Search Results (34)

Background: Pancreatic cancer (PC) is a refractory malignancy with a dismal prognosis. For unresectable PC, gemcitabine plus nab-paclitaxel (GnP) is widely used as first-line chemotherapy. During treatment, patients may require unplanned hospitalization (UPH) due to tumor progression, biliary obstruction, or chemotherapy-related adverse events. Although UPH during chemotherapy may be linked to poorer survival, its prognostic impact as a time-dependent clinical event during active treatment has not been empirically evaluated in unresectable PC. We investigated the prognostic impact of UPH occurring during first-line GnP therapy. Objective: To clarify the association between UPH during first-line GnP and overall survival (OS). Methods: We retrospectively analyzed 189 patients with histologically confirmed unresectable PC who received first-line GnP at our institution between February 2016 and February 2023. The occurrence of UPH during GnP and the reason for the first UPH were categorized. Associations with OS were assessed using the Kaplan–Meier method and Cox proportional hazards models, including a time-varying covariate (TVC) analysis. Risk factors for UPH were examined with logistic regression. Results: UPH occurred in 76 patients (40.2%) during GnP. Pancreatic head tumors and pre-treatment biliary drainage were significantly more frequent in the UPH group. Median OS was 10.88 months in the UPH group versus 19.23 months in the non-UPH group; UPH was a significant adverse prognostic factor (hazard ratio [HR] 1.97, p < 0.01). In multivariable analysis incorporating a TVC, UPH remained an independent predictor of worse prognosis (HR 3.02, p < 0.01). Reasons for first UPH were progression (n = 28), recurrent biliary obstruction (RBO; n = 26), GnP-related adverse event (AE; n = 16), and other (n = 6). Hospitalization due to progression or RBO was associated with poorer survival. Pancreatic head location was identified as a risk factor for UPH. Conclusions: UPH during first-line GnP is an independent adverse prognostic factor in patients with unresectable PC, even after accounting for TVC. In pancreatic head cancer, closer monitoring for biliary and obstructive complications may be particularly important during treatment. Full article

Background: In patients with curatively resected pancreatic adenocarcinoma who have undergone neoadjuvant chemotherapy (NACT), evidence supporting the benefit of additional adjuvant chemotherapy (ACT) remains limited. We aim to identify favorable factors contributing to survival benefits in resected pancreatic adenocarcinoma after NACT. Methods: This is a retrospective cohort study of pancreatic adenocarcinoma patients who underwent NACT followed by curative surgical resection between 2008 and 2023 at a single academic institution. Univariate and multivariable analyses were conducted to identify factors contributing to disease-free survival (DFS) and overall survival (OS). Results: A total of 230 patients with a median age of 68 years (IQR, 62–72 years) were included. All patients underwent curative surgical resection. Of these, 42% received neoadjuvant modified (m) FOLFIRINOX (96/230), 15% received gemcitabine plus nab-paclitaxel (GEM-NAB) (34/230), and 43% received gemcitabine, docetaxel, and capecitabine (GTX) (100/230). In univariate analysis, lower College of American Pathologists (CAP) tumor regression grade (TRG) (0–1 vs. 2–3, median DFS: 29.8 vs. 14.2 months, p = 0.0081) and receipt of ACT (Yes vs. No, median DFS: 22.2 vs. 12.4 months, p < 0.0001) demonstrated significant associations with superior DFS. Multivariable analysis identified receipt of ACT as an independent predictor of superior DFS (HR 0.55, 95% CI: 0.39–0.78, p = 0.0007) and OS (HR 0.49, 95% CI: 0.33–0.71, p = 0.0002). However, the NACT regimen (mFOLFIRINOX vs. GEM-NAB) and the transition between neoadjuvant and adjuvant therapy (de-escalation vs. continuation vs. change) did not correlate with DFS or OS. The duration of perioperative chemotherapy showed a trend toward improved survival outcomes, though not statistically significant (6 months vs. <6 months: DFS, 19.4 vs. 16.2 months, p = 0.1448; OS, 49.6 vs. 30.4 months, p = 0.0623). In the following subgroup analyses, receipt of ACT provided DFS/OS benefits in patients who did not achieve a major pathologic response, pN0, or R0 resection (DFS: p = 0.0003; OS: p < 0.0001). However, it did not provide DFS/OS benefits in those who achieved a major pathologic response with pN0/R0 to NACT (DFS: p = 0.8036; OS: p = 0.1877). Conclusions: In resected pancreatic adenocarcinoma following NACT, receiving ACT was associated with favorable survival outcomes. Additional ACT appears to benefit patients who did not achieve a major pathologic response (pN0 or R0) to neoadjuvant therapy, with limited benefit for those who achieved a major response with pN0/R0. The specific NACT regimen (mFOLFIRINOX vs. GEM-NAB) and changes in ACT from NACT did not significantly influence survival outcomes in our cohort. Full article

Background/Objectives: This nationwide population-based study investigated the overall survival (OS) of patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy. Methods: Data from the National Health Insurance Service linked to the Korea Central Cancer Registry were used. Patients with mPC receiving first-line chemotherapy (2012–2019) were included and followed up until 2020. The gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX groups were matched according to age, sex, and comorbidities. Results: In total, 8652 patients with mPC were treated with chemotherapy. GnP and FOLFIRINOX have been administered since 2016 and 2017, respectively. The median OS increased annually from 6 months in 2012–2013 to 10 months in 2018–2019. The median OSs in the GnP and FOLFIRINOX groups were significantly longer than those in patients receiving gemcitabine ± erlotinib. A total of 1134 patients from both the GnP and FOLFIRINOX groups were selected using propensity score matching. Before matching, the median OS was longer in the FOLFIRINOX group than in the GnP group (p = 0.0029). After matching, however, there was no significant difference in the median OS between the two groups (11 vs. 11 months, respectively, p = 0.2438). Conclusions: Patients with mPC receiving chemotherapy have shown improved OS since the introduction of GnP and FOLFIRINOX. After matching, OS did not differ between the GnP and FOLFIRINOX groups. Full article

The novel Oxathiazinane derivative GP-2250 (Misetionamide) displays antineoplastic activity in vitro and in vivo, as previously shown in pancreatic cancer cells and in patient-derived mouse xenografts (PDX). Currently, GP 2250 is under phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC). GP-2250 in combination with Gemcitabine displays a high synergistic capacity in various primary and established pancreatic cancer cell lines. Additionally, in the eight PDX models tested, the drug combination was superior in reducing tumor volume with an aggregate tumor regression (ATR) of 74% compared to Gemcitabine alone (ATR: 10%). Similarly, in a PDX maintenance setting following two weeks of treatment with nab-Paclitaxel plus Gemcitabine, the combination of GP-2250 plus Gemcitabine resulted in outstanding tumor control (ATR: 79%) compared to treatment with Gemcitabine alone (ATR: 60%). Furthermore, GP-2250 reduced the ratio of tumor-initiating CD133⁺ markers on the surface of PDAC cells in spheroid cultures, indicating a possible mechanism for the synergistic effect of both substances. Considering the high tolerability of GP 2250, these results may open up a new approach to maintenance therapy with GP-2250/Gemcitabine combination following nab-Paclitaxel plus Gemcitabine as first-line treatment. Full article

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals. Full article

Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1β. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC. Full article

Pancreatic cancer (PC) is one of the most lethal tumors in Europe with an overall 5-year survival rate of 5%. Since 1992, gemcitabine (Gem) has been the treatment of choice for metastatic disease with significant improvement in median overall survival (OS) compared to fluorouracil. A good performance status (PS) at diagnosis appears to be a strong predictive factor for better survival. Overall, 50% of PC are metastatic or locally advanced at diagnosis, and more than 70% of the resected patients will experience a recurrence, with a median OS ranging from 4 to 10 months (mos). FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and Nab-paclitaxel (Nab-p) plus Gem have recently increased survival of patients with metastatic PC, over Gem. Treatment with FOLFIRINOX is generally considered more effective with respect to the doublet, with toxicity concerns, FOLFIRINOX achieves an overall response rate (ORR) of 31.6%, while for Nab-p plus Gem ORR is 23%; however, FOLFIRINOX was associated with higher rates of grade 3 and higher adverse events. Although the international guidelines indicate that both regimens can be used as first-line therapy for patients with metastatic PC, FOLFIRINOX is the most widely used; Nab-p plus Gem is more frequently used in patients with lower PS. In this review, we critically analyze these two regimens to give a pragmatic guide to treatment options. Full article

Outcomes and prognostic factors of second-line gemcitabine plus nab-paclitaxel (GnP) after modified FOLFIRINOX (mFFX) for unresectable pancreatic cancer were unclear. We retrospectively analyzed consecutive patients with unresectable pancreatic cancer treated with GnP after first-line mFFX treatment between March 2015 and March 2022 at our hospital. A total of 103 patients were included. Median overall survival (OS) from the start of first-line and second-line treatments was 14.9 months and 7.2 months, respectively. Median progression-free survival (PFS) was 3.6 months. Performance status, modified Glasgow prognostic score, and neutrophil-to-lymphocyte ratio were independently associated with OS. Our prognostic model using these parameters classifies patients into good (n = 70) and poor (n = 33) prognosis groups. Median OS and PFS were longer in the good prognosis group than in the poor prognosis group (OS: 9.3 vs. 3.8 months, p < 0.01; PFS: 4.1 vs. 2.3 months, p < 0.01). Grade 3/4 adverse events were observed in 70.9% of patients, with neutropenia being the most frequent. While GnP as second-line treatment was well-tolerated, efficacy of second-line gemcitabine plus nab-paclitaxel was notably limited, particularly in the poor prognosis group. Full article

Survival remains poor even after resection of pancreatic cancer and the postoperative recurrence rate is extremely high. Thus, neoadjuvant treatment may improve outcomes for resectable pancreatic cancer (RPC). This study evaluated the efficacy of neoadjuvant therapy for radiologically judged RPC. A prospectively maintained institutional database was reviewed to identify patients who underwent potentially curative resection of radiologically judged RPC. Patient characteristics and intermediate-term outcomes were compared between groups that received neoadjuvant treatment or upfront surgery (UFS). We identified 353 eligible patients, including 55 patients who received neoadjuvant chemoradiotherapy (CRT group), 53 patients who received neoadjuvant gemcitabine plus nab-paclitaxel (GnP group), and 245 patients who underwent UFS (UFS group). The cumulative rates of pancreatic cancer recurrence at 2 years after pancreatic surgery were 49.5% in the UFS, 48.1% in the CRT group, and 52.7% in the GnP group. The recurrence rate tended to be improved after neoadjuvant treatment, although the difference was not significant at this follow-up point. While the clinical TNM classifications were noticeably different from the final pathological findings, the clinical and pathological TNM classifications were more similar in the groups that underwent neoadjuvant treatment. Neoadjuvant treatment can help identify good surgical candidates and avoid unnecessary laparotomy. Our results also suggest that neoadjuvant therapy might help improve the preoperative diagnostic accuracy for patients with RPC. Full article

Modified FOLFIRINOX (mFFX) and Gemcitabine plus nab-paclitaxel (GnP) are effective first-line chemotherapies for unresectable advanced pancreatic cancer (APC); however, both lead to peripheral neuropathy (PN). Aims: To evaluate the impact of first-line mFFX-induced PN on the efficacy of second-line GnP in patients with APC. Methods: A database containing patients with APC was retrospectively analyzed to evaluate patients who received second-line GnP after first-line mFFX failure between September 2014 and January 2021. The efficacy and safety of GnP were compared between patients with PN ≥ Grade 2 (PN group) and PN ≤ Grade 1 (non-PN group) at the start of second-line GnP. Cox proportional hazards analysis was also performed to examine the effect on overall survival (OS) and time-to-treatment failure (TTF). Results: Fifty-nine patients (PN group, 18 patients; non-PN group, 41 patients) were included. Median OS and TTF in the PN versus non-PN group were 7.7 versus 5.7 months (p = 0.19) and 3.8 versus 2.7 months (p = 0.18), respectively. Multivariate analysis showed that PN (≥Grade 2) was not a significant factor affecting either OS (hazard ratio (HR) 0.66, 95% confidence interval [CI] 0.33–1.31, p = 0.24) or TTF (HR 0.71, 95% CI 0.38–1.33, p = 0.28). No significant difference was observed in the relative dose intensity of GEM or nab-PTX, and incidence of adverse events. Conclusions: mFFX-induced PN has little impact on the efficacy and safety of second-line GnP in patients with APC. Second-line GnP could be a possible treatment option regardless of the presence of PN. Full article

Background: Gemcitabine/nab-paclitaxel therapy (GnP) is widely used to treat pancreatic cancer (PC), but chemotherapy-induced peripheral neuropathy (CIPN) is common. The CIPN is also reported to be related by microvascular damage as the basis for toxic neuropathy. However, no sufficient treatment options are available for CIPN. Mirogabalin is a novel drug for treating peripheral neuropathy. We investigated the effects of mirogabalin on CIPN due to GnP. Methods: Patients who had received GnP for PC and had taken mirogabalin for CIPN, were included. Patients completed a questionnaire about their symptoms before and after taking mirogabalin. The outcome was the change in numbness and tingling scores on the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Chemotherapy-Induced Peripheral Neuropathy (EORTC-QLQ-CIPN20), numerical rating scale, and adverse events (AEs). Results: Increased numbness and tingling severity (1.84 vs. 1.76; p = 0.63) and interference (1.42 vs. 1.44; p = 0.80) were not seen in any of the 25 enrolled patients. The scores on the sensory subscale of the EORTC-QLQ-CIPN improved significantly after treatment (17.5 vs. 15.7; p = 0.02). Adverse events occurred in 22 patients (88%), but there were no serious AEs (≥grade 3). Conclusions: Mirogabalin may control the progression of CIPN caused by GnP and significantly improved sensory neuropathy. However, as the incidence of AEs is high, mirogabalin should be used with caution. (UMIN:R000044039). Full article

Salvage chemotherapy for patients with unresectable pancreatic cancer (UR-PC) who have been treated with gemcitabine and nab-paclitaxel (GnP), and 5-fluorouracil (5-FU)/l-leucovorin (LV) plus nanoliposomal irinotecan (nal-IRI), has not been fully established. We retrospectively reviewed data from 17 patients with UR-PC who initiated 5-FU/l-LV plus oxaliplatin (FOLFOX) as salvage chemotherapy at our hospital between June 2020 and August 2021, after treatment with GnP and 5-FU/LV plus nal-IRI. The primary endpoint was tumor response. The secondary endpoints were progression-free survival (PFS) and adverse events (AEs). The response and disease control rates were 5.9% (1/17) and 17.6% (3/17), respectively. The median PFS was 1.8 months (range: 0.4–5.2 months). Eight patients (47.1%) experienced grade 3 nonhematologic AEs, while none experienced grade 3 hematologic AEs. Two patients with controlled disease had homologous recombination deficiency (HRD)-associated gene mutations in cancer panel testing. The FOLFOX regimen benefit for UR-PC patients treated with GnP and 5-FU/LV plus nal-IRI may be limited to patients with HRD-associated gene mutations. Full article

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. Full article

An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients with UR-LAPC. This was a retrospective study of 63 consecutive patients with UR-LAPC treated at our department in a Japanese cancer referral center between February 2015 and July 2018. We excluded patients who underwent other regimens and those enrolled in another prospective study. The CRT group (n = 25) exhibited significantly better progression-free survival (PFS) and overall survival (OS) than the CTx group (n = 20, PFS 17.9 vs. 7.6 months, p = 0.044; OS 29.2 vs. 17.4 months, p < 0.001). In the multivariate analyses, CRT following induction chemotherapy was identified as an independent prognostic factor for OS. Seven (15.6%) patients underwent conversion surgery, all of whom were in the CRT group. The R0 resection rate was 85.7% (6/7). In summary, patients with UR-LAPC experienced favorable treatment outcomes after receiving GnP as the first-line chemotherapy, especially when receiving additional CRT. Thus, this treatment strategy represents a promising treatment option for selected patients with UR-LAPC. Full article

Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5–77%) and neuropathy (range 0–22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials. Full article