 ratio using the central automated randomization system offered by the O-trial online system (https://plus.o-trial.com/) and accept total mesorectal excision after 2 or 4 cycles of CAPOX (oxaliplatin 130 mg/m2, once daily on day 1, every 21 days and capecitabine 1000 mg/m2, twice daily on days 1 to 14, every 21 days). The primary endpoint is the proportion of patients with pathological no-tumor regression (pTRG 3), which is determined postoperatively by each sub-center and verified by the primary center.DiscussionCOPEC trial is designed to verify that the preoperative CAPOX chemotherapy for low- and intermediate-risk stage II/III rectal cancer could achieve a good response judgment after 2 cycles and obtain the tumor pathological response rate after 2 cycles of CAPOX. We hope the COPEC trial could help in establishing a consensus standard of low- and intermediate-risk rectal cancer and the early identification of stage II/III rectal patients with low- and intermediate-risk who are poorly responding to NCT.Trial registrationClinicaltrial.gov NCT04922853. Registered on June 4, 2021.

Prediction of pathological response grading for esophageal squamous carcinoma after neoadjuvant chemoradiotherapy based on MRI imaging using PDX.

To confirm the efficacy of magnetic resonance-diffusion weighted imaging (MR-DWI) in esophageal squamous cell carcinoma (ESCC) early pathological response prediction and assessment to neoadjuvant chemoradiotherapy (nCRT) using patient-derived xenografts (PDXs). PDX-bearing mice were randomly divided into two groups: the experimental group receiving cisplatin combined with radiotherapy, whereas the control group receiving normal saline. MRI scans were performed in treatment groups in the before, middle, and end of treatment. The correlations between tumor volumes, ADC values and tumor pathological response at different time nodes were explored. Then, expression of proliferation marker and apoptotic marker were detected using immunohistochemistry, and apoptosis rate was detected by TUNEL assay to further verify the results observed in the PDX models. The ADC values of the experimental group were significantly higher than the control group in the both middle and end stage of treatment (all P< 0.001), however, significant difference was only observed in tumor volume at the end stage of treatment (P< 0.001). Furthermore, the △ADCmid-pre in our study may able to identify tumors with or without pCR to nCRT at an early stage, due to these changes were prior to the changes of tumor volume after treatment. Finally, TUNEL results also showed that the apoptosis rate of the experiment groups increased the most in the middle stage of treatment, especially the groups with pCR, but the highest apoptosis rate occurred in the end of the treatment. Further, the two PDX models with pCR exhibited the highest levels of apoptotic marker (Bax), and lowest levels of proliferation marker (PCNA and Ki-67) in the both middle and end stage of the treatment. ADC values could be used to determine the tumor's response to nCRT, especially in the middle stages of treatment and before the tumor tissue morphology changes, and further, the ADC values were consistent with the potential biomarkers reflecting histopathological changes. Therefore, we suggest that radiation oncologists could refer to the ADC values in the middle stages of treatment when predicting the tumor histopathological response to n CRT in patients with ESCC.

Outcomes of Stage IIIa and Well-Selected Stage IIIb or Oligometastatic Stage IV Non-Small Cell Lung Cancers Managed by Multimodal Therapy Including Immunotherapy and Surgery

Abstract Background Resectable locally advanced non-small cell lung cancers (NSCLCs) are managed by multimodal approaches including systemic therapies followed by surgery. The recent inclusion of immunotherapy in neoadjuvant protocols has significantly improved tumor responses. In selected situations, bulky N2, N3 or oligometastatic NSCLCs with treated metastasis have shown excellent regression following chemo-immunotherapy and could be considered for surgery. Aims We here compare the oncological outcomes of stage IIIA (single N2) with stage IIIB (bulky N2, N3) or oligometastatic stage IV NSCLCs managed by chemo-immunotherapy followed by surgery. Methods We reviewed all patients treated in our institution between April 2017 and June 2022 for a locally advanced or oligometastatic NSCLC with chemo-immunotherapy followed by surgery in our prospectively collected database. We recorded, for each patient, the clinico-pathological characteristics, perioperative complications and oncological outcomes. Results Forty-eight patients (27 single station N2 stage IIIA (group 1) and 21 bulky N2, N3 or oligometastatic NSCLC (group 2)) were identified. Patient characteristics were comparable between groups. Surgery consisted in lobectomy (81%), bilobectomy (17%) or pneumonectomy (2%). Complete resection was achieved in 46 (95%) patients with R1 resection in two patients due to lymph node effraction. Complete tumor pathological response was achieved in 26% in group 1 and 33% in group 2. Postoperative morbidity was 48% in group 1 and 81% in group 2 (p=0.05). There was no mortality. Median follow-up was 16 months (IQR: 9-32). Progression-free survival was 6 months (IQR: 3-18) in group 1 and 5 months (IQR: 2-7) in group 2 (p=0.04). Overall recurrence rate was 40% (comparable between groups (p=0.08)) and consisted, in majority, of distant metastasis. Overall survival was comparable between groups (p=0.05). Conclusions The inclusion of immunotherapy in induction protocols has improved tumor response and allowed to consider advanced NSCLCs for surgical resection with good postoperative and oncological outcomes.

Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients.

Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns. Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method. Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC <40%; no difference was observed in terms of OS between RTC <40% and RTC ≥40% groups. Tumor stage before NAC, BC sub-type, and vascular invasion are significant and independent factors associated with pCR. Patients with pCR and with RTC <40% have longer DFS, DDFS, and OS compared with patients with pPR.

The role of image-guided volume-adapted high-dose-rate endorectal brachytherapy boost in total neoadjuvant treatment of distal locally advanced rectal cancer.

3611 Background: Endorectal brachytherapy has been used as palliative or preoperative treatment for advanced or locally advanced rectal cancer, with moderate radiation induced toxicity. This study aimed to explore the efficacy of high-dose-rate 192Ir brachytherapy combined with external beam radiotherapy (EBRT) in total neoajuvant treatment (TNT) of distal rectal cancer. Methods: From January 2017 to December 2022, eligible rectal adenocarcinoma patients were assessed as clinical stage II -III, with primary tumor located in distal rectum (≤5 cm from anal verge). The local staging was determined using endorectal ultrasound and magnetic resonance imaging (MRI). In addition, cases included in this study underwent preoperative semiweekly endorectal brachytherapy of 8-12Gy/2-3F/1-1.5w, followed by EBRT of 45-50.4Gy/25-28F, fluorouracil-based concurrent and consolidation chemotherapy. The brachytherapy was image-guided volume-adapted, and delivered by multi-channel 192Ir source applicators with different diameters. Radiation proctitis was graded from 0 to 4 using Radiation Therapy Oncology Group (RTOG) criteria. Results: A total of 40 cases were enrolled in this retrospective study, biopsy-proven and diagnosed as clinical stage II (n = 8), stage III (n = 32). The rates of T4 and positive circumferential resection margin (CRM) were 35% and 87.5% respectively. The median value of the interval from completion of radiotherapy to operation was 86 days (interquartile range: 75-98 days). After neoadjuvant treatment, 2 cases were undergoing the watch-and-wait strategy with sustained clinical complete response (cCR), 38 patients received operation and R0 resection rate was 97.4%. The pathological complete response (pCR) rate was 28.9%, and major pathological regression rate was 67.5%. The theoretical rate of anus preservation was 62.5%, including 6 of 21 cases underwent abdominoperineal resection but achieved pCR, 17 cases underwent low anterior resection or intersphincteric resection, and 2 cases with sustained cCR. After a median follow-up of 37 months (range 12-68 months), the 3-year disease-free survival, local-regional reccurence-free survival and overall survival was 81.1% (95%CI: 64.3%-91.2%), 94.9% (95%CI: 80.6%-98.5%) and 96.9% (95%CI: 82.1%-99.4%), respectively. No patients experienced Grade ≥3 radiation proctitis. The median Wexner fecal incontinence score of anus-preserving cases was 1 (range 0-8). Subgroup analysis showed that the complete response rate (pCR or sustained cCR) was lower in cases received 2 fractions brachytherapy than those received 3 fractions (27.8% vs 36.4%). Conclusions: The addition of image-guided volume-adapted high-dose-rate 192Ir endorectal brachytherapy boost to TNT could improve the pathological tumor response and anus preservation rate in distal locally advanced rectal cancer.