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Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models., Methods/design: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples., Conclusions: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024., Trial Registration: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20., (© 2024. The Author(s).)

Background: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting., Materials and Methods: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [ 18 F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([ 18 F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13., Results: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes., Conclusions: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [ 18 F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics., Competing Interests: Disclosure CC declares personal honoraria for advisory board roles from Bayer. ADS declares personal honoraria for educational activities from Amgen. LA declares personal honoraria for educational activities from Pfizer. EM declares personal honoraria advisory board and speaker roles for Amgen, Bayer, Eisai, Merck Serono, Pierre Fabre, Roche, Servier, Incyte, ESMO; Travel grant: AstraZeneca, Pierre Fabre. FC declares personal honoraria advisor and speaker roles for Roche, Amgen, Merck Serono, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly and institutional research grants from Bayer, Roche, Merck Serono, Amgen, AstraZeneca, Takeda. MCP declares personal honoraria for educational activities from Astellas, AstraZeneca, Pfizer, and institutional grants for support to research activities from AstraZeneca, Bayer, Roche. AA declares personal honoraria for advisory board roles from AstraZeneca, Amgen, MSD, Servier. All other authors have declared no conflicts of interest. Data sharing De-identified individual data might be available after publication upon reasonable request to the corresponding author by presenting a complete research proposal., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: Comparison of first-line FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NabGem) in patients with metastatic pancreatic ductal adenocarcinoma. Patients & methods: The authors analyzed data from 160 patients with metastatic pancreatic adenocarcinoma receiving first-line FFN (n = 43) or NabGem (n = 117). Results: FFN and NabGem were similar in median progression-free survival (24.43 vs 26.28 weeks; hazard ratio [HR]: 0.88) and medial overall survival (47.43 vs 42.86 weeks; HR: 0.90). Of the 43 patients receiving FFN, 26 (60.4%) were treated with second-line NabGem; 14/117 (12.0%) patients receiving NabGem received second-line FFN (p < 0.0001). In the FFN → NabGem and NabGem → FFN groups, median overall survival was 51.2 and 71.6 weeks (HR: 0.69; p = 0.15). In patients receiving NabGem, second-line FFN, compared with FOLFOX/CAPOX or FOLFIRI, improved median progression-free survival 2 (25.6 vs 12.1 weeks; HR: 0.47; p = 0.0067) and median overall survival 2 (39.0 vs 19.14 weeks; HR: 0.49; p = 0.032). Conclusion: First-line FFN and NabGem promote similar clinical outcomes. Second-line FFN should be considered after NabGem.

Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II-III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3-4 side effects. Higher rates of thrombocytosis ( p < 0.0001) and peripheral edema ( p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear., Methods: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes., Results: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks ( p  = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks versus 23.07 weeks) or OS2 (47.86 weeks versus 42.00 weeks). The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups., Conclusion: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated at our institution were retrospectively analysed to reach this goal. The group characteristics were similar: 35 patients were treated with the FOLFIRINOX regimen and 21 patients with Gemcitabine Nab-Paclitaxel. The number of patients undergoing surgery was 14 in the FFN group (40%) and six in the GemNab group (28.6%). The median Disease-Free Survival (DFS) was 77.10 weeks in the FFN group and 58.65 weeks in the Gem Nab group ( p = 0.625), while the median PFS in the unresected group was 49.4 weeks in the FFN group and 30.9 in the GemNab group ( p = 0.0029, 95% CI 0.138-0.862, HR 0.345). The overall survival (OS) in the resected population needs a longer follow up to be completely assessed, while the median overall survival (mOS) in the FFN group was 72.10 weeks and 53.30 weeks for the GemNab group ( p = 0.06) in the unresected population. Surgery is a valuable option for LAPC patients and it is able to induce a relevant survival advantage. FOLFIRINOX and Gem-NabPaclitaxel should be offered as first options to pancreatic cancer patients in the locally advanced setting.

Rationale: Paraneoplastic limbic encephalitis (PLE) is one of the most common causes of neurologic paraneoplastic syndromes, with unclear pathogenesis. While several reports published in the last decades showed the occurrence of PLE in a variety of cancers, only a few cases have been associated with colon cancer., Patient Concerns: In February 2017, a 54-year-old man with clinical history of radically resected colon cancer started first line chemotherapy with FOLFOXIRI plus bevacizumab, after radiological diagnosis of multiple liver and bone metastases. During the third cycle of treatment, the patient developed psychomotor agitation and hallucinations followed by severe consciousness level reduction and cognitive impairment., Diagnoses: Magnetic resonance imaging showed hyperintense signals in both hippocampal areas, insula and right cingulate gyrus on fluid attenuated inversion recovery, diffusion weighted imaging, and T2-weighted images, highly suggestive of limbic encephalitis. Other causes (brain metastases, toxicity of chemotherapeutic agents, and infections) were excluded., Interventions: Empirical immunosuppressive treatment (high-dose immunoglobulins and corticosteroids) was administered and chemotherapy was resumed., Outcomes: A slowly progressive improvement in neurological condition has been observed, even though radiological signs of limbic encephalitis are still evident., Lessons: The present case highlights the complex diagnostic process of PLE, and the lack of a standard treatment. Moreover, the absence of correlation between PLE and tumor progression or tumor burden, and the opportunity of treating underlying neoplasm is discussed.

Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure. Since the role of daily corticosteroids in improving cabazitaxel efficacy or ameliorating its safety profile has not been adequately investigated so far, we compared outcomes of patients receiving cabazitaxel with or without daily corticosteroids in a retrospective single-Institution cohort of mCRPC patients. Patients and methods: Medical records of deceased patients with documented mCRPC treated with cabazitaxel following prior docetaxel between January, 2011 and January, 2017 were reviewed at the single participating center. Patients who were receiving daily doses of systemic corticosteroids other than low dose daily prednisone or prednisolone (<= 10 mg a day) were excluded. The primary end point of this analysis was overall survival (OS). Secondary end-points were exposure to cabazitaxel as well as incidence of grade 3-4 adverse events. Univariable and multivariable Cox proportional hazards regression was used to evaluate prednisone use and other variables as potentially prognostic for overall survival. Results: Overall, among 91 patients, 57 patients received cabazitaxel concurrently with low dose prednisone and 34 patients did not receive concurrent prednisone. The median overall survival of the population was 9.8 months (interquartile range, 9 to 14). Patients receiving prednisone had an overall survival of 9 months (interquartile range, 8 to 12) vs.14 months (interquartile range, 9.4 to 16.7) for patients not treated with prednisone. Approximately 45% of patients had a >30% PSA decline at 12 weeks. Prednisone use was not significantly prognostic for overall survival or PSA decline ≥30% rates on regression analyses. Importantly, a >30% PSA decline at 12, but not at 3, 6, 9 weeks, was prognostic for improved survival at multivariate analysis Conclusions: The data presented here support the hypothesis that omitting daily corticosteroids in cabazitaxel-treated patients has no negative impact on either survival or safety profile. In the large prospective trial CABACARE, cabazitaxel-treated patients will be randomized to receive or not receive daily prednisone. The CABACARE (EudraCT n. 2016-003646-81) study is currently ongoing at University Federico II of Naples and at other multiple participating centers in Italy., Competing Interests: Competing Interests: Carlo Buonerba & Giuseppe Di Lorenzo: Research Support to Institution from Astellas, Sanofi and Quercegen Pharmaceuticals, personal fees from for Sanofi (unrelated to this work) Guru Sonpavde: Grants from Boehringer-Ingelheim, grants from Bayer, grants from Onyx-Amgen, personal fees from Pfizer, personal fees from Genentech, personal fees from Novartis, personal fees from Argos, grants and personal fees from Merck, personal fees from Sanofi, personal fees from Agensys, personal fees from Clinical Care Options, personal fees from Astrazeneca, personal fees from Uptodate, personal fees from Biotheranostics, personal fees from Exelixis, personal fees from Bristol-Myers-Squibb, personal fees from Janssen, personal fees from Amgen, personal fees from Eisai, personal fees from NCCN (National Comprehensive Cancer Network), outside the submitted work.