Non-resectable Patients Research Articles

The Relationship between Treatment Response and Overall Survival in Borderline, Non-Resectable and Resectable Pancreatic Cancer Patients Treated with Neoadjuvant FOLFIRINOX.

Background: The National Comprehensive Cancer Network (NCCN)-recommended treatment for patients with borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) involves a combination of neoadjuvant FOLFIRINOX chemotherapy and the curative surgical resection of the tumor. This study seeks to identify the clinical, radiological, laboratory, and pathologic predictors that can anticipate the oncological outcomes of patients. Methods: In this study, we conducted a retrospective analysis of patients who had undergone curative surgical resection for BRPC, LAPC, or resectable disease with high-risk features after receiving neoadjuvant FOLFIRINOX at two institutions. We evaluated by means of multivariate analysis whether clinical and laboratory response, tumor markers, radiological response, and pathologic tumor response grade correlated with overall survival (OS) and disease-free survival (DFS). Results: The study enrolled a total of 70 patients with BRPC, LAPC, and resectable disease with high-risk features who underwent resection after neoadjuvant FOLFIRINOX. Age above 65 years and fewer than nine cycles of chemotherapy (OR 4.2; 95% CI 1.4-12.0; p-value 0.007); locally advanced tumors after neoadjuvant treatment (NAT) (OR 7.0; 95% CI 1.9-25.7; p-value 0.003); and lymph node disease and histological tumor regression grade 2 and 3 (OR 4.3; 95% CI 0.9-19.2; p-value 0.05) were risk factors linked to adverse OS and DFS. The median OS and DFS were 33 (22-43.9) months and 16.5 (11.3-21.6) months, respectively. Conclusions: Classification as a LA tumor after NAT was the only preoperative radiological factor that predicted adverse survival in patients undergoing curative surgery after NAT. Other clinical, biochemical, and radiological measures of response were not found to predict OS. Patient age, the cumulative administration of more than eight cycles of chemotherapy, and a significant pathological response were associated with better OS. The results of this study are important for treatment decision-making and prognostication in patients with BRPC and LAPC.

Improving the Reliability of Medical Diagnostic Models through Rule-Based Decision Deferral

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and accurate assessment of tumor resectability is crucial for determining appropriate treatment. AI-based models have shown promise in classifying tumor resectability, but reliability concerns have impeded clinical implementation. We propose extending the AI-based VasQNet model for classifying tumor resectability on AI-generated segmentations of computed tomography scans (CTs) to improve the models’ reliability. This extension allows VasQNet to defer decisions when the AI-generated segmentations violate pre-established rules on vascular anatomy, tumor location, and tumor size. We conducted experiments using CTs of (borderline) resectable and non-resectable PDAC patients. We evaluated the performance of the baseline VasQNet and the extended VasQNet with rule-based decision deferral (RBDD) by comparing their classifications to a ground-truth provided by a radiologist, employing agreement as a metric. Our results demonstrate that the extended VasQNet achieved a significantly higher agreement (90%) with the radiologist’s classification than the baseline VasQNet (67%). Notably, 17/31 (54%) deferred decisions would have been incorrect had they not been deferred. Our study demonstrates the effectiveness of RBDD in improving the reliability of clinical diagnostic models through the exemplification of VasQNet. In conclusion, RBDD can enhance the reliability of clinical diagnostics models, facilitating integration into clinical practice. The documented code is available on GitHub (https://github.com/PHAIR-Consortium/Vessel-Involvement-Quantifier).

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

Immune checkpoint inhibition in patients with NRAS mutated and NRAS wild type melanoma: a multicenter Dermatologic Cooperative Oncology Group study on 637 patients from the prospective skin cancer registry ADOREG

BackgroundMelanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Patients and methodsAdvanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. ResultsAmong 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS-mutated (NRASmut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRASmut patients and 41% [95% CI, 35–48] in NRAS-wild type (NRASwt) patients; 2-year OS was 54% [95% CI, 48–61] in NRASmut patients and 57% [95% CI, 50–64] in NRASwt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRASmut patients and 53% [95% CI, 41–67] in NRASwt patients; 2-year OS was 58% [95% CI, 49–70] in NRASmut patients and 62% [95% CI, 51–75] in NRASwt patients). The ORR to anti-PD1 was 35% for NRASwt patients and 26% for NRASmut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (>5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. ConclusionsThe PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRASwt and NRASmut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status.

Abstract 2315: Temporal changes in circulating tumor cells and circulating tumor DNA in patients with resectable pancreatic ductal adenocarcinoma

Abstract Background: Circulating tumor cells (CTCs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA) are minimally invasive biomarkers that carry vital tumor onset, progression, and metastasis information, which is crucial for cancer diagnosis, prognosis, and management. We report here our longitudinal study of these circulating biomarkers in resectable pancreatic ductal adenocarcinoma (PDAC) patients. Although the overall 5-year survival rate of PDAC is low (~6%), truly resectable patients are expected to have better outcomes than non-resectable PDAC patients, especially if liquid biopsy can help guide anticancer treatment selection. Method: We evaluated temporal changes in CTCs, cfDNA, and ctDNA in peripheral blood samples in a cohort of patients with resectable PDAC treated with pre-operative chemotherapy and surgical excision. Five PDAC survivors in complete remission for three years without evidence of disease served as negative controls. Samples of peripheral blood were collected prior to the start of treatment and every two weeks while patients underwent neoadjuvant chemotherapy, followed by surgical excision of the pancreatic tumor. CTCs were enumerated using a previously reported microfluidic device [1] that integrates immunoaffinity-based isolation with size-based filtration, while cfDNA and ctDNA were measured using quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR). Results: Among the initial seven patients who have completed the treatment sequences [2], CTCs were detectable in all patients (100%) at some points during treatment, but only 50% of patients had detectable CTCs before the start of chemotherapy. Median cfDNA concentrations were comparable to those negative controls throughout treatment. Using ddPCR to analyze peripheral blood samples, KRAS mutations were detected in in 71% of patients during anticancer therapy, but only in 29% patients prior to treatment. Overall, the majority of circulating biomarkers (81% for CTCs and 91% for ctDNA) were detected in blood samples collected after the start of neoadjuvant therapy and before surgery. Conclusion: This study suggests that a longitudinal study of circulating biomarkers provides additional data compared to single-point liquid biopsy, and that biologic “release” of biomarkers due to therapy can increase detectability. -Further study is needed to determine the clinical utility of liquid biopsy for resectable PDAC patients. [1] Chen, et al., Angew. Chem. Int. Ed., 58, 2019, 7606-7610. [2] Dopico, et al., Biosensors, 12, 2022, 206. Citation Format: Yang Zhang, Pablo J. Dopico, Minh-Chau N. Le, Zhijie Yang, Youxiang Wang, Sherise C. Rogers, Thomas J. George, Hugh Z. Fan. Temporal changes in circulating tumor cells and circulating tumor DNA in patients with resectable pancreatic ductal adenocarcinoma [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 2315.

New Challenges in the Management of Cholangiocarcinoma: The Role of Liver Transplantation, Locoregional Therapies, and Systemic Therapy.

Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15-35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.

Radiothérapie et immunothérapie : avant, pendant ou après ?

Locally-advanced non-small cell lung cancer (NSCLC) stage III patients, represent one quarter of the whole NSCLC patients at diagnosis. Historical studies and the LACE meta-analysis showed the superiority of concurrent chemo-radiotherapy over sequential radiotherapy with a survival benefit of 5% at five years. The main advance in recent years has been the PACIFIC trial, which compared durvalumab with placebo for one year, after induction chemo-radiotherapy, in non-resectable stage III patients. Maintenance durvalumab survival advantage was obvious, with a median survival of 47.5 months in the experimental arm, compared to 29.1 months in the placebo arm (HR = 0.68), with a median follow-up exceeding 5 years, such survival benefit being absent in patients whose tumor had an oncogenic addictive mutation. Durvalumab association with other immune checkpoint inhibitors (anti CD73, anti NKG2A) appears promising in phase 2 trials, in such maintenance indication, phase 3 results being awaited. Feasibility of chemo-immunotherapy association with concurrent radiotherapy is currently assessed in many preliminary studies, with a specific focus on pulmonary safety. Neo-adjuvant immunotherapy before radio-chemotherapy is less extensively studied, with only fragmentary available data. The improvement or immunotherapy strategies, in association with chemo-radiotherapy in stage III non-resectable NSCLC patients, is thus possible in close future, even though PACIFIC trail results will be difficult to outperform.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

KS05.6.A Oral DNA vaccination targeting VEGFR2 combined with the anti-PD-L1 antibody avelumab in patients with progressive glioblastoma - final results. NCT03750071

Abstract Background Vascular endothelial growth factor receptor (VEGFR)2 overexpression on glioblastoma endothelia serves as a target for VEGFR2 primed T cells using VXM01 DNA vaccine encoding for VEGFR2. VXM01 is delivered in a bacterial Ty21a carrier suitable for oral administration. A previous phase I/II study in 14 patients with progressive glioblastoma showed a positive correlation of of VEGFR2 specific T cells as well as altered intra-tumoral immunity with prolonged overall survival. One partial response was reported with VXM01 alone. The current trial aimed at intensifying the efficacy signal and testing the co-administration of a checkpoint inhibitor. Material and Methods A multicentre, open-label phase I/II study (EudraCT 2017 003076 31) included 28 patients (25 non-resectable, 3 resectable) with progressive glioblastoma after standard chemoradiotherapy. VXM01 was administered on day 1, 3, 5, 7 followed by boostings q4w. Avelumab (800 mg) was given intravenously q2w. Treatment continued up to week 96 followed by a 2-year observation period. Endpoints included safety and tolerability, objective response rate (ORR), clinical response using immune-response assessment in Neurooncology criteria (iRANO), and immunological assays like ELISpot, FACS, and tumor immune biomarkers. Results Treatment with VXM01 106 or 107 CFU plus avelumab was completed in all patients. No treatment-related toxicities were observed. Three partial responses (according to iRANO) with tumor reductions of 58, 81 and 95% to baseline, respectively, were reported in the non-resectable patients (Objective response rate (ORR) was 12% (3/25)). Two of these patients were progression-free &amp;gt; 12 months. Best response in 3 additional non-resectable patients was SD including one patient progression-free &amp;gt; 6 months. In one resected patient, tumor shrinkage of 30% each was observed after initial treatment before resection as well as subsequent to incomplete resection, associated with survival &amp;gt; 18 months, and accompanied by an increase of intratumoral CD8+ T-cells. Conclusion VXM01 in combination with avelumab was safe and produced detectable peripheral VEGFR-2-specific immune responses. Three non-resected patients had an objective response, three more patients experienced best response stable disease. For future studies a patient enrichment strategy based on immune biomarkers might be envisaged.

Tumor-infiltrating neutrophils and peripheral neutrophil-to-lymphocyte ratio conversely predicted the prognosis of patients with non-small cell lung cancer

Increasing evidence indicates that neutrophil-associated prognostic markers, such as, tumor-associated neutrophils (TANs), neutrophil-to-T cell ratio (NTR) and neutrophil-to-lymphocyte ratio (NLR), are strongly correlated with the survival of patients with non-small cell lung cancer (NSCLC). However, either the association or the difference in their predictive efficacies remains unknown. To this aim, we investigated the influence of intratumoural TANs and peripheral NLR on the clinical outcome of NSCLC patients using tumor tissues, peripheral blood indexes, and clinicopathological data of 133 patients diagnosed with NSCLC. Additionally, Kendall correlation analysis was performed to identify the association between TANs and NLR. Our results revealed that intratumoural TANs were effective prognostic factors for favorable overall survival (OS), but were not associated with disease-free survival (DFS) in the subgroup analysis of 84 postoperative patients and progression-free survival (PFS) in 49 non-resectable NSCLC patients. Elevated NTR also indicated favorable prognosis, with high intratumoural NTR being correlated with prolonged OS and high stromal NTR being correlated with prolonged DFS. In contrast, peripheral NLR predicted dismal OS and DFS of patients receiving curative surgery. Furthermore, neither intratumoural nor stromal TANs were found to be associated with NLR, indicating that they were independent inflammatory indexes in predicting the prognosis of NSCLC. In conclusion, we discovered that TANs and NLR independently and oppositely predicted the clinical outcome of NSCLC patients, providing new sights on the role of neutrophil in tumor biology and survival prediction.

Resection and transplantation for hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Treatment of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) has markedly improved in recent years. Liver resection and, for HCC, liver transplantation are essential components of curative treatment in the nonmetastatic stage. In the current S3guideline, the role of the interdisciplinary tumor board is strengthened for the individual therapy decision. Overall, liver transplantation offers the best long-term results in terms of survival and relapse rate for selected patients. For liver resection, the use of minimally invasive resection techniques can significantly reduce perioperative morbidity and mortality compared to open liver surgery, so that it can be used both as acurative therapeutic approach and as part of bridging strategies for liver transplantation. The 5‑year survival rate after liver transplantation in selected, nonresectable patients who fulfil and also those who do not fulfil the Milan criteria is above 70%, compared with about 30% without liver transplantation under locoregional therapy. The following article reports the status of evidence-based surgical therapy for HCC and iCCA based on the recommendations of the current German S3guideline. The differentiated local therapy of HCC in cirrhosis is based on many patient- and tumor-specific factors. In addition to surgical resection, liver transplantation plays an important role as acurative therapy for patients with irresectable HCCs regardless of whether they meet the Milan criteria. For resectable iCCA or HCC without cirrhosis in the nonmetastatic stage, surgical resection represents the treatment of choice.

POSB20 Health Technology Assessment (HTA) of BRAF/MEK Inhibitors in Non-Resectable Metastatic BRAFV600 Melanoma Patients

Today, the orally administered BRAF/MEK inhibitors, Dabrafenib/Trametinib, Encorafenib/Binimetinib and Vemurafenib/Cobimetinib, constitute one of the most frequently prescribed therapeutic regimens for the treatment of non-operable metastatic melanoma with a BRAF-V600 mutation.

Selection Criteria for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy With Special Emphasis on Laparoscopy as an Efficient Tool.

The aim of the study was to assess diagnostic tools implemented in selecting candidates for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with special emphasis on diagnostic laparoscopy. A total of 229 patients underwent laparoscopy between January 2011 and December 2015 with peritoneal carcinomatosis and were analyzed retrospectively to study the role of laparoscopy in selecting patients for CRS and HIPEC. After initial laparoscopy, 101 (44%) of patients underwent CRS and HIPEC with 128 (56%) being aborted. The most prevalent overall exclusion criterion was extensive small bowel disease with a prevalence of 107 (47%) patients. The rate of complete cytoreduction (CCR0 and CCR1) in patients who were deemed initially operable during laparoscopy was 96%. The most prevalent primary tumor site was the stomach with a prevalence of 36,7%. The overall median peritoneal cancer index (PCI) score of the excluded patients were 16.8 and 4.6 in the CRS and HIPEC group. Port-site metastasis was 3.1% and bowel perforation rate 3.0%. Laparoscopy is a proper selection tool in patients with peritoneal metastases for multimodal treatment. Sensitivity for detecting non-resectable patients is high and the morbidity and mortality low.

Rigosertib and Cholangiocarcinoma: A Cell Cycle Affair.

Rigosertib is multi-kinase inhibitor that could represent an interesting therapeutic option for non-resectable patients with cholangiocarcinoma, a very aggressive hepatic cancer with limited effective treatments. The Western blotting technique was used to evaluate alterations in the expression of proteins involved in the regulation of the cell cycle of cholangiocarcinoma EGI-1 cells. Our results show an increase in EMI1 and Cyclin B protein levels after Rigosertib treatment. Moreover, the phosphorylation of CDK1 is significantly reduced by Rigosertib, while PLK1 expression increased after 24 h of treatment and decreased after 48 h. Finally, we evaluated the role of p53. Its levels increase after Rig treatment, and, as shown in the cell viability experiment with the p53 inhibitor Pifithrin, its activity is necessary for the effects of Rigosertib against the cell viability of EGI-1 cells. In conclusion, we hypothesized the mechanism of the action of Rigosertib against cholangiocarcinoma EGI-1 cells, highlighting the importance of proteins involved in the regulation of cell cycles. The CDK1-Cyclin B complex and p53 play an important role, explaining the Block in the G2/M phase of the cell cycle and the effect on cell viability

Surgical or medical strategy for locally-advanced, stage IIIA/B-N2 non-small cell lung cancer: Reproducibility of decision-making at a multidisciplinary tumor board

BackgroundStage IIIA/B-N2 is a very heterogeneous group of patients and accounts for one third of NSCLC at diagnosis. The best treatment strategy is established at a Multidisciplinary Tumor Board (MTB): surgical resection with neoadjuvant or adjuvant therapy versus definitive chemoradiation with immune checkpoint inhibitors consolidation. Despite the crucial role of MTBs in this complex setting, limited data is available regarding its performances and the reproducibility of the decision-making. MethodsUsing a large cohort of IIIA/B-N2 NSCLC patients, we described patient’s characteristics and treatment strategies established at the initial MTB: with a “surgical strategy” group, for potentially resectable disease, and a “medical strategy” group for non-resectable patients. A third group consisted of patients who were not eligible for surgery after neoadjuvant treatment and switched from the surgical to the medical strategy. We randomly selected 30 cases (10 in each of the 3 groups) for a blinded re-discussion at a fictive MTB and analyzed the reproducibility and factors associated with treatment decision. ResultsNinety-seven IIIA/B-N2 NSCLC patients were enrolled between June 2017 and December 2019. The initial MTB opted for a medical or a surgical strategy in 44% and 56% of patients respectively. We identified histology, tumor size and localization, extent of lymph node involvement and the presence of bulky mediastinal nodes as key decision-making factors. Thirteen patients were not eligible for surgical resection after neoadjuvant therapy and switched for a medical strategy. Overall concordance between the initial decision and the re-discussion was 70%. The kappa correlation coefficient was 0.43. Concordance was higher for patients with limited mediastinal node invasion. Survival did not appear to be impacted by conflicting decisions. ConclusionsReproducibility of treatment decision-making for stage IIIA/B-N2 NSCLC patients at a MTB is moderate but does not impact survival.

Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients.

Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established. A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated. Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration. In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours-potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.

In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells.

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.

Mathematical model predicts response to chemotherapy in advanced non-resectable non-small cell lung cancer patients treated with platinum-based doublet.

We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004–2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers.

580P - Quality of life during 1st-line FOLFOXIRI+/- panitumumab in RAS wild-type metastatic colorectal cancer: Results from the randomized VOLFI trial (AIO KRK-0109)

BackgroundThis trial evaluated activity and safety of mFOLFOXIRI + panitumumab (P) vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. Here, we report the quality of life data. MethodsProspective 2:1 randomized, phase II trial comparing mFOLFOXIRI (Ox 85mg/m2, Iri 150mg/m2, 5FU 3000mg/m2 cont. 48h, LV 200mg/m2) + P 6mg/KG (arm A) with FOLFOXIRI (Ox 85mg/m2, Iri 165mg/m2, 5FU 3200mg/m2 cont. 48h, LV 200mg/m2; arm B), both arms q2w. Cohort 1: irresectable mCRC; cohort 2: chance of secondary resection of metastatic lesions. Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), toxicity, quality of life (QoL, QLQ-C30). Between-treatment differences in QoL were assessed from baseline to disease progression, and to discontinuation of 1st-line treatment, using analysis of covariance (ANCOVA). ResultsA total of 96 patients were randomized (63 arm A, 33 arm B). There were significantly higher ORR (87.3% vs. 60.6%, p=0.004), ETS (85.7% vs 60.0%, p=0.01) and DpR (58.9% vs. 40.9%) in the P arm compared to FOLFOXIRI alone. QoL analyses was performed in 51 patients in arm A and 26 patients in arm B. There were no statistically significant differences between treatment arms from baseline to progression or to discontinuation. Although significantly more secondary resections of metastases were achieved in the P arm of cohort 2 (75.0% vs. 36.4%, p=0.05), QoL was not different between cohorts 1 and 2 and the treatment arms, respectively. Toxicity or patient wish as the reason for end of therapy were not different between the treatment arms A and B (12.7% vs. 21.2% and 0% vs 6.1%, respectively). Grade III/IV toxicities were numerically higher in the P arm (81.3% vs. 66.7%). This increase was mainly due to toxicities such as diarrhea (25.0% vs 12.1%), mucositis (9.4 vs. 0%), rash (14.1% vs. 0%), and fatigue (7.8% vs. 0%). ConclusionsmFOLFOXIRI plus P results in significantly higher response rates compared to FOLFOXIRI in RAS wild-type mCRC. Although toxicity was increased, QL reporting was similar in both arms. Therefore, intensive upfront therapy with modified FOLFIRINOX+P represents a valuable treatment option in patients with the need of a highly active 1st-line therapy. Clinical trial identificationNCT01328171. Legal entity responsible for the studyArbeitsgemeinschaft Internistische Onkologie (AIO). FundingAmgen. DisclosureM. Geissler: Honoraria (institution), Advisory / Consultancy: Amgen. D. Modest: Honoraria (institution), Advisory / Consultancy: Amgen. V. Heinemann: Honoraria (institution), Advisory / Consultancy: Amgen. All other authors have declared no conflicts of interest.

Abstract 3767: Characterization of the protumorigenic role of MSLN in peritoneal metastases in pancreatic cancer

Abstract Peritoneal metastases develop in 70-80% of nonresectable patients with pancreatic cancer, and the onset of clinically significant ascites is associated with rapid demise. Mesothelin (MSLN) is a GPI-linked cell-surface glycoprotein expressed in &amp;gt;90% of pancreatic ductal adenocarcinomas (PDAC) but not in healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, multiple therapeutics targeting MSLN have already reached clinic. Overexpression of MSLN has been implicated in increased aggressiveness of PDAC, both in laboratory models and in patients. Here, we have used CRISPR-Cas9 gene editing to delete MSLN from the KLM-1 pancreatic cancer cell line (MSLN KO) and have examined the growth of these cells in culture and in nude mice compared to mock deleted cells (WT). The cells were also transduced to express GFP/Luciferase(Luc) in order to allow for monitoring of tumor by bioluminescence imaging (BLI) in the mouse intraperitoneal (IP) cavity. MSLN KO and WT cells grew at the same rate in culture and as subcutaneous xenografts in nude mice. But when cells were inoculated IP, KO cells grew poorly compared to WT cells or did not grow at all. When MSLN KO cells grew, visible tumors were located primarily at the inoculation site. In contrast, WT cells grew extensive metastases throughout the IP cavity. GFP/Luc+ tumor cells adhered to the mesothelial lining of the peritoneum could be detected by BLI and histology as early as 24h post IP injections. By 72h, the MSLN KO tumors had significantly decreased microvascular density as determined by CD31 staining, lower metastatic dissemination and growth as detected by BLI and H&amp;E staining, and decreased proliferation as determined by Ki67 quantification. These differences were maintained even at timepoints out to 2 weeks. Our results suggest that MSLN might enhance peritoneal carcinomatosis of PDAC by positively regulating vascular remodeling/angiogenesis and tumor cell proliferation within the IP cavity. The mechanism of MSLN action has been previously ascribed to activation of MAPK or NF-kB pathways or signaling through MUC16, the only known binding partner of MSLN. However, we found no changes in phosphorylated p38 or ERK, nor in total levels of the NF-kB target OCT-2 upon KO of MSLN expression. Since we also observed protumorigenic effect of MSLN in a MUC16 deficient pancreatic cancer cell line, it is unlikely that MUC16 is responsible for the protumorigenic activity of MSLN. We are currently performing comprehensive molecular studies to uncover key upstream and downstream signaling factors responsible for the protumorigenic effects of MSLN in peritoneal dissemination. Citation Format: Leela Rani Avula, Michael Rudloff, Salma El-Behaedi, Danielle Arons, Xianyu Zhang, Christine Alewine. Characterization of the protumorigenic role of MSLN in peritoneal metastases in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3767.

Final results and OS of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer (mCRC).

3511 Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.