Interventions to support adherence to oral anticancer therapies: research challenges, lessons learned, and strategies to overcome them from Australia and Switzerland.

Not monitoring adherence to oral anticancer therapies (OAT) can lead to poor clinical outcomes, including premature death as reported by Foulon et al. (Acta Clin Belg 66(2):85-96, 2011) and Greer et al. (Oncologist 21(3):354-76, 2016). Barriers to the implementation of supportive cancer care interventions in medication adherence occur with multiple hospital sites, cancer diagnoses, and numerous healthcare professionals. This commentary describes challenges and strategies from two OAT adherence trials in Australia and Switzerland to assist researchers in the design and implementation of future interprofessional trials.

[2020 oncology update]. / Oncologie.

The COVID-19 pandemic that has swept around the world in early 2020 has changed our daily practice and habits. Fortunately, however, 2020 also brings its share of new approaches and therapeutic combinations as well as new therapies. These advances are improving the outcomes and quality of life of our patients across the spectrum of oncological diseases. This article summarises the latest oncological advances and novelties for 2020 in the following tumor entities : lung, breast, digestive, gynecological, urological and ENT.

La pandémie de Covid-19 survenue début 2020 dans le monde entier aura bouleversé notre pratique quotidienne et nos habitudes. Heureusement, sur le plan thérapeutique, l'année 2020 apporte également son lot de nouvelles approches et combinaisons thérapeutiques ainsi que l'introduction de nouvelles molécules, permettant d'améliorer le pronostic vital et la qualité de vie de nos patients, dans de nombreux domaines. Cet article résume les dernières avancées et nouveautés oncologiques de l'année 2020 dans les domaines suivants : poumon, sein, sphère digestive, gynécologique, urologique et ORL.

Systemic therapy in younger and elderly patients with advanced biliary cancer: sub-analysis of ABC-02 and twelve other prospective trials.

BACKGROUND: Outcomes in younger (<40 years) and elderly (≥70 years) patients with advanced biliary cancer (ABC) receiving palliative chemotherapy are unclear. This study assessed outcomes in those receiving monotherapy or combination therapy in thirteen prospective systemic-therapy trials. METHODS: Multivariable analysis explored the impact of therapy on progression-free (PFS) and overall survival (OS) in two separate age cohort groups: <70 years and ≥70 years, and <40 years and ≥40 years. RESULTS: Overall, 1163 patients were recruited (Jan 1997-Dec 2013). Median age of entire cohort: 63 years (range 23-85); 36 (3%) were <40, 260 (22%); ≥70. Combination therapy was platinum-based in nine studies. Among patients <40 and ≥70 years, 23 (64%) and 182 (70%) received combination therapy, respectively. Median follow-up was 42 months (95%-CI 37-51). Median PFS for patients <40 and ≥40 years was 3.5 and 5.9 months (P = 0.12), and OS was 10.8 and 9.7 months, respectively (P = 0.55). Median PFS for those <70 and ≥70 years was 6.0 and 5.0 months (P = 0.53), and OS was 10.2 and 8.8 months, respectively (P = 0.08). For the entire cohort, PFS and OS were significantly better in those receiving combination therapy: Hazard Ratio [HR]-0.66, 95%-CI 0.58-0.76, P < 0.0001 and HR-0.72, 95%-CI 0.63-0.82, P < 0.0001, respectively; and in patients ≥70 years: HR-0.54 (95%-CI 0.38-0.77, P = 0.001) and HR-0.60 (95%-CI 0.43-0.85, P = 0.004), respectively. There was no evidence of interaction between age and treatment for PFS (P = 0.58, P = 0.66) or OS (P = 0.18, P = 0.75). CONCLUSIONS: In ABC, younger patients are rare, and survival in elderly patients in receipt of systemic therapy for advanced disease, whether monotherapy or combination therapy, is similar to that of non-elderly patients, therefore age alone should not influence decisions regarding treatment.

[Curative treatment for esophageal cancer: results of a multidisciplinary consensus]. / Traitement curatif du cancer de l'oesophage: consensus multidisciplinaire multicentrique.

The management of patients with resectable cancer of the esophagus or gastroesophageal junction is currently not standardized. A multi- disciplinary regional consensus has been developed and is presented in this article. The standard workup includes an upper endoscopy, ultrasonography and a CT-scan. For locally advanced tumors, surgery should be associated with either preoperative radiochemotherapy orperioperative chemotherapy after discussion in multidisciplinary tumor board. Before the operation, smoking and alcohol cessation is imperative and nutritional status should be optimized. Nowadays, surgery is well standardized and generally performed minimally invasive accesses. After surgery, clinical and oncological follow-up is necessary.

International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus.

BACKGROUND: Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature. METHODS: The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations. RESULTS: In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I-III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (≥T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I-II tumors (≥T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable. CONCLUSIONS: The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus.

A pharmacist-led interprofessional medication adherence program improved adherence to oral anticancer therapies: The OpTAT randomized controlled trial.

BACKGROUND: Oral anticancer therapies such as protein kinase inhibitors (PKIs) are increasingly prescribed in cancer care. We aimed to evaluate the impact of a pharmacist-led interprofessional medication adherence program (IMAP) on patient implementation (dosing history), persistence (time until premature cessation of the treatment) and adherence to 27 PKIs prescribed for various solid cancers, as well as the impact on patients' beliefs about medicines (BAM) and quality of life (QoL). METHODS: Patients (n = 118) were randomized 1:1 into two arms. In the intervention arm, pharmacists supported patient adherence through monthly electronic and motivational feedback, including educational, behavioral and affective components, for 12 months. The control arm received standard care plus EM without intervention. All PKIs were delivered in electronic monitors (EMs). Medication implementation and adherence were compared between groups using generalized estimating equation models, in which relevant covariables were included; persistence was compared with Kaplan‒Meier curves. Information on all treatment interruptions was compiled for the analysis. Questionnaires to evaluate BAM and QoL were completed among patients who refused and those who accepted to participate at inclusion, 6 and 12 months post-inclusion or at study exit. RESULTS: Day-by-day PKI implementation was consistently higher and statistically significant in the intervention arm (n = 58) than in the control arm (n = 60), with 98.1% and 95.0% (Δ3.1%, 95% confidence interval (CI) of the difference 2.5%; 3.7%) implementation at 6 months, respectively. The probabilities of persistence and adherence were not different between groups, and no difference was found between groups for BAM and QoL scores. No difference in BAM or QoL was found among patients who refused versus those who participated. The intervention benefited mostly men (at 6 months, Δ4.7%, 95% CI 3.4%; 6.0%), those younger than 60 years (Δ4.0%, 95% CI 3.1%; 4.9%), those who had initiated PKI more than 60 days ago before inclusion (Δ4.5%, 95% CI 3.6%; 5.4%), patients without metastasis (Δ4.5%, 95% CI 3.4%; 5.7%), those who were diagnosed with metastasis more than 2 years ago (Δ5.3%, 95% CI 4.3%; 6.4%) and those who had never used any adherence tool before inclusion (Δ3.8%, 95% CI 3.1%; 4.5%). CONCLUSIONS: The IMAP, led by pharmacists in the context of an interprofessional collaborative practice, supported adherence, specifically implementation, to PKIs among patients with solid cancers. To manage adverse drug events, PKI transient interruptions are often mandated as part of a strategy for treatment and adherence optimization according to guidelines. Implementation of longer-term medication adherence interventions in the daily clinic may contribute to the improvement of progression-free survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484064.

Gender differences in tumor characteristics, treatment and survival of colorectal cancer: A population-based study.

BACKGROUND: The importance of sex and gender as modifiers of health and disease is increasingly recognized. The aim of this study was to analyze gender differences in incidence, tumor characteristics, treatment and relative survival (RS) in colorectal cancer (CRC). METHODS: Observational population-based study including patients diagnosed with CRC in the Netherlands between 2010 and 2020. Stratified by localization (colon/rectum) and age (18-55/56-70/≥71years), gender differences in incidence, tumor characteristics, treatment and RS were analyzed. Multivariable regression was used to analyze the influence of gender on treatment and RS. RESULTS: The age-standardized incidence per 100,000 person-years of colon and rectal cancer is higher among men than women (colon: 41.2 versus 32.4, rectum: 22.8 versus 12.6). Besides differences in patient- and tumor characteristics, differences in treatment allocation and RS were observed. Most strikingly, women aged ≥ 71 years with stage IV colon cancer are less often treated with systemic therapy (31.3 % versus 28.4 %, adjusted odds ratio (OR) 0.63, 95 % CI 0.48-0.83) and more often receive best supportive care only (47.6 % versus 40.0 %, adjusted OR 1.58, 95 % CI 1.19-2.11). CONCLUSION: Statistically significant and clinically relevant gender differences in incidence, patient- and tumor characteristics and treatment allocation are observed in patients with CRC. Reasons for differences in treatment allocation deserve further investigation.

Esophageal cancer T-staging on MRI: A preliminary study using cine and static MR sequences.

OBJECTIVES: To evaluate the added value of cine MR in addition to static MRI for T-Staging assessment of esophageal cancer (EC). MATERIALS AND METHODS: This prospective monocentric study included 54 patients (mean age 66.3 ± 9.4 years, 46 men) with histologically proven EC. They underwent MRI on a 3 T-scanner in addition to the standard workup. Acquisitions included static and cine sequences (steady-state-free-precession and real-time True-FISP during water ingestion). Three radiologists independently assessed T-staging and diagnosis confidence by reviewing (1) static sequences (S-MRI) and (2) adding cine sequences (SC-MRI). Inter-reader agreement was performed. MRI T-staging was correlated to reference standard T-staging (histopathology or consensus on endoscopic ultrasonography and imaging findings) and to clinical outcome by log-rank test. RESULTS: Both S-MRI and SC-MRI T-staging showed a significant correlation with reference T-staging (rs = 0.667, P < 0.001). SC-MRI showed a slightly better performance in distinguishing T1-T3 from T4 with a sensitivity, specificity and AUC of 76.5% (95% CI: 50.1-93.2), 83.8% (68-93.8) and 0.801 (0.681-0.921) vs 70.6% (44-89.7), 83% (68-93.8) and 0.772 (0.645-0.899) for S-MRI. Compared to S-MRI, SC-MRI increased inter-reader agreement for T4a and T4b (κ = 0.403 and 0.498) and T-staging confidence. CONCLUSION: MRI is accurate for T-staging of EC. The addition of cine sequences allows better differentiation between T1-T3 and T4 tumors with increased diagnostic confidence and inter-reader agreement.

Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data.

BACKGROUND: The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. OBJECTIVE: The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations. METHODS: The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. RESULTS: The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. CONCLUSIONS: The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30090.

A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma-A Proof of Antigen Discovery Feasibility in Three Patients.

Despite the promising therapeutic effects of immune checkpoint blockade (ICB), most patients with solid tumors treated with anti-PD-1/PD-L1 monotherapy do not achieve objective responses, with most tumor regressions being partial rather than complete. It is hypothesized that the absence of pre-existing antitumor immunity and/or the presence of additional tumor immune suppressive factors at the tumor microenvironment are responsible for such therapeutic failures. It is therefore clear that in order to fully exploit the potential of PD-1 blockade therapy, antitumor immune response should be amplified, while tumor immune suppression should be further attenuated. Cancer vaccines may prime patients for treatments with ICB by inducing effective anti-tumor immunity, especially in patients lacking tumor-infiltrating T-cells. These "non-inflamed" non-permissive tumors that are resistant to ICB could be rendered sensitive and transformed into "inflamed" tumor by vaccination. In this article we describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade. We incorporate into the schedule of standard of care (SOC) chemotherapy adjuvant setting a vaccine platform comprised of autologous dendritic cells loaded with personalized neoantigen peptides (PEP-DC) identified through our own proteo-genomics antigen discovery pipeline. Furthermore, we add nivolumab, an antibody against PD-1, to boost and maintain the vaccine's effect. We also demonstrate the feasibility of identifying personalized neoantigens in three pancreatic ductal adenocarcinoma (PDAC) patients, and we describe their optimal incorporation into long peptides for manufacturing into vaccine products. We finally discuss the advantages as well as the scientific and logistic challenges of such an exploratory vaccine clinical trial, and we highlight its novelty.

Determining and interpreting correlations in lipidomic networks found in glioblastoma cells.

BACKGROUND: Intelligent and multitiered quantitative analysis of biological systems rapidly evolves to a key technique in studying biomolecular cancer aspects. Newly emerging advances in both measurement as well as bio-inspired computational techniques have facilitated the development of lipidomics technologies and offer an excellent opportunity to understand regulation at the molecular level in many diseases. RESULTS: We present computational approaches to study the response of glioblastoma U87 cells to gene- and chemo-therapy. To identify distinct biomarkers and differences in therapeutic outcomes, we develop a novel technique based on graph-clustering. This technique facilitates the exploration and visualization of co-regulations in glioblastoma lipid profiling data. We investigate the changes in the correlation networks for different therapies and study the success of novel gene therapies targeting aggressive glioblastoma. CONCLUSIONS: The novel computational paradigm provides unique "fingerprints" by revealing the intricate interactions at the lipidome level in glioblastoma U87 cells with induced apoptosis (programmed cell death) and thus opens a new window to biomedical frontiers.