Histopathological Complete Response Research Articles

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Primary safety and short-term efficacy results for cohort E.

326 Background: The standard neoadjuvant treatment in Japan for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is DTX + CDDP + 5-FU (DCF). In addition, immune checkpoint inhibitors (ICIs) have shown a survival benefit for ESCC and are promising as neoadjuvant treatment for several cancers. We previously reported that neoadjuvant CDDP + 5-FU + nivolumab (Nivo) or DCF + Nivo therapy was tolerable and showed promising efficacy for ESCC. However, the efficacy of neoadjuvant treatment and safety of subsequent surgery remain unclear for 5-FU + l-LV + L-OHP + DTX (FLOT), the global standard of care for perioperative esophagogastric adenocarcinoma, plus ICI for ESCC. Methods: JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant chemotherapy in ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer therapy. The primary endpoint was the incidence of dose-limiting toxicity (DLT) from the initial dose to postoperative day 30. The secondary endpoints included adverse events during the perioperative period and at 30 days and the objective response rate, R0 resection rate, histopathological complete response rate, and completion rate of the protocol treatment including planned chemotherapy as below followed by R0 resection. Among five study cohorts, patients in cohort E were planned to receive four courses of FLOT+Nivo–5-FU (2600 mg/m2), l-LV (200 mg/m2), L-OHP (85 mg/m2), DTX (50 mg/m2), and Nivo (240 mg)–on day 1 every 2 weeks. Results: Of the 12 patients enrolled in cohort E (median age [range]: 64.5 [53-71] years, PS 0/1: 12/0, clinical stage I/II/III/IVA: 4/5/3/0), 4 developed DLT (grade 3 mucositis, erythema multiforme, and pneumonitis, n=1 each; grade 5 pneumonitis, n=1), which was within the prespecified range of safety (n ≤ 4). Other grades≥3 adverse events were neutropenia (n=7), leukopenia (n=6), fever, fatigue, febrile neutropenia, rash, elevated amylase, elevated hepatic enzyme, hypotension, and thrombocytopenia (n=1 each) during FLOT + Nivo, and anastomotic leakage (n=1) during the postoperative period. One patient discontinued FLOT + Nivo due to DLT of erythema multiforme, eleven patients (91.7%) completed the protocol treatment and R0 resection rate achieved 91.7% (11/12). In cohort E, the objective response rate in patients with measurable lesion was 0% (0/4). However, 5 patients (41.7%) achieved a pathological complete response, and 6 (50.0%) achieved a pathological complete response in primary tumors among 12 patients. Conclusions: Neoadjuvant FLOT + Nivo followed by surgery for locally advanced ESCC was tolerated and showed promising efficacy. Clinical trial information: NCT03914443 .

Clinical, histopathological and immunohistochemical evaluation of ultraviolet A1 treatment in early-stage mycosis fungoides.

Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphomas primarily involving the skin. Early-stage MF is characterised by non-specific skin lesions and non-diagnostic biopsies. While skin-focused treatments, such as PUVA and narrowband UVB (nbUVB), are the most frequently recommended treatments, the UVA1 efficacy has been researched in recent years. The purpose of this study was to evaluate the clinical, histopathological and immunohistochemical aspects of UVA1 treatment in patients with early-stage MF. The modified severity weighted assessment scale (mSWAT) was used for total skin body scoring before and after treatment. Skin punch biopsies were taken from the patients before and after treatment. UVA1 therapy was performed five times each week. This study included 26 patients with early-stage MF. The total number of UVA1 sessions varied between 15 and 34. Complete response was observed in 8 (30.8%) of 26 patients (30.8%). The median mSWAT score decreased statistically significantly from 7.1 to 2.0 after treatment (p < .001). Histopathological complete response was observed in 2 (9.5%) of 21 patients. A statistically significant decrease in dermal interstitial infiltrate was observed on histopathological examination after treatment (p = .039). Epidermal CD4/CD8 levels decreased statistically significantly higher from a median of 2.5-1.2 in the complete clinical response group after treatment (p = .043). According to our results, UVA1 treatment has an effect on early-stage MF in terms of clinical, histopathological and immunohistochemistry.

Response Evaluation after Neoadjuvant Chemotherapy for Resectable Gastric Cancer

Background: The method of response evaluation following neoadjuvant chemotherapy (NAC) in resectable gastric cancer has been widely debated. An essential prerequisite is the ability to stratify patients into subsets of different long-term survival rates based on the response mode. Histopathological measures of regression have their limitations, and interest resides in CT-based methods that can be used in everyday settings. Methods: We conducted a population-based study (2007–2016) on 171 consecutive patients with gastric adenocarcinoma who were receiving NAC. Two methods of response evaluation were investigated: a strict radiological procedure using RECIST (downsizing), and a composite radiological/pathological procedure comparing the initial radiological TNM stage to the pathological ypTNM stage (downstaging). Clinicopathological variables that could predict the response were searched for, and correlations between the response mode and long-term survival rates were assessed. Results: RECIST failed to identify half of the patients progressing to metastatic disease, and it was unable to assign patients to subsets with different long-term survival rates based on the response mode. However, the TNM stage response mode did achieve this objective. Following re-staging, 48% (78/164) were downstaged, 15% (25/164) had an unchanged stage, and 37% (61/164) were upstaged. A total of 9% (15/164) showed a histopathological complete response. The 5-year overall survival rate was 65.3% (95% CI 54.7–75.9%) for TNM downstaged cases, 40.0% (95% CI 20.8–59.2%) for stable disease, and 14.8% (95% CI 6.0–23.6%) for patients with TNM progression, p &lt; 0.001. In a multivariable ordinal regression model, the Lauren classification and tumor site were the only significant determinants of the response mode. Conclusions: Downsizing, as a method for evaluating the response to NAC in gastric cancer, is discouraged. TNM re-staging by comparing the baseline radiological CT stage to the pathological stage following NAC is suggested as a useful method that may be used in everyday situations.

Abstract 1745: Targeting therapeutic resistance of esophageal adenocarcinoma through modulating the epithelial-to-mesenchymal transition via NFκB-mediated signaling

Abstract Esophageal adenocarcinoma (EAC) is the major subtype of esophageal cancer in Westernized countries, characterized by rising incidence and poor prognosis with a five-year survival rate less than 20%. Only 15% of EAC patients have a complete histopathological response to standard chemotherapy, indicating the urgent need to identify mechanisms associated with therapeutic resistance for improved therapeutic efficacy and patient outcomes. Herein, we performed transcriptional profiling utilizing tissues collected from EAC patients prior to treatment initiation. First, EAC patients (n=67) were stratified into 5 therapeutic response groups based on the changes in TNM pre- to post-treatment; second, bioinformatic approaches were utilized to identify molecular changes associated with response to treatment and patient survival. Third, we employed OE19 and OE33 human EAC cell lines to investigate the efficacy of cranberry proanthocyanidins (C-PAC), a promising anti-inflammatory and anti-cancer agent which shows synergistic effects with carboplatin in other cancer types, at mitigating molecular pathways which drive therapeutic resistance. Our therapeutic response data set revealed epithelial-mesenchymal transition (EMT) as a top pathway associated with differential response to therapy and patient survival. Subsequent gene-set enrichment analysis identified that EMT is significantly associated with NFκB and STAT3 signaling pathways, two nodes with documented proinflammatory roles in EAC progression. Deconvolution analysis was conducted further supporting EMT enrichment creates an immune-suppressive tumor microenvironment in EAC patients. Next, EAC cell viability, migration and interrogation of EMT signaling proteins were conducted following treatment with paclitaxel and carboplatin (chemo drugs) alone or in combination with C-PAC. Combination treatment of C-PAC and chemo drugs significantly inhibited EAC cell viability and migration capability, compared to cells treated with chemo drugs alone, with synergistic effects observed in OE33 cells. Moreover, combination treatment also significantly decreased NFκB1 expression and expressions of EMT markers and transcription factors (Snail, MMP-2, MMP-9, and Vimentin) whereas cells treated only with chemo drugs showed minimal modulation. Knockdown experiments of NFκB1 using RNA interference are underway to investigate the relationship between canonical NFκB1 signaling and EMT. Primary cell lines and organoids developed from isolated EAC patient tissues will also be used in the future to validate experimental findings. The results suggest C-PAC may be used as a safe and novel therapeutic strategy to improve chemotherapy efficacy targeting EAC. Citation Format: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Michelle P. Lee, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, Amy B. Howell, Laura A. Kresty. Targeting therapeutic resistance of esophageal adenocarcinoma through modulating the epithelial-to-mesenchymal transition via NFκB-mediated signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1745.

Evaluation of Adjuvant Chemotherapy Survival Outcomes Among Patients With Surgically Resected Pancreatic Carcinoma With Node-Negative Disease After Neoadjuvant Therapy

Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT). To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS). A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology. Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT. The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis. In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04). The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

Identification of Novel Molecular Subgroups in Esophageal Adenocarcinoma to Predict Response to Neo-Adjuvant Therapies.

Simple SummaryGene expression of esophageal adenocarcinoma is highly heterogeneous. In general, these cancers have poor prognosis and unpredictable responses to chemo- and radiotherapy. Investigating expression profiles from RNA from pre-treatment biopsies are highly attractive to investigate the existence of diverse biological groups and signatures associated with the clinical response to current treatment strategies. We identified and validated three distinct biological esophageal adenocarcinoma subgroups and identified immune signatures with association to therapy response using RNA sequencing. These findings aid in understanding biological mechanisms’ underlying response to neo-adjuvant treatment.Esophageal adenocarcinoma (EAC) is a highly aggressive cancer and its response to chemo- and radiotherapy is unpredictable. EACs are highly heterogeneous at the molecular level. The aim of this study was to perform gene expression analysis of EACs to identify distinct molecular subgroups and to investigate expression signatures in relation to treatment response. In this prospective observational study, RNA sequencing was performed on pre-treatment endoscopic EAC biopsies from a discovery cohort included between 2012 and 2017 in one Dutch Academic Center. Four additional cohorts were analyzed for validation purposes. Unsupervised clustering was performed on 107 patients to identify biological EAC subgroups. Specific cell signaling profiles were identified and evaluated with respect to predicting response to neo-adjuvant chemo(radio)therapy. We identified and validated three distinct biological EAC subgroups, characterized by (1) p38 MAPK/Toll-like receptor signaling; (2) activated immune system; and (3) impaired cell adhesion. Subgroup 1 was associated with poor response to chemo-radiotherapy. Moreover, an immune signature with activated T-cell signaling, and increased number of activated CD4 T memory cells, neutrophils and dendritic cells, and decreased M1 and M2 macrophages and plasma cells, was associated with complete histopathological response. This study provides a novel molecular classification for EACs. EAC subgroup 1 proved to be more therapy-resistant, while immune signaling was increased in patients with complete response to chemo-radiotherapy. Our findings give insight into the biology of EACs and in cellular signaling mechanisms underlying response to neo-adjuvant treatment. Future implementation of this classification will improve patient stratification and enhance the development of targeted therapies.

Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer.

This study analyzed the long-term survival after pathological complete response (pCR) with and without nodal metastases and associated recurrence following multimodal treatment of esophageal cancer. The recurrence pattern after pCR is of importance for different postoperative surveillance strategies. A cohort of 890 patients with esophageal cancer received neoadjuvant therapy followed by transthoracic esophagectomy. Only patients with pCR of the primary tumor with and without nodal metastasis were analyzed. A clinicopathological database was set up and completed with long-term follow up information on recurrent disease. The specimen of 201 patients (23%) demonstrated pCR, 84% without (ypT0N0) and 16% with residual nodal disease (ypT0N+). For ypT0N0 patients, the 5-year overall survival was significantly higher than for patients with metastatic nodes (77% vs. 24%) (p < 0.0001). Sixty-eight percent of patients had no evidence of tumor recurrence, whereas 32% had proven relapse. For patients with and without tumor recurrence, 5-year survival rates were 14% and 93%, respectively (p < 0.0001). For patients with recurrent disease, median survival time was 27 for locoregional, 44 for distant, and 24 months for combined recurrence (p = 0.302). In the multivariable Cox-regression analysis, node-positive disease predicted both locoregional and metastatic recurrence. Pathological CR offers long-term survival in patients without nodal metastases but outcome significantly deteriorates with the presence of nodal metastases. Follow-up recommendations may therefore be adopted in patients with pCR. Furthermore, "watch-and-wait" surveillance strategies with suspected clinical complete response have to be considered with caution.

Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials

BackgroundEpstein–Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV−/MSS GCs who received either surgery only or perioperative treatment.MethodsEBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival.ResultsIn the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV−/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV−/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV−/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype.ConclusionsIn resectable GC, MSI-high had favorable outcome compared to EBV−/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.

Ablative-Transarterial Radioembolization resulting in complete histopathological response of hepatocellular carcinoma in the resected liver specimen after salvage hepatectomy.

IntroductionHepatocellular carcinoma (HCC) is a common disease. Many patients at the time of diagnosis of HCC are in advanced stages and cannot benefit from curative treatment. Palliative treatments remain the only treatment option. Advances in palliative treatment can occasionally downstage HCC and induce enough liver hypertrophy to allow salvage hepatectomy to be performed on patients with initially unresectable HCC. We herein present a patient who underwent salvage hepatectomy after successful Ablative-Transarterial Radioembolization (A-TARE) with complete histopathologic response in the resected liver specimen.Case reportA 67-year old obese patient presented with a 9.7 cm HCC at liver segment 8, with local tumour extension to involve segments 4,5 and 7. Initial workup suggested the tumour to be unresectable. A-TARE with yttrium-90 microspheres was given. Further workup 4 months after A-TARE showed the tumour to be downstaged with adequate hypertrophy of future liver remnant. Salvage hepatectomy became possible and the patient underwent salvage trisectionectomy 5 months after A-TARE. He recovered uneventfully from the operation. Histopathological examination of the resected liver specimen showed no viable tumour cells inside a fibrous mass which corresponded to the radiologic residual tumour.DiscussionSalvage hepatectomy should be offered to patients after tumour downstaging with A-TARE as viable malignant cells are likely to persist. Complete response with no viable tumour cells in the resected liver specimen, to our knowledge, has never been reported in literature.ConclusionA-TARE was able to induce complete histopathological response in a patient who initially presented with a large and unresectable HCC mass.

Abstract 354: Mucinous phenotype is associated with response to neoadjuvant chemotherapy in microsatellite instable resectable gastric cancer

Abstract Background: Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) have been shown to be positive prognostic factors for long term survival in resectable gastric cancer (GC) in several studies. However, the benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcome of patients with EBV+ and MSI-high GCs treated with surgery only in the Dutch D1/D2 trial, and treated with chemotherapy or chemoradiotherapy after preoperative chemotherapy and surgery in the CRITICS trial. Patients and methods: EBV was determined in tumor tissue using EBV-encoded RNA in situ hybridization (EBER-ISH). PCR and/or immunohistochemistry were performed to determine MSI status. Results were correlated to histopathological response, morphological tumor characteristics and survival. Results: In the Dutch D1/D2 trial 10.5% (47/447) of tumors were EBV+ and 10.5% (47/447) were MSI-high. In the CRITICS trial 5.5% (25/451) of tumors were EBV+ and 5.5% (25/451) were MSI-high tumors. In the Dutch D1/D2 trial, five-year overall survival probability was 51.1% for EBV+, 46.8% for MSI-high, and 42.5% for EBV-/MSS (P=0.19). In the CRITICS trial, five-year overall survival was 56.0% for EBV+, 47.3% for MSI-high, and 36.5% for EBV-/MSS (P=0.22). In the CRITICS trial, 3 (12.5%) MSI-high tumors showed moderate to complete histopathological response. Interestingly, all three showed a mucinous phenotype. Eight (36.4%) EBV+ and 114 (29.9%) EBV-/MSS tumors showed moderate to complete histopathological response. None of the EBV+ GCs showed mucinous differentiation. Conclusions: The favorable outcome of GC patients with resectable EBV+ or MSI-high tumors compared to EBV-/MSS tumors remains after perioperative chemotherapy. In MSI-high tumors significant histopathological response to neoadjuvant chemotherapy was found only in those with a mucinous phenotype. Citation Format: H.D. Biesma, A.T.T.D. Soeratram, K. Sikorska, I.A. Caspers, H.F. van Essen, J.M.P. Egthuijsen, A. Mookhoek, D.M. Hoek, W. Vos, H.W.M. van Laarhoven, M. Nordsmark, D.L. van der Peet, F.A.R.M. Warmerdam, M.M. Geenen, O.J.L. Loosveld, J.E.A. Portielje, M. Los, E. Meershoek - Klein Kranenbarg, H.H. Hartgrink, J. van Sandick, C.J.H. van de Velde, M. Verheij, A. Cats, B. Ylstra, N.C.T. van Grieken, On behalf of the CRITICS investigators. Mucinous phenotype is associated with response to neoadjuvant chemotherapy in microsatellite instable resectable gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 354.

Abstract 1418: Proanthocyanidins enhance chemotherapy-induced esophageal adenocarcinoma cell death

Abstract Esophageal adenocarcinoma (EAC) is a devastating cancer characterized by rising incidence and poor prognosis. The five-year survival rate is 20% due to late stage diagnosis and ineffective treatment. It is estimated that only 15% of EAC patients have a complete histopathological response to standard chemotherapy. Thus, new strategies are urgently needed to improve therapeutic efficacy and patient survival. Our recent analysis of prechemotherapy endoscopic biopsies of EAC patients revealed differential response to neoadjuvant therapy. Differential response was reflected by two-year mortality of 9.1% in therapy responsive patients (Complete responders, no residual tumor), 22.2% in strong responders (improved TNM), 25.0% in intermediate responders (stable TNM), 42.9% in poor responders (worse TNM) and 77.8% in non-responders (worse TNM and metastasis). Transcriptomic analysis revealed differential response to therapy is linked to immune defense, inflammation (IL-4, IFNs), cell adhesion, signal transduction and angiogenesis regulation. Similar pathways were mitigated by cranberry proanthocyanidins (C-PAC) in a rat surgical model for EAC. Herein, we investigated C-PAC pretreatment alone or in combination with Paclitaxel and Carboplatin (chemo drug) on EAC cell viability (Calcein-AM), gene expression (RNA-seq) and select protein levels (Western blot). C-PAC pre-treatment and co-treatment enhance chemotherapy-induced EAC cell death, with the greatest synergistic effects in chemo-resistant OE33 cells. C-PAC pretreatment followed by chemo drugs decreased cell viability by an additional 50% and 17% compared to chemo drugs alone in OE33 cells and OE19 cells, respectively. Greater reductions were noted with pretreatment of C-PAC, followed by co-treatment with chemo drugs (64.9% in OE33 and 49.4% in OE19 cells). C-PAC enhanced chemo drug-induced EAC cell death via increased DNA damage, apoptosis and ECM degradation as evidenced by induction of phosphorylated H2AX and cleaved caspase-3, as well as inhibition of BCLXL and MMP9. C-PAC also mitigated elevated levels of P53, a gene with a well-documented role in EAC progression and therapeutic resistance. Transcriptome analysis of cells treated with C-PAC and chemo drugs is underway and will be compared to signaling networks differentially expressed in patients stratified by treatment responsiveness. Results suggest that C-PAC pretreatment may offer a non-toxic intervention strategy for enhancing chemotherapeutic efficacy. Citation Format: Yun Zhang, Katherine Weh, Connor Howard, Kiran Lagisetty, Dyke McEwen, Jules Lin, Rishindra M. Reddy, Andrew Chang, David G. Beer, Amy Howell, Laura A. Kresty. Proanthocyanidins enhance chemotherapy-induced esophageal adenocarcinoma cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1418.

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy.

BACKGROUNDLiver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.AIMTo analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone. METHODSIn this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney-U tests.RESULTSFourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, P value < 0.001). CONCLUSIONOur data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.

Clinical parameters predictive for sphincter-preserving surgery and prognostic outcome in patients with locally advanced low rectal cancer

BackgroundAlthough controversial, there are data suggesting that clinical parameters can predict the probability of sphincter preserving procedures in rectal cancer. The purpose of this study was to investigate the association between clinical parameters and the sphincter-preserving surgery rate in patients who had undergone neoadjuvant combination therapy for advanced low rectal cancer.MethodsIn this single center study, the charts of 540 patients with locally advanced rectal cancer who had been treated with induction chemotherapy-and/or neoadjuvant concomitant radiochemotherapy (nRCT) over an 11-year period were reviewed in order to identify patients with rectal cancer ≤6 cm from the anal verge, who had received the prescribed nRCT only. Univariate and multivariate analyses were used to identify pretreatment patient- and tumor associated parameters correlating with sphincter preservation. Survival rates were calculated using Kaplan-Meier analyses.ResultsTwo hundred eighty of the 540 patients met the selection criteria. Of the 280 patients included in the study, 158 (56.4%) underwent sphincter-preserving surgery. One hundred sixty-four of 280 patients (58.6%) had a downsizing of the primary tumor (ypT < cT) and 39 (23.8%) of these showed a complete histopathological response (ypT0 ypN0). In univariate analysis, age prior to treatment, Karnofsky performance status, clinical T-size, relative lymphocyte value, CRP value, and interval between nRCT and surgery, were significantly associated with sphincter-preserving surgery. In multivariate analysis, age (hazard ratio (HR) = 1.05, CI95%: 1.02–1.09, p = 0.003), relative lymphocyte value (HR = 0.94, CI95%: 0.89–0.99, p = 0.029), and interval between nRCT and surgery (HR = 2.39, CI95%: 1.17–4.88, p = 0.016) remained as independent predictive parameters.ConclusionsThese clinical parameters can be considered in the prognostication of sphincter-preserving surgery in case of low rectal adenocarcinoma. More future research is required in this area.

Complete pathologic response after two-stage cytoreductive surgery with HIPEC for bulky pseudomyxoma peritonei: proof of concept

Introduction Pseudomyxoma peritonei (PMP) is a rare disease characterized by the progressive accumulation of mucinous ascites and peritoneal implants. The optimal treatment for PMP includes the association of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). For patients with a large burdensome disease, the completeness of cytoreduction sometimes requires maximal effort surgery. The aim of this article is to provide proof of concept for two stage cytoreductive surgery (CRS) in this category of patients. Methods and materials A two stage CRS and HIPEC with oxaliplatin was proposed for patients with bulky PMP including important involvement of the serosal surfaces of the bowel or colon who had an impaired nutritional status. The residual disease at the end of the first stage was less than 5 mm of thickness on several implants. Clinical, surgical and histopathological variables were analyzed. Results All eight patients completed the two-stage strategy. Mortality was nil. One Clavien Dindo grade 3 event occurred in each stage. After a median follow up of 29.5 months, all patients were alive and free of recurrence. All of the patients had histopathological complete response on the specimens obtained from the residual sites during the second stage surgery. Conclusions Two-stage surgical strategy is feasible for bulky PMP patients and it is associated with little high-grade morbidity and enhanced visceral sparing.

EORTC-1203-GITCG - the \u201cINNOVATION\u201d-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group

Background10–20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC.MethodsThis is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms:Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator’s choice in Europe, and cisplatin/capecitabine in Asia.Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery.Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1.Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P.DiscussionDepending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC.Trial registrationThis article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047; EudraCT: 2014–000722-38.

PS02.120: NEOADJUVANT CHEMOTHERAPY VERSUS NEOADJUVANT CHEMORADIOTHERAPY FOR CANCER OF THE OESOPHAGUS OR GASTRO-OESOPHAGEAL JUNCTION: LONG-TERM RESULTS

Abstract Background NeoRes I is a randomized phase II trial comparing neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy in the treatment of resectable oesophageal cancer. Methods Patients with biopsy-proven adenocarcinoma or squamous cell carcinoma in the oesophagus or gastro-oesophageal junction (Siewert type I and II), T1N1 or T2–3N0–1 and M0-M1a (AJCC 6th edition) were randomized to receive three 3-weekly cycles of cisplatin 100 mg/m2 day 1 and fluorouracil 750 mg/m2/24 hours, days 1–5 with or without the addition of concurrent radiotherapy 40 Gy, 2 Gy/fraction, 5 days a week, followed by oesophageal resection with two-field lymphadenectomy. Primary endpoint was complete histopathological response rate. Survival and recurrence patterns were evaluated as secondary endpoints. Results Between 2008 and 2013, 181 patients were enrolled in 10 participating institutions in Sweden and Norway. Patients were well matched for pre-treatment characteristics T3: 64,1%, T2: 34,8%, T1: 1,1%. Adenocarcinoma: 72,4%, squamous cell carcinoma: 27,6%. Proximal/middle: 16,6%, distal: 65,2%, cardia (Siewert type II): 18,2%. &lt; 60 years: 36,5%, 60–75 years: 63,5%. Treatment-related complications have previously been described with no significant differences between the treatment groups although postoperative complications were more severe in the chemoradiotherapy group. At the time of this analysis, median follow-up time for living patients was 63 months. Overall 5-year survival was better among those who achieved complete histopathological response (74,9%, 95% CI 54,2–87,2% versus 39,3%, 95% CI 30,6–47,8%, P = 0002). Despite the previously reported higher rate of tumour tissue response in those who received neoadjuvant chemoradiotherapy, this was not translated into better survival. Five-year progression-free survival was 38,6%, 95% CI 28,4–48,6% (chemoradiotherapy) versus 32,4%, 95% CI 22,9–42,4% (chemotherapy), P = 0,48. Five-year overall survival was 41,2%, 95% CI 30,9–51,3% (chemoradiotherapy) versus 38,9%, 95% CI 28,7- 49,0% (chemotherapy), P = 0,95. There were no differences in recurrence patterns between the two treatment-groups. Conclusion This is to our knowledge the largest completed randomized trial comparing neoadjuvant chemotherapy with neoadjuvant chemoradiotherapy followed be oesophageal resection in patients with cancer in the oesophagus or gastro-oesophageal junction. We found no overall or progression-free survival advantages by adding radiotherapy, despite better tumour tissue response. Disclosure All authors have declared no conflicts of interest.

Feasibility of Extended Dissection of Lateral Pelvic Lymph Nodes During Laparoscopic Total Mesorectal Excision in Patients with Locally Advanced Lower Rectal Cancer: A Single-Center Pilot Study After Neoadjuvant Chemotherapy.

BackgroundThe feasibility of additional dissection of the lateral pelvic lymph nodes (LPLNs) in patients undergoing total mesorectal excision (TME) combined with neoadjuvant chemotherapy (NAC) for locally advanced rectal cancer (LARC) is controversial. The use of laparoscopic surgery is also debated. In the present study, we evaluated the utility of laparoscopic dissection of LPLNs during TME for patients with LARC and metastatic LPLNs after NAC, based on our experience with 19 cases.Material/MethodsTwenty-five patients with LARC with swollen LPLNs who underwent laparoscopic TME and LPLN dissection were enrolled in this pilot study. The patients were divided into 2 groups: those patients with NAC (n=19) and without NAC (n=6). Our NAC regimen involved 4 to 6 courses of FOLFOX plus panitumumab, cetuximab, or bevacizumab.ResultsThe operative duration was significantly longer in the NAC group than in the non-NAC group (648 vs. 558 minutes, respectively; P=0.022). The rate of major complications, defined as grade ≥3 according to the Clavien-Dindo classification, was similar between the 2 groups (15.8% vs. 33.3%, respectively; P=0.4016). No conversion to conventional laparotomy occurred in either group. In the NAC group, a histopathological complete response was obtained in 2 patients (10.5%), and a nearly complete response (Tis N0 M0) was observed in one patient (5.3%). Although the operation time was prolonged in the NAC group, the other perioperative factors showed no differences between the 2 groups.ConclusionsLaparoscopic LPLN dissection is feasible in patients with LARC and clinically swollen LPLNs, even after NAC.

Complete histopathological regression in rectal cancer after neoadjuvant chemoradiotherapy and sphincter preserving surgical treatment

Background/Aim. Multimodal approach to locally advanced rectal cancer treatment results in better disease outcome. Preoperative chemoradiotherapy improves disease local control, reduces risk of local recurrence and in the majority of patients with complete or substantial regression of the tumors significantly improves survival rates. According to the literature data, approximately 20% of patients had achieved complete histopathological response (pCR) after neoadjuvant chemoradiation therapy. The aim of this study was to evaluate overall survival in rectal cancer patients treated with preoperative chemoradiotherapy and sphincter preserving surgery. Methods. This retrospective study included 191 patients. Patients received preoperative radiation therapy and chemotherapy-chemoradiation therapy (CRT) followed by operation that favorized sphincter preservation with total mesorectal excision (TME) from June 2000 until December 2010. Diagnosis was established according to the following algorithm: patient history, digital rectal examiantion, colonoscopy with biopsy and histopathology verification, and preoperative clinical staging. Patients with tumors located below promontorium were included in the study and patients with metastatic disease and local recurrence were excluded from the study. For tumors located below the promontorium preoperative radiotherapy was used with total dose of 50.4 Gy, divided into daily doses of 1.8 Gy, during 28 days. Chemotherapy followed radiotherapy with 5- fluorouracil and folic acid (Leucovorin?) on days 1, 2, 10, 11, 20 and 21. Six to ten weeks after neoadjuvant therapy, magnetic resonance imaging (MRI) to restage tumors and operation were performed. Results. Of all patients that received preopertive chemoradiation, 163 had radical sphincter preservig surgery and 28 patients had paliative operations. Histopathological examination of the specimens showed that the complete histopathological regression was achieved in 21.4% of the patients, downstaged was found in 63.2% of them and unchanged stage was found in 15.3% of the patients. The five-year survival rate was 63.3% and 50.5 % in the patients with pCR and patients with incomplete histopathological regression, respectively. Survival rates between two groups were not statistically significant (p &gt; 0.05). Conclusion. The preoperative chemoradiotherapy is very important in achieving optimal clinical care for patients with locally advanced rectal cancer.

Abstract 1488: Altered skeletal muscle mitochondrial function and redox biology with chemotherapy and exercise in a colorectal cancer mouse model

Abstract Background: Chemotherapy improves outcomes for patients with gastrointestinal cancer, but carries associated morbidity. Platinum-based chemotherapy adversely impacts fitness, invivo mitochondrial function, and cellular redox status in humans, however the mechanisms are poorly understood. Exercise interventions mitigate against this, but interactions between the effect of the cancer, chemotherapy, and exercise intervention are poorly understood. Using a colorectal cancer (CRC) mouse model we investigated changes in skeletal muscle oxidative phosphorylation (OxPhos) capacity and redox biology with chemotherapy and exercise. Method: SCID mice (n=48) were randomized to laparotomy with (Ca) or without (NCa) orthotopic caecal injection of DLD-1 CRC cells. CRC established over 8 weeks then mice were randomized to 1) 3 cycles of intra-peritoneal (IP) chemotherapy (Chemo; 5FU 5mg/kg, Oxaliplatin 10mg/kg and Leucovorin 90mg/kg) followed by interval exercise-training 2) Chemo and no exercise 3) IP saline sham (Sal) with exercise or 4) Sal with no exercise. Blood was collected pre and post-Chemo and at death (post-exercise), and markers of oxidative stress measured. Soleus muscle mitochondrial function was analyzed using high-resolution respirometry. Measurements included maximum OxPhos capacity (PI+II+β), Complex I and II capacities and the ratio of octanoyl-carnitine to pyruvate-supported respiration (FAO). Histopathological caecal examination was undertaken to determine cancer response. Results: Chemotherapy alone resulted in 37% lower OxPhos capacities in sham mice (p=0.011), whilst FAO was 40% lower (p=0.004). Cancer alone resulted in 38% lower OxPhos capacities (p=0.012). In combination with cancer, chemotherapy resulted in OxPhos capacities that were 42% lower than in mice with cancer but no chemotherapy (p=0.007), along with 51% lower Complex I (p&amp;lt;0.001) and 42% lower Complex II (p=0.007) capacities. In sham mice (NCaSal), exercise resulted in 33% greater Complex II activities (p=0.042), but exercise did not alter mitochondrial function in any other group. Total plasma protein content (TPPC) increased with time in the CaSal (+32%) and the NCaSal mice (+23%), whilst it decreased with chemotherapy (CaChemo -20%, NCaChemo -10%). Oxidative stress increased with chemotherapy and exercise, however exploratory interaction analyses are ongoing. Complete histopathological response was seen in 2 of 6 CaChemoEx animals. No other complete response was seen. Conclusion: Chemotherapy and cancer alone were associated with a loss of oxidative capacity, with a greater reduction when combined. Chemotherapy alone and with cancer caused a shift away from FAO and reduction in TPPC. Though we demonstrated an exercise effect in sham mice, exercise did not increase OxPhos capacity, nor did it ameliorate the effects of cancer and chemotherapy. A more intense exercise intervention may be required. Citation Format: Malcolm Andrew West, Alexandrina Roman, Ronan Astin, Sian Pugh, Bernadette Fernandez, Annette Hayden, Judith Cave, Eleanor Jaynes, John N. Primrose, Sandy Jack, Michael P. Grocott, Andrew Murray, Martin Feelisch, Alexander Mirnezami, Timothy Underwood. Altered skeletal muscle mitochondrial function and redox biology with chemotherapy and exercise in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1488. doi:10.1158/1538-7445.AM2017-1488

EORTC1527/JCOG1609INT: Diffusion-weighted MRI (DW-MRI) assessment of liver metastasis to improve surgical planning (DREAM).

TPS3633 Background: For patients with initially unresectable colorectal liver metastases (CRLM) with good clinical response to chemotherapy, the presence of disappearing liver metastases (DLMs) diagnosed by CT is a major independent prognostic factor. DW-MRI as well as contrast enhanced (CE)-MRI is recommended to detect and characterize CRLM. However, the correlation between radiological and pathological complete response has not been fully investigated using these latest imaging and pathology techniques. Our main aim is to demonstrate the added value of DW-MRI, CE-MRI to that of CT alone to provide precise assessment of the viability of DLMs. In addition, we aim to optimize the therapeutic management of CRLM patients. No prospective study has been conducted to determine the predictive value of DW-MRI combined with CE-MRI in confirming sites of DLMs and assessing their true status. Methods: This is the first collaborative study between EORTC, ESSO and JCOG with an integrated quality assurance program for imaging, surgery and pathology. Patients with unresectable CRLM will receive standard systemic chemotherapy and liver resection if resectable. Both CT and MRI (DW-MRI, CE-MRI and T1/T2) will be used to identify confirmed DLMs (cDLMs). cDLMs will be either resected or, if resection is not possible, followed-up without resection until 2 years after surgery to evaluate the true status of the cDLMs. The primary endpoint is negative predictive value (NPV) of DW-MRI, CE-MRI, T1/T2 and CT in confirming the status of cDLMs using as reference either the histopathological complete response or the absence of a local recurrence at the site of cDLMs during the follow up period of 2 years. The study aims at excluding a NPV≤0.85 and is powered under the alternative that the NPV≥0.95. The planned sample size is 92 evaluable (resected or left behind) cDLMs, with a 1-sided alpha of 5% and a power of 90% adjusting for within-patient correlation between cDLMs of 0.2 and an average number of 2 cDLMs per patient. Approximately 400 patients will be registered from European, Japanese and US sites over 3 years. As of February 2017, 2 patients have been enrolled. Clinical trial information: NCT02781935.