Trastuzumab plus pertuzumab for HER2-amplified advanced colorectal cancer: Results from the drug rediscovery protocol (DRUP).

BACKGROUND: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'. METHODS: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. RESULTS: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. CONCLUSIONS: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.

BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

Nationwide treatment and outcomes of intrahepatic cholangiocarcinoma.

BACKGROUND: Most data on the treatment and outcomes of intrahepatic cholangiocarcinoma (iCCA) derives from expert centers. This study aimed to investigate the treatment and outcomes of all patients diagnosed with iCCA in a nationwide cohort. METHODS: Data on all patients diagnosed with iCCA between 2010 and 2018 were obtained from the Netherlands Cancer Registry. RESULTS: In total, 1747 patients diagnosed with iCCA were included. Resection was performed in 292 patients (17%), 548 patients (31%) underwent palliative systemic treatment, and 867 patients (50%) best supportive care (BSC). The OS median and 1-, and 3-year OS were after resection: 37.5 months (31.0-44.0), 79.2%, and 51.6%,; with systemic therapy, 10.0 months (9.2-10.8), 38.4%, and 5.1%, and with BSC 2.2 months (2.0-2.5), 10.4%, and 1.3% respectively. The resection rate for patients who first presented in academic centers was 33% (96/292) compared to 13% (195/1454) in non-academic centers (P < 0.001). DISCUSSION: Half of almost 1750 patients with iCCA over an 8 year period did not receive any treatment with a 1-year OS of 10.4%. Three-year survival was about 50% after resection, while long-term survival was rare after palliative treatment. The resection rate was higher in academic centers compared to non-academic centers.

Predictive Genetic Biomarkers for the Development of Peritoneal Metastases in Colorectal Cancer.

Metastatic colorectal cancer (CRC) is a common cause of cancer-related mortality, of which peritoneal metastases (PMs) have the worse outcome. Metastasis-specific markers may help predict the spread of tumor cells and select patients for preventive strategies. This exploratory pilot study aimed to gain more insight into genetic alterations in primary CRC tumors, which might be a predictive factor for the development of PM. Forty patients with T3 stage CRC were retrospectively divided in three groups: without metachronous metastases during 5-year follow-up (M0, n = 20), with metachronous liver metastases (LM, n = 10) and with metachronous PM (PM, n = 10). Patients with synchronous metastases were excluded. Primary formalin-fixed paraffin-embedded tumor samples were analyzed via comprehensive genome sequencing (TSO500 analysis) to identify DNA alterations and RNA fusion transcripts in 523 genes and 55 genes, respectively. Thirty-eight samples were included for final analysis. Four M0 tumors and one PM tumor were microsatellite instable. BRAF mutations were uniquely identified in three microsatellite-stable (MSS) PM tumors (37.5%, p = 0.010). RNA analysis showed an additional FAM198A-RAF1 fusion in one PM sample. BRAF p.V600E mutations were only present in PM patients with MSS tumors. Greater attention should be paid to BRAF-mutated tumors in relation to the development of metachronous PM.

Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis.

PURPOSE: DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. METHODS: Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% (DPYD*2A and c.1679T>G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. RESULTS: In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 DPYD*2A, 13 c.2846A>T, and-when pooled-93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P = .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P = .007) was found in c.1236G>A variant carriers, whereas no differences were found for DPYD*2A and c.2846A>T carriers. CONCLUSION: In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.

Population-based impact of COVID-19 on incidence, treatment, and survival of patients with pancreatic cancer.

BACKGROUND: The COVID-19 pandemic has put substantial strain on the healthcare system of which the effects are only partly elucidated. This study aimed to investigate the impact on pancreatic cancer care. METHODS: All patients diagnosed with pancreatic cancer between 2017 and 2020 were selected from the Netherlands Cancer Registry. Patients diagnosed and/or treated in 2020 were compared to 2017-2019. Monthly incidence was calculated. Patient, tumor and treatment characteristics were analyzed and compared using Chi-squared tests. Survival data was analyzed using Kaplan-Meier and Log-rank tests. RESULTS: In total, 11019 patients were assessed. The incidence in quarter (Q)2 of 2020 was comparable with that in Q2 of 2017-2019 (p = 0.804). However, the incidence increased in Q4 of 2020 (p = 0.031), mainly due to a higher incidence of metastatic disease (p = 0.010). Baseline characteristics, surgical resection (15% vs 16%; p = 0.466) and palliative systemic therapy rates (23% vs 24%; p = 0.183) were comparable. In 2020, more surgically treated patients received (neo)adjuvant treatment compared to 2017-2019 (73% vs 67%; p = 0.041). Median overall survival was comparable (3.8 vs 3.8 months; p = 0.065). CONCLUSION: This nationwide study found a minor impact of the COVID-19 pandemic on pancreatic cancer care and outcome. The Dutch health care system was apparently able to maintain essential care for patients with pancreatic cancer.

Fecal levels of SCFA and BCFA during capecitabine in patients with metastatic or unresectable colorectal cancer.

BACKGROUND: Gut bacteria-derived short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are considered to have beneficial metabolic, anti-inflammatory as well as anti-carcinogenic effects. Previous preclinical studies indicated bidirectional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. This study investigated the effect of three cycles of capecitabine on fecal SCFA and BCFA levels and their associations with tumor response, nutritional status, physical performance, chemotherapy-induced toxicity, systemic inflammation and bacterial abundances in patients with colorectal cancer (CRC). METHODS: Forty-four patients with metastatic or unresectable CRC, scheduled for treatment with capecitabine (± bevacizumab), were prospectively enrolled. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2) and after (T3) three cycles of capecitabine. Tumor response (CT/MRI scans), nutritional status (MUST score), physical performance (Karnofsky Performance Score) and chemotherapy-induced toxicity (CTCAE) were recorded. Additional data on clinical characteristics, treatment regimen, medical history and blood inflammatory parameters were collected. Fecal SCFA and BCFA concentrations were determined by gas chromatography-mass spectrometry (GC-MS). Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. RESULTS: Fecal levels of the SCFA valerate and caproate decreased significantly during three cycles of capecitabine. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance and chemotherapy-induced toxicity were not significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At all time points, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. CONCLUSIONS: The present study provided first indications for a potential role of SCFA and BCFA during capecitabine treatment as well as implications for further research. TRIAL REGISTRATION: The current study was registered in the Dutch Trial Register (NTR6957) on 17/01/2018 and can be consulted via the International Clinical Trial Registry Platform (ICTRP).

Cannabinoid consumption among cancer patients receiving systemic anti-cancer treatment in the Netherlands.

PURPOSE: Despite the inconclusiveness regarding health effects of cannabinoids among cancer patients, studies from non-European countries suggest that the medical-intended consumption of such products by this patient group is significant. The current study analyses cannabinoid usage among oncology patients receiving systemic treatment in the Netherlands. METHODS: The current study included adult patients receiving intravenous systemic therapy at Maastricht Comprehensive Cancer Centre, for a solid malignancy. Participants were asked to complete an anonymous questionnaire including questions on demographic variables, clinical variables and cannabinoid consumption. RESULTS: A total of 153 patients with solid cancer were included in this study. Almost 25% reported usage of cannabinoids for medical purposes, with 15% of the patients currently using the substance. Additionally, 18% of non-users considered future medical usage. In 48% of the cases, consumption was reported by the oncologist. The proposed anti-cancer effect was reported by 46% of the users as motivation for consumption. Current users were mainly palliative patients and 54% of the users were undergoing immunotherapy. Intention of treatment and type of therapy were predictive factors for consumption. Cannabinoid-oil was the most frequently used way of consumption. CONCLUSION: This study underlines the high number of cannabinoid users among oncology patients in the Netherlands in presumed absence of clinical guidance. It highlights the essence of a pro-active role of the clinician, assessing cannabinoid usage and educating the patients on the most recent evidence regarding its potential benefits and risks. Further studies on clinical decision making and efficacy of cannabinoids are recommended, to improve clinical guidance.

PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma.

BACKGROUND AND AIMS: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)-a novel prognostic biomarker-describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers (high vs low NFD). NFD is different than perineural invasion (PNI), defined as nerve fiber trunks invaded by cancer cells. Here, we aim to explore differences in immune cell populations and survival between high and low NFD patients. APPROACH AND RESULTS: We applied multiplex immunofluorescence (mIF) on 47 pCCA patients and investigated immune cell composition in the tumor microenvironment (TME) of high and low NFD. Group comparison and oncological outcome analysis was performed. CD8+PD-1 expression was higher in the high NFD than in the low NFD group (12.24 × 10-6 vs. 1.38 × 10-6 positive cells by overall cell count, p = 0.017). High CD8+PD-1 expression was further identified as an independent predictor of overall (OS; Hazard ratio (HR) = 0.41; p = 0.031) and recurrence-free survival (RFS; HR = 0.40; p = 0.039). Correspondingly, the median OS was 83 months (95% confidence interval (CI): 18-48) in patients with high CD8+PD-1+ expression compared to 19 months (95% CI: 5-93) in patients with low CD8+PD-1+ expression (p = 0.018 log rank). Furthermore, RFS was significantly lower in patients with low CD8+PD-1+ expression (14 months (95% CI: 6-22)) compared to patients with high CD8+PD-1+ expression (83 months (95% CI: 17-149), p = 0.018 log rank). CONCLUSIONS: PD-1+ T-cells correlate with high NFD as a prognostic biomarker and predict good survival; the biological pathway needs to be investigated.

Treatment and overall survival of four types of non-metastatic periampullary cancer: nationwide population-based cohort study.

BACKGROUND: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin. METHODS: Patients diagnosed with non-metastatic periampullary cancer in 2012-2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan-Meier analysis and multivariable Cox regression analyses, stratified by origin. RESULTS: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55-0.69) and DC (HR = 0.69; 95% CI 0.48-0.98), but not AC (HR = 0.87; 95% CI 0.62-1.22) and DA (HR = 0.85; 95% CI 0.48-1.50). CONCLUSION: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA.

Physical Activity Is Associated with Improved Overall Survival among Patients with Metastatic Colorectal Cancer.

Regular physical activity (PA) is associated with improved overall survival (OS) in stage I-III colorectal cancer (CRC) patients. This association is less defined in patients with metastatic CRC (mCRC). We therefore conducted a study in mCRC patients participating in the Prospective Dutch Colorectal Cancer cohort. PA was assessed with the validated SQUASH questionnaire, filled-in within a maximum of 60 days after diagnosis of mCRC. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week. American College of Sports and Medicine (ACSM) PA guideline adherence, tertiles of moderate to vigorous PA (MVPA), and sport and leisure time MVPA (MVPA-SL) were assessed as well. Vital status was obtained from the municipal population registry. Cox proportional-hazards models were used to study the association between PA determinants and all-cause mortality adjusted for prognostic patient and treatment-related factors. In total, 293 mCRC patients (mean age 62.9 ± 10.6 years, 67% male) were included in the analysis. Compared to low levels, moderate and high levels of MET-hours were significantly associated with longer OS (fully adjusted hazard ratios: 0.491, (95% CI 0.299-0.807, p value = 0.005) and 0.485 (95% CI 0.303-0.778, p value = 0.003), respectively), as were high levels of MVPA (0.476 (95% CI 0.278-0.816, p value = 0.007)) and MVPA-SL (0.389 (95% CI 0.224-0.677, p value < 0.001)), and adherence to ACSM PA guidelines compared to non-adherence (0.629 (95% CI 0.412-0.961, p value = 0.032)). The present study provides evidence that higher PA levels at diagnosis of mCRC are associated with longer OS.

The Role of Intestinal Microbiota in Metastatic Colorectal Cancer Patients Treated With Capecitabine.

BACKGROUND: Previous pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment. PATIENTS AND METHODS: Patients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region. RESULTS: Thirty-three patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. Of the 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (ß-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine. CONCLUSION: This is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.

Real-world evidence of adjuvant gemcitabine plus capecitabine vs gemcitabine monotherapy for pancreatic ductal adenocarcinoma.

The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR: 0.71, 95% CI 0.56-0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57-0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.

Trends in Use and Perceptions About Triplet Chemotherapy Plus Bevacizumab for Metastatic Colorectal Cancer.

Importance: Triplet chemotherapy with fluorouracil, folinic acid, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-B) is an effective first-line treatment option for patients with metastatic colorectal cancer (mCRC). However, the degree of implementation of FOLFOXIRI-B in daily practice is unknown. Objectives: To evaluate the current adoption rate of FOLFOXIRI-B in patients with mCRC and investigate the perspectives of medical oncologists toward this treatment option. Design, Setting, and Participants: This 1-week, multicenter, cross-sectional study in the Netherlands used a flash mob design, which facilitates ultrafast data generation (flash) through the engagement of numerous researchers (mob). During the study week (March 1-5, 2021), patient data were retrieved from electronic health records of 47 hospitals on patients with mCRC who were referred to a medical oncologist between November 1, 2020, and January 31, 2021. Interviews were simultaneously conducted with 101 medical oncologists from 52 hospitals who regularly treat patients with mCRC. Exposure: First-line systemic treatment as determined by the treating physician. Main Outcomes and Measures: The FOLFOXIRI-B prescription rate was the main outcome. Current practice was compared with prescription rates in 2015 to 2018. Eligibility for treatment with FOLFOXIRI-B was estimated. An exploratory outcome was medical oncologists' reported perspectives on FOLFOXIRI-B. Results: A total of 5948 patients in the Netherlands (median age [interquartile range], 66 [57-73] years; 3503 [59%] male; and 3712 [62%] with left-sided or rectal tumor) were treated with first-line systemic therapy for synchronous mCRC. A total of 282 patients with mCRC underwent systemic therapy during the study period (2021). Of these 282 patients, 199 (71%) were treated with intensive first-line therapy other than FOLFOXIRI-B, of whom 184 (65%) were treated with oxaliplatin doublets with or without bevacizumab; 14 (5%) with irinotecan doublets with or without bevacizumab, panitumumab, or cetuximab; and 1 (0.4%) with irinotecan with bevacizumab. Fifty-four patients (19%) were treated with fluoropyrimidine monotherapy with or without bevacizumab, 1 patient (0.4%) with panitumumab monotherapy, and 3 (1%) with immune checkpoint inhibitors. In total, 25 patients (9%; 95% CI, 6%-12%) were treated with first-line FOLFOXIRI-B compared with 142 (2%; 95% CI, 2%-3%) in 2015 to 2018. During the study period, 21 of 157 eligible patients (13.4%) in the Netherlands were treated with FOLFOXIRI-B. A total of 87 medical oncologists (86%) reported discussing FOLFOXIRI-B as a treatment option with eligible patients. A total of 47 of 85 (55%) generally communicated a preference for a chemotherapy doublet to patients. These oncologists reported a significantly lower awareness of guidelines and trial results. Toxic effects were the most reported reason to prefer an alternative regimen. Conclusions and Relevance: The findings of this study suggest that FOLFOXIRI-B prescription rates have marginally increased in the last 5 years. Considering that most medical oncologists discuss this treatment option, the prescription rate found in this study was below expectations. Awareness of guidelines and trial data seems to contribute to the discussion of available treatment options by medical oncologists, and the findings of this study suggest a need for repeated and continuing medical education.

A population-based study on incidence, treatment, and survival in ampullary cancer in the Netherlands.

INTRODUCTION: Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016. METHODS: Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease. RESULTS: In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010-2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients. CONCLUSION: Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy.

Nationwide treatment and outcomes of perihilar cholangiocarcinoma.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) is a rare tumour that requires complex multidisciplinary management. All known data are almost exclusively derived from expert centres. This study aimed to analyse the outcomes of patients with pCCA in a nationwide cohort. METHODS: Data on all patients diagnosed with pCCA in the Netherlands between 2010 and 2018 were obtained from the Netherlands Cancer Registry. Data included type of hospital of diagnosis and the received treatment. Outcomes included the type of treatment and overall survival. RESULTS: A total of 2031 patients were included and the median overall survival for the overall cohort was 5.2 (95% CI 4.7-5.7) months. Three-hundred-ten (15%) patients underwent surgical resection, 271 (13%) underwent palliative systemic treatment, 21 (1%) palliative local anti-cancer treatment and 1429 (70%) underwent best supportive care. These treatments resulted in a median overall survival of 29.6 (95% CI 25.2-34.0), 12.2 (95% CI 11.0-13.3), 14.5 (95%CI 8.2-20.8) and 2.9 (95% CI 2.6-3.2) months respectively. Resection rate was 13% in patients who were diagnosed in non-academic and 32% in academic centres (P < .001), which resulted in a survival difference in favour of academic centres. Median overall survival was 9.7 (95% CI 7.7-11.7) months in academic centres compared to 4.9 (95% CI 4.3-5.4) months in non-academic centres (P < .001). CONCLUSIONS: In patients with pCCA, resection rate and overall survival were higher for patients who were diagnosed in academic centres. These results show population-based outcomes of pCCA and highlight the importance of regional collaboration in the treatment of these patients.

Nerve fibers in the tumor microenvironment in neurotropic cancer-pancreatic cancer and cholangiocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are both deadly cancers and they share many biological features besides their close anatomical location. One of the main histological features is neurotropism, which results in frequent perineural invasion. The underlying mechanism of cancer cells favoring growth by and through the nerve fibers is not fully understood. In this review, we provide knowledge of these cancers with frequent perineural invasion. We discuss nerve fiber crosstalk with the main different components of the tumor microenvironment (TME), the immune cells, and the fibroblasts. Also, we discuss the crosstalk between the nerve fibers and the cancer. We highlight the shared signaling pathways of the mechanisms behind perineural invasion in PDAC and CCA. Hereby we have focussed on signaling neurotransmitters and neuropeptides which may be a target for future therapies. Furthermore, we have summarized retrospective results of the previous literature about nerve fibers in PDAC and CCA patients. We provide our point of view in the potential for nerve fibers to be used as powerful biomarker for prognosis, as a tool to stratify patients for therapy or as a target in a (combination) therapy. Taking the presence of nerves into account can potentially change the field of personalized care in these neurotropic cancers.

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors.

PURPOSE: To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. METHODS: In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. RESULTS: Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC0-t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0-t was contained within the no-effect limits (0.8-1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. CONCLUSION: A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

Trends in treatment and overall survival among patients with proximal esophageal cancer.

BACKGROUND: The management of proximal esophageal cancer differs from that of tumors located in the mid and lower part of the esophagus due to the close vicinity of vital structures. Non-surgical treatment options like radiotherapy and definitive chemoradiation (CRT) have been implemented. The trends in (non-)surgical treatment and its impact on overall survival (OS) in patients with proximal esophageal cancer are unclear, related to its rare disease status. To optimize treatment strategies and counseling of patients with proximal esophageal cancer, it is therefore essential to gain more insight through real-life studies. AIM: To establish trends in treatment and OS in patients with proximal esophageal cancer. METHODS: In this population-based study, patients with proximal esophageal cancer diagnosed between 1989 and 2014 were identified in the Netherlands Cancer Registry. The proximal esophagus consists of the cervical esophagus and the upper thoracic section, extending to 24 cm from the incisors. Trends in radiotherapy, chemotherapy, and surgery, and OS were assessed. Analyses were stratified by presence of distant metastasis. Multivariable Cox proportional hazards regression analyses was performed to assess the effect of period of diagnosis on OS, adjusted for patient, tumor, and treatment characteristics. RESULTS: In total, 2783 patients were included. Over the study period, the use of radiotherapy, resection, and CRT in non-metastatic disease changed from 53%, 23%, and 1% in 1989-1994 to 21%, 9%, and 49% in 2010-2014, respectively. In metastatic disease, the use of chemotherapy and radiotherapy increased over time. Median OS of the total population increased from 7.3 mo [95% confidence interval (CI): 6.4-8.1] in 1989-1994 to 9.5 mo (95%CI: 8.1-10.8) in 2010-2014 (logrank P < 0.001). In non-metastatic disease, 5-year OS rates improved from 5% (95%CI: 3%-7%) in 1989-1994 to 13% (95%CI: 9%-17%) in 2010-2014 (logrank P < 0.001). Multivariable regression analysis demonstrated a significant treatment effect over time on survival. In metastatic disease, median OS was 3.8 mo (95%CI: 2.5-5.1) in 1989-1994, and 5.1 mo (95%CI: 4.3-5.9) in 2010-2014 (logrank P = 0.26). CONCLUSION: OS significantly improved in non-metastatic proximal esophageal cancer, likely to be associated with an increased use of CRT. Patterns in metastatic disease did not change significantly over time.