Gemcitabine Monotherapy Research Articles

Gemcitabine/nab-paclitaxel in first line treatment of advanced pancreatic cancer - head-to-head comparison with the mFOLFIRINOX regimen.

Metastatic pancreatic ductal carcinoma (mPDAC) is one of the most lethal malignancies. The European Society for Medical Oncology (ESMO) guidelines recommend a gemcitabine doublet + nab-paclitaxel (Gem/Nab-P) or a modified FOLFIRINOX regimen (mFOLFIRINOX) as options for systemic chemotherapy. Gemcitabine monotherapy is an option for patients in a worse performance status (PS). Indirect comparisons of pivotal trials with Gem/Nab-P and mFOLFIRINOX vs. gemcitabine monotherapy (PRODIGE-4 and MPACT) indicated longer overall survival (OS) in patients treated with mFOLFIRINOX. However, it should be taken into account that the MPACT study with Gem/Nab-P included patients with an overall worse performance status. A direct comparison of these chemotherapy regimens was lacking. Indirect comparisons from real practice show their comparable effectiveness in terms of OS, progression-free survival and overall response rate. The safety profile is consistently different. The recently published phase II/III GENERATE trial, which directly compared Gem/Nab-P and mFOLFIRINOX in treatment-naïve mPDAC patients, demonstrated significantly longer OS in Gem/Nab-P-treated patients exceeding 17 months with a lower incidence of non-hematologic toxicity. The results sparked a lively discussion at the ESMO 2023 Congress. The comparison of Gem/Nab-P and mFOLFIRINOX was also addressed by prof. Prager in his presentation at the PragueONCO 2024 conference. Prager, who highlighted comparable efficacy of both regimens and better safety of Gem/Nab-P and demonstrated the benefit of Gem/Nab-P also in patients older than 70 years and those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. It should also be taken into account that the choice of first line treatment determines the therapeutic options in the 2nd line. If the Gem/Nab-P regimen is used in the first line, pegylated liposomal irinotecan (nal-IRI) in combination with 5-fluorouracil and leucovorin (5-FU/LV) can be used in the second line. This regimen demonstrated prolongation of OS compared to 5-FU/LV in phase III study NAPOLI-1. In patients pretreated with the mFOLFIRINOX regimen, gemcitabine monotherapy or Gem/Nab-P can be used in the second line. Early examination of molecular predictive parameters will enable the identification of cases for which appropriate targeted therapy or immunotherapy is available.

Efficacy and safety of apatinib in the treatment of patients with platinum‑resistant ovarian cancer: A systematic review and network meta‑analysis.

At present, the optimal therapeutic approach for the treatment of platinum-resistant recurrent ovarian cancer remains to be fully elucidated. The present systematic review and network meta-analysis aimed to elucidate the relative efficacy and safety of apatinib, administered either as monotherapy or in conjunction with chemotherapy, compared with chemotherapy alone, for the treatment of platinum-resistant recurrent ovarian cancer. The PubMed, Embase and Wanfang Data electronic databases were searched, where the search spanned from the conception of the databases until April 2023. A quality evaluation was conducted and R software was used for network meta-analysis. Following inclusion and exclusion criteria screening, the present analysis included 17 clinical trials, combining data from 1,228 patients with platinum-resistant recurrent ovarian cancer categorized into the following three treatment cohorts: i) 555 patients who received apatinib plus chemotherapy; ii) 229 patients who received apatinib alone; and iii) 444 patients who underwent conventional chemotherapy. Results of the present study demonstrated that the co-administration of apatinib with either tegiol [odds ratio (OR), 2.54; 95% CI, 1.06-6.11] or etoposide (OR, 2.12; 95% CI, 1.20-3.74) significantly improved the objective response rate (ORR) compared with that following apatinib monotherapy. By contrast, gemcitabine monotherapy resulted in inferior ORR efficacy compared with that following apatinib (OR, 0.47; 95% CI, 0.23-0.95). In addition, combinations of apatinib with etoposide (OR, 1.32; 95% CI, 1.06-1.64) or paclitaxel (OR, 1.52; 95% CI, 1.04-2.23) demonstrated a significantly improved disease control rates (DCR) compared with those following apatinib alone. According to the area under the cumulative ranking analysis, apatinib and paclitaxel in combination was the most efficacious treatment modality in terms of DCR. In terms of safety, the incidence of adverse events, such as hand-foot syndrome [relative risk (RR), 4.23; 95% CI, 1.80-9.95] and hypertension (RR, 4.80; 95% CI, 1.53-15.05), was found to be significantly higher in patients treated with apatinib-containing therapies, compared with those treated with chemotherapy alone. Consequently, the present meta-analysis highlighted the potential of apatinib, particularly in combination with chemotherapy, as a therapeutic strategy for patients with platinum-resistant recurrent ovarian cancer.

Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma: a real-world study.

Little progress has been made in recent years using first-line chemotherapy, including gemcitabine combined with nab-paclitaxel, FOLFIRINOX, and NALIRIFOX, for advanced pancreatic adenocarcinoma (APC). In addition, the optimal second-line chemotherapy regimen has not been determined. This study aimed to compare the effectiveness of different types of second-line chemotherapy for APC. Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil- and gemcitabine-based chemotherapy as first-line treatment, respectively. Demographic and clinical features, except age and liver metastasis, were comparable between the two groups (P < 0.05). The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil- and gemcitabine-based combined regimen for first-line therapy, respectively (HR = 1.244, 95% CI = 1.090-1.419; P < 0.001). The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care, respectively (HR = 0.766, 95% CI = 0.677-0.867; P < 0.001). The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination therapy. A 5-fluorouracil- or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

Adjuvant 5-fluorouracil and portal vein infusion chemotherapy followed by gemcitabine for pancreatic cancer.

Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. 5-fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were OS and treatment completion. Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1-, 3-, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1-, 3-, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

A durable response to gemcitabine monotherapy in metastatic cardiac angiosarcoma

Introduction: Primary cardiac angiosarcoma is a rare neoplasm with high rates of local recurrence and distant metastasis for which optimum treatment is poorly defined. Case Report: We present the case of a 49-year-old man with cardiac angiosarcoma with distant metastases who exhibits durable response to gemcitabine monotherapy. At initial diagnosis, he underwent complete resection with adjuvant Adriamycin and Ifosfamide for four cycles as well as external beam radiation for possible residual disease. He had recurrence with liver and bone metastases four years later. He received Gemcitabine and Docetaxel for six cycles followed by Gemcitabine monotherapy with no evidence of recurrence for the next three years. Conclusion: This patient’s consistent response to gemcitabine maintenance therapy in metastatic cardiac angiosarcoma adds to relative paucity of data regarding the management of this rare malignancy, offering insight into best practice and hope for patients afflicted with this disease.

Efficacy and safety of different chemotherapy regimens in patients with disseminated pancreatic cancer over 65 years old

Aim. To evaluate the effectiveness and tolerability of systemic chemotherapy in elderly patients with metastatic pancreatic cancer (mPC) in real clinical practice.Materials and methods. The study included patients with mPC over 65 years of age who received first-line chemotherapy at the N. N. Blokhin National Medical Research Center of Oncology for the period from 2004 to 2023. Any previous antitumor chemotherapy for mPC was an exclusion criterion. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were ORR, median progression-free survival, median OS, chemotherapy tolerability.Results. The study included 148 patients aged 65 to 86 years with mPC who received first-line chemotherapy. Median progression-free survival among the entire population was 5.2 months. One-year OS among all patients was 32 %. The 1-year OS in mFOLFIRINOX group was 43.4 % and in gemcitabine group – 19.6 %. In a subgroup analysis, median OS with combination treatment was higher than in the gemcitabine monotherapy group (median OS 8.4 months vs. 6.8 months, p = 0.009). Patients with ECOG 2–3 also benefited from combination chemotherapy. Median OS was 8.9 months versus 3.9 months in gemcitabine (p = 0.008). The frequency of an objective response with triple chemotherapy was 66.1 %. In 30.8 % of cases, grade 3–4 neutropenia developed with mFOLFIRINOX, but febrile neutropenia developed only in three patients (5.8 %). The incidence of grade 3–4 adverse events was low, and these chemotherapy regimens were well tolerated.Conclusion. Conducting a triple chemotherapy regimen in elderly patients with mPC is an effective treatment option with an acceptable range of toxicity.

First-line treatment patterns among patients with metastatic pancreatic ductal adenocarcinoma in the real-world setting.

e16320 Background: Treatment options for patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) have historically been limited. FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) are both recommended first line (1L) treatments that have shown efficacy vs. gemcitabine monotherapy in clinical trials. More recently, small subgroups of pts have benefitted from regimens that include irinotecan liposome injection, targeted therapies, and checkpoint inhibitors (CPIs). To better understand treatment patterns in current practice, we examined the distribution of 1L therapies in a RW cohort of mPDAC pts diagnosed between 2015 and 2022. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated 1L treatment within 90 days of their diagnosis for metastatic disease were included in the study. Regimens were grouped into the following categories: FFX, GnP, gemcitabine monotherapy, FOLFOX, FOLFIRI, capecitabine/5-FU monotherapy, irinotecan liposome injection-containing regimens, CPI monotherapy, PARP inhibitors and other targeted therapy-containing regimens, no 1L, and other regimens (comprised of combinations of FFX and GnP components as well as other chemotherapeutic agents). Results: Of the 5,358 pts eligible for inclusion in the study, the majority received GnP (33%, 1,785 pts) or FFX (23%, 1,254 pts) in 1L. The next largest segment of pts did not receive 1L therapy (23%, 1,229 pts). Just 6% (345 pts) received gemcitabine monotherapy. The remaining 14% of pts received therapies other than the three primary 1L mPDAC treatments: 4% (207 pts) received FOLFOX, 2% (109 pts) received capecitabine/5-FU monotherapy, 2% (96 pts) received an irinotecan liposome injection-containing regimen, 0.7% (39 pts) received FOLFIRI, 0.5% (28 pts) received CPI monotherapy, and 0.5% (26 pts) received PARP inhibitors or other targeted therapies. 4% (240 pts) received various other chemotherapy combinations (comprised of combinations of FFX and GnP components and a small number of other chemotherapeutic agents, with ≤40 pts per combination). FFX pts were the youngest, with a mean age of 64yrs, compared to 70yrs for gemcitabine + nab-paclitaxel (p &lt; .001). Gemcitabine monotherapy pts were the oldest (mean = 73yrs, p &lt; .001 vs. GnP) and were more likely to have metastatic disease and an ECOG ≥2 (p &lt; .001 vs. GnP). Conclusions: There are limited 1L treatment options for mPDAC. Since the and PRODIGE and MPACT trials, FFX, GnP, or gemcitabine monotherapy have been the primary recommended 1L treatments for most pts with mPDAC. While recent years have seen an increase in the availability of targeted and CPI therapies appropriate for small subgroups of mPDAC pts, in a RW sample, almost all pts received one of the three standard therapies.

Therapeutic Outcome of Multidisciplinary Treatment in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Analysis.

There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.

Experience of seven Spanish centres with echoendoscopically implanted 32P microparticles associated with chemotherapy in locally advanced pancreatic adenocarcinoma.

e16358 Background: 32P brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in locally advanced pancreatic cancer (LAPC). The device to implant it is approved in unresectable LAPC in combination with gemcitabine-based chemotherapy. Our aim is to present the preliminary efficacy and safety results of a series that brings together the experience of seven centres in Spain. Methods: After being assessed by a multidisciplinary committee and meeting eligibility criteria (Table 1), patients signed consent to receive intratumoural 32P by EUS within the international observational registry OSPREY (March 2022-February 2024). Complications associated with intratumoural 32P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS], distant and locoregional, and overall survival [OS]) were analysed. Results: Thirteen patients (7 females; age 65 years [range 48, 79]; 10 ECOG 1) with unresectable LAPC (7 in head, 3 in uncinate and 3 in body; tumour size 36.8 mm [range 25, 60]) were included. The median time from tumour diagnosis to procedure was 5 months [1.4, 28.9]. Only 4 patients (30 %) had received a previous line of treatment. Eleven patients (85%) received gemcitabine-based chemotherapy concomitant with intratumoural 32P (8 gemcitabine plus nabpaclitaxel; 3 gemcitabine monotherapy). There were no complications or AEs related to 32P injection or EUS. A total of 7 patients (54%) had chemotherapy-related AEs, with 2 cases of G3 neutropenia; 6 had G1-2 toxicities: neutropenia (1), thrombopenia (2), anaemia (1), nausea (1), asthenia (1), diarrhoea (1) and constipation (1). Two patients underwent surgery after intratumoural treatment. With a median follow-up of 17.3 months after injection, 8 patients (61.5 %) have progressed, all of them distantly, and three also locoregionally. The median PFS since 32P injection is 8.4 months (95% CI 2.7, NR). Six patients are alive at the end of follow-up (46.2 %) with a median OS since 32P injection of 13.8 months 95% CI [10, NR]. At data cut-off, five patients remain on-treatment. Conclusions: Our initial experience suggests that intratumoural 32P associated with gemcitabine-based chemotherapy is safe. Patients after 32P injection achieve long overall survival. Our ongoing prospective registry will allow evaluation of the oncological outcomes of this therapy at longer follow-up times. [Table: see text]

Real-world evidence of systemic treatment practices for biliary tract cancer in Japan: Results of a database study.

To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan. Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed. The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days. These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy.

Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p=.007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p=.019). Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

A Retrospective Study of Gemcitabine Plus Nab-Paclitaxel for Advanced Pancreatic Cancer Refractory to Gemcitabine Monotherapy.

This study aimed to investigate the efficacy and safety of gemcitabine (GEM) plus nab-paclitaxel (nab-PTX), termed GnP, which is limited, in patients with advanced pancreatic cancer (PC) who show good tolerance to GEM monotherapy prior to being refractory to it. We retrospectively analyzed the data of patients with locally advanced or metastatic PC who received GEM followed by GnP between December 2014 and March 2019, regardless of the treatment line. A total of 14 patients who received GnP after becoming refractory to GEM were included in this study. Eight patients were included in the nab-PTX-naïve group, seven of whom were treated with GEM monotherapy as first-line chemotherapy, and one was refractory to GEM monotherapy after modified FOLFIRINOX treatment. The other six patients were included in the nab-PTX reintroduction group. In this group, all patients received GnP followed by GEM maintenance therapy to prevent adverse events, such as peripheral neuropathy and fatigue. Two patients in the nab-PTX-naïve group showed partial response and none in the reintroduction group; median progression-free survival was 7.6 and 1.4 months and median overall survival was 9.4 and 6.2 months, respectively. In the safety analysis, grade 3 anemia and peripheral neuropathy were observed in one patient in the nab-PTX reintroduction group, while the remaining adverse events were of grade 1 or 2. GnP is safe and effective even in patients with GEM-refractory PC, and GEM treatment followed by GnP can be an effective treatment option for patients with nab-PTX-naïve PC.

Pancreatic adenocarcinoma third line systemic treatments: a retrospective cohort study

BackgroundChemotherapy for metastatic pancreatic adenocarcinoma (PDAC) primarily relies on FOLFIRINOX (LV5FU- irinotecan – Oxaliplatine) and Gemcitabine – Nab-Paclitaxel in the first-line setting. However, second-lines remain less well-defined and there is limited data regarding third-line treatments. The objective of our study was to determine the proportion of patients advancing to third line chemotherapy, to outline the various third-line chemotherapy regimens used in routine practice and to evaluate their respective efficacy.MethodsA retrospective single-center cohort from 2010-2022 compiled baseline characteristics, treatment outcomes and survival of PDAC patients who received at least one chemotherapy line in a French tertiary-center. Overall survivals (OS) were analyzed using a Cox multivariable model.ResultsIn total, 676 patients were included, with a median follow-up time of 69.4 months, (Interquartile Range (IQR) = 72.1). Of these, 251 patients (37%) that proceeded to 3rd-line chemotherapy. The median PFS in 3rd line was 2.03 months, [CI95%: 1.83, 2.36]. The median 3rd line overall survival was 5.5 months, [CI95%: 4.8, 6.3]. In multivariable analysis erlotinib-based chemotherapy was found to be deleterious (HR=2.38, [CI95%: 1.30, 4.34], p=0.005) compared to fluoropyrimidine-based chemotherapy in terms of 3rd line overall survival while gemcitabine monotherapy showed a tendency towards negative outcomes. First and 2nd line chemotherapies sequence didn’t influence 3rd line outcome.ConclusionIn our cohort, one-third of treated patients proceeded to 3rd line chemotherapy resulting in a 5.5 months median 3rd line OS, consistent with treatments at advanced stage. Our results argue against the use of erlotinib and gemcitabine monotherapy.

Phase 3 KEYNOTE-992 study of pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer (MIBC).

TPS720 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for patients (pts) with MIBC who seek a bladder-preserving alternative to radical cystectomy and/or not candidates for radical cystectomy. The anti–PD-1 antibody pembrolizumab is approved for metastatic bladder cancer and non–muscle-invasive bladder cancer (NMIBC). The randomized, double-blind, phase 3 KEYNOTE-992 study (NCT04241185) is evaluating efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in pts with MIBC who chose bladder preservation. Methods: Eligibility criteria include adultswho have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted. Approximately 636 pts will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV or placebo IV every 6 weeks for up to 9 cycles, both with CRT. Investigator’s choice of chemotherapy will be specified before random assignment. Pts will be stratified by ECOG PS (0 and 1 vs 2), PD-L1 combined positive score (&lt;10 vs ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). Radiosensitizing chemotherapy will be cisplatin monotherapy (35 mg/m2 IV weekly on day 1), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly on days 1 and 4). Radiation therapy will be conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Imaging via CT and CT urography or magnetic resonance urography will be performed 10 weeks after completion of CRT, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). Primary end point is bladder-intact event-free survival (defined as time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause) as assessed by blinded independent central review and/or central pathology review. Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04241185 .

Safety and efficacy of chemotherapy for patients with unresectable pancreatic cancer concomitant with collagen disease: A multicenter retrospective observational study.

650 Background: In patients with collagen disease, such as rheumatoid arthritis, steroids and immunomodulators are often used for treatment. These treatments increase the risk of adverse events, including infections; thus, cancer patients with collagen disease are often excluded from clinical trials of chemotherapy for cancer. Therefore, evidence is lacking regarding the safety and efficacy of chemotherapy for pancreatic cancer concomitant with collagen diseases. Methods: This was a multicenter, retrospective study in Japan. Patients who started first-line chemotherapy or chemoradiotherapy for unresectable pancreatic cancer between January 2015 and December 2019 and had concurrent collagen diseases were included. We evaluated adverse events (AEs), discontinuation of anticancer treatment due to AEs, progression-free survival (PFS) and overall survival (OS). Results: A total of 52 patients were enrolled from 20 institutions in Japan, and a total of 101 regimens were administered. Concomitant collagen diseases included rheumatoid arthritis (n=35), systemic lupus erythematosus (n=5), Sjögren's syndrome (n=4), vasculitis syndrome (n=3), dermatomyositis/polymyositis (n=2), polymyalgia rheumatica (n=1), systemic sclerosis (n=1), and Behçet’s disease (n=1). The most common regimens for pancreatic cancer were gemcitabine/nab-paclitaxel (GnP, n=40), S-1 monotherapy (n=18), gemcitabine monotherapy (n=15), modified FOLFIRINOX (n=10), S-1 concurrent radiotherapy (n=5), and FOLFOX (n=4). Treatment discontinuation due to AEs occurred in 21 regimens (20.8%). The most common causes of discontinuation were thrombosis in 4 regimens, interstitial lung disease (ILD) in 3 regimens, and fatigue in 3 regimens. Infection as an adverse event was observed in 7 regimens (6.9%). By regimen, GnP had the highest discontinuation rate for adverse events of 37.5% and an incidence of ILD of 15.0%. The median PFS was 5.6 months in first-line therapy, and the median OS was 11.1 months. By regimen, the median PFS (5.8 months) and median OS (13.3 months) for metastatic patients receiving first-line GnP were comparable to those in previous reports on GnP for patients without collagen disease. Conclusions: Patients with pancreatic cancer concomitant with collagen disease have a high discontinuation rate due to AEs, and attention should be given to the occurrence of thrombosis and ILD.

The effect of germline DNA repair mutations on radiosensitivity in pancreatic ductal adenocarcinoma.

703 Background: The association between homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC) and sensitivity to platinum-based chemotherapy highlights the need to further understand how germline DNA repair mutations influence the efficacy of different therapies. Given the recent ALLIANCE data that chemotherapy alone is an acceptable standard of care to enhance R0 resection, the focus has shifted towards the contribution of radiotherapy. However, the relationship between germline DNA repair mutations in general and radiosensitivity remains less understood. This study explores the relationship between germline mutations and the Radiosensitivity Index (RSI) gene signature. Methods: After obtaining institutional review board approval, a retrospective analysis was performed of patients who had both RSI and germline mutation testing (i.e., BRCA1, BRCA2, BLM, ATM, MLH1, MSH2, MSH6, PMS2, and BARD mutations) between 1999 and 2023 at a single institution. Student T, Chi squared, Kaplan Meier (KM), Cox univariate log regression (UVA), and Mann-Whitney U (MWU) tests were used for statistical analyses. Results: A total of 25 patients were included, 13 with mutations and 12 without. MWU analysis demonstrated a significant difference in RSI values, where patients with mutations exhibited greater radiosensitivity (mean 0.379 vs. 0.464, p=0.040). The median age at diagnosis, max diameter of tumor, and baseline CA 19-9 were 67 years (range 47 – 77), 3.4 cm (range 0.8 – 8.2), and 288 (9.5 – 26,100), respectively. Most of the tumors were resectable (84%), stage IIB (36%), and grade 2 (68%). All patients underwent resection, with the majority without neoadjuvant therapy (96%). Most patients received chemotherapy (n=18; 72%), most commonly gemcitabine monotherapy (n=14/18). A majority also received radiation therapy (n=15; 60%), with 93% receiving chemoradiation (n=14/15). The median follow-up was 20.8 months. KM analysis yielded a median overall survival (OS) of 20.0 months (95% CI: 7.1-33.0) and progression-free survival (PFS) of 15.1 months (95% CI: 12.3-18.0) for the entire cohort. At the time of analysis, 15.4% of patients with mutations were alive (&gt;10 years), compared to none without mutations (p=0.157). There were no statistically significant differences between the two cohorts for clinical outcomes on KM analysis. On UVA, worse OS was correlated with stage III (HR 7.9, 95% CI 1.2 – 50.2) and IV (HR 11.8, 95% CI 1.4 – 102.3). No other variables were associated with OS on UVA or on mutant-only subgroup analysis. Conclusions: Our findings demonstrate an increased radiosensitivity in patients with germline DNA repair mutations, suggesting these cancers might be more susceptible to radiation-induced DNA damage. Since our results are constrained by the small sample size, further studies are needed to understand the relationship between PDAC with DNA repair mutations.

HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first line treatment.

647 Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs patient’s quality of life. In other gastrointestinal cancer, infusion pump free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen by its convenience. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for metastataic pancreatic cancer. Methods: HGCSG1803 study has conducted as a multicenter, non-randomized, single arm, phase II study in Japan. The chemotherapy-naïve patients with metastatic pancreatic cancer were eligible. S-1 (40 mg/m2) orally intake twice daily for 14-day followed by a 14-day rest, and intravenous 65 mg/m2 of L-OHP and 100 mg/m2 of IRI on day 1 and day 15 every four weeks were continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST ver1.1, with a threshold of 10% and an expected value of 30%. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Results: Between Jan 2020 and May 2022, forty patients were enrolled and 39 patients were included in full analysis set (one patient were excluded because of consent withdrawal). Median age was 66 (range, 41-75), female/male were 16/23, ECOG PS 0/1; 32/7, UGT1A1 wild /heterozygous for *6 or *28 allele 27/12, liver/lung/peritoneal metastasis 28/9/11, respectively. The median relative dose intensities of S-1, irinotecan, and oxaliplatin were 76%, 72%, and 70%, respectively. Objective response rate and disease control rate were 43.6% (95%CI 27.8-60.4%) and 76.9% (95%CI 60.4-89.1%), respectively. In the median follow-up time was 13.7 months, median progression free survival and overall survival were 4.3 months (95%CI 2.5-6.2 months) and 11.1 months (95%CI 7.2-14.9 months), respectively. Four patients discontinued protocol therapy due to adverse events (AE) without disease progression. Grade 3 or higher AE that occurred in more than 5% of patients were leucopenia (21%), hypokalemia (21%), neutropenia (18%), anemia (15%), hyponatremia (15%), ALT elevation (10%), anorexia (8%), nausea (5%), and febrile neutropenia (5%). One patient died due to protocol therapy (drug induced pneumonitis). Conclusions: OX-IRIS showed high response rate with manageable safety, and the primary endpoint was met. This new triplet regimen could be a useful first line treatment option for patients with metastatic pancreatic cancer. Clinical trial information: jRCTs011190008 .

Pharmacogenomic study of gemcitabine on the safety and efficacy in patients with metastatic pancreatic cancer (GENESECT study): Analysis of a subpopulation.

651 Background: In the GENESECT study, we examined the relationships between gemcitabine (GEM) metabolism-related germline genetic polymorphisms (GPs) and treatment efficacy and safety. However, no significant GPs were found because approximately 70% of the patients were treated with nab-paclitaxel, which has a different metabolic process than GEM. In the present study, a subanalysis including only GEM monotherapy patients was performed. Methods: Of the 159 patients analyzed in the GENESECT study, only the GEM monotherapy patients were selected. The endpoints were the carbohydrate antigen 19-9 (CA19-9) response (reduction ≥50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs from the viewpoint of efficacy, and neutropenia ≥Grade 3 and thrombocytopenia ≥Grade 3 in relation to GPs from the viewpoint of safety. The analyzed genes included those encoding GEM transporters and metabolic enzymes ( SLC29A1, ABCC5, CDA, DCK, RRM1/2), and a tumor cell proliferation enzyme ( COX-2). Statistical analysis included univariate and multivariate logistic regression analyses. The significance level was set to 5%. Results: Data of 50 patients were analyzed. AA genotype in ABCC5 1146A&gt;G (rs7636910) was associated with a significantly higher percentage of CA19-9 responses compared to AG/GG (52.9% vs 21.2%, p = 0.023), and the association remained significant on multivariate analysis (OR: 6.255, p = 0.014). Patients with AA genotype in ABCC5 1146A&gt;G tended to be associated with PFS, but this was not statistically significant (HR: 0.464, p = 0.074). On the other hand, there was no significant association between CA19-9 responses and DCK-1205C&gt;T (rs4694362), TT/CT genotype in DCK-1205C&gt;T was significantly associated with prolonged PFS compared to CC (median, 127 vs 48 days, p = 0.002), and the association remained significant on multivariate analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS, and the presence of second-line chemotherapy was the only relevant factor. In terms of safety, no GPs were significantly associated with either neutropenia or thrombocytopenia. Conclusions: The results suggest that ABCC5 and DCK might be related to the efficacy of treatment with GEM, but further research is needed. Clinical trial information: UMIN000012720 .

Abstract C070: Management of resectable pancreatic adenocarcinoma: Results from a data-driven approach across University of California system

Abstract Introduction Practice guidelines for resection of surgical candidates in pancreatic adenocarcinoma are consensus-driven to ensure patients receive standardized care, but current evidence regarding peri-operative strategies regarding systemic and chemoradiation treatment is based on retrospective and metanalysis, which may lead to wide variation in implementation. Methods We used a database containing deidentified data patients with pancreatic adenocarcinoma who received surgical resections across five California academic medical centers to assess peri-operative outcomes and treatment strategies. We identified length of post-operative stay, rates of post-surgical hospital readmissions, pre-operative CA19-9 values, rates, type, duration and amount of neo-adjuvant, adjuvant, and chemoradiation therapy using structured data from EMR records at these sites. ANOVA, t-test and fisher exact tests were used to determine statistical significance of differences across institutions. Cox regression models were used to determine significance in survival differences between populations. Results. We identified 2,564 patients with PDAC diagnosis who had a surgical resection of the pancreas across five University of California sites. 1948 received pancreaticoduodenectomy, 549 received distal pancreatectomies, and 67 received total pancreatectomies. Median LOS was 8.0 days, with 7-day, 30-day, and 90-day readmission rates of 7.6, 17.7 and 23.2% respectively. There were significant differences in these rates across the five medical centers, though no association with site volume. Rate of completion of 6 months of peri-operative 5-FU based systemic therapy was 62% across all sites, but only 47% for 12 cycles of FOLFIRINOX. Patients receiving at least some NAC therapy more likely to complete the recommend six months than those who did not get any systemic therapy prior to surgical resection (77.8% vs 49.3%, p-value&amp;lt;0.001, Logistic regression with Wald test for significance). There were significant differences in the timing of peri-operative therapy across the sites, as well as the frequency of using pre- and post-operative chemo-radiation. Pre-operatively CA19-9, as well as use of perioperative Gemcitabine/Abraxane or FOLFIRINOX over Gemcitabine monotherapy were significant predictors of overall survival. Conclusion Post-operative length of stay and readmission rates were significantly different across these institutions, suggesting differential efficacy in supportive care strategies. Similarly, there is significant variation of peri-operative systemic therapy strategies. Patients receiving neoadjuvant systemic therapy are significantly more likely to complete the guideline recommended six months of treatment. Rates of peri-operative chemoradiation were significantly different across medical centers, without corresponding difference in overall survival. By comparing practice differences across institutions, we may better understand how these differences affect efficacy. Citation Format: Travis Zack, Amir Ashraf-Ganjouei, Kurt Giles, Mohammed Adam, Julian Hong, Margaret Tempero, Eric Collisson. Management of resectable pancreatic adenocarcinoma: Results from a data-driven approach across University of California system [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C070.

Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms.

Pancreatic cancer is one of the gastrointestinal tumors with the lowest survival rate and the worst prognosis. At the time of diagnosis, the majority of patients have missed the opportunity for radical surgical resection and opt for chemotherapy as their primary treatment choice. And drug resistance emerges during the application of the most widely used chemotherapeutic regimens such as modified FOLFIRINOX regimen, gemcitabine monotherapy or 5-Fluorouracil combination therapy, which further reduces the therapeutic efficacy. Therefore, it is urgent to explore better treatment strategies for pancreatic cancer. In recent years, more and more studies have found that natural products have significant anti-pancreatic cancer properties. In this paper, we reviewed the possible mechanisms by which natural products inhibit the proliferation and invasion of pancreatic cancer cells, including the possible mechanisms of targeting the inhibition of the growth and proliferation regulatory pathways of pancreatic cancer cells, inducing apoptosis and autophagy of pancreatic cancer cells, inhibiting the EMT process of pancreatic cancer cells, and inhibiting the angiogenesis of pancreatic cancer. Meanwhile, natural products have also hindered the progress of their basic and clinical research due to the complexity of their composition and the limitation of biological extraction technology. Further exploration of the specific molecular mechanisms of natural products to inhibit the proliferation and invasion of pancreatic cancer cells, optimization of purification and preparation techniques, and enrichment of basic and clinical trials to verify their efficacy and safety may be the future direction of natural products in the field of anti-pancreatic cancer research.