bluuebunny/crossref_metadata_2025 huggingface dataset:
Are adverse events (AEs) during first-line FOLFIRINOX (FFX) more frequent in real-world (RW) patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not proceed to second-line therapy?
Authors: Paluri Ravi Kumar , Silver Michelle , Cockrum Paul , Dennen Syvart
Published: January 2024

630

Background: mPDAC patients (pts) that tolerate 1L FFX may increase their survival with 2L therapy, most often gemcitabine + nab-paclitaxel (GnP). However, some pts discontinue treatment due to the toxic effects of 1L FFX and consequently experience disease progression and reduced survival. Reasons for discontinuation are typically not available in RW sources. To assess whether AEs are more frequent per unit time in pts that stop treatment after 1L, we calculated the RW incidence rates (IRs) of AEs during 1L treatment for two RW cohorts: mPDAC pts treated with 1L FFX and no 2L (FFX-only) vs. pts treated with 1L FFX and 2L GnP (FFX + GnP). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2021 who initiated treatment with 1L FFX ≤90 days from their metastatic diagnosis were included. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for AEs v5. Pts were required to have ≥1 year of follow-up unless death occurred first. We evaluated differences in IRs of AEs per pt-month of 1L treatment for statistical significance using the test-based method. Results: 587 pts met study inclusion criteria. 300 pts received FFX-only prior to death or end of follow-up, while 287 received FFX + GnP. For FFX-only vs. FFX + GnP pts, median age was 66 vs. 64 (IQR: 59–71 vs. 57–69), 57% in both groups were male, 70% vs. 69% were white, 55% vs. 62% had an ECOG of 0–1, and 8% vs. 3% had an ECOG of 2. Median 1L duration of therapy (DoT) was 2.1 (IQR: 0.7–5.0) vs. 4.6 months (IQR: 2.1–7.4). Among ungraded AEs, fatigue was more frequent per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts (IR=0.037 vs. 0.027; p=.041). AEs based on lab values were higher per pt-month of 1L therapy for FFX-only vs. FFX + GnP pts for grade 3/4 thrombocytopenia (IR=0.012 vs. 0.006, p=.013), grade 1/2 anemia (IR=0.203 vs. 0.142, p<.001), grade 1/2 and 3/4 hypokalemia (IR=0.099 vs. 0.074, p<.001; IR=0.040 vs. 0.028, p=.010), grade 1/2 elevated ALT (IR=0.138 vs. 0.098, p<.001), grade 1/2 and 3/4 elevated AST (IR=0.150 vs. 0.109, p<.001; IR=0.018 vs. 0.011, p=.021), and grade 1/2 and 3/4 elevated ALP (IR=0.172 vs. 0.123, p<.001; IR=0.034 vs. 0.025, p=.035). IRs of all other AEs were numerically higher for FFX-only pts but differences were not statistically significant. Conclusions: A RW cohort of mPDAC pts receiving FFX-only experienced more AEs per pt-month of 1L and reduced likelihood of proceeding to subsequent lines of therapy compared to pts treated with FFX + GnP. Identifying predictive biomarkers may distinguish FFX non-responders and obviate AEs.
Patterns of surgery and adjuvant therapy in pancreatic carcinoid tumor: An NCDB analysis.
Authors: Lanoue Connor , Braaten Marco , Bine Christopher Reese , Silberstein Peter T.
Published: January 2024

631

Background: Pancreatic Carcinoid Tumor (PCT) is a neuroendocrine tumor (NET) of the gastrointestinal (GI) tract composed of Argentaffin cells. Of the primary pancreatic cancers, NETs are exceedingly rare in comparison to pancreatic adenocarcinoma, accounting for less than 2% of pancreatic cancer diagnoses. PCTs constitute for only a subset of these and hold a better prognosis than adenocarcinoma (What Is a Pancreatic Neuroendocrine Tumor? | American Cancer Society, n.d.). GI carcinoid tumors classically originate in the appendix, ileum, or rectum, and are seldom a primary neoplasm of the pancreas. PCTs generate secretory products with Serotonin being the most frequently isolated. Some cases may produce a carcinoid syndrome with characteristic diarrhea, cutaneous flushing, and bronchospasm (Ha & Tan, 2012). Surgical resection is the hallmark of treatment, though other modalities of management are available. Due to the rarity of PCT, no significant study exists in the literature analyzing the association of survival with receipt of surgery or predictors of receipt of surgery. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with PCT from 2004 to 2019 using the histology codes 8240 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, Binary Logistic Regression and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 29 and statistical significance was set at α = 0.05. Results: 2237 patients with PCT formed the final sample, with an average age of 61 years of age. 724 patients (32.3%) underwent surgery of the primary site, 72 (3.2%) received adjuvant chemotherapy, and 9 (0.4%) received adjuvant radiation. Surgery alone was associated with the longest median survival ( 198.5 months) compared to the other treatments ( Adjuvant chemotherapy=155.3 months, Adjuvant radiation=122.7 months, No surgery=73.95 months; p<0.05). After controlling for covariates, receipt of surgery was independently associated with decreased overall mortality ( HR=.380; p<0.05). Decreased age, lower grade tumors, and fewer positive regional lymph nodes were significantly associated with increased odds of receiving surgery. Additionally, treatment at an academic facility and private insurance status was associated with significantly higher rates of surgery. Patients who did not receive surgery were significantly older, had later stage disease, higher co-morbidity scores, and larger tumor size. Income level and race had no effect on treatment selection. Conclusions: This study found that surgery alone without adjuvant therapy is independently associated with improved survival. Favorable clinical characteristics may be contributing to this discrepancy in survival. Further exploration of treatment strategies in PCT may benefit patients through the creation of definitive treatment guidelines to manage this disease.
Trends in incidence and survival of early-stage pancreatic ductal adenocarcinoma in the United States.
Authors: Perrotta Gerardo , Abboud Yazan , Osipov Arsen , Mohamed Ghada , El Helou Mohamad , Pandol Stephen Jacob , Lo Simon K. , Gaddam Srinivas
Published: January 2024

633

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival with nearly 80% mortality within the first year after diagnosis. There have been modest incremental improvements in survival over the last decade, however the reason for this improvement is unclear. The aim of this study is to evaluate the trends of diagnosis and survival in the last two decades using large public national databases. Methods: Incidence rates of PDAC between 2001 and 2020 (age-adjusted to the 2000 US standard population) were evaluated in the United States Cancer Statistics (USCS) database, representing approximately 98% of the US population. The data was analyzed with SEER*Stat using Joinpoint regression. A survival analysis was subsequently conducted using the American College of Surgeons’ (ACS) National Cancer Database (NCDB), of PDAC cases diagnosed between 2004 and 2015.Survival outcomes were stratified by AJCC stage. Kaplan-Meier survival curves were generated, and log-rank tests were conducted to assess differences in survival between stages. Cox proportional hazards model was employed to estimate hazard ratios and adjust for potential confounders. The analysis was performed with IBM SPSS 24. Results: From 2001 to 2020, the age-adjusted incidence rate of early-stage PDAC increased from 1.1 to 2.8 (per 100,000 person-years), while locally advanced PDAC increased from 3.6 to 4.3, and from 6.4 to 7.7 for metastatic PDAC (all p<0.01). The Annual Percent Change (APC) was 5.7 for Early-Stage PDAC (95% CI 5.1-6.4), 1.4 for locally advanced (95% CI 0.8-1.9), and 0.8 for Metastatic PDAC (95% CI 0.6-1.1). The incidence rate ratio (IRR) almost doubled for early-stage PDAC, increasing from 0.10 to 0.19. Conversely, for metastatic and locally advanced stages, the IRR decreased from 0.58 to 0.52 and 0.32 to 0.29, respectively. Survival analysis revealed 5-year overall survival rates of 74%, 69%, 57%, and 33% for stages 0, IA, IB, and IIA, respectively, with an overall improvement from 2004 to 2015. This increase was consistent among all age groups, genders, and races. Stages IA and IB demonstrated larger increases 45.9% and 56.6%, respectively (IA: 47% in 2004 to 75% in 2015; IB: 38% in 2004 to 68% in 2015). Conclusions: This study highlights a marked increase in the incidence of early-stage PDAC, surpassing the overall incidence increase, suggesting improving diagnostic capabilities over the last two decades. Furthermore, the substantial improvement in 5-year survival rates for stages IA and IB indicates progress in the management of early-stage PDAC. These findings emphasize the importance of continued efforts in early detection and treatment strategies for PDAC.
Associations between BMI, morphomics and survival in 528 patients with metastatic pancreatic cancer.
Authors: Gunchick Valerie , Brown Edward , Wang Stewart , Su Grace , Sahai Vaibhav
Published: January 2024

637

Background: Literature describing associations between patient body mass index (BMI) and survival in pancreatic ductal adenocarcinoma (PDA) remains inconsistent. This heterogeneity may be due to studies using pre-diagnosis BMI and including few metastatic patients despite high prevalence at diagnosis. Furthermore, BMI may not adequately reflect other body compositions such as those reflected via morphomic variables (subcutaneous fat, visceral fat, muscle, and fascia) that may have unique associations with survival. In this study, we sought to explore the relationships between detailed body composition in patients with metastatic PDA on both overall survival (OS) and progression-free survival (PFS). Methods: We evaluated data and scans from a phase 3 clinical trial in which 528 patients with metastatic PDA with no prior chemotherapy were randomized to either FOLFIRINOX or modified FOLFIRINOX plus devimistat. No differences in response rate, median PFS or OS were observed. Of the 528 enrolled patients, 377 had baseline CT scans eligible for morphomic evaluation for which Analytic Morphomics was used to measure body composition. For analysis, morphomic variables were summed across the T10-T12 and L1-L4 vertebrae and then divided into tertiles. BMI at diagnosis was evaluated in tertiles and per WHO standards. Cox proportional hazards models and cubic splines were used to evaluate associations between BMI, morphomic variables and PFS, OS. Univariate and multivariate models were evaluated. Kaplan-Meier plots were created to evaluate median survival times between those in the highest and lowest tertiles (R v4.3.1). Results: We did not observe an association between BMI and PDA patient survival: HR (95% CI) comparing BMI ≥30 (obese) to 18.5-24.9 (healthy weight), PFS 0.96 (0.66, 1.39), p-trend=0.80; OS 0.87 (0.64, 1.18), p-trend=0.30. However, multiple morphomic variables were significantly associated with PFS and/or OS in univariate and multivariate models when comparing the highest to lowest tertile. More subcutaneous fat was associated with longer median OS (12.4 vs 10.5 mos, p=0.006; HR (95% CI) 0.41 (0.25-0.68), p-trend=0.001). More dense visceral fat was associated with shorter median PFS (6.0 vs 9.1 mos, p=0.05, HR (95% CI) 1.52 (1.00-2.33), p-trend=0.047). A higher muscle to fascia ratio was associated with longer PFS (9.3 vs 6.5 mos, p=0.03; HR (95% CI) 0.58 (0.38-0.88), p-trend=0.01) and median OS (13.9 vs 10 mos, p=0.005; HR (95% CI) 0.53 (0.38-0.76), p-trend=0.0004). Conclusions: BMI was not associated with PFS or OS in this large prospective study of patients with metastatic PDA receiving chemotherapy. However, morphomic variables including subcutaneous fat area, visceral fat density, and the muscle to fascia ratio were statistically significantly associated with metastatic PDA patient survival.
Germline testing in patients with early-onset pancreatic cancer (EOPC).
Authors: Ehsan Hamid , Symanowski James Thomas , Krishnan Arunkumar , Athens Aly , Wilson Katherine , Tobik Katie , Elrefai Sara , Salem Mohamed E. , Hwang Jimmy J. , Chang Darryl , Kadakia Kunal C.
Published: January 2024

639

Background: EOPC, defined as pancreatic cancer (PC) diagnosed at 60 years of age or younger, is associated with significant life years lost. Approximately 5-10% of average-onset PC have an underlying germline etiology. Currently NCCN & ASCO guidelines recommend germline testing in all pts w PC. However, there is limited data regarding to what extent pts with EOPC pursue recommended germline testing. We examined the findings from genetic evaluation in EOPC. Methods: A retrospective review of EOPC pts at the Levine Cancer Institute who underwent clinical genetic assessment between January 2019 and December 2021 was performed. Data on clinicodemographic, family history, and genetic testing results were obtained and analyzed descriptively. Results: We identified 69 EOPC pts who were evaluated by genetics. Baseline characteristics include median age of 55 years (range 25-60) with 52% male, 48% white, 23% black, and 52% with current or prior tobacco use. At presentation, 41% and 59% had metastatic and non-metastatic disease, respectively. Eight (12%) pts declined germline testing. Among the 61 who underwent germline testing, 30 (49%) pts had negative testing, 21 (34%) had only variants of uncertain significance, and 10 (16%) had pathogenic/likely pathogenic germline variants (PVs). The most frequently seen PVs were ATM (20%), BRCA1 (20%), BRCA2 (10%), MLH1 (10%), NTHL1 (10%), PTCH1 (10%), CFTR (10%) and one (10%) with multiple pathogenic germline findings including RAD51 and BRCA1. Among the 10 pts with PVs, only two reported any first or second-degree family members with cancer. Conclusions: In this cohort of EOPC at a large community multi-site cancer center, 16% of patients had germline PVs, higher than reported in older patients with PC. Only 20% of pts w PVs reported first or second-degree family members with cancer and highlights the importance to recommend germline testing independent of family history even among EOPC cohorts. Further investigation to clarify reasons for refusal of germline testing in EOPC should be evaluated.
Impact of facility volume on outcomes in patients with pancreatic cancer treated with radiotherapy.
Authors: Rajan Arvind , Gleeson Elizabeth , Pham Veronica , Bodek Benjamin Ethan , Goodman Karyn A.
Published: January 2024

644

Background: The impact of facility volume on overall survival (OS) outcomes in patients with pancreatic cancer (PC) treated with radiotherapy (RT), both standard chemoradiation (CRT) and stereotactic body radiation therapy (SBRT) is not well-defined. Methods: This retrospective study analyzed 16,315 patients with locally advanced (LA) or borderline resectable (BR) PC from the National Cancer Database (2004-2019) who received neoadjuvant RT or RT without surgery across RT facilities with low- (<10 cases/yr), intermediate- (10-20 cases/yr), and high-volumes (>20 cases/yr) of PC cases. Log rank and cox regression were used for univariable and multivariable survival analysis, and Kaplan-Meier curves were generated. Results: Patients were largely treated at low (n=8055) volume centers, followed by intermediate (n=3783), and high (n=4477). Approximately half of the cohort were male (51.4%), and predominantly white (82.5%), and non-Hispanic (92%). On univariable analysis (Table), high-volume centers had improved survival outcomes in the overall population, as well as in both SBRT and CRT subsets (p<0.0001). On multivariable analysis, treatment during the most recent time period: 2016-2019 (HR 0.646, p<0.001), receiving care at a high-volume center (HR 0.844, p<0.001), use of SBRT (HR 0.915, p<0.001), administration of multiagent chemotherapy (HR 0.706, p<0.001) and undergone surgical resection (HR 0.405, p<0.001) were associated with improved OS. In a subgroup analysis of patients receiving SBRT, median OS was 22.6 months for high-volume, 20.0 for intermediate-volume and 18.4 months at low-volume centers (p<0.001). Conclusions: Patients receiving RT for LAPC or BRPC at high-volume centers had longer OS compared to those receiving radiation at intermediate- or low-volume centers. In those undergoing SBRT, treatment at high-volume centers had improved OS compared to intermediate- and low-volume centers. These findings suggest that radiation oncologists’ expertise is critical for providing high-quality RT in PC, especially for SBRT.[Table: see text]
A qualitative exploration of perceptions and experiences towards physical activity among patients with pancreatic ductal adenocarcinoma undergoing treatment.
Authors: Nguyen Tyra , Gresham Gillian , Luna-Lupercio Bianca , Raines Carolina , Gong Jun , Osipov Arsen , Hendifar Andrew Eugene , Shirazipour Celina
Published: January 2024

646

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) experience significant symptom burden due to the disease and its treatment, thus limiting their ability to participate in physical activity (PA) and engage in daily activities. PA can have many physical and psychosocial benefits, and exploring its value and how to deliver it to patients with PDAC could support their health and well-being. Therefore, the objective of this qualitative research was to explore perceptions and experiences of PA among PDAC patients undergoing active treatment. Methods: Qualitative semi-structured interviews were conducted with individuals with PDAC. Participation was optional and open to individuals in the DigiSTEPS prospective trial evaluating associations between PA measures, performance status, and patient-reported outcomes (NCT03757182). Interviews were conducted virtually. Data were analyzed using inductive thematic analysis. Results: Ten patients (50% male, 80% white, mean age=70 years) participated in the interviews. While clinical approaches may often be informational and seek to educate PDAC patients regarding the importance of PA and the benefits of PA participation, findings suggest that participants understand the benefits of PA and are interested in being active. However, cancer symptoms and treatment-related side effects are substantial barriers that are hard to surmount. A further barrier was the dissonance in self-perceptions, particularly the contrast in their functional abilities and body composition pre- to post-cancer diagnosis. We identified four action items to support patients in overcoming these barriers: clinicians can leverage trust in their team to provide evidence-based information on how to be active; distribute wearable activity monitors which can increase motivation; harness virtual PA opportunities during more symptomatic periods; and provide PA trainers with cancer knowledge to tailor programming. Conclusions: This research highlights the importance of tailoring PA discussion and approaches based on a PDAC patient’s phase in the cancer survivorship continuum, their stage at diagnosis, and treatment type. In addition, clinical teams and trainers should consider patient concerns related to body image and develop programs that address the barriers identified in this research. Clinical teams may benefit from integrating access to counselling psychologists to address these concerns and promote PA in positive and adaptive ways. Clinical trial information: NCT03757182 .
Stereotactic radiotherapy plus anti PD-1 therapy in patients with locally advanced unresectable pancreatic cancer: Results from a phase 1/2 clinical trial (CA209-9KH).
Authors: Vosmik Milan , Stanislav John , Dvorak Josef , Mohelníková-Duchoňová Beatrice , Melichar Bohuslav , Lohynska Radka , Ryška Aleš , Krempova Johana , Sirak Igor
Published: January 2024

649

Background: The outcomes after the treatment for pancreatic ductal adenocarcinoma (PDAC) are generally disappointing. Except for MSI high tumors, PDAC is considered to be resistant to immune checkpoint inhibitors (ICI). Radiotherapy is thought to be a potential option to foster the effect of ICI. This investigator-initiated trial evaluated safety and efficacy of combining stereotactic radiotherapy (SRT) and ICI. Methods: In this open-label, multicenter phase 1/2 study, patients (pts) aged ≥ 18 years with histologically confirmed locally advanced unresectable PDAC with no distant metastases were enrolled after initial four cycles of induction chemotherapy with FOLFIRINOX. The experimental treatment consisted of SRT (32 Gy in 4 fractions/4 weeks) and sequential nivolumab (N) therapy (3mg/kg every two weeks) administered until disease progression or unacceptable toxicity. After N discontinuation pts could continue treatment with standard chemotherapy regimens. The primary end point was safety (events graded according to NCI CTCAE 4.03 criteria). The secondary objectives were progression free survival (PFS), overall survival (OS), evaluation of selected biomarkers, and quality of life (QoL; EORTC QLQ-C30 questionnaire). The PFS and OS were defined as the time from enrollment to event (i.e., did not include 3-month of ICT and screening). Results: A total of 22 pts. were screened, and 15 pts. were enrolled. Median age was 58 (range 38-74) years, and 53 % were males. All tumors were microsatellite (MS) stable or had unknown MS status. All patients underwent SRT according to the study protocol and all started N. The median number of N cycles was 11 (range 2-17). The toxicity of SRT was low and non-significant. The toxicity of N therapy was expectable. No Grade 4-5 toxicity was observed. Three pts. discontinued therapy because of toxicity (liver test elevation in two cases and unmanageable arthralgia). Median PFS and OS were 8.1 and 13.0 months, resp.; 12-month PFS and OS were 0 % and 66.7%, resp.; and 24-month OS was 8.9 %. The level of selected biomarkers correlated with clinical or radiological disease control. The QoL assessed by pts during the therapy was acceptable, deterioration of QoL in most cases occurred with tumor progression. Conclusions: The toxicity of SRT and N therapy was low and acceptable. There was no unexpected toxicity of combination of SRT of PDAC primary tumor and N, but this regimen did not lead to any long-term treatment responses. Trial registration: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432. The study was financially supported by Bristol-Meyer-Squibb. Clinical trial information: NCT04098432 .
Timing of primary tumor resection after systemic chemotherapy initiation among patients with metastatic colon cancer.
Authors: Buhaya Munir , Jafry Baqir , Kazmi Syed Mohammad Ali , Huang Emina
Published: January 2024

65

Background: In patients with resectable, metastatic colon cancer, the optimal timing of definitive resection of the primary tumor after initiation of chemotherapy remains unclear. Our goal is to identify factors that influence the interval between chemotherapy and definitive surgical management, and its impact on overall survival. We hypothesize that patients with shorter chemotherapy-to-surgery intervals (less than 60 days or about 2 months) compared to 61-180 days (2-6 months) or greater than 180 days (> 6 months), will have the worst overall survival. Methods: We conducted a retrospective analysis of all patients diagnosed with metastatic colon cancer from 2004-2016 who underwent resection of both primary tumor and distant metastatic site from the National Cancer Database (NCDB). Among those who received chemotherapy prior to surgery, we calculated the interval days between initiation of chemotherapy and primary tumor resection. Descriptive analysis, logistic regression, and overall survival was performed comparing patients with chemotherapy-to-surgery intervals of <60, 60-180, and >180 days. Results: A total of 2,238 patients were included, of which 143 (6%), 1446 (65%), and 649 (29%) were in the <60, 60-180, and >180 days groups, respectively. Similar distribution of patients across groups was observed for age, gender, insurance status, income, education level, distance travel, and Charlson-Deyo scores. Poorly differentiated tumors were more frequent in the <60 days group (12% vs 2-9% for other grades, p=0.001) as well as presence of lymphovascular invasion (8% vs 4%, p = 0.006). The odds of receiving care at an academic facility were lower in the <60 days group (OR: 0.52, 95% CI 0.273-0.994). Overall survival was significantly reduced in the <60 days group compared to 60-180 days (HR= 0.562, 95% C: 0.38-0.82). Conclusions: In this retrospective study from a national database, shorter chemotherapy-to-surgery interval (<60 days) was associated with poorly differentiated tumors and lymphovascular invasion. The odds of receiving surgery in <60 days of receiving chemotherapy was lower in academic/research facilities. A reduction in overall survival was observed in the shorter interval (<60 days) group compared to longer intervals. More research is needed to define the optimal chemotherapy-surgery interval and factors that influence this.
Pharmacogenomic study of gemcitabine on the safety and efficacy in patients with metastatic pancreatic cancer (GENESECT study): Analysis of a subpopulation.
Authors: Yokokawa Takashi , Tsuji Daiki , Hatori Masahiro , Suzuki Kenichi , Kawakami Kazuyoshi , Nakao Masahiko , Yano Takuya , Arakawa Yuichiro , Matsuo Keisuke , Ohashi Yasukata , Ozaka Masato , Sasahira Naoki , Sakata Yasuhiko , Kogure Yuki , Tamaki Shinya , Wada Atsushi , Taki Yusuke , Ishii Hiroshi , Itoh Kunihiko , Yamaguchi Masakazu
Published: January 2024

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>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>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>T (rs4694362), TT/CT genotype in DCK-1205C>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 .
Preliminary results of a phase II study of surufatinib plus sintilimab, nab-paclitaxel and gemcitabine (AG) as first-line therapy in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Zhang Dong-Sheng , Liu Fu-Rong , Lu Yun-Xin , Bai Bing , Zhang Yang , Wang Zhi-Qiang , Liu Yu , Chen Jian-Wen , Wang Feng , Xu Rui-Hua
Published: January 2024

659

Background: Advanced pancreatic adenocarcinoma (PDAC) had poor survival and limited therapeutic options. Surufatinib is a potent, small-molecule tyrosine kinase inhibitor (TKI), selectively targeting VEGF receptors (VEGFR) 1, 2, and 3, FGFR 1, and CSF-1R. Recent studies showed that small molecule anti-vascular inhibitor combined with a PD-1 inhibitor exhibited encouraging efficacy in PDAC. This study is to assess the efficacy and safety of surufatinib plus sintilimab (an anti-PD-1 antibody),nab-paclitaxel and gemcitabine(AG) as first-line therapy for mPDAC pts. Here we report the preliminary results. Methods: Eligible pts ≥18 years old with histologically confirmed mPDAC, ECOG PS 0-1, with at least one measurable lesion were enrolled. Pts received surufatinib (250mg, orally daily), sintilimab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m2, I.V., D1, D8, Q3W) and gemcitabine (1000mg/m2,I.V.,D1, D8, Q3W). Based on Simon’s Two-stage design, 11 patients would be enrolled in stage 1; if 3 or more responses were observed, the trial would continue to stage 2, and additional 21 patients would be enrolled. The total sample size was 32. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results: At cutoff date of Aug 25, 2023, 15 pts were enrolled and received at least one time treatment. Median age was 60 years (range 45-68), male 53.3%, ECOG PS 1 100%, 66.7% of pts had more than 3 sites of metastasis. The most common metastatic sites were lymph nodes (66.7%) and liver (60.0%). 12 pts had received at least one tumor assessment. Six out of 11 evaluable pts responded during stage 1, allowing for enrollment to continue with a planned 21 additional patients in stage 2. Eight pts achieved partial response (PR), 3 pts achieved stable disease (SD), and the confirmed ORR (c-ORR) was 50.0% (6/12) (95% confidence interval [CI]: 21.1-78.9), and the DCR was 91.7% (11/12) (95% CI: 61.5-99.8). The median time to response (TTR) was 2.95 months (95% CI: 2.79-3.06), and median PFS was not reached yet. 15 pts underwent safety evaluation. The most common AEs of all grades were white blood cell count decreased (66.7%), neutrophil count decreased (60.0%), and anemia (53.3%), and grades ≥ 3 were blood cell count decreased (33.3%), neutrophil count decreased (33.3%), and diarrhea (13.3%). Conclusions: Surufatinib plus sintilimab, along with AG showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of mPDAC. This trial is ongoing and warrants further exploration in mPDAC. Clinical trial information: NCT05481476 .
Phase II study of the safety and efficacy of discontinuing pegfilgrastim for pancreatic adenocarcinoma treated with FOLFIRINOX.
Authors: Yanagi Masahiro , Terashima Takeshi , Yamashita Tatsuya , Yamamoto Makoto , Kido Hidenori , Nakagawa Hidetoshi , Seki Akihiro , Nio Kouki , Yamashita Taro
Published: January 2024

663

Background: The original FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) for pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of febrile neutropenia (FN), and pegfilgrastim has been used to reduce the risk. However, it remains unclear how long pegfilgrastim needs to continue. This study evaluated the safety and efficacy of FOLFIRINOX after discontinuing pegfilgrastim in PDAC patients. Methods: This prospective phase II trial included patients with PDAC who received the first three courses of FOLFIRINOX, with primary pegfilgrastim prophylaxis for FN, and did not experience FN. The patients continued on FOLFIRINOX without pegfilgrastim from the fourth course. The primary endpoint was development of FN. The secondary endpoints included relative dose intensity (RDI), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The threshold and expected development of FN were 20% and 7%, respectively, at a one-sided significance level of 0.10 and statistical power of 80%. Based on this hypothesis, we calculated the number of patients needed to be 33. Results: In total, 34 patients (20 male, median age 66 years) were enrolled from August 2017 to September 2021. Twenty-three patients were unresectable, and 11 were borderline resectable. FN developed in one patient. Grade 4 neutropenia was observed in six patients, grade 3 neutropenia in 10 (29.4%), anemia in four (11.8%), diarrhea in two (5.9%), and malaise, lung infection, peripheral sensory neuropathy, colitis, and biliary tract infection in one (2.9%) each. Twenty-two patients required dose reduction, mainly because of neutropenia. Mean RDIs at the sixth course of oxaliplatin, irinotecan, leucovorin, acute infusion of fluorouracil, and continuous infusion of fluorouracil were 77.0%, 88.2%, 81.8%, 84.4%, and 87.6%, respectively. ORR, median PFS, and median OS were 44.1%, 15.8 months, and 25.8 months, respectively. Conclusions: FOLFIRINOX can be continued safely with a low incidence of FN after discontinuing pegfilgrastim in PDAC patients who did not experience FN during the first three courses of FOLFIRINOX, if the drug dose is reduced appropriately for neutropenia from the fourth course. Clinical trial information: UMIN000028055 .
Factors associated with the receipt of surgery in acinar cell carcinoma of the pancreas.
Authors: Chaddha Jasleen Kaur , Bine Christopher Reese , Silberstein Peter T.
Published: January 2024

668

Background: Acinar cell carcinoma of the pancreas (PACC) accounts for 1-2% of adult pancreatic tumors. Clinically, this malignancy presents as a hypersecretory syndrome as lipase is released into circulation. Median overall survival is 18 to 47 months. Aggressive surgical resection is associated with long-term survival in PACC patients. This appears to be the treatment of choice for most localized pancreatic cancers, however, there are no clear treatment guidelines or standardized protocols for PACC due to its rarity. Further, no significant study has analyzed the factors correlated with receiving this surgery. This study aims to uncover the possible factors associated with the receipt of tumor resection in patients with PACC. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with PACC from 2004 to 2019 using the histology code 8550 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Multilevel Logistic Regression were performed, and data were analyzed using SPSS version 29. Statistical significance was set at α = 0.05. Results: 1430 patients with PACC were queried. 600 (41.95%) patients received surgical resection. Surgical patients experienced longer overall survival than non-surgical patients (87.5 months vs. 25.3 months, P < 0.01). Of the surgical patients, wider surgical margins and complete tumor resection were associated with improved survival (P<0.001). Stage I and II disease, well and moderately differentiated disease, and receiving treatment at an academic/research facility were associated with an increased likelihood of receiving surgery (P<0.001). Metastasis at the time of diagnosis was associated with a decreased likelihood of receiving surgery (P<0.001). Income status, race, insurance status, and age did not appear to be significant predicting factors of surgery. Of the initial sample, 219 (15.31%) patients received adjuvant chemotherapy, 8 (0.55%) patients received adjuvant radiation, and 4 (0.28%) patients received both adjuvant chemotherapy and radiation. Adjuvant therapies did not appear to impact the overall survival of PACC patients. Conclusions: This study confirms that tumor resection is associated with increased survival in patients with PACC. Improved survival with surgery is correlated to wider surgical margins and complete tumor resection. It appears that patients with well or moderately differentiated disease, stage I or II disease, and treatment at an academic/research facility are more likely to receive surgery. PACC patients with metastasis to distant sites are less likely to receive surgery. The efficacy of adjuvant therapy remains unclear. Further studies are needed to better understand the factors involved in receiving surgery and other treatment modalities as part of PACC treatment.
FOLFIRINOX plus high intensity focused ultrasound for locally advanced/borderline resectable pancreatic ductal adenocarcinoma: A prospective single arm phase II trial.
Authors: Lee Dong Ho , Lee Jae Young , Lee Sang Hyub , Jang Jin-Young
Published: January 2024

670

Background: FOLFIRINOX has been the standard regimen for locally advanced pancreatic cancer (LAPC) for palliation and borderline resectable pancreatic cancer (BRPC) for neoadjuvant treatment. According to the results of animal studies, concurrent use of high intensity focused ultrasound (HIFU) and chemotherapy can enhance the drug delivery to the target tissue. In this phase II trial, we aimed to evaluate the safety and therapeutic efficacy of FOLFIRINOX plus HIFU for patients with LAPC or BRPC. Methods: This study was designed as a prospective single center phase II trial (Study identifier: NCT05262452). We prospectively enrolled 60 patients (M:F=35:25; median age, 67.0 years old) with LAPC (n=23) or BRPC (n=37). The median tumor size was 4.0 cm (Interquartile range, 2.7-4.6). All patients were treated by FOLFIRINOX (oxaliplatin, 85mg/m2 of body-surface area; irinotecan, 180mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion) every 2 weeks until disease progression. HIFU was combined in the first 4 cycles of chemotherapy with following parameters: intensity of 2.0 kw/cm2, duty cycle of 1%, exposure time of 3 seconds and PRF of 10Hz. Follow-up contrast enhanced CT was taken every 4 cycles for the response evaluation using response evaluation criteria for solid tumor 1.1. Overall survival (OS) and progression-free survival were estimated using Kaplan-Meier method. All analyses were intention-to-treat. Results: Two patients withdrew the consent, and two patients could not complete planned 4 cycles of FOLFIRINOX plus HIFU treatment owing to sepsis from severe neutropenia related to chemotherapy. Among 56 patients who completed the 4 cycle of FOLFIRINOX plus HIFU and continued chemotherapy, partial response was achieved in 36 patients (60.0%, 36/60), and stable disease in 20 patients. Regarding the adverse effect (AE), 32 of 60 patients experienced grade 3 (n=22) or grade 4 (n=10) AE, all of them were related to FOLFIRINOX chemotherapy. No AE related to HIFU was observed. The estimated OS was 94.8%, 75.9% and 67.6% at 6-, 12- and 18 months, respectively. Regarding the PFS, the 6-, 12- and 18-month PFS was 91.9%, 70.3% and 56.2%, respectively. Conclusions: FOLFIRINOX plus HIFU was safe and effective treatment for LAPC/BRPC, providing 60.0% of partial response rate without any additional AE to chemotherapy. Clinical trial information: NCT05262452 .
Prognostic factors for GEM + nab-PTX combination therapy in elderly patients with pancreatic cancer.
Authors: Watabe Kazuki , Ohno Izumi , Sakai Miho , Takahashi Tomoya , Yamada Nana , Tohyama Shodai , Sekine Yu , Sugihara Jihei , Ohuchi Mayu , Nagashima Hiroki , Takahashi Koji , Okitsu Kohichiro , Kan Motoyasu , Ohyama Hiroshi , Ohtsuka Masayuki , Kato Naoya
Published: January 2024

678

Background: Japanese Clinical Practice Guidelines for Pancreatic Cancer 2022 recommends gemcitabine (GEM) + nab-paclitaxel (nab-PTX) therapy (GnP regimen) as the first line chemotherapy for elderly patients with pancreatic cancer. In Japan, it is reported that about 69% of pancreatic cancer patients are elderly, and Only few group reported the safety of GnP regimen. In this study, we investigated the anti-tumor efficacy and prognostic factors of GnP regimen in patients with pancreatic cancer at our hospital, with a particular focus on age. Methods: 160 patients who started GnP therapy as the first line treatment for unresectable pancreatic cancer between February 2016 and December 2021 were included in the study. 70 years of age or older was defined as elderly, and patient background and treatment efficacy were compared in two groups: non-elderly patients (n=84) and elderly patients (n=76). Prognostic factors were also compared between the overall population and the elderly. Results: Patients with a primary lesion in the pancreatic head were 32 (38.1%) of the non-elderly patients and 35 (46.1%) of the elderly patients. 60 patients (71.4%) of the non-elderly and 38 (50.0%) of the elderly had distant metastases. The median overall survival was 16.0 months for the non-elderly and 17.7 months for the elderly, with no significant difference (p=0.93). Significant prognostic factors for the overall subject population were ECOG PS (HR 1.80, p=0.019), liver metastasis (HR 2.36, p<0.01), CRP (HR 1.91, p<0.01) and NLR (HR 2.65, p<0.01). The only significant prognostic factor in the elderly was liver metastasis (HR 2.59, p<0.01). Conclusions: GnP regimen in pancreatic cancer can be expected to have the same antitumor effect in elderly patients as in non-elderly patients. However, significant prognostic factors were reduced in the elderly, we need to identify specific factors to determine the indication for treatment in the elderly patients.
Pulsed low dose rate radiation to mitigate tumor-permissive responses in pancreatic cancer-associated fibroblasts: Introducing the HOST-factor.
Authors: Cukierman Edna , Franco-Barraza Janusz , Luong Tiffany , Raghavan Kristopher , Wong Jessica Karen , Vendramini Costa Debora Barbosa , Francescone Ralph , Gardiner Jaye C. , Reddy Sanjay S. , Handorf Elizabeth A. , Meyer Joshua E.
Published: January 2024

682

Background: Pancreatic ductal adenocarcinoma (PDAC) features a distinctive tumor microenvironment comprising cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix (ECM), forming functional CAF units (CAF u). The current total neoadjuvant therapy (TNT), involving conventional chemoradiotherapy (CRT), yields suboptimal responses while promoting a tumor-permissive CAF u state. To address this, we explored pulsed low dose rate radiation (PLDR)-based TNT, as an alternative to CRT, to treat three-dimensional in vivo-like human PDAC CAF u cultures. We assessed gemcitabine combined with PLDR versus CRT using theHOST Factor, a “harmonized output of stroma traits” factor, comprising several established CAF u functional indicators, which inform on the functional status of the PDAC microenvironment. Methods: The unique CAF u functional values used corresponded to: i) ECM anisotropy; ii) persistent cell-ECM signaling; iii) sustained cytokine-induced activation; iv) cytoskeletal bundling; and v) systemic features of fibroblastic activation. The validity of the resultant HOST factor was assessed using the unit’s ECM ability to elicit fibroblastic activation, indicated by a high αSMA/F-actin ratio value. Results: Ex-vivo CRT led to a HOST factor that was 2-fold greater than chemotherapy alone (p=0.6), which was functionally gauged as a tumor-permissive CAF u. In contrast, PLDR averted CRT-induced tumor-permissive response and established a 6-fold lower HOST factor, suggestive of a “normalized” CAF u, when compared to the HOST factor value established when using conventional TNT (P=0.0016 vs. CRT, and P= 0.0086 vs. gemcitabine alone). The multi-parameter HOST factor validity was confirmed as CRT treated CAF u’s ECM activated human pancreatic fibroblasts (αSMA/F-actin = 70% ± 29) while PLDR-treated CAF u's ECM failed to do so (αSMA/F-actin = 32% ± 26), reaching a 30% mean rank difference (P <0.0001). Conclusions: PLDR mitigates conventional CRT-based TNT-induced tumor-permissive responses, restoring the fibroblastic units' tumor-suppressive function. These results lend support to a phase 1 trial designed to evaluate whether radiation with PLDR-based TNT, constitutes a safe and more effective treatment for PDAC patients. The novel HOST factor is being used to appraise specimens from NCT04452357.
Genomics and transcriptomics of pancreatic adenosquamous carcinoma.
Authors: Kania Brooke Elizabeth , Baca Yasmine , Riedlinger Gregory , Goel Sanjay , Lou Emil , Weinberg Benjamin Adam , Khushman Moh'd M. , Xiu Joanne , Gulhati Pat
Published: January 2024

691

Background: Pancreatic cancer (PC) is anticipated to become the 2nd leading cause of cancer-related deaths by 2030. Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of PC with histology including squamous adenomatous features (≥30% squamous histology), while pancreatic squamous cell cancer (PSCC) consists purely of squamous cells. We evaluated genomic, transcriptomic and prognostic differences between PASC, PSCC and pancreatic ductal adenocarcinoma (PDAC). Methods: 8951 PC tumors (83 PASC, 22 PSCC & 8846 PDAC) tested at Caris Life Sciences with WTS (Illumina, Novaseq) and NextGen DNA sequencing (NextSeq, 592 genes and NovaSeq, WES) and IHC were analyzed. Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) analysis (time of tissue collection to last contact) was obtained from insurance claims and calculated with KM method. Statistical significance was determined using Chi-square/Fisher-Exact and adjusted for multiple comparisons (q<0.05). Results: No age or sex differences were seen between PDAC (median 68yo) and PASC (median 68.5yo), however PSCC was more prevalent in younger pts (median 62.5yo, q<0.05). Mutation rates of CDKN1B (3% vs 0.2%), SF3B1 (8 vs 2%), PTEN (5 vs 0.8%), BCL9 (4 vs 0.4%), AXIN1 (4 vs 0.2%) and CASP8 (3 vs 0.2%) and amplifications of AKT2 (5 vs 2%), ZNF384 (1 VS 0.1%), HMGA2 (7 vs 0.7%) and ROS1 fusions (1 vs 0.04%) all trended higher in PASC than PDAC (p<0.05). Several YAP signaling and squamous differentiation genes were significantly differentially expressed among histologies (table). PD-L1 IHC was higher in PASC vs PDAC (37 vs 14%, q<0.05); with a trend towards higher MSI-H (6 vs 1%) & TMB-H (6 vs 2%) in PASC vs PDAC (p<0.05). Higher infiltration of CD4+ T cells into the TME was seen in PASC vs PDAC (non-zero %, 73% vs 23%, q<0.05). Several immune genes ( CD274, IDO1, LAG3, & CTLA4) had higher expression in PASC vs PDAC (fold change 1.3-3.1, q<0.05). The MAP kinase pathway activation score (MPAS) was lower in PASC vs PDAC (median score -0.48 vs 0.25), while the IFN gamma signature was higher in PASC vs PDAC (median -0.24 vs -0.33) [both q<0.05]. There was increased OS for PASC compared to PSCC (12.6 vs 4.7 mo, HR=0.43, CI=0.25-0.75, p=0.002); no significant difference in OS was observed between PASC and PDAC. Conclusions: This is the largest molecular profiling analysis of PASC, which is characterized by unique genomic alterations, and is associated with higher PD-L1 expression, immune related gene expression, CD4+ T cell infiltration and IFN gamma signature, and lower MAPK activation. PASC is associated with better OS compared to PSCC. These findings may provide subtype-specific therapeutic opportunities for PASC and PSCC pts.[Table: see text]