Abstract
Background
Large pragmatic studies of patients who received 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) as initial treatment for localized pancreatic ductal ...adenocarcinoma (PDAC) are lacking. This study aimed to provide realistic estimates of oncologic outcomes in these patients.
Methods
This international retrospective cohort study included all consecutive patients presenting with localized PDAC who received at least 1 cycle of (m)FOLFIRINOX as initial treatment in 5 referral centers from the United States and the Netherlands (2012-2019). Primary outcome was median overall survival (OS), calculated from the date of tissue diagnosis, assessed using Kaplan-Meier estimates. Log-rank test was used to compare OS between groups. A Cox proportional hazards regression model was used to assess prognostic baseline factors for OS. All statistical tests were 2-sided.
Results
Overall, 1835 patients were included, of whom 958 (52.2%) had locally advanced (LA), 531 (28.9%) had borderline resectable (BR), and 346 (18.9%) had potentially resectable (PR) PDAC. The median number of (m)FOLFIRINOX cycles was 6 (interquartile range = 4-8). Subsequent treatment included second chemotherapy (12.9%), radiotherapy (49.0%), and resection (37.9%). The resection rate was 17.6% for LA, 53.1% for BR, and 70.5% for PR PDAC (P < .001). The margin-negative resection rate (>1 mm) was 55.2% for LA, 62.6% for BR, and 79.2% for PR PDAC (P < .001). The median OS was 18.7 months (95% confidence interval CI = 17.7 to 19.9 months) for LA, 23.2 months (95% CI = 21.0 to 25.7 months) for BR, and 31.2 months (95% CI = 26.2 to 36.6 months) for PR PDAC (P < .001). The median OS for 695 patients who underwent a resection was 38.3 months (95% CI = 36.1 to 42.0 months). Independent prognostic factors at baseline for worse OS were more advanced stage, worse performance status, baseline carbohydrate antigen (CA) 19-9 > 500 U/mL, and body mass index ≤18.5 kg/m2.
Conclusions
This large international cohort study provides realistic estimates of resection rates and survival in patients with LA, BR, and PR PDAC who started (m)FOLFIRINOX treatment in PDAC referral centers.
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and ...targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients,
TRK
inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline
BRCA
mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15–25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline
BRCA1/2
mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.
Abstract An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic ...cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging computed tomography (CT) or magnetic resonance imaging (MRI), but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC–CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions.
In the context of cancer, whether or not to choose pregnancy termination represents a difficult and multifaceted decision. In this editorial, members of The Oncologist editorial team attempt to ...contextualize the potential implications of the recent Supreme Court decision in Dobbs v. Jackson Women’s Health Organizationfor patients with cancer.
Evaluation of: Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: a randomized controlled ...trial. JAMA 304(10), 1073-1081 (2010).
Over the last decade, adjuvant therapy in the treatment of resected pancreas adenocarcinoma has had its value established. Such treatment incrementally increases 5-year survivorship and delays time to tumor recurrence. The backbone of adjuvant therapy is the single-agent gemcitabine, based primarily on results from the Charité Onkologie Clinical (CONKO)-001 study. Based on the combined results of the European Study Group for Pancreas Cancer (ESPAC)-1 and ESPAC-3 trials, Neoptolemos and colleagues have established both bolus 5-fluorouracil and leucovorin and gemcitabine as standard options for resected pancreatic cancer. Gemcitabine remains the main standard therapy based on its ease of administration and a more favorable toxicity profile; however, there is now a clearly validated alternate option of 5-fluororuacil and leucovorin based on the results of ESPAC-3. Moving forward, the integration of novel cytotoxic and targeted agents into adjuvant therapy, along with refining the role of neoadjuvant therapy for patients with resectable pancreas cancer, will hopefully accrue a more substantial improvement in outcome for patients with resected pancreas adenocarcinoma.
BACKGROUND:Increasing numbers of survivors of critical illness are at risk for physical, cognitive, and/or mental health impairments that may persist for months or years after hospital discharge. The ...post–intensive care syndrome framework encompassing these multidimensional morbidities was developed at the 2010 Society of Critical Care Medicine conference on improving long-term outcomes after critical illness for survivors and their families.
OBJECTIVES:To report on engagement with non–critical care providers and survivors during the 2012 Society of Critical Care Medicine post–intensive care syndrome stakeholder conference. Task groups developed strategies and resources required for raising awareness and education, understanding and addressing barriers to clinical practice, and identifying research gaps and resources, aimed at improving patient and family outcomes.
PARTICIPANTS:Representatives from 21 professional associations or health systems involved in the provision of both critical care and rehabilitation of ICU survivors in the United States and ICU survivors and family members.
DESIGN:Stakeholder consensus meeting. Researchers presented summaries on morbidities for survivors and their families, whereas survivors presented their own experiences.
MEETING OUTCOMES:Future steps were planned regarding 1) recognizing, preventing, and treating post–intensive care syndrome, 2) building strategies for institutional capacity to support and partner with survivors and families, and 3) understanding and addressing barriers to practice. There was recognition of the need for systematic and frequent assessment for post–intensive care syndrome across the continuum of care, including explicit “functional reconciliation” (assessing gaps between a patient’s pre-ICU and current functional ability at all intra- and interinstitutional transitions of care). Future post–intensive care syndrome research topic areas were identified across the continuum of recoverycharacterization of at-risk patients (including recognizing risk factors, mechanisms of injury, and optimal screening instruments), prevention and treatment interventions, and outcomes research for patients and families.
CONCLUSIONS:Raising awareness of post–intensive care syndrome for the public and both critical care and non–critical care clinicians will inform a more coordinated approach to treatment and support during recovery after critical illness. Continued conceptual development and engagement with additional stakeholders is required.
Background Prisoners are recognised as a high-risk population and prisons as high-risk locations for the transmission of hepatitis c virus (HCV) infection. Injecting drug use (IDU) is the main driver ...of HCV infection in prisoners and harm reduction services are often suboptimal in prison settings. HCV prevalence and incident data in prisoners is incomplete which impacts the public health opportunity that incarceration provides in identifying, treating and preventing HCV infection. The aim of this study is to identify new HCV infection and associated risk factors in an Irish male prison. Methods We conducted a follow up (18-month) cohort study on prisoners who had previously tested negative, self-cleared or had been successfully treated for HCV infection. We conducted the study in a male medium security prison located in Dublin Ireland (Mountjoy Prison) using HCV serology, a review of medical records and a researcher-administered questionnaire. Results 99 prisoners with a mean age of 33.2 yrs. participated in the study and 82(82.8%) completed a research-administered questionnaire. Over half (51%) had a history of drug use from a young age (14.8 yrs.), 49.9% a history of heroin use and 39% a history of IDU. The prevalence of HIV and hepatitis B virus core antibody was 3% and HCV antibody was 22.2%. No new HCV infections were identified in those who had never been infected (n = 77), had self-cleared (n = 9) or achieved sustained virological response (n = 12). Small numbers of prisoners continued to engage in risk-behaviour including, IDU both in the prison (n = 2) and the community (n = 3), sharing syringes (n = 1) and drug taking paraphernalia (n = 6) and receiving non-sterile tattoos (n = 3). Conclusion Despite the high numbers of Irish prisoners with a history of IDU and HCV infection, new HCV infection is low or non-existent in this population. Small numbers of prisoners continue to engage in risk behaviour and larger studies are required to further understand HCV transmission in this cohort in an Irish and international context. Keywords: Hepatitis C, HCV, Prisoner, Prison, Incident, Harm reduction, Medication assisted treatment, MAT
We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, ..."Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles.
This study compared results of nanoparticle number concentration measurements collected from 74 instruments hosted across 50 laboratories, providing users with useful discussion and reference data to assess and benchmark their measurement capability.
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