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Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer diagnoses, and approximately 35% of patients with NSCLC are diagnosed at an early stage (I–IIIA). This study aimed to describe epidermal growth factor receptor (EGFR) testing, patient characteristics, and overall survival (OS) among patients with early-stage NSCLC in Denmark. Patients with early-stage NSCLC registered in the Danish Lung Cancer Registry in 2013–2018 were followed through 2019. We described EGFR testing, descriptively summarised patient characteristics, and calculated OS by EGFR testing and mutation status. The association between EGFR mutation (EGFRm) and all-cause mortality was estimated using Cox proportional-hazards regression, in subgroups defined by stage at diagnosis, age at diagnosis, comorbidity, and receipt of surgery. In 2013–2018, 21,282 patients with NSCLC were registered in the Danish Lung Cancer Registry, of whom 8758 were diagnosed at an early stage. Of those, 4071 (46%) were tested for EGFRm at diagnosis. Median OS was 5.7 years among patients with EGFRm-positive status (n = 361) and 4.4 years among patients with EGFRm-negative status (n = 3710). EGFRm-positive status was associated with lower all-cause mortality in all subgroups. This study contributes to population-based evidence on the epidemiology of early-stage NSCLC treated in routine clinical practice.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard-of-care first-line (1L) treatment for EGFR mutation-positive advanced/metastatic non-small cell lung cancer. In 2015, osimertinib, a third-generation EGFR-TKI, received US accelerated approval for second-line (2L) EGFR T790M-positive non-small cell lung cancer treatment. The objective of this US study was to characterize treatment patterns, attrition, and survival in EGFR mutation-positive non-small cell lung cancer, after 1L first-/second-generation EGFR-TKI treatment.We retrospectively analyzed 1029 patients diagnosed with stage IIIB/IV non-small cell lung cancer from 1 January, 2011 to 31 December, 2018 using the US electronic medical record CancerLinQ DiscoveryFrom 1 January, 2011 to 31 December, 2014 ( 2015 cohort), 519 patients received 1L EGFR-TKIs and 510 between 1 January, 2015 and 31 December, 2018 (≥ 2015 cohort). Median follow-up from advanced diagnosis was 19.8 months (interquartile range: 9.9-33.4 months). Twenty-eight percent of patients (288/1029) died without receiving 2L, and 52% (539/1029) initiated 2L with 35% (186/539) receiving osimertinib; in the 2015 and ≥ 2015 cohorts, the same proportion initiated 2L (52%; 272/519 vs 267/510, respectively). Median overall survival from advanced diagnosis for patients initially diagnosed with stage I-IIIA disease was 43.3 months (95% confidence interval 30.9-73.7), vs 26.4 months (95% confidence interval 24.4-28.1) for stage IIIB-IV; all-cause mortality hazard ratio: 1.56 (95% confidence interval 1.2-2.0; p = 0.001).We identified disease stage, performance status, and central nervous system metastasis as survival predictors, highlighting the importance of optimal 1L treatment selection. Over a quarter of patients died before initiating 2L; half progressed after 1L and received 2L, of whom a third received 2L osimertinib.

Purpose To investigate real-world clinical outcomes in patients with BRCA-mutated (BRCAm), HER2-negative metastatic breast cancer (mBC) according to BRCA and hormone receptor (HR) status. Methods Patients diagnosed with HER2-negative mBC between 01 January 2010 and 31 December 2018 were retrospectively identified from the American Society of Clinical Oncology’s CancerLinQ Discovery® database. Time to first subsequent therapy or death (TFST) from date of mBC diagnosis and start of first-line treatment for mBC and overall survival (OS) from date of mBC diagnosis were investigated according to BRCA status (BRCAm, BRCA wild type [BRCAwt] or unknown BRCA [BRCAu]) and HR status (positive/triple negative breast cancer [TNBC]). Follow-up continued until 31 August 2019 (i.e. minimum of 8 months). Results 3744 patients with HER2-negative mBC were identified (BRCAwt, n = 460; BRCAm, n = 83; BRCAu, n = 3201) (HR-positive, n = 2738). Median (Q1, Q3) age was 63.0 (54.0, 73.0) years. Median (95% confidence interval [CI]) TFST (months) from mBC diagnosis was as follows: HR-positive, 7.7 (5.0, 11.2), 8.3 (6.6, 10.2) and 9.4 (8.7, 10.1); TNBC, 5.4 (3.9, 12.4), 5.6 (4.7, 6.6) and 5.4 (5.0, 6.2) for BRCAm, BRCAwt and BRCAu, respectively. Median (95% CI) OS (months) was as follows: HR-positive, 41.1 (31.5, not calculable), 55.1 (43.5, 65.5) and 33.0 (31.3, 34.8); TNBC, 13.7 (11.1, not calculable), 14.4 (10.7, 17.0) and 11.7 (10.3, 12.8) for BRCAm, BRCAwt and BRCAu, respectively. Conclusion When stratified by HR status, TFST and OS were broadly similar for patients with HER2-negative mBC, irrespective of BRCA status. Further global real-world studies are needed to study outcomes of this patient population.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC). Objective Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs. Methods This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence. Results Among 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis. Conclusions Rates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00261-8.

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

Introduction: The preferred first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive (EGFRm) advanced/metastatic non-small lung cancer (NSCLC) are EGFR-tyrosine kinase inhibitors (TKIs). However, most patients treated with 1L first- or second-generation (1G/2G) EGFR-TKIs acquire resistance; the EGFR T790M mutation is observed in ~30–50% of patients. We report real-world NSCLC treatment and T790M testing patterns in South Korea and Taiwan. Methods: Retrospective medical record review of EGFRm advanced/metastatic NSCLC patients from routine practice. 1G/2G EGFR-TKI initiation 1 January 2015–31 December 2017 (follow-up end date: last available medical record or August 2019). Study measures: demographic/disease characteristics, 1L/2L treatment, T790M testing. Results: In South Korea, 70% (164/235) and in Taiwan 89% (89/100) experienced 1L disease progression (median [range] follow-up: 22 [2.3–50.7] months). Of those with disease progression, 68% (111/164) and 62% (55/89) had T790M testing in South Korea and Taiwan, respectively. In South Korea, 43% (48/111) were T790M-positive with 88% (n=42/48) receiving osimertinib (mostly 2L). In Taiwan, 18% (10/55) were T790M-positive; 100% received osimertinib. Overall, 73% (120/164) and 63% (63/100) in South Korea and Taiwan, respectively, received 2L therapy, predominantly pemetrexed-containing regimens. Among patients with disease progression, 9% (14/164) and 24% (21/89) died before receiving 2L therapy in South Korea and Taiwan, respectively. Conclusion: In both countries

Epidermal growth factor receptor (EGFR) mutations (EGFRm) are common oncogene drivers in non-small cell lung cancer (NSCLC). This real-world study explored treatment patterns and time to receive EGFRm test results in patients with advanced EGFRm NSCLC.A cross-sectional medical chart review was completed May-August 2020 in Australia, Canada, Germany, Italy, South Korea, Taiwan, UK, and USA. Eligible patients had advanced NSCLC and a positive EGFRm test result January-December 2017. Data were abstracted from NSCLC diagnosis to end of follow-up (31 March 2020) or patient's death whichever occurred earlier. The index date was the date of EGFRm confirmation.223 physicians provided data for 1,793 patients. Patients' mean age was 64.7 years, 54 % were male, 30.7 % had no history of smoking. Overall, 78 % of EGFRm test results were received ≤ 2 weeks after request (range of median 7-14 days across countries). Median time from advanced NSCLC diagnosis to EGFRm test result was 18 days (median range 10-22 days across countries). Over a third (37 %) of patients received a systemic treatment prior to EGFRm result; chemotherapy (25 %) and EGFR-TKI (15 %) were most commonly prescribed; post-EGFR test-result was EGFR-TKI (68 %); 80 % of patients initiated EGFR-TKI at any time point post-NSCLC diagnosis. Of those receiving a first-line EGFR-TKI post-EGFRm testing, 84 % received a TKI alone, 12 % in combination with chemotherapy, and 3 % with other treatments. Median time from first-line EGFR-TKI initiation post-EGFRm testing to first subsequent treatment was 19.8 months.Over one-fifth of patients wait14 days for their EGFRm test results, affecting their likelihood of receiving first-line EGFR-TKI with 20 % of patients never receiving EGFR TKI treatment. There was significant inter-country variability in the proportion of patients receiving EGFR TKIs. Our study highlights the need to improve EGFRm testing turnaround times and treatment initiation across countries.

Background: Limited epidemiological data exist on the real-world outcomes in patients with BRCA-mutated (BRCAm), HER2− metastatic breast cancer (mBC). This study describes clinical outcomes in this population according to germline BRCA mutation (gBRCAm) and hormone receptor (HR) status. Methods: Patients diagnosed with HER2− mBC between January 1, 2010 and December 31, 2018 were retrospectively selected from the American Society of Clinical Oncology (ASCO)’s CancerLinQ Discovery® database. The primary objective was to describe, as a surrogate for progression-free survival, the time to first subsequent therapy or death (TFST; whichever came first), calculated from date of mBC diagnosis, according to gBRCAm status (gBRCAm, gBRCA wild-type [gBRCAwt] or unknown gBRCA [gBRCAu]) and HR status (+/−). TFST was also calculated from first-line systemic therapy initiation. The secondary objective was to describe overall survival (OS), calculated from date of mBC diagnosis. Kaplan-Meier medians and 95% confidence intervals (CIs) were estimated. Results: 3744 patients with HER2− mBC were identified (gBRCAwt, n=460; gBRCAm, n=83; gBRCAu, n=3201); 2738 patients were HR+. Median (Q1, Q3) age was 63.0 (54.0, 73.0) years. Median (95% CI) TFST (months), calculated from date of mBC diagnosis, was 9.2 (8.6, 9.9) in HR+ patients, 5.4 (5.1, 6.0) in HR− patients, and 7.1 (5.0, 9.2), 6.9 (6.1, 8.1) and 8.4 (7.9, 9.1) in gBRCAm, gBRCAwt and gBRCAu cohorts, respectively. Median (95% CI) OS (months) was 34.30 (32.70, 36.40) in HR+ patients, 12.0 (11.1, 13.3) in HR− patients, and 31.5 (23.1, 42.8), 34.7 (28.9, 44.5), 27.6 (26.1, 29.5) in gBRCAm, gBRCAwt and gBRCAu cohorts, respectively. Median TFST and OS stratified by both HR and BRCA mutation status are shown in Table 1. Conclusions: When stratified by HR status, median TFST and OS were broadly similar for patients with mBC, regardless of BRCA mutation status, as captured in the CancerLinQ Discovery® database. Outcomes may have been affected by class of first-line treatment received in a time preceding poly (ADP-ribose) polymerase inhibitor introduction as a targeted treatment for BRCAm patients. Further studies will be required to support these findings. Funding: This study was funded by AstraZeneca. Table 1. Median TFST and OSCohort TFST, n (events)a,bMedian TFST from mBC diagnosis, months (95% CI)Median TFST from first-line treatment initiation, months (95% CI)OS, n (events)aMedian OS, months(95% CI)gBRCAm, HR+(n=47)45 (40)7.7 (5.0, 11.2)6.6 (3.2, 9.0)47 (21)41.1 (31.5, NR)gBRCAm, HR−(n=29)20 (19)5.4 (3.9, 12.4)3.1 (2.2, 8.9)29 (18)13.7 (11.1, NR)gBRCAwt, HR+(n=296)277 (234)8.3 (6.6, 10.2)6.5 (5.7, 8.7)296 (128)55.1 (43.5, 65.5)gBRCAwt, HR−(n=130)113 (101)5.6 (4.7, 6.6)4.1 (3.4, 5.2)130 (91)14.4 (10.7, 17.0)gBRCAu, HR+(n=2395)2174 (1949)9.4 (8.7, 10.1)7.3 (6.9, 8.0)2395 (1431)33.0 (31.3, 34.8)gBRCAu, HR−(n=609)466 (425)5.4 (5.0, 6.2)4.2 (3.7, 4.6)609 (448)11.7 (10.3, 12.8)an refers to the number of patients at risk.bFor patients with no indication of a further line of therapy or death, TFST was censored at the last activity date.CI, confidence interval; gBRCAm, germline BRCA-mutated; gBRCAu, unknown germline BRCA mutation; gBRCAwt, germline BRCA wild-type; HR, hormone receptor; NR, not reached; OS, overall survival; TFST, time to first subsequent therapy or death. Citation Format: Robert S Miller, Stella Mokiou, Aliki Taylor, Miao Jiang, Ping Sun, Susan McCutcheon. Real-world clinical outcomes of patients with BRCA-mutated (BRCAm) HER2-negative metastatic breast cancer: A CancerLinQ® study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-66.

Introduction Celiac disease (CeD) is a lifelong immune-mediated enteropathy in which dietary gluten triggers an inflammatory reaction in the small intestine. This retrospective cohort study examines healthcare resource utilization (HRU) and costs between patients with CeD and matched controls. Methods Patients with CeD (cases) with an endoscopic biopsy and ≥2 medical encounters with a CeD diagnosis between January 1, 2010, and October 1, 2015, were identified in the MarketScan databases. The date of the first claim with a CeD diagnosis on or after the endoscopic biopsy was the index date. Cases were matched 1:1 to patients without CeD (controls) on demographic characteristics and Deyo-Charlson Comorbidity Index score. Clinical characteristics, all-cause, and CeD-related HRU and costs (adjusted to 2017 US dollars) were compared between cases and controls during the 12 months before (baseline) and 24 months after (follow-up) the index date. Results A total of 11,008 cases (mean age 40.6 years, 71.3% women) were matched to 11,008 controls. During the follow-up, a higher proportion of cases had all-cause and CeD-related HRU including inpatient admissions, emergency department visits, gastroenterologist visits, dietician visits, endoscopic biopsies, and gastroenterology imaging (all P ≤ 0.002). Incremental all-cause and CeD-related costs were in the first ($7,921 and $2,894) and second ($3,777 and $935) year of follow-up, driven by outpatient services costs. Discussion In this US national claims database analysis, there was evidence of an increase in both all-cause and CeD-related HRU and related costs in patients with CeD compared with matched patients without CeD, suggesting a significant economic burden associated with CeD.

Background In diseases where there is a large subjective component, such as celiac disease (CD), patient reported-outcomes (PRO) endpoints are highly relevant. However, there is a gap in knowledge about which PRO endpoints and instruments should be used for clinical trials for treatment of celiac disease. Objectives To identify patient-centered symptom, impact, and health-related quality of life (HRQoL) concepts in CD and relevant PRO instruments, and to gather expert input on concepts and instruments to inform selection of PRO endpoints for use in clinical trials of new CD treatments. Methods A targeted literature review was conducted to identify symptom, impact, and HRQoL concepts, including those captured in PROs further reviewed against U.S. Food and Drug Administration standards for development and validation as endpoints. US and European clinicians, payers, and a patient advocate (n = 21) were interviewed to assess the identified concepts’ relative importance in measuring treatment benefit and to gauge the value of potential PROs as endpoints for market access/reimbursement. Results Thirty-four published studies were identified: 27 elucidated patient-centered concepts and 7 detailed the development or validation of PRO instruments. The Celiac Disease Symptom Diary and Celiac Disease Patient Reported Outcome instrument were deemed most appropriate for use as endpoints; however, each had limitations related to conceptual coverage, evidence for measurement properties, and feasibility for use in clinical trials. Experts reported gastrointestinal symptoms as most important to treat, with extra-intestinal symptoms burdensome from the patient perspective as well. Payers emphasized measuring both frequency and severity of symptoms and targeting patients nonresponsive to the gluten-free diet for treatment. Conclusions With emerging treatment options for CD, further work is needed to operationalize PRO symptom endpoints that are meaningful to patients, valued by payers, and acceptable to regulators in demonstrating efficacy.

Most patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) acquire resistance to first-line (1L) first- or second-generation (1G/2G) EGFR-TKIs; therefore, it is important to optimize 1L treatment to improve patient outcomes. To retrospectively examine treatment patterns in locally advanced/metastatic NSCLC using MarketScan® Commercial and Medicare Supplemental Databases (all US census regions). Adults with a lung cancer diagnosis code between 1 January 2015–31 March 2018 were analyzed from diagnosis (index) through a variable-length follow-up. Patients had ≥ 1 pharmacy claim for 1G/2G EGFR-TKIs on or within 60 days post-index. Data were stratified by presence or absence of central nervous system (CNS) metastases (30 days pre-index through study end). 578 patients were included (median age 63 years, 64% female). Median follow-up was 13.5 months. The most frequently prescribed 1L EGFR-TKI was erlotinib (414/578, 72%). Median time to 1L treatment discontinuation was 8.2 (95% confidence interval (CI) 6.9, 9.0) months in patients diagnosed with CNS metastases at any time, and 7.7 (95% CI 6.9, 8.9) months in patients without CNS metastases. 270/578 patients (47%) discontinued 1L EGFR-TKIs; 209/270 (77%) initiated second-line (2L) therapy, most frequently osimertinib (96/209, 46%). In an analysis of US claims data, nearly half of patients discontinued 1L EGFR-TKIs, and 46% who initiated 2L received osimertinib. As nearly a quarter of patients who discontinued 1L EGFR-TKIs did not receive 2L treatment, this study highlights the need for optimal 1L treatment in EGFRm locally advanced/metastatic NSCLC.

PURPOSE In 2014, the ASCO developed CancerLinQ (CLQ), a health technology platform for oncology. The CLQ Discovery (CLQD) database was created to make data available for research and this paper provides a summary of this database. METHODS This study described the clinical and demographic characteristics of the 12 most common cancers in the CLQD database. We included patients with a new malignant tumor diagnosis between January 1, 2013, and December 31, 2018, of the following cancers: breast, lung and bronchus, prostate, colon and rectum, melanoma of the skin, bladder, non-Hodgkin lymphoma, kidney and renal pelvis, uterus, leukemia, pancreas, and thyroid. Patients with an in-situ diagnosis were excluded. Summary statistics and Kaplan-Meier survival estimates were calculated for each tumor. RESULTS From 2013 to 2018, 491,360 patients were diagnosed with the study tumors. Breast cancer (139,506) was the most common, followed by lung and bronchus (70,959), prostate (63,303), and colon and rectum (53,504). The median age at diagnosis (years) was 61, 68, 68, and 64 in breast, lung and bronchus, prostate, and colon and rectum cohorts, respectively. Compared to the SEER 5-year overall survival estimates for several tumor types were higher in the CLQD database, possibly because of incomplete mortality capture in electronic health records. CONCLUSION This paper presents the first description of the CLQD database since its inception. CLQ will continue to evolve over time, and the breadth and depth of this data asset will continue to grow. ASCO and CLQ's long-term goal is to improve the quality of patient care and create a sustainable database for oncology researchers. These results demonstrate that CLQ built a scalable database that can be used for oncology research.

Graft-versus-host disease (GVHD) is the leading cause of nonrelapse mortality among patients who receive allogeneic hematopoietic cell transplantation (allo-HCT). In its acute form (aGVHD), GVHD involves the skin, liver, and gastrointestinal (GI) tract, with GI involvement most strongly associated with poor prognosis. This retrospective cohort study used US healthcare claims data for 2008 to 2015 to identify patients who developed GI aGVHD after allo-HCT performed as curative treatment for hematologic malignancy and compared them with patients who did not develop aGVHD in terms of outcomes related to survival, infections, healthcare resource utilization (HRU), and costs. Whereas the patients without aGVHD saw a 66% improvement in 1-year survival between 2009 and 2015, this effect was not observed in patients with GI aGVHD. Compared with patients without evidence of aGVHD, patients with GI aGVHD were 3.9-fold more likely to develop an infection in the year after allo-HCT. Similarly, patients who developed GI aGVHD were 4.3-fold more likely to have an inpatient admission after allo-HCT discharge, and such an admission cost on average 47% more than an admission for patients without aGVHD. Our findings confirm that GI involvement in aGVHD is associated with higher mortality, risk of infection, HRU, and cost compared with absence of aGVHD.

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in patients with hematologic malignancies but carries a significant risk of graft-versus-host disease (GVHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GVHD (aGVHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treating SR GI aGVHD. Data were collected from patients' medical records; criteria for extraction included no more than 1 allo-HCT and at least 1 dose of vedolizumab as treatment for SR GI aGVHD (ie, stage 1 to 4 GI aGVHD following ≥1 previous treatment regimen(s) containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites who had received 1 to 10 doses of vedolizumab 300 mg i.v. (median 3 doses) as treatment for SR GI aGVHD. The overall response rate at 6 to 10 weeks after vedolizumab initiation was 64%, and OS at 6 months was 54%. There were 29 SAEs, including 12 infections; 3 SAEs were considered possibly related to vedolizumab, 2 of which were infections. Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 nonserious infections and 1 serious infection with confirmed GI origin in 8 patients; there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting from prospective trials are needed. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:4 pages:720-727 ispartof: location:United States status: published

Celiac disease (CD) is an immune-mediated gastrointestinal (GI) disorder driven by innate and adaptive immune responses to gluten. Presentation of CD has changed over time, with non-GI symptoms, such as anemia and osteoporosis, presenting more commonly. With improved screening and diagnostic methods, the reported prevalence of CD has increased globally, and there is considerable global variation in diagnostic and treatment practices. The objective of this study was to describe the current state of CD diagnosis and treatment patterns. A targeted review of literature from MEDLINE, Embase, the Cochrane Library, and screening of relevant conference abstracts was performed. The generally recommended diagnostic approach is GI endoscopy with small bowel biopsy; however, in selected patients, biopsy may be avoided and diagnosis based on positive serology and clinical symptoms. Diagnosis often is delayed; the average diagnostic delay after symptom onset is highly variable and can last up to 12 years. Barriers to accurate and timely diagnosis include atypical presentation, lack of physician awareness about current diagnostic criteria, misdiagnosis, and limited access to specialists. Currently, strict adherence to a gluten-free diet (GFD) is the only recommended treatment, which is not successful in all patients. Only one-third of patients are monitored regularly following diagnosis. Unmet needs for CD include improvements in the accuracy and timeliness of diagnosis, and the development of treatments for both refractory CD and GFD nonresponsive CD. Further research should investigate the impact of education about gluten-free eating and the availability of gluten-free foods support adherence and improve outcomes in patients with CD.

Mutations in exons 18-21 of the epidermal growth factor receptor gene (EGFR) can confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer (NSCLC). Deletions in exon 19 or the exon 21 L858R substitution comprise approximately 85% of mutations, but comparatively few data are available on the remaining "uncommon" mutations. We conducted a systematic literature review to identify evidence on uncommon EGFR mutations in locally advanced/metastatic NSCLC (PROSPERO registration number: CRD42019126583). Electronic screening and congress searches identified studies published in 2012-2020 including patients with locally advanced/metastatic NSCLC and uncommon EGFR mutations (excluding T790M). We assessed the prevalence of uncommon mutations (in studies using direct sequencing of exons 18-21), and compared response to treatment and progression-free survival (PFS) in patients with common versus uncommon mutations and in those with exon 20 mutations versus other uncommon mutations. We identified 64 relevant studies. Uncommon mutations constituted 1.0-18.2% of all EGFR mutations, across 10 studies. The most frequently reported uncommon mutations were G719X (0.9-4.8% of all EGFR mutations), exon 20 insertions (Ex20ins; 0.8-4.2%), L861X (0.5-3.5%), and S768I (0.5-2.5%). Patients with common mutations typically experienced better treatment response and longer PFS on EGFR-TKIs than patients with uncommon mutations; Ex20ins mutations were associated with less favourable outcomes than other uncommon mutations. This review shows that uncommon mutations may comprise a clinically significant proportion of the EGFR mutations occurring in NSCLC, and highlights disparities in EGFR-TKI sensitivity between different uncommon mutations.

The prevalence of celiac disease (CD) has rapidly increased over recent decades, but costs related to CD remain poorly quantified. This systematic review assessed the economic burden of CD in North America and Europe. MEDLINE, EMBASE, EconLit, and the Cochrane Library databases were systematically searched to identify English-language literature from 2007 to 2018 that assessed costs, cost effectiveness, and health resource utilization for CD. Forty-nine studies met the inclusion criteria, of which 28 (57.1%) addressed costs of testing and diagnosis; 33 (67.3%) were from Europe. The cost per positive CD diagnosis of testing patients already undergoing esophagogastroduodenoscopy for other indications ranged from 1300 Canadian dollars ($Can) in Canada (2016 value) to €44,712 in the Netherlands (2013 value). Adding the CD test was cost effective when it combined diagnostic modalities (e.g., serology and biopsy). Direct annual excess costs to a US payer per diagnosed CD patient totaled $US6000 (2013 value) more than for a person without CD, chiefly due to outpatient care. Hospitalizations, emergency visits, and medication use were more common with CD. After initiating a gluten-free diet (GFD), patients visited primary care providers less often, used more medications, and missed fewer days from school and work. Most of the few available economic studies of CD assess testing and diagnosis costs, especially in Europe. Methods of testing generally are considered cost effective when they combine diagnostic modalities in symptomatic patients. Most costs to a payer of managing CD derive from outpatient care. Following GFD initiation, patients lose fewer days from work and school than pretreatment.

Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This 6(th) paper in the series (see box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes and their implications and challenges. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, wellbeing and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and to obtain valid and precise results. As pragmatic trials are often open-label a less subjective outcome can reduce bias. Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making as well as feasible in terms of executing the trial in the context of interest. Therefore this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.

A systematic literature review was conducted to quantify populations of patients with primary breast cancer in whom bone metastases were detected at study start or during follow-up. Searches were performed in PubMed and EMBASE using terms related to breast cancer and bone metastases. Articles had to have been published 01/01/99–31/12/13, and to report data on the proportion of patients with bone metastases among patients with breast cancer. In total, 156 articles were included in the meta-analysis. A median of 12% of patients with stage I–III breast cancer developed bone metastases during a median follow-up of 60 months. Of patients who developed metastatic disease during follow-up, 55% (median) had bone metastases. Of those with metastatic breast cancer at study start, 58% (median) had bone metastases. These data help to inform on the global burden of bone metastases by defining patient populations that are at risk of developing bone metastases., SCOPUS: re.j, info:eu-repo/semantics/published

There is limited comparative evidence of the outcomes of different types of surgical management in patients with malignant melanoma in Europe. To address that gap we conducted a systematic literature review to summarize studies reporting outcomes of surgical procedures in patients with malignant melanoma in Europe. Medline was searched for European studies published in English, between 2004 and 2014 reporting surgical outcomes in adults with cutaneous malignant melanoma. We identified 23 studies that evaluated 18 332 patients treated surgically between 1979 and 2009 from 11 European countries. Most of the studies (21/23) were observational; the two remaining studies were randomized controlled trials (RCTs). Studies compared the effect of a range of surgical interventions on a range of clinical outcomes, more commonly overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Wider excisions were not associated with improved survival in patients with melanoma thickness ≥2 mm in both studies (RCTs), however, recent results based on long-term follow-up data associate 3 cm excision margins (vs. 1 cm) with favourable survival outcomes. There was some evidence that complete lymph node dissection after positive sentinel lymph node offers survival benefits over therapeutic lymph node dissection. Sentinel lymph node biopsy was not shown to be associated with significant OS benefits, however, it was overly related with higher rates of DFS/RFS. This review highlights the difficulties of making comparisons between different types of surgical procedures for malignant melanoma. As surgery remains the main treatment, this is an important field, and further evidence, particularly from RCTs, is needed.

ObjectivesNon-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases.MethodsWe conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions.ResultsWe identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials.ConclusionsThere has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies.

Cutaneous malignant melanoma (CMM) incidence is increasing globally, making a thorough understanding of the disease and its outcomes essential for optimizing care. In this population-based, retrospective study, we investigated stage-specific survival and recurrence/progression rates of CMM among patients diagnosed in Stockholm County Council during 2005-2012, before the wide introduction of targeted therapy. A total of 3554 CMM patients from the Stockholm Melanoma Register were included. Information on comorbidities, progression, death, and treatments was obtained from nationwide registers and hospital electronic medical records. Unadjusted five-year survival varied from 91.4% for stage I to 24.6% for stage IV patients. Stage, age and gender were predictors of survival, with gender an independent predictor of survival for stages IA and IIA. 74.6% of patients remained recurrence/progression-free during follow-up, with five-year recurrence/progression-free survival rates varying from 85.3% to 12.9% among stage I and IV patients, respectively. In addition to stage, male gender, age, and circulatory system comorbidities increased the risk for recurrence/progression. No statistically significant differences in progression rate for operated and non-operated patients could be detected, possibly due to high rate (98.9%) of surgery. Our estimates of survival and recurrence rates are consistent with historical and global expectations and can serve as a baseline to gauge population-level improvements with use of novel melanoma treatments. This article is protected by copyright. All rights reserved.

7064 Background: Overall survival (OS) is the gold standard outcome in clinical cancer research but many clinical trials cannot assess long-term OS. Real-world data sources can be used to calculate long-term OS, but only if vital status is accurately captured. Methods: The primary goal was to assess concordance of death dates from CLQD and an external source, and the effect of incorporation of external death data on estimates of OS. CLQD obtains electronic medical record (EMR) data from participating US oncology sites. Under-reporting of vital status is a common problem with EMR data; we investigated the value of including death data from a commercially available database, obituarydata.com (OBD) into CLQD. OBD pulls death data from published obituaries across the US. A matching algorithm is used to match patients in CLQD and OBD. OBD death data from breast, lung, ovarian, and pancreatic cancer patients diagnosed between 2010–2018 supplemented the CLQD in this study. OS was calculated using Kaplan-Meier estimation; Pearson correlation was used for comparing time to death. Results: The addition of OBD modestly changes OS estimates (see Table). Among a subset of patients with death dates in both CQLD and OBD, dates were highly correlated for breast (r = 0.98), lung (r = 0.93), ovarian (r = 0.99), and pancreatic (r = 0.88) cancers. When date differences existed, they were ≤10 days for > 95% of the patients. These results suggest death dates are reliable in CLQD EMRs. OS curves were as expected, with OS decreasing by stage and age at diagnosis. Conclusions: Incorporating OBD modestly improves OS estimates and shows that when death data is present in CLQD, it is reliable. Future enhancements will focus on improving sensitivity of mortality ascertainment with external data linkages, without compromising specificity. [Table: see text]

Bone is the most common metastatic site associated with breast cancer. Using a database of women with breast cancer treated at Guy's Hospital, London 1976-2006 and followed until end 2010, we determined incidence of and survival after bone metastases.We calculated cumulative incidence of bone metastases considering death without prior bone metastases as a competing risk. Risk of bone metastases was modelled through Cox-regression. Survival after bone metastases diagnosis was calculated using Kaplan-Meier methodology.Of the 7064 women, 589 (22%) developed bone metastases during 8.4 years (mean). Incidence of bone metastases was significantly higher in younger women, tumour size5 cm, higher tumour grade, lobular carcinoma and ≥ four positive nodes, but was not affected by hormone receptor status. Median survival after bone metastases diagnosis was 2.3 years in women with bone-only metastases compared with1 year in women with visceral and bone metastases. There was a trend for decreased survival for patients who developed visceral metastases early, and proportionately fewer patients in this group.Incidence of bone metastases has decreased but bone metastases remain a highly relevant clinical problem due to the large number of patients being diagnosed with breast cancer.

Background Bone is a frequent site for metastases among women with breast cancer. We conducted a study using the General Practice Research Database (GPRD), with linkage to the National Cancer Registry (NCR) and Hospital Episode Statistics (HES), to estimate the incidence of bone metastases in women with breast cancer in the United Kingdom. Methods We identified all women in the GPRD aged 20–99 with a first-time diagnosis of breast cancer between 2000 and 2006. To address potential underreporting, we developed and validated an algorithm to serve as a proxy for bone metastases. Bone metastases were defined as (1) a bone cancer diagnosis code on the same day or following breast cancer diagnosis date, or (2) another metastasis code plus codes consistent with bone metastases diagnosis or treatment using the algorithm. We sent questionnaires to a sample of general practitioners to validate these definitions. Results We included 13,207 breast cancer patients (median age at diagnosis of 61 years) who contributed 70,885 person-years of follow-up. The majority of patients had stage 1 or 2 breast cancer (90.4%), and 2.6% had metastatic breast cancer at diagnosis. We identified 788 women (6.0%) with bone metastases after a median follow-up of 5.4 years. Questionnaire results validated the diagnosis of bone metastases in 88% of patients with a bone cancer code and for 70% identified with the algorithm. Conclusion This is the first time the GPRD has been linked to HES and NCR to study the epidemiology of bone metastases, adding important information on the burden of bone metastasis.

Fernanda Costa Svedman,1 Demetris Pillas,2 Aliki Taylor,2 Moninder Kaur,2 Ragnar Linder,3 Johan Hansson1 1Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; 2Centre for Observational Research, Amgen Ltd, Uxbridge, UK; 3IMS Health Sweden, Stockholm, Sweden Background: Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. Method: We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. Results: Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%–100% (stage I), 65%–92.8% (stage II), 41%–71% (stage III), and 9%–28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%–44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%–95% for negative SN (stage I/II) and 35%–75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%–90% for negative and 35%–58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. Conclusion: The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it is difficult to make detailed comparisons. Large population-based studies that include stage-specific survival and recurrence in Europe are therefore important. Keywords: cutaneous malignant melanoma, cancer, survival, recurrence, Europe, stage&nbsp

Cutaneous malignant melanoma (CMM) incidence is increasing globally, making a thorough understanding of the disease and its outcomes essential for optimizing care even more urgent. In this population-based, retrospective study, we investigated stage-specific survival and recurrence/progression rates of CMM among patients diagnosed in Stockholm County Council during 2005-2012, before the wide introduction of targeted therapy. A total of 3,554 CMM patients from the Stockholm Melanoma Register were included. Information on comorbidities, progression, death, and treatments was obtained from nationwide registers and hospital electronic medical records. Unadjusted 5-year survival varied from 91.4% for stage I to 24.6% for stage IV patients. Stage, age and gender were predictors of survival, with gender an independent predictor of survival for stages IA and IIA. 74.6% of patients remained recurrence/progression-free during follow-up, with 5-year recurrence/progression-free survival rates varying from 85.3% to 12.9% among stages I and IV patients, respectively. In addition to stage, male gender, and age, circulatory system comorbidities increased the risk for recurrence/progression. No statistically significant differences in progression rate for operated and non-operated patients could be detected, possibly due to high rate (98.9%) of surgery. Our estimates of survival and recurrence rates are consistent with historical and global expectations and can serve as a baseline to gauge population-level improvements with use of novel melanoma treatments.

Objective Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. Methods Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. Results There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0–12.0] and 8.3 [range, 6.0–11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1–42.3), 20.5 (95% CI, 17.7–24.8), 12.7 (95% CI, 10.4–14.2), and 9.8 (95% CI, 6.6–14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4–37.3) and 18.7 (95% CI, 11.0–23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. Conclusions Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records.

Olivia Le Saux,1 Aliki Taylor,2 Victoria Chia,3 Demetris Pillas,2 Moninder Kaur,2 Gilles Freyer11Department of Medical Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite Cédex, France; 2Center for Observational Research, Amgen Ltd, Uxbridge, UK; 3Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA Purpose: The purpose of this study was to evaluate the prevalence of comorbidities and adverse events (AEs), and determine the treatment patterns according to platinum-sensitivity status in patients with advanced (stage IIIB–IV) or recurrent epithelial ovarian cancer (EOC). Methods: A cross-sectional study was carried out in France with patients over 18 years, diagnosed with advanced (stage IIIB–IV) or recurrent EOC between 2009 and 2012. A total of 23 physicians (oncologists and gynecologists) participated, contributing 127 patients. Data were abstracted by participating physicians into a case report form. Results: Of the 127 patients included, 92 (72.4%) had advanced EOC and 35 (27.6%) had recurrent EOC. A total of 73 comorbidities were reported in 44 patients (34.6%). Vascular (10.2%), metabolic (7.1%), respiratory (5.5%), and psychiatric disorders (5.5%) were the most common types of comorbidities reported. Prevalence of AEs was 74.8%, of which 12.6% were classified as serious. The most common AEs were anemia (16.5%), hematologic events (12.6%), taste change (11.8%), and headache (7.1%). Throughout the follow-up period, twelve patient deaths were reported (six due to disease progression). Of 35 patients with recurrent disease, 16 were highly platinum sensitive (recurrence >12 months after stopping platinum-based therapy), eleven were partially platinum sensitive (recurrence 6–12 months after stopping platinum-based therapy), seven were platinum resistant (recurrence within 6 months of stopping platinum-based therapy or progression while receiving second- or later-line platinum-based therapy), and one was platinum refractory (recurrence within 6 months from the start of first-line platinum-based therapy). Conclusion: In this cross-sectional study of advanced and metastatic ovarian cancer patients, approximately one-third of patients were diagnosed with comorbidities, and approximately three-quarters were diagnosed with AEs (12.6% with severe AEs). Keywords: ovarian neoplasms, platinum sensitivity, drug-related side effects, comorbidity

Contains fulltext : 152566.PDF (Publisher’s version ) (Open Access) BACKGROUND: From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported. METHODS: The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey. RESULTS: In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformite Europeenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme. CONCLUSIONS: There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.

Contains fulltext : 153716.pdf (Publisher’s version ) (Closed access) BACKGROUND: The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients. METHOD: Individual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known. RESULTS: Data from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9-57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7-44.5%]); KRAS exon 3 (3.8% [2.9-4.9%]); KRAS exon 4 (6.2% [5.0-7.6%]); NRAS exon 2 (2.9% [2.1-3.9%]); NRAS exon 3 (4.2% [3.2-5.4%]); NRAS exon 4 (0.3% [0.1-0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p=0.001), gender (p=0.030), and by country (p=0.028). CONCLUSIONS: This analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients.

To assess and characterize the temporal variation in ovarian cancer incidence and mortality by age within countries in the Americas, Europe, Asia, and Oceania.Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program in the United States (U.S.) were used to assess ovarian cancer incidence rates (1998-2008) and mortality rates, (1988-2007 for 12-month survival, 1988-2006 for 24-month survival, and 1988-2003 for 60-month survival), stratified by age at diagnosis. Data from GLOBOCAN were used to calculate country-specific incidence rates for 2010 and 2020 and case-fatality rates for 2010.A statistically significant decrease in Annual Percent Change (APC) of ovarian cancer incidence was observed in the U.S. for all women (-1.03%), among women who were diagnosed at65 years of age (-1.09%) and among women who were diagnosed at ≥65 years of age (-0.95%). There was a statistically significant increase in the observed APC for survival at 12-months (0.19%), 24-months (0.58%), and 60-months (0.72%) for all women; however, 5-year survival for advanced stage (III or IV) disease was low at less than 50% for women65 years and less than 30% for women ≥65 years. Global results showed a wide range in ovarian cancer incidence rates, with China exhibiting the lowest rates and the Russian Federation and the United Kingdom exhibiting the highest rates.Ovarian cancer survival has shown modest improvement from a statistical perspective in the U.S. However, it is difficult to ascertain how clinically relevant these improvements are at the population or patient level.

Background Hepatic metastases develop in approximately 50% of colorectal cancer (CRC) cases. We performed a review and meta-analysis to evaluate survival after resection of CRC liver metastases (CLMs) and estimated the summary effect for seven prognostic factors. Methods Studies published between 1999 and 2010, indexed on Medline, that reported survival after resection of CLMs, were reviewed. Meta-relative risks for survival by prognostic factor were calculated, stratified by study size and annual clinic volume. Cumulative meta-analysis results by annual clinic volume were plotted. Results Five- and 10-year survival ranged from 16% to 74% (median 38%) and 9% to 69% (median 26%), respectively, based on 60 studies. The overall summary median survival time was 3.6 (range: 1.7–7.3) years. Meta-relative risks (95% confidence intervals) by prognostic factor were: node positive primary, 1.6 (1.5–1.7); carcinoembryonic antigen level, 1.9 (1.1–3.2); extrahepatic disease, 1.9 (1.5–2.4); poor tumor grade, 1.9 (1.3–2.7); positive margin, 2.0 (1.7–2.5); >1 liver metastases, 1.6 (1.4–1.8); and >3 cm tumor diameter, 1.5 (1.3–1.8). Cumulative meta-analyses by annual clinic volume suggested improved survival with increasing volume. Conclusion The overall median survival following CLM liver resection was 3.6 years. All seven investigated prognostic factors showed a modest but significant predictive relationship with survival, and certain prognostic factors may prove useful in determining optimal therapeutic options. Due to the increasing complexity of surgical interventions for CLM and the inclusion of patients with higher disease burdens, future studies should consider the potential for selection and referral bias on survival.

Background Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. Method We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. Results Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%–100% (stage I), 65%–92.8% (stage II), 41%–71% (stage III), and 9%–28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%–44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%–95% for negative SN (stage I/II) and 35%–75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%–90% for negative and 35%–58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. Conclusion The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it is difficult to make detailed comparisons. Large population-based studies that include stage-specific survival and recurrence in Europe are therefore important.

Malene Schou Nielsson,1 Rune Erichsen,1 Trine Frøslev,1 Aliki Taylor,2 John Acquavella,2 Vera Ehrenstein11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research International, Amgen Ltd Thousand Oaks, CA, USA Background: The purpose of this study was to estimate the positive predictive value (PPV) of the coding for bisphosphonate treatment in selected cancer patients from the Danish National Patient Registry (DNPR).Methods: Through the DNPR, we identified all patients with recorded cancer of the breast, prostate, lung, kidney, and with multiple myeloma. We restricted the study sample to patients with bisphosphonate treatment recorded during an admission to Aalborg Hospital, Denmark, from 2005 through 2009. We retrieved and reviewed medical records of these patients from the initial cancer diagnosis onwards to confirm or rule out bisphosphonate therapy. We calculated the PPV of the treatment coding as the proportion of patients with confirmed bisphosphonate treatment.Results: We retrieved and reviewed the medical records of 60 cancer patients with treatment codes corresponding to bisphosphonate therapy. Recorded code corresponded to treatment administered intravenously for 59 of 60 patients, corresponding to a PPV of 98.3% (95% confidence interval 92.5–99.8). In the remaining patient, bisphosphonate treatment was also confirmed but was an orally administered bisphosphonate; thus, the treatment for any bisphosphonate regardless of administration was confirmed for all 60 patients (PPV of 100%, 95% confidence interval 95.9–100.0).Conclusion: The PPV of bisphosphonate treatment coding among cancer patients in the DNPR is very high and the recorded treatment nearly always corresponds to intravenous administration.Keywords: bisphosphonate, neoplasm metastases, predictive value of tests, validation studies