bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of providers’ prescribing patterns with postsurgical opioid use among cancer patients undergoing curative-intent surgery.
Authors: Xu Yuan , Cuthbert Colleen Ann , Karim Safiya , Kong Shiying , Dort Joseph C. , Quan May Lynn , Hinther Ashley V. , Cheung Winson Y.
Published: May 2019

6530

Background: Patients with cancer are vulnerable to chronic opioid use. Although opioid use may be appropriate, preliminary data suggest that a significant proportion may be using opioids inappropriately. This study aims to evaluate the association between the history of the providers’ opioid-prescribing patterns and post-surgical opioid use in cancer patients undergoing curative-intent surgery. Methods: This population-based study included all patients diagnosed with common solid tumors who received curative-intent surgery and were non-opioid users prior to surgery between 2009 and 2015 in Alberta, Canada. Based on previously published methods, a new persistent opioid user was defined as opioid-naïve prior to surgery and who subsequently filled at least one opioid prescription between 60 and 180 days after surgery. The opioid-prescribing patterns of a patient’s most responsible provider (MRP) were measured as the mean daily dosage (oral morphine equivalent, OME) that was prescribed to all other patients by that provider prior to the surgical date. Multivariable logistic regression was performed to identify associations between the MRP’s prescribing patterns and the patient’s opioid use after surgery. Results: 14,780 patients met the inclusion criteria and were associated with 2,880 MRPs, among which 2,364 (16%) patients became new persistent opioid users after surgery. Multivariate analysis demonstrated that patients with MRPs who routinely prescribed higher doses of opioids (≥60 vs. 0-59 mg OME: OR = 2.33, P < 0.0001) for their patients were associated with a greater risk of new persistent opioid use after surgery. In addition, those with a higher Charlson comorbidity index (P = 0.006), visited more prescribers (P < 0.0001), had a specific tumor type (breast, colorectal, lung, prostate, melanoma or kidney vs. others, P < 0.0001), received adjuvant chemotherapy (OR = 1.37, P < 0.0001), and received adjuvant radiation (OR = 1.3, P = 0.0004) were also associated with greater risk of new persistent opioid use after surgery. Conclusions: Our results suggest that prescribers with a history of prescribing higher opioid doses are an important predictor of chronic opioid use among cancer patients undergoing curative-intent surgery. Awareness of physician prescribing practices and their unintended consequences may inform strategies to minimize persistent post-operative opioid use in cancer patients.
Evaluation of quality of life, satisfaction and cost of care in metastatic colorectal cancer patients receiving ambulatory chemotherapy.
Authors: Chansriwong Phichai , Sirilerttrakul Suwannee , Wannakansophon Nopakan , Tangteerakoon Patamaporn , Vongterapak Suluck , Jirajarus Manmana , Ckumdee Sineenuch , Sirachainan Ekaphop
Published: May 2019

6536

Background: Colorectal cancer is an important health problems in Thailand; chemotherapy remains the most suitable treatment for metastatic patients. Chemotherapy treatment that was once delivered only in hospital environments is now administered at patient's home that helping patients to live normal lives during receiving chemotherapy. The chemotherapy regimens are based on a 48 hours 5-fluorouracil infusion combined that need patients to be hospitalized, consequence to decrease QOL and increase cost of treatment. Aims: Compares the QOL score, patients’ satisfaction and cost difference in treating ambulatory chemotherapy (AC) patients compared with inpatient treatment. Methods: An observational cohort which enrolled 156 patients at the Ramathibodi hospital from Dec 2015 to Nov 2016. AC administered by the central venous access device (CVAD). The regimen as FOLFOX or FOLFIRI, 5-FU were in the elastomeric infusion pump and administered at the patients’ home. Nurse coordinators followed up with the patients by phone. The FACT-G and FACT-C scale, patients’ satisfaction and cost of treatment questionnaire were collected at time of enrolment, 2 months and end of treatment. Results: 156 patients are enrolled that 111 patients treated with AC and 45 patients treated with inpatient. 134 returned the questionnaire (response rate 86%). Intention to treat analysis revealed significantly improved in social wellbeing and FACT-G (p <0.001) in AC group. Significant higher administration, service and overall satisfaction score in AC group. The AC reduced cost about 483 US dollars per cycle of chemotherapy. Conclusions: Ambulatory chemotherapy helps colorectal cancer patients to live normal lives by administer treatment at patients' home and results to significantly improve in quality of life especially in social wellbeing and more satisfaction. Moreover, ambulatory chemotherapy reduced cost of chemotherapy treatment.
Esophageal cancer in Hispanic patients: A demographic analysis of the National Cancer Database.
Authors: Ricardo Juan , Conte Jorge , Alkayali Talal , Salem Ahmed , Huston Jamie , Shridhar Ravi , Meredith Kenneth L
Published: May 2019

6561

Background: Hispanics are the fastest-growing minority accounting for 18% of the US population. The National Cancer Institute estimated 17,290 new cases of esophageal cancer (EC) in the US in 2018. Hispanics are reported to have lower EC prevalence. We sought to interrogate the demographic patterns of EC in Hispanics. Secondary objective was to examine evidence of socioeconomic disparities and differential therapy. Methods: We queried the National Cancer Database to identify patients with EC between 2005–2015. Patients were divided into two groups, Hispanic vs Non-Hispanic (NH). Demographics compared were age, sex, tumor data, surgical intervention, type of treatment, insurance status, income, residence area, and Charlson/Deyo score. Pearson’s Chi-square test was used to compare categorical variables. Groups were matched by propensity score-matched analysis (PSM). Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. P-value ≤0.05 was considered significant. Results: We identified 85,004 patients with EC; 3,205 were Hispanic (3.8%). In this US population we identified significant disparities between the Hispanic and NH groups. Statistically significant differences among Hispanics included higher prevalence of squamous EC (24.7% vs 19.6%), higher likelihood of stage IV cancer diagnosis (40.7% vs. 34.8%), younger age, higher uninsured status (10.4% vs 3%) with income < $38,000 (26.4% vs 15.9%), and Charlson/Deyo score 0 (72.3% vs 70.7%) when compared to NH. However, Hispanics were less likely to have surgical intervention (29% vs 36.3) and overall less likely to receive any type of treatment (30.1% vs 26.1%). PSM showed that any treatment, insurance status and lower income were predictors of survival. Treated Hispanics survived longer than NH (median survival 17 vs 15 months). Overall survival at 5 years was 22% vs 17%, respectively, p < 0.05. Conclusions: Despite lower prevalence of EC in Hispanics compared to NH, there is a disproportionately higher number of metastatic and untreated cases among Hispanics. This disparity may be explained by Hispanics' limited access to medical care exacerbated by their socioeconomic and insurance status. Further clinical and epidemiologic research is warranted to reveal other factors impacting these health disparities.
Australian population-based study of single- versus multi-fraction palliative radiotherapy for bone metastases.
Authors: Ong Wee Loon , Foroudi Farshad , Millar Jeremy Laurence
Published: May 2019

6568

Background: Single fraction palliative radiotherapy (SFRT) has been shown to be equivalent to multi-fraction radiotherapy (MFRT) for bone metastases symptom management. Remuneration for radiotherapy (RT) in Australia are largely determined by fractions delivered. We aim to determine the use of SFRT for bone metastases in Australia. Methods: We did a population-based linkage study of multiple administrative healthcare databases in Victoria, Australia: the Victorian Radiotherapy Minimum Data Set (VRMDS), the Victorian Cancer Registry (VCR), and the Birth, Death and Marriage registry (BDM). All patients with solid tumour (excluding primary bone cancer) who received palliative radiotherapy for bone metastases between 2012 and 2017 were included. The primary outcome was use of SFRT. The Cochrane-Armitage test for trend was used to evaluate SFRT use over time. Multivariable logistic regression was used to identify factors associated with SFRT use. Results: A total of 15,668 courses of RT for bone metastases were delivered to 10,351 patients. The overall proportion of SFRT was 18% (2,746/ 15,668). There was no significant change in SFRT use over time, from 18% in 2012 to 20% in 2017 (P = 0.06). Older patients were more likely to have SFRT (mean age 69.4 vs. 68.2, P < 0.001). Patients who had lung cancer (21%) and prostate cancer (19%) were more likely to have SFRT compared to other tumour types (P < 0.001). Spine RT was associated with lower use of SFRT compared to other treatment sites (14% vs. 22%, P < 0.001). Patients from remote area were more likely to have SFRT compared to patients from major cities (22% vs. 17%, P < 0.001). Patients treated in private institutions were less likely to have SFRT compared to those treated in public institutions (10% vs. 22%, P < 0.001). In multivariate analyses, patients’ age, tumour type, area of residence, and treatment institutions were independently associated with SFRT use. Conclusions: This is the largest Australian population-based cohort treated with RT for bone metastases, with low utilisation of SFRT over time. There is large variation in SFRT use depending on patient-, tumour-, geographical and institutional factors. Further work is needed to increase uptake, and reduce unwarranted variation, in SFRT use.
A novel patient-centric approach between sites, CRO, and sponsor to accelerate FPI and drive more patients into oncology protocols.
Authors: Kowalczyk Krystyna , Henry Rhonda U. , Conte Bellinda
Published: May 2019

6573

Background: According to the Journal of Clinical Oncology, 50% of sites performing clinical trials never enroll a patient. And on top of that, it can take several months to activate a site for an oncology clinical trial; precious time that patients cannot afford when they’ve had a cancer diagnosis and precious time sponsors need when developing new compounds for market. While many patients are interested in participating in trials, they are limited in their opportunities because they do not live near a research site or work with a physician performing clinical trials. So with this crisis in the oncology field, research needs to be more efficient and inclusive. Methods: A combined partnership of sites, physicians, CRO and sponsor leveraging Just-in-Time enrollment methodology helped expedite clinical trial enrollment and diversify trial access driving faster first patient enrolled and expanding the potential patient denominator. Results: This on-demand methodology augmented existing sites that had access to oncology patients by providing broader access, faster, and with no quality loss. Strong partnerships between CRO and sponsor then facilitated two-week site activation allowing every identified patient to be converted to a study subject. This methodology was repeated across seven protocols driving patents on trials within six weeks of trial available. Conclusions: The benefits of this Just-in-Time methodology touch all areas of clinical trials: Patients have greater clinical trial access: A larger denominator of patients across broader geographies have local access to portfolios of clinical trials; Trials start to enroll faster: Patients can be randomized into oncology clinical trials within two weeks of study start up driving trial time to completion; Sites have more trial options to consider: Sites have a broader portfolio of trials to access on demand without added administrative burden; Trials complete faster: Sponsors accrue patients faster driving expedited timelines and accelerating drug development.
Reporting of patient reported outcome (PRO) in clinical trials: A systematic review of clinical trials.
Authors: Vidal-Fisher Liat , Vidal Boixader Laura , Andrianov Vasily , Curtis Kelly Kevelin , Shepshelovich Daniel , Moss Keren Rachel
Published: May 2019

6590

Background: Clinically relevant outcomes as improvements in overall survival (OS) or quality of life (QOL) should guide decision-making. The FDA encourages the implementation of patient-centric measures in clinical trials. Over the past decade a growing number of protocols have included PROs in their outcome measures. We aimed to evaluate the frequency at which PRO measures, incorporated into clinical trials, are made publicly available, when trial results are published. Methods: We searched Citeline Trialtrove database, a registry of clinical trials, for randomized phase 3 trials of patients with non-small cell lung cancer (NSCLC), recruiting during 2006-2016, with PRO listed. We excluded trials evaluating supportive treatment, and those unpublished. We identified publications associated with the trial, and extracted various parameters, including whether or not PRO outcome was published. Results: Of 158 NSCLC trials identified, 99 listed at least 1 PRO. 24 trials were excluded (supportive care, unpublished). The commonly used scales were EORTC-QLQ C30, QLQ-LC13, LCSS, FACT-L, and EQ-5D. Study sponsor was industry in 45 trials, and industry-academic in 12 trials. Of 75 trials analyzed, 41 (55%) published the results of the PRO endpoint. Only 37% of the 75 included a comprehensive report of PRO, and many publications referenced the PRO briefly. Of 41 trials that reported PRO, only 21 (51%) provided information about missing PRO data. 59 trials were published as full-text, of which 40 (68%) reported the PRO, and 53% reported the PRO more than 6 months after the initial full publication. Of the trials that showed PFS benefit, with no OS benefit, 22/34 (65%) published the results of the PRO endpoints. Conclusions: Despite a growing emphasis on QOL and the inclusion of PROs in oncology clinical trials, and despite patient and healthcare provider efforts to record PRO data, a significant number of NSCLC randomized trials do not report the PRO. The collection of PRO data should result in routine, timely and appropriate reporting as part of the trial outcome publication, to allow for a thorough assessment of investigational clinically relevant treatment effect.
Clinical utility and reimbursement for expanded genomic panel testing in adult oncology.
Authors: Hsiao Susan Jean , Sireci Anthony , Pendrick Danielle , Freeman Christopher , Yang Jessica , Schwartz Gary K. , Mansukhani Mahesh M. , Carvajal Richard D. , Oberg Jennifer A.
Published: May 2019

6593

Background: The routine use of large next generation sequencing (NGS) cancer panels is required to identify the increasing number of, but often uncommon actionable alterations present across multiple tumor histologies to guide therapy. Inconsistent coverage and variable payment is hindering adoption of these tests into clinical practice. A review of clinical utility, coverage and reimbursement was conducted in a cohort of adult oncology patients who received expanded genomic panel testing as part of their clinical care. Methods: The Columbia Combined Cancer Panel (CCCP), a 467 gene panel designed to detect single nucleotide variants, indels, and copy number variations in solid and liquid tumors was performed in a CLIA-certified laboratory at Columbia University Irving Medical Center. Clinical utility categories included: immediate change in management; informed future treatment options; provided diagnostic/prognostic information; and other impact. Claims were submitted between 1/1/17 and 4/30/18. Carriers were categorized into commercial, managed-government, and government plans. Results: 300 tumors underwent NGS. Reimbursement data were available for 258 cases. 57% of testing was performed for a treatment-resistant, recurrent, or high stage cancer, or for a cancer of rare/mixed histology (21%). Findings were clinically actionable in 183 cases (61%). Results led to an immediate change in management (n = 6, 2%), informed future treatment options (n = 140, 47%), and provided diagnostic/prognostic information (n = 29, 10%). Only 57 tests (22%) received coverage. In 59% of denials (118/201), a clinically-actionable result was found. Commercial plans reimbursed 29/119 tests (24%) and managed-government plans reimbursed 28/54 tests (52%). Government plans provided no coverage for 85 tests. On average, insurers reimbursed 10% of the total CCCP service charges: 12.5% for commercial and 22% for managed-government plans. Conclusions: Expanded genomic testing identified clinically-impactful alterations in 61% of cases. Limited coverage and low reimbursement remain a barrier and broader reimbursement policies are needed to adopt expanded genomic testing that benefits patients into clinical practice.
Quality of life (QOL) in patients undergoing CAR-T therapy versus stem cell transplant (SCT).
Authors: Sidana Surbhi , Dueck Amylou C. , Burtis Michelle , Griffin Joan M. , Thanarajasingam Gita , Warsame Rahma M. , Thompson Carrie A. , Cheville Andrea L. , Gertz Morie A. , Yost Kathleen J. , Dispenzieri Angela , Villasboas Bisneto Jose , Paludo Jonas , Ansell Stephen M. , Rajkumar S. Vincent , Bennani Nabila Nora , Johnston Patrick B. , Siddiqui Mustaqeem Ahmad , Lin Yi , Kumar Shaji
Published: May 2019

6594

Background: Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients in addition to efficacy, compared with established forms of cellular therapy like SCT. Methods: QOL was evaluated prospectively in patients undergoing CAR-T therapy, autoSCT & alloSCT for hematologic malignancies. QOL was assessed with FACT-G at baseline, 2 weeks and monthly for 6 months thereafter. Functional well-being (FWB), physical WB (PWB) emotional WB (EWB) & social WB (SWB) and change over time were compared across groups. Results: 45 patients were recruited (CAR-T: 10; Auto SCT: 22; Allo SCT: 13) with follow up for 2 weeks & 1 month available for 23 &15 patients, respectively (Table). There was no statistically significant difference in baseline total QOL scores (p=0.13), though scores were lower in the alloSCT group (85,84,68). EWB &FWB were numerically higher in the CAR-T group, followed by autoSCT group. At 2 weeks, overall QOL decreased by only 2 points in CAR-T group vs. 22 & 18 points in auto & alloSCT groups (p=0.09). Change in PWB vs. baseline was less pronounced in the CAR-T group (-1, -9, -13, p=0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in auto & alloSCT groups, respectively (p=0.34). Importantly, PWB had at least returned to baseline in the CAR-T group. Conclusions: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant decline in QOL compared with auto & allo SCT, and may experience fewer physical side effects in the short-term. Accrual & follow-up are ongoing. [Table: see text]
Association between age, risk of severe (Grade 3-4) immune-related adverse events (sirAE), and mortality in patients receiving immune checkpoint inhibitors (ICI).
Authors: Alahmadi Asrar , Nelson Ariel Ann , Al-Kindi Sadeer , Liu Fang , Mendiratta Prateek , Mangla Ankit , Ramaiya Nikhil H. , Hoimes Christopher J.
Published: May 2019

6597

Background: ICI are used in the treatment of advanced malignancies with on-target adverse events of non-tumor inflammation. Many studies have shown conflicting safety results with regard to older vs younger adults where 65 - 70 years of age has been used as the discrete cut-off variable. We sought to investigate the incidence and the association between age and sirAE using age as a continuous variable at a large tertiary cancer center. Methods: Under IRB approval, our ICI outcomes database was queried for those who were hospitalized and received an immunosuppressant. Charts were individually reviewed to identify hospital admissions due to a sirAE (a grade 3 or 4 AE per CTCAE v4.0) and all-cause mortality at 12 months post ICI start. Non-linear analyses using Cox regression models with penalized smoothed splines were performed to explore association between age and sirAE. Results: There were 6.3% of 1043 patients who had a sirAE, and a total of 83 sirAE events. Mean age was 64± 13 years.ICI included anti-PD-1 (77.8%), anti-CTLA-4 (18.1%), and anti PD-L1 (4.1%). Pts with sirAE had a thirty day, and one year mortality of 12% and 49%, respectively. These events included: colitis (30.1%), pneumonitis (16.9%), hepatitis (10.8%), hypophysitis (6%), and thyroiditis (6%). There were 5 neurologic and 4 myocarditis/myositis sirAEs. The 1-year cumulative incidences of sirAE and all-cause mortality were 8.4%, and 48%, respectively. Spline analysis showed a U-shaped association between age and hazard of sirAE (P = 0.03). Every 10 years above age 60 was associated with increased sirAE (HR 1.65 [1.14-2.40], P = 0.008), while every 10 years below 60 was associated with increased sirAE (HR 1.50 [0.99-2.27], P = 0.054). However, age and mortality showed a linear association (P = 0.003). Conclusions: We observed a curvilinear U-shaped association between age and the risk of sirAE, with minimum risk at age of 60, compared with a linear relationship between age and mortality. Further studies are needed to understand this relationship and its impact on outcomes, clinical care, and underlying host immune context.
Online advertising and marketing claims by providers of proton beam therapy: Are they guideline based?
Authors: Corkum Mark Thomas , Liu Wei , Palma David A. , Dinniwell Robert Edward , Bauman Glenn , Warner Andrew , Mishra Mark Vikas , Louie Alexander V.
Published: May 2019

6599

Background: Proton beam therapy (PBT) is a radiotherapy platform that purports an improved therapeutic ratio by way of a rapid radiation dose fall-off. Despite this technology being hindered by significant capital and patient costs, the number of centres offering PBT is increasing exponentially. Consensus guidelines support PBT use in a limited number of disease sites or on clinical trials. As patients frequently obtain information about PBT from hospital or cancer centre websites, the purpose of this study was to evaluate direct to consumer advertising (DTCA) content and claims made by proton therapy centre (PTC) websites. Methods: English PTC websites worldwide were identified using the Particle Therapy Co-Operative Group website. Data abstraction of website content was performed independently by two investigators. Eight international guidelines were consulted to determine indications for PBT. Univariate and multivariate logistic regression models were used to identify website characteristics that were associated with a higher likelihood to make non-evidence-based claims of PBT such as improved disease control or cure. Results: From the 48 PTCs with 46 English websites, most (58%) did not provide any references for claims made regarding PBT. These included: improved disease control or cure (61%), fewer side effects (85%), or was the standard of care (13%). Prostate (87%), head and neck (87%) and pediatric (83%) cancers were the most frequently listed PBT-indicated disease sites, consistent with international guidelines. However, pancreatobiliary (52%), breast (50%) and esophageal (44%) cancers were frequently advertised despite not being endorsed in any consensus guidelines. On multivariate analysis, an increasing number of listed disease sites and claims of being a regional PTC leader were associated with indicating that PBT offers greater disease control or cure. The availability of PBT through a clinical trial was mentioned on 57% of websites. Conclusions: PTC websites often contain information and DTCA claims inconsistent with international consensus guidelines. As online marketing information may have significant influence on patient decision-making, alignment of such information with accepted guidelines and consensus opinion should be adopted by PBT providers.
A randomized study comparing physician-directed or fixed-dose dexamethasone replacement following incomplete steroid premedication for docetaxel chemotherapy.
Authors: Hsu Tina , Stober Carol , Fergusson Dean , Daigle Kelly , Moledina Noorza , Pond Gregory Russell , Vandermeer Lisa , Canil Christina M. , Hutton Brian , Hilton John Frederick , Clemons Mark J.
Published: May 2019

6610

Background: Prior to receiving docetaxel-based chemotherapy patients often incorrectly take all or part of their steroid-premedication. The lack of standardised steroid-replacement strategies can lead to variability in care and delays in starting chemotherapy while nursing/pharmacy/physicians establish an individualized patient plan, which can use up valuable chemotherapy chair time. A randomised controlled trial comparing a fixed-oral dose of dexamethasone and physician-directed replacement was performed. Methods: Patients who missed at least one dose of steroid-premedication were randomised to either standard replacement with dexamethasone 8mg orally or physician-directed replacement (any steroid, dose or route). The primary outcome was time from randomisation to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin rashes. Results: Sixty patients were randomized. Most patients were enrolled during cycle 1 (47.5%) and cycle 2 (22%) of docetaxel. The most frequent total doses of dexamethasone omitted were 24 mg (27%), 12 mg (20%), and 8 mg (19%). There were 7 different replacement strategies used by physicians. The most frequently used strategies were: dexamethasone 8mg IV (34.5%), 12mg IV (17.2%) and 20mg IV (13.8%). Patients in the fixed-dose arm received docetaxel earlier than patients in the physician-choice arm, at a median of 47.5 and 61 minutes after randomization (mean = 62.2 vs 83.4 minutes) (p = 0.033). No significant difference in rates of acute (0 vs 2)/delayed allergic reactions (1 vs 0), fluid retention (2 vs 1), or skin rashes (1 vs 0) was observed between the fixed-dose and physician-choice arms respectively. Conclusions: This is the first randomised trial to compare steroid-replacement strategies in this patient population. Fixed-dose replacement with dexamethasone 8 mg PO should be the preferred standard of care, as it reduces both the time to starting docetaxel and treatment variability, with no apparent increase in toxicity. Clinical trial information: NCT02815319.
Practice variation on hospital level in the systemic treatment of metastatic colorectal cancer in the Netherlands: A population-based study.
Authors: Keikes Lotte , Koopman Miriam , Stuiver Martijn M. , Lemmens Valery , van Oijen Martijn G.H. , Punt Cornelis J. A.
Published: May 2019

6612

Background: Population-based data on the implementation of guidelines for cancer patients in daily practice are scarce. Therefore, we evaluated practice variation patterns and associated variables in the systemic treatment of metastatic colorectal cancer (mCRC) between 2008 and 2015 in the Netherlands. Methods: We selected a random sample of adult mCRC patients diagnosed from 2008 to 2015 from the National Cancer Registry in 20 Dutch hospitals. We examined the influence of patient, demographic and tumor characteristics on the odds of being treated with systemic therapy according to the current guideline and assessed its association with survival. Results: Our study population consisted of 2222 mCRC patients of whom 1307 patients received systemic therapy for mCRC. Practice variation was most obvious in the use of bevacizumab and anti-EGFR therapy in patients with (K)RAS wild-type tumors. Administration rates did not differ between hospital types but fluctuated between individual hospitals for bevacizumab (8-92%; p<0·0001) and anti-EGFR therapy (10-75%; p=0·05). Bevacizumab administration was inversely correlated to higher age (OR:0·2; 95% CI: 0·1-0·3) comorbidity (OR:0·6; 95% CI: 0·5-0·8) and the presence of metachronous metastases (OR:0·5; 95% CI: 0·3-0·7), but patient characteristics did not differ between hospitals with low or high bevacizumab administration rates. Exposure to bevacizumab (HR:0·8; 95% CI: 0·7-0·9) and anti-EGFR therapy (HR:0·6; 95% CI: 0·5-0·8) was associated with prolonged survival. Conclusions: We identified significant inter-hospital variation in targeted therapy administration for mCRC patients, which may affect outcome. Age and comorbidity were inversely correlated with non-administration of bevacizumab, but did not explain inter-hospital practice variation. Our data strongly indicate that practice variation is based on individual strategy of hospitals rather than guideline recommendations or patient-driven decisions. Individual hospital strategies are an additional factor that may explain the observed differences between real-life data and results obtained from clinical trials.
Economic impact of the 31-gene expression profile test in the Medicare-eligible population with cutaneous melanoma.
Authors: Monzon Federico A. , Kurley Sarah , Perry Lauren , Dossett Lesly Ann , Vetto John T. , Mathews Charles
Published: May 2019

6630

Background: Sentinel lymph node biopsy (SLNB) is recommended as a staging procedure for patients with cutaneous melanoma (CM), but SLNB is associated with additional surgical risks and costs. The SLN positivity rate is approximately 12-16% overall and varies by age. Older patients have lower SLN positivity rates despite a higher metastatic rate. A 31-gene expression profile (31-GEP) test classifies 5-year metastatic risk (Classes 1A [lowest risk], 1B, 2A, and 2B [highest risk]), including SLN metastasis. As previously demonstrated using a large multicenter database, patients with Class 1A, T1-T2 (≤2.0 mm thickness) CM have an overall SLN positivity likelihood < 5%, below the NCCN guideline threshold for SLNB. The aim of this study was to determine the relative cost impact of patient management via traditional care versus using the 31-GEP test to guide SLNB and surveillance plans for 16,572 patients ≥65 years (Medicare-eligible) with T1-T2 CM who are SLNB-eligible. Methods: Decision tree models were used to compare management strategies (surveillance, SLNB) according to traditional care based on SLNB staging and with 31-GEP test utilization. Models used T category from AJCC TNM staging guidelines and SEER data for incidence estimations. Model outcomes included total Medicare costs of melanoma treatment and patient management. Cost impact of the 31-GEP test was calculated based on the difference in Medicare costs between the traditional care and 31-GEP test paradigms. Results: Under the paradigm in which the 31-GEP guided SLNB and surveillance in patients ≥65 years with T1-T2 CM who are eligible for SLNB, 11,157 fewer SLNBs would be performed per year, a 67% reduction in SLNB procedures in this population. This would result in a net annual cost savings of $68M, a 31% reduction in total costs. Use of the 31-GEP testing to guide surveillance in patients ≥65 with T3-T4 melanoma, in addition to T1-T2 melanoma, were also analyzed and also demonstrated a reduction in costs. Conclusions: Results from this study suggest that using the 31-GEP test to guide SLNB and surveillance offers substantial cost savings compared to traditional care for Medicare-eligible patients.
Pathological response and survival with neoadjuvant therapy in melanoma: A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).
Authors: Menzies Alexander M. , Rozeman Elisa A. , Amaria Rodabe Navroze , Huang Alexander Chan Chi , Scolyer Richard A. , Tetzlaff Michael T. , Van De Wiel Bart A. , Lo Serigne , Tarhini Ahmad A. , Tawbi Hussein Abdul-Hassan , Burton Elizabeth M. , Karakousis Giorgos , Ascierto Paolo Antonio , Spillane Andrew , Davies Michael A. , Van Akkooi Alexander Christopher Jonathan , Mitchell Tara C. , Long Georgina V. , Wargo Jennifer Ann , Blank Christian U. ,   International Neoadjuvant Melanoma Consortium (INMC)
Published: May 2019

9503

Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p < 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p < 0.001), including in those with IT (100% vs 72%, p < 0.001) and TT (88% vs 43%, p < 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.
Salvage therapy after failure from anti-PD-1 single agent treatment: A Study by the German ADOReg melanoma registry.
Authors: Weichenthal Michael , Ugurel Selma , Leiter Ulrike M. , Satzger Imke , Kähler Katharina C. , Welzel Julia , Pföhler Claudia , Feldmann-Böddeker Ingrid , Meier Friedegund Elke , Terheyden Patrick , Haferkamp Sebastian , Herbst Rudolf , Ulrich Jens , Utikal Jochen , Kreuter Alexander , Gutzmer Ralf , Schadendorf Dirk , Mohr Peter
Published: May 2019

9505

Background: In melanoma, potential benefits of therapies after PD-1 inhibitor failure, including those BRAF positive patients who have already received combined BRAF-/MEK inhibitors before anti PD-1 are poorly defined. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients after anti-PD-1 failure. Methods: From the ADOReg registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 200 cases was reached. 1) Ipilimumab naive patients with unresectable metastatic cutaneous or mucosal melanoma. 2) Failure from treatment with a single agent anti PD-1 antibody. 3) Known BRAF status and, in case of BRAF-V600 mutation, BRAF-/MEK-inhibitor treatment prior to anti PD-1 treatment. 4) Consecutive systemic treatment started within a maximum of 6 months after anti PD-1 failure. Objectives: Rate of objective remissions (ORR), disease control (DCR), survival (OS), tolerability and disease patterns correlated to the use of different treatments after PD-1 treatment failure in real-life conditions in Germany. Results: In total 23.5 % of the patients received ipilimumab single agent, 38.5 % received the combination of ipilimumab and nivolumab (Ipi/Nivo), and the remaining various regimens. (Table) Ipi/Nivo resulted in an ORR significantly higher than for Ipi alone (p=0.02). In 18 patients receiving BRAF-/MEK inhibitor re-challenge, ORR was comparable to Ipi/Nivo. Conventional Chemotherapy was still in frequent use (dacarbazine n =33; other n=17), but response rates were low (ORR 6%). Some remission were also achieved by use of talimogene laherparepvec (n=2 out of 4). Conclusions: Treatment patterns of patients after anti-PD-1 failure differ remarkably. Although lower than reported in treatment naive patients, the combination of Ipilimumab and Nivolumab appeared favorable as compared to all other regimens, except for BRAF-/MEK inhibitor re-challenge which produced similar remission rates. Still, chemotherapies including dacarbazine are in clinical practice, though giving only poor outcome. [Table: see text]
Comprehensive molecular profiling of metastatic melanoma to predict response to monotherapy and combination immunotherapy.
Authors: Pires Da Silva Ines Esteves Domingues , Menzies Alexander M. , Newell Felicity , Wilmott James S. , Carlino Matteo S. , Ferguson Peter M. , Edwards Jarem , Spillane Andrew , Shannon Kerwin , Saw Robyn , Thompson John F. , Rizos Helen , Mann Graham J. , Johansson Peter , Hayward Nicholas , Scolyer Richard A. , Waddell Nic , Long Georgina V.
Published: May 2019

9511

Background: Several factors have been proposed as biomarkers for response to PD1 therapy, including tumor mutational burden (TMB), immune gene expression, PD-L1 expression and TILs, while few specific mechanisms of resistance have been identified. The relative importance of these factors or detailed examination of biomarkers of response to combination immunotherapy have yet to be explored. Methods: Cutaneous metastatic melanoma (MM) patients (pts) treated with anti-PD-1 (PD1) +/- anti-CTLA-4 (CTLA4) were selected. Pre-treatment tumors underwent whole genome sequencing (WGS), RNA sequencing (RNAseq) and immunohistochemistry (IHC; TILs and PD-L1). Results: Tumors from 77 pts treated with PD1 (n = 53) or PD1+CTLA4 (n = 24) underwent WGS. Higher TMB (p = 0.0001), lower structural variant (SV) burden (p = 0.001) and higher neoantigen load (p = 0.001) were associated with response. There was no difference in the expression of specific genes reported to confer resistance (JAK1/2, PTEN or BAF/PBAF complex members) or response (SERPINB3/4, ARID) in responders vs non-responders. RNAseq was performed on 53/77 samples; IFN and TCR signalling pathways were enriched in responders. Cytolytic activity (CYT, p = 0.002), T cell proportion estimated by CIBERSORT (p = 0.002) and confirmed by IHC (p = 0.033), and PD-L1 expression (IHC, p = 0.026) were also higher in responders. Multivariate analysis including DNA (TMB, SV count), RNA (six gene IFN expression signature - IFNG.6; effector T cell gene expression signature; chemokine gene expression; CYT), IHC (PD-L1, TILs) and clinical factors (sex, age, RECIST Sum of diameters, LDH) identified TMB and IFNG.6 as independent predictors of response (AUC = 0.83). 15 outliers with discordant molecular features and clinical outcomes had varying profiles, including 5 non-responders with high TMB, but low IFNG.6 expression, suggestive of a failure of immune activation. Conclusions: Comprehensive clinical and genomic analysis demonstrated that TMB and IFNG expression independently predict response, suggesting defects in both immune recognition or activation in non-responders.
Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600–mutant melanoma.
Authors: Liszkay Gabriella , Gogas Helen , Mandalà Mario , Arance Fernandez ANA Maria , Garbe Claus , Schadendorf Dirk , Dummer Reinhard , Ascierto Paolo Antonio , Robert Caroline , Pickard Michael D , Sandor Victor , Gollerkeri Ashwin , Flaherty Keith
Published: May 2019

9512

Background: BRAF/MEK-inhibitor combinations have a central role in the treatment of BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Because of these meaningful improvements in outcome, mature landmark analyses of PFS and OS, as well as analyses of some prognostic subgroups, require long-term follow-up. Here we report an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), safety and tolerability, and analyses of results by prognostic subgroups including elevated lactate dehydrogenase (LDH) and degree of organ involvement was conducted after an additional 12 months’ follow-up. Results: At data cutoff, there were 116, 113, and 138 deaths in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 48.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 39% (HR, 0.61 [95% CI, 0.48–0.79). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–8.2). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67). Landmark OS and PFS results, as well as subgroup analyses and updated safety and tolerability, will be presented. Conclusions: Updated PFS and OS results for COMBO 450 from the COLUMBUS trial continue to represent new benchmarks for combined BRAF/MEK-inhibitor combinations for treatment of BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.
Impact of body composition on outcomes from anti-programmed death-1 (PD-1) treatment.
Authors: Young Arissa , Quach Henry T. , Davis Elizabeth J. , Moslehi Javid , Williams Grant R. , Johnson Douglas Buckner
Published: May 2019

9516

Background: Obesity is associated with improved outcomes in melanoma patients (pts) treated with PD-1, whereas low muscle mass, known as sarcopenia, has been associated with poor outcomes in many cancers. We sought to assess the impact of body composition on PD-1 outcomes. Methods: We analyzed pre-treatment CT scans at the L3 slice using Slice-o-matic software (Tomovision V. 5.0) to determine skeletal muscle, visceral adipose, and subcutaneous adipose tissue parameters for 104 pts with metastatic melanoma who received PD-1 monotherapy. We assessed sarcopenia using skeletal muscle index (SMI=skeletal muscle area/m2). We also quantified total adipose tissue index (TATI), and skeletal muscle gauge (SMG = SMI x skeletal muscle density [SMD]). We stratified pts into high/low groups using previously published cutoffs and assessed toxicity (tox), progression-free and overall survival (PFS/OS), and response rate (RR) by group. Results: Sarcopenia (low SMI) was negatively associated with any tox (39% vs. 60%, p=0.04) but not OS, PFS, or RR. Adiposity (TATI) was not associated with outcomes. By contrast, SMG was significantly associated with OS (median 35.5 vs. 16.0m, p=0.01 for high vs. low SMG). Interestingly, when incorporating TATI with SMG, we found that high SMG/high TATI pts (high muscle/high fat) have superior clinical outcomes (Table). Notably, low SMG/high TATI pts (low muscle/high fat) had seemingly the worst outcomes. Conclusions: We found that high SMG, a measure incorporating muscle area and density, was associated with improved OS in PD1 treated pts. Further, pts with high adiposity and high SMG had superior outcomes, potentially identifying the population responsible for the favorable effect of obesity in these pts. Validation and combination treated cohorts will be presented. [Table: see text]
Clinical validation of a prognostic 11-gene assay in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma (CM).
Authors: Garbe Claus , Sinnberg Tobias , Niessner Heike , Sülberg Heiko , Eigentler Thomas K. , Amaral Teresa
Published: May 2019

9518

Background: AJCC comprises two markers (Breslow thickness and ulceration) to subdivide stage II CM patients into groups with relatively low, average, or high risk of death. Recent updates of clinical guidelines (NCCN, AAD) suggest that patient management be further tailored to an individual prognosis, e.g. through gene expression profiling (GEP). The aim of this single center study was to clinically validate a prognostic GEP-based risk score (MelaGenix) for stage II CMs. Methods: All obtainable, formalin-fixed paraffin-embedded (FFPE) primaries of AJCC stage II CMs from the Central Malignant Melanoma Registry of Germany archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome (data exchange overseen by independent data clearing house) to determine GEP low- vs. high-score groups with a pre-specified GEP score cut-off (≤0.00 > ). Melanoma specific survival (MSS) was evaluated by Kaplan-Meier (KM) analysis and prognostic performance was assessed by multivariate Cox regression. Results: Study cohort comprised 245 stage II primaries (IIA/B/C n = 118/78/49). Median follow-up was 40 months, 5y/10y MSS was 86/75%, median thickness was 3.0 mm, 142 tumors were ulcerated. GEP low-score group had 5y&10y MSS of 92%; GEP high-score group had 5y/10y MSS of 82/67%. KM log-rank was significant (p = .018); GEP score contributed independent prognostic information in multivariate Cox regression (p = .024 HR = 1.45 [1.05 – 2.00]) vs. covariates pT categories (p = .002 HR = 1.59 [1.19 - 2.13]) and age (p = .001 HR 1.05 [1.02 - 1.09]). Conclusions: MelaGenix has been validated as an independent predictor of MSS in stage II patients and refines prognosis beyond AJCC. MelaGenix could serve as an important prognostic decision tool regarding patient management, especially whether adjuvant systemic treatment is appropriate – once drugs become available. It seems reasonable to include this score in future clinical trials. [Table: see text]