Discrepancy Between Radiographic and Pathological Response Assessment in Neoadjuvant Treatment for Pancreatic Cancer: A Comparison Between Neoadjuvant Chemotherapy and Neoadjuvant Chemoradiotherapy

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

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

The optimal mode of neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC) has not been well characterized. Our study compared neoadjuvant chemotherapy (NCT) with neoadjuvant chemoradiotherapy (NCRT) for patients with ESCC. Data from ESCC patients receiving NCRT or NCT combined with esophagectomy between 2010 and 2018 from the National Cancer Center in China were retrospectively collected. Long-term survival, pathological response, and perioperative mortality and morbidity were compared between the NCRT and NCT groups. A Cox proportional hazards model and propensity score matching (PSM) were used to minimize bias due to potential confounding. Out of 327 eligible patients with ESCC in our study, 90 patients were identified in each group by PSM. The complete pathologic response (pCR) rate in the NCRT group was markedly higher than that in the NCT group (before PSM: 35.1% vs. 6.0%; after PSM: 38.9% vs. 5.6%; both P < 0.001). The rates of 30-day or 90-day mortality were comparable between the two groups, but the NCRT group had a longer postoperative hospital stay (P < 0.001 before PSM and P = 0.012 after PSM) and more postoperative complications (P < 0.001 before PSM and P = 0.014 after PSM), especially, anastomotic leaks (P = 0.001 before PSM and P = 0.013 after PSM). No significant differences in 5-year overall survival (OS) (P = 0.439) or 5-year relapse-free survival (RFS) (P = 0.611) were noted between unmatched groups, but the trend favored NCRT in the propensity score-matched group (77.3% vs. 61.3%; hazard ratio [HR] 1.57; 95% confidence interval [CI] 0.86-2.87; P = 0.141 for OS, and 77.8% vs. 60.5%; HR 1.72; 95% CI 0.95-3.11; P = 0.073 for RFS). Multivariate analysis showed that only ypT and ypN stages were independent predictors of OS before and after PSM (both P < 0.05). There was no difference in survival between the NCT and NCRT groups, although a trend favored NCRT related to the significantly higher pCR rates. Prospective head-to-head clinical trials to compare these two types of neoadjuvant therapies in ESCC are warranted.

The relationship between the radiographic portal vein-superior mesenteric vein (PV-SMV) involvement and pathological PV-SMV (pPV) invasion has been established in upfront surgery cases of pancreatic cancer (PC); however, evidence remains limited for patients receiving neoadjuvant therapy (NAT). This study aimed to evaluate the association of radiographic findings with pPV invasion in patients treated with NAT, and to examine whether this association differs between patients treated with neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT). We retrospectively analyzed patients with PC whose tumors contacted the PV-SMV on radiographic imaging before or after NAT. The relationship between radiographic findings and pPV invasion was evaluated in subgroups defined by pre- and post-NAT imaging findings. Tumor size, PV-SMV contact length, and contact angle were significantly reduced in post-NAT imaging. Radiographic PV-SMV involvement showed limited association with pPV invasion in the entire cohort. The overall pPV invasion rate was 15% and did not differ between the NAC and NACRT groups (17% vs. 13%, p=0.790). Among patients with a pre-NAT tumor size of <20mm, the pPV invasion rate was significantly lower in the NACRT group than in the NAC group (29% vs. 0%, p=0.007). This difference was not observed in patients with a pre-NAT tumor size≥20mm (12% vs. 19%, p=0.438). Across other radiographic classifications, pPV invasion rates remained comparable between treatment groups. The association of radiographic findings with pPV invasion differs between patients treated with NAC and NACRT in patients with small tumors.

Decision letter: Neutrophil-mediated fibroblast-tumor cell il-6/stat-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study

202 Background: Neoadjuvant chemotherapy with or without radiotherapy are the common treatments for locally advanced squamous-cell esophageal cancer(ESCC). There is no sufficient data to choose between these two effective therapies. The aim of our retrospective study was to compare the clinical efficacy between these two strategies of complete pathological response (pCR), postoperative morbidity, mortality, and overall and disease-free survival in patients with locally advanced ESCC. Methods: Patients with stage T2-4N0-1M0 squamous-cell esophageal cancer at our institution were recruited, including patients who underwent NCRT (1 cycle of cisplatin and 5-fluorouracil with concurrent radiotherapy) or NCT (2 cycles of cisplatin and 5-fluorouracil only ) before esophagectomy. Results: From January 2009 to October 2015, a total of 177 patients were analyzed, with 72 received NCRT and the remaining 105 received NCT. The pathological complete response (pCR) rate was 22.2% (n = 16) in NCRT group and 9.5% (n = 10) in NCT group ( P= 0.019). The postoperative mortality was 1.4% in NCRT group, versus 4.8% in NCT group. The postoperative morbidity was 20.8% in NCRT group, versus 27.6% in NCT group. There was no significant difference in recurrence between the two groups ( P= 0.397). 1-,2-,3-year overall survival rates in NCRT and NCT group were 87%, 74%, 51% and 81%, 64%, 51%, respectively ( P= 0.527), and 1-,2-,3-year DFS rates were 77%, 54%, 50% and 65%, 54%, 46%, respectively( P= 0.379). Conclusions: For patients with locally advanced squamous-cell esophageal cancer, the addition of radiotherapy to neoadjuvant chemotherapy may result in higher complete pathological response with acceptable postoperative mortality and morbidity, while the long-term survival benefit is not significant.

Objective To compare the efficacy of neoadjuvant chemoradiotherapy (NCRT) and neoadjuvant chemotherapy (NCT) in treating locally advanced esophageal squamous cell carcinoma. Methods We retrospectively analyzed a total of 177 patients who received NCRT (72 patients) or NCT (105 patients) combined with surgery for esophageal squamous cell carcinoma from January 2009 to October 2015 in the Affiliated Cancer Hospital of Zhengzhou University. The survival rate was analyzed using the Kaplan-Meier method. Results Among the 177 patients (clinical stage cT2-4N0-1M0), the 2-and 3-year sample sizes were 44 and 26 in the NCRT group, and 47 and 28 in the NCT group. The pathological complete response (pCR) rate was significantly higher in the NCRT group than in the NCT group (22% vs. 10%, P=0.019). There were no significant differences in the incidence of postoperative complications, mortality, and recurrence rate between the two groups (all P>0.05). The 2-and 3-year overall survival rates for the NCRT group were 74% and 51%, versus 64% and 51% for the NCT group (P=0.527); the 2-and 3-year disease-free survival rates for the NCRT group were 54% and 50%, versus 54% and 46% for the NCT group (P=0.379). Conclusions Compared with NCT, NCRT significantly increases the pCR rate without increasing postoperative complications and mortality in esophageal squamous cell carcinoma patients. However, since the survival rate is similar between the two groups, the efficacy of NCRT and NCT remains to be verified by further prospective, multi-centered, and large-sample studies. Key words: Esophageal neoplasms/chemotherapy; Esophageal neoplasms/chemoraidotherapy; Adjuvant chemoradiotherapy; Prognosis

Clinical trials of neoadjuvant therapy for resectable pancreatic cancer are being conducted worldwide. The present study aimed to evaluate the treatment effect of neoadjuvant chemoradiotherapy (NACRT) compared with that of neoadjuvant chemotherapy (NAC) for patients with resectable pancreatic cancer. Patients with resectable pancreatic cancer who underwent surgical resection following NACRT or NAC between December 2011 and March 2017 were included in this study. Clinicopathological factors were compared using propensity score-matched analyses. A total of 347 patients were included; 170 underwent NACRT, and 177 underwent NAC. In the propensity score-matched cohort, the posttreatment CA19-9 level was significantly lower in the NACRT group. Pathological lymph node metastasis was significantly less and pathological tumor response was better in the NACRT group. Median overall survival was comparable (56.3months in NACRT group and 50.5months in NAC group). Disease-free survival did not differ significantly, but local recurrence was significantly less in the NACRT group. In the whole cohort, multivariate analysis showed that portal vein resection, transfusion, residual cancer, and absence of adjuvant chemotherapy were independent factors associated with poor overall survival. Logistic regression analysis showed that NAC, combined portal vein resection, and margin-positive resection were risk factors for local recurrence. Neoadjuvant chemoradiotherapy showed a stronger local control effect than NAC for resectable pancreatic cancer, but overall survival and disease-free survival were not significantly different between treatment groups. The present study suggests that more effective systemic treatment, as well as local control, is crucial even in patients with resectable pancreatic cancer.

To quantify the rate of pathological complete response (PCR) in a tertiary care hospital in Pakistan, and to explore the association of pathological complete response with tumour histology, tumour grade, and histological subtype based on receptors.Descriptive study.Combined Military Hospital, Rawalpindi, Pakistan from January 2016 to December 2018.Data for 110 patients was retrospectively extracted from the medical records for the last three years. Inclusion criteria comprised of patients with non-metastatic breast cancer staged as cT1- 4 N0-1-2 breast cancer who received neoadjuvant systemic therapy, and undergone subsequent surgical procedures and adjuvant treatment as required. Assessment of pathological response was performed on the final (surgical) histopathology specimen. Complete pathological response (PCR) was evaluated according to Austrian Breast and Colorectal Cancer Study Group, and Neo-Breast International Group criteria as no invasive cancer in the breast or nodes; noninvasive breast residuals allowed (ypT0/is ypN0).The mean age of the study group was 47.21±9.5 years with an age range of 27 - 68 years. Among 110 patients undergoing neoadjuvant systemic therapy and surgery, the rate of pathological complete response was found to be 27.2% (30/110). Univariate analysis showed that pathological complete response was significantly associated with age category, tumour grade, cancer subtype, lymphovascular invasion, and Trastuzumab administration. The occurrence of pathological complete response was significantly different among different cancer subtype groups, being highest (42.8%) among triple-negative cancer subtype, followed by HR-ve/Her+ve, HR+ve/Her+ve, and HR+ve/Her-ve (40.0%, 34.4%, and 13.0% respectively, p=0.022).Achieving PCR after neoadjuvant chemotherapy is quite promising keeping into consideration that PCR a potential marker for progression-free survival and overall survival. Tumour grade, age of the patient, Her2 positive subtype, anti-Her2 directed therapy, and negative lymphovascular invasion are found to be potential predictors of complete pathological response.Breast cancer, Chemotherapy, Neoadjuvant systemic therapy, Pathological complete response, Surgery.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528.

BackgroundNeoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC.MethodsThis retrospective study analyzed 337 ESCC resection specimens from 2020–2021 at the Pudong-Branch (Cohort 1) and 114 from 2021–2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations.ResultsThe approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment.ConclusionThis work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12575-024-00234-5.

Although neoadjuvant treatment has become the standard of care for patients with locally advanced esophageal cancer, previous studies comparing neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT) have demonstrated inconclusive results. Our study cohort included 3978 patients from 85 institutions. Those who underwent NAC or NACRT followed by surgery for esophageal squamous cell carcinoma (ESCC) were eligible for inclusion. We used the inverse probability of treatment weighting (IPTW) method to compare the outcomes between NAC and NACRT. Among the 3978 patients, 3777 (94.9%) received NAC and 201 (5.1%) received NACRT. After IPTW adjustment, the NACRT group had more patients with pathologically downstaged diseases and significantly better pathological response compared with the NAC group (p<0.001); however, 5-year overall survival (OS), recurrence-free survival (RFS), and regional recurrence-specific survival (RRSS) were comparable between the groups. Subgroup analysis stratifying patients according to cT category showed that among cT1-2 patients, those in the NACRT group had significantly longer 5-year OS, RFS, and RRSS than those in the NAC group (P = 0.024, < 0.001, and 0.020, respectively). In contrast, no significant differences were observed among cT3-4a patients. The competing risks regression model showed comparable subdistribution hazard ratios for 10-year cancerous and noncancerous deaths between the NAC and NACRT groups. Compared with NAC, NACRT for ESCC did not promote better survival despite better therapeutic effects and did not increase noncancerous deaths.

Neoadjuvant chemoradiotherapy (NCRT) is recommended as the treatment standard for locally advanced esophageal squamous cell carcinoma (ESCC). The use of immunotherapy in the neoadjuvant setting has gained attention. Multiple, clinical trials have explored the efficacy and safety of neoadjuvant immunochemotherapy (NICT). We evaluated the differences in clinicopathologic outcomes and the patterns of lymphatic spread among patients receiving neoadjuvant chemotherapy (NCT), NCRT, and NICT before esophagectomy for locally advanced ESCC. A total of 702 patients with ESCC who completed transthoracic esophagectomy followed neoadjuvant therapy were included. Pathological characteristics, including pathologic complete response (pCR), tumor regression grade (TRG) score and patterns of lymphatic spread, were evaluated. Compared with the NCT group, the NCRT group and NICT group had an advantage in pathological response (P < 0.05). The pCR rate was 8.1% in the NCT group, 29.9% in the NCRT group, and 23.6% in the NICT group. The TRG score (P < 0.05) and pathologic T stage (P < 0.05) in the NCT group were significantly higher. Compared with NICT, NCRT can significantly reduce the rate of lymph node metastasis rate in station 1R (0 vs. 3.4%, P < 0.05) and 2R (1.1% vs. 6.8%, P < 0.05). Subgroup analysis according to the tumor location distribution showed that NICT group had higher lymph node metastasis rate 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. NCRT or NICT followed by surgery may result in a promising pCR rate and show a better performance in therapeutic response of primary lesion. For patients with lymph node metastasis in station 1R and 2R, NCRT should be the optimal preoperative treatment strategy.

4062 Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m2 of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490 .

Simple SummaryFor high-grade soft tissue sarcomas (STS), combined modality treatment with surgery and radiation therapy is the standard of care. The addition of chemotherapy has been shown to decrease the risk of local recurrence and improve survival. Evaluating treatment response with surrogate modalities such as MRI, CT and PET imaging have substantial limitations. Pathologic necrosis of the surgical specimen is a direct indicator of the effect of treatment on tumor cells. Studies in STS and other malignancies have shown that increasing rates of treatment-induced tumor necrosis correlate with improvement of oncological outcomes and survival. However, the relationship between pathologic response and outcomes of specific neoadjuvant treatments for STS remains indeterminate. We hypothesized that sequential neoadjuvant chemotherapy and radiation yields higher rates of pathologic complete response (pCR) than neoadjuvant radiation or chemotherapy alone. Our results indicate that neoadjuvant chemotherapy and radiation yields superior pCR compared to other neoadjuvant regimens.(1) Background: Pathologic necrosis of soft tissue sarcomas (STS) has been used to determine treatment response, but its relationship to neoadjuvant treatments remains indeterminate. In this retrospective, single institution study, we hypothesized that neoadjuvant chemoradiation (NA-CRT) yields higher rates of pathologic complete response (pCR) than neoadjuvant radiation (NA-XRT) or chemotherapy (NA-CT) alone. (2) Methods: Patients with extremity STS between 2011–2020 who received neoadjuvant treatment were included. pCR was defined as percent necrosis of the surgical specimen greater than or equal to 90%. (3) Results: 79 patients were analyzed. 51.9% of the population were male with a mean age of 58.4 years. 49.4% identified as Non-Hispanic White. Twenty-six (32.9%) patients achieved pCR while 53 (67.1%) did not. NA-CT (OR 15.82, 95% CI = 2.58–96.9, p = 0.003 in univariate (UVA) and OR 24.7, 95% CI = 2.88–211.2, p = 0.003 in multivariate (MVA), respectively) and NA-XRT (OR 5.73, 95% CI = 1.51–21.8, p = 0.010 in UVA and OR 7.95, 95% CI = 1.87–33.7, p = 0.005 in MVA, respectively) was significantly associated with non- pCR when compared to NA-CRT. The analysis also demonstrated that grade 3 tumors, when using grade 2 as reference, also had significantly higher odds of achieving pCR (OR 0.23, 95% CI = 0.06–0.80, p = 0.022 in UVA and OR 0.16, 95% CI = 0.04–0.70, p = 0.015 in MVA, respectively). (4) Conclusion: NA-CRT yields superior pCR compared to other neoadjuvant regimens. This extends to higher grade tumors.