bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographic factors associated with financial toxicity: Results from the multisite cost study.
Authors: Parikh Divya Ahuja , Ragavan Meera Vimala , Dutta Ritika , Edwards Jeffrey , Maitra Debeshi , Patel Manali I.
Published: May 2019

e18362

Background: Financial toxicity (FT) is a major cause of distress for cancer patients. We have previously reported that FT was high among patients at a county hospital and a tertiary academic center. In this study, we sought to compare factors associated with FT at these institutions. Methods: Patients with clinic visits were asked to fill out an 11-item validated FT survey, the COST tool, and demographic questions from 10/2017 - 2/2018 at the county hospital and 7/2015 - 10/2018 at the academic center. We used a logistic regression model to analyze demographic factors associated with FT. Results: Mean COST score was significantly higher at the county hospital (28.7) compared to the academic center (20.4) (p < 0.001). Distribution of cancer stage was similar between the institutions. Patients at the county hospital were more likely to have an annual household income (AHI) < $25K (p < 0.001), and be insured by Medi-cal (p < 0.001). Patients at the academic center were more likely to be White (p < 0.001). Monthly OOP spending was more likely to be > $500 at the academic center (p < 0.001). Conclusions: Overall, FT was higher at the county hospital as compared to the academic center. FT at both institutions was associated with higher OOP spending and lower AHI. However, variations in FT among other demographic factors may reflect differences in care delivery systems and patient populations. Our study demonstrates that demographic groups at risk for FT differs between institutions suggesting the factors that contribute financial toxicity are complex and variable. Thus local assessments of FT may be necessary for individual health systems to develop targeted interventions to improve FT among their patients.[Table: see text]
Monthly parts a and b costs by service and line of therapy for FDA-approved/NCCN category 1 treatments for patients with metastatic pancreatic cancer.
Authors: Muldoon L. Daniel , Hirsch Jared , Dieguez Gabriela , Cockrum Paul
Published: May 2019

e18365

Background: Real-world evidence is lacking regarding costs for FDA-approved/NCCN Category 1 treatments for patients with metastatic pancreatic cancer (m-PANC). We analyzed costs by service in the Medicare fee-for-service (FFS) population by chemotherapy regimen and line of therapy (LOT). Methods: Patients with m-PANC were identified using ICD-9/10 diagnosis codes in the 2013-2017 Medicare 100% Limited Data Set claims, which include all Medicare paid FFS claims, except professional services, for 45 million Medicare FFS beneficiaries. We studied mean monthly costs by service category, regimen, and LOT. Patients in our study had two or more claims with a pancreatic cancer (PANC) diagnosis more than 30 days apart and one or more claims with a secondary malignancy (metastasis) diagnosis on or after the first PANC diagnosis date. We defined index date as the earliest metastasis diagnosis date. We excluded patients with pre-index non-PANC malignancies and those without 6 months pre-index and 3 months (or until death, if earlier) post-index Medicare FFS enrollment. LOTs were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. We analyzed the FDA-approved/NCCN Category 1 treatments used most commonly in first line (1L): gemcitabine monotherapy, gemcitabine/nab-paclitaxel, and FOLFIRINOX; and in second or third line (2L, 3L): liposomal irinotecan. Results: Mean monthly Parts A and B (excluding professional) costs for 1L gemcitabine monotherapy were lower than gemcitabine/nab-paclitaxel or FOLFIRINOX ($5,267, $9,116, and $8,046, respectively). Part B drug costs other than chemotherapy were higher for FOLFIRINOX than gemcitabine/nab-paclitaxel or gemcitabine monotherapy ($3,881, $1,155, and $827, respectively). Inpatient services were similar across 1L regimens ($2,721-$3,303). Despite disease progression, mean monthly 2L and 3L costs for liposomal irinotecan were $10,809 and $12,225, respectively. Part B drugs other than chemotherapy ($2,133-$2,509) were comparable to 1L regimens, but inpatient services ($2,306-$2,405) were lower. Conclusions: The mean monthly cost increased by LOT for m-PANC FDA-approved/NCCN category 1 regimens. Interestingly, Part A inpatient costs decreased in 2L and 3L, while Part B drug costs other than chemotherapy were comparable.
Use of a modified Delphi panel to define value of combination therapy in oncology.
Authors: Broder Michael , Patel Harshali , Wessler Zac , Gibbs Sarah , Yermilov Irina , Lemay Jeffrey
Published: May 2019

e18369

Background: Treatment regimens involving 2+ novel oncologics have improved health outcomes in several tumor types. These regimens have significantly higher costs than single agents and older treatments (e.g., chemotherapies), which are still widely used to treat different cancers. Our goal was to determine if current concepts of “value,” such as those described by ICER and other frameworks, adequately capture the value of combination therapies. Methods: Using a RAND/UCLA modified Delphi panel, 8 experts from various backgrounds were provided with a review of current concepts of value and asked to rate them on measurability, relevance, and necessity to determine a combination therapy’s value from 4 perspectives (patient, physician, payer, society). After the first round of ratings, panelists met in person and discussed areas of disagreement. Ratings were repeated, and results used to quantitatively summarize group opinion on concepts recommended for inclusion in a value definition. Results: In both rating rounds, experts agreed treatment, clinical evidence, and health outcomes as important domains in determining value. Experts disagreed on whether societal/cultural beliefs, disease factors (i.e., rarity of cancer, unmet need, burden of disease), and other elements of value (e.g., insurance value, reduction in uncertainty, treatment affordability) needed to be incorporated into value assessments of combinations. Responses differed by perspective. Concepts on which there was disagreement decreased post-meeting (23% to 9%). Conclusions: Experts agreed that “value” for 2+ novel oncologics would have a similar definition to value for all high cost oncology therapies. Four key research opportunities to characterize the value of combination therapy emerged: societal context and patient preference may affect value assessments but are not widely considered in current models; some important benefits are not recognized by patients and may be missed by traditional value assessments; given typical patient and societal preferences, cancer treatments may be systematically undervalued vis a vis other health conditions; and combination therapies may present challenges for recently promulgated value frameworks.
Role of advanced practice providers (APP) in meeting rising demands on oncology practices.
Authors: Bapat Bela , Smith Yolaine , Klink Andrew , Nabhan Chadi , Feinberg Bruce A.
Published: May 2019

e18372

Background: The role of advanced practice providers (APPs), nurse practitioners (NPs) and physician assistants (PAs), is expanding in oncology for myriad reasons including improving access to care by closing the gap between demand for services and physician availability. This is especially true in oncology, where the shortage of oncologists and increasingly cited physician burnout is creating challenges for many practices and communities. Methods: We surveyed US physicians to understand their practices’ use of APPs, their role in patient treatment and support as well as their impact on practice workflow. Data were collected using web-based instrument between Sep 2018 and Nov 2018. Responses have been summarized using descriptive statistics. Results: Among 163 oncologists and hematologists surveyed, 74.2% (n = 121) employed NPs, 39.9% (n = 65) employed PAs, and 19.0% (n = 31) did not employ any APPs in their practice. Amongst practices that employed ≥1 APP (n = 132; 81.0%), over 40% of physicians reported a 1:3 APP: physician ratio. Most (62.1%) physicians stated that APPs only evaluated and saw returning patients, whereas 35.6% physicians used APPs to evaluate and see both new and return patients. More than 60% of physicians stated that APPs enhanced their practice efficiency, enabled physicians to focus more on complex patient cases, and made their workload manageable. By employing APPs, 52.3% of physicians were able to increase their patient caseload. The majority (57.6%) of physicians reported that they would employ more APPs in the next 3 years if resources were available, and 41.7% of physicians reported that APPs would likely take on additional responsibility in the next 3 years. Conclusions: Most community oncology practices in the US are employing APPs and are finding significant value in the APP roles by delegating various aspects of patient care to them. Most community practices are considering increasing the number of employed APPs and to expand the breadth of their responsibility. Integrating APPs into oncology practices is likely to have a larger impact on quality of patient care and potential mitigation of physician burnout.
Community oncologists perceptions and readiness to implement Medicare Access and CHIP Reauthorization Act (MACRA).
Authors: Bapat Bela , Smith Yolaine , Klink Andrew , Nabhan Chadi , Feinberg Bruce A.
Published: May 2019

e18374

Background: The Medicare Access and CHIP Reauthorization Act (MACRA) was introduced in 2015 with the intention of transforming healthcare administration to improve the quality of care and lower its cost. Understanding challenges facing physicians in how to implement MACRA and recognizing their perceptions regarding these challenges are critical steps to the success of this program and future transformation efforts. Methods: In this study, US oncologists attending live meetings were surveyed on their perceptions of MACRA. Data were collected in 2 time periods: period 1 spanned Nov 2016 to Jun 2017 and period 2 spanned Sep 2018 to Nov 2018. Each physician attended a live meeting in each period. Data were collected in period 1 using audience response system technology and web-based surveys; period 2 data were collected using web-based surveys only. We aimed to compare responses between periods 1 and 2 to assess whether perceptions and challenges changed. Results: There were 97 community oncologists and/or hematologists who responded to both periods. Of the responding physicians, 31.2% were participating in the Oncology Care Model program. A greater proportion of physicians expressed some level of confidence in executing MACRA requirements and achieving financial success in period 2 compared to period 1 (74.2% vs 52.4%; P< 0.01). Additionally, more physicians in period 2 reported having the resources and staffing needed to manage changes required by MACRA (24.7% vs 11.4%; P= 0.02). Strategies in place to improve on compliance with MACRA did not significantly change between both periods (34.2% vs. 28.9%; P = 0.45). Confidence that MACRA would improve patient outcomes in the long-term was expressed by 33.0% in period 2, which was significantly higher than in period 1 (17.6%; P= 0.02). However, most physicians in period 1 were not confident that MACRA would reduce cost of care (89.6%), but this improved to 61.9% in period 2 ( P< 0.01). Conclusions: Over time, oncologists seem more confident about their practices’ readiness for implementing MACRA. However, they remain skeptical of MACRA’s likelihood of improving quality or cost of cancer care and appear to need better strategies to assure sustainability.
Acute kidney injury in childhood cancer: An insight from Kids' Inpatient Database.
Authors: Elsabbagh Eman M , Hashmat Shireen
Published: May 2019

e18379

Background: Oncology patients are at high risk for Acute Kidney Injury (AKI). AKI may occur due to direct injury from primary cancer, nephrotoxic effects of chemotherapy, hematopoietic stem-cell transplantation or following comorbidities like sepsis and metabolic disturbance. AKI is associated with prolonged hospital stay, high healthcare cost and increased mortality in critically ill patients. Despite the increased risk and these associations, the national rate and clinical outcome of AKI among pediatric oncology patients is not well described. Objective: Define AKI incidence and health outcomes among pediatric oncology patients in the United States (U.S.). Methods: We performed a retrospective cohort analysis of the Health Cost and Utilization Project (HCUP) Kids’ Inpatient 2000-2012 Database (KID) for patient ≤ 20 years of age. Patients with principal diagnosis of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas (Hodgkin and non-Hodgkin), brain tumor, neuroblastoma, bone tumors (Ewing’s Sarcoma and Osteosarcoma) and hepatoblastoma were reviewed. Encounters for chemotherapy were excluded. Patients with medical diagnosis of AKI were identified using ICD-9-CM codes. We performed descriptive statistics to characterize the cohort in terms of demographic factors (age, race, sex, insurance type), hospital characteristics and comorbidities. Data weights were applied to sampled patients to provide national estimates. The in-hospital mortality rate, total charges, and hospital length of stay (LOS) were compared between cancer patients with and without AKI using bivariable analyses. Results: A total of 266,113 admissions were included for analysis. The cohort was comprised of 4,761 patients with AKI, with an overall incidence 18 per 1,000 admissions. The median age was 13 years. Males (58.45%), and whites (55.4%) were more commonly affected. South and west regions (59%) of the U.S. had higher frequency of AKI. AML was the most common diagnosis associated with AKI (4.1%). Patients with AKI had significantly higher mortality rates (21.78% vs. 1.36%, p < 0.0001), longer median LOS (15 days vs. 4 days, p < 0.0001) and higher median total charges per hospitalization ($132,712 vs $18,856) when compared to patients without AKI. Conclusions: AKI in pediatric oncology patients is significantly associated with increased in-hospital mortality, LOS, and higher healthcare cost in pediatric oncology patients. This area needs focused research and quality improvement initiatives.
Efficacy and cost-effectiveness of HER2+ early breast cancer therapies.
Authors: Fonseca Magalhães Filho Marcos , Aguiar Pedro Nazareth , Haaland Benjamin , Del Giglio Auro , Lopes Gilberto
Published: May 2019

e18380

Background: Human Epidermal Growth Factor Receptor 2 (HER2) overexpression occurs in up to 25% of breast cancer (BC) cases. Patients with HER2+ tumors have a poor prognosis even when the disease is detected at an early stage with a recurrence rate of 15-19%. The aim of this study is to assess the best approach (pertuzumab plus trastuzumab [T+P], trastuzumab for 12 months [T12], trastuzumab for 6 months [T6], or T-DM1) in terms of evidence-based medicine and cost-effectiveness. Methods: The authors extracted individual patient data and estimated Invasive Disease-Free Survival (IDFS) and Overall Survival (OS) over a 30-years lifetime horizon. We considered only direct costs from adjuvant treatment as well as recurrence treatment from a Brazilian payer perspective. Heart events were considered for utility and cost analysis. After the base case, the authors assessed cost-effectiveness among N+ patients. In the meta-analysis, we included individual patient data for the intention-to-treat (ITT) population and Bayesian comparisons for subgroup analysis (HR+/HR- and N+/N). Results: We included individual patient data from 12,753 patients. The 4-year IDFS rate was 92.9% for T+P, 89.8% for T12 (HR 1.37, 95%CI 1.16-1.63) and 87.1% for T6 (HR 1.73, 95%CI 1.45-2.06). The 4-year OS rate was 96.7% for T+P, 95% for T12 (HR 1.37, 95%CI 1.07-1.75) and 93% for T6 (HR 1.82, 95%CI 1.42-2.34). T+P, T12 and T6 had similar efficacy among patients with HR+ tumors. T+P and T12 were superior to T6 among HR- patients. T+P was superior to T12 and T6 among N+ patients. T+P, T12 and T6 had similar efficacy among N- patients. In the base case, T+P had an ICER of $332,903 compared to T12. T12 had an ICER of $42,774 compared to T6. Among N+ patients, T+P had an ICER of $308,019 compared to T12. Among patients without complete response after neoadjuvant treatment, T-DM1 had an ICER of $3,233 compared to trastuzumab. Conclusions: T+P had a modest benefit in terms of 4-years IDFS and OS, although it was not cost-effective due to its high cost. T12 remained above the cost-effectiveness threshold compared to T6, but further studies are needed in order to define patients for T6. T-DM1 was cost-effective compared to trastuzumabe for patients who did not achieve complete response after neoadjuvant treatment.
Utility of tumor genomic profiling in guiding targeted therapy and referral for clinical trials in the community practice.
Authors: Xu Yiqing , Yio Jiang , Yang Amber , Bayewitz Ashrei , Benasher Daniel , Fu Lung
Published: May 2019

e18381

Background: Next-generation sequencing (NGS), which enables tumor genomic profiling with limited tumor specimen for the guidance of targeted therapy, has been widely used in oncology practice. It also reports mutations of which no approved therapy is available, but potential therapies approved in a different tumor type may be reasonable to try, based on molecular mechanisms or limited data, either in clinical trials or off trial treatment. The utility of this information in the community practice is unclear. Methods: We performed a retrospective analysis on the usage of NGS result on patients with lung or colorectal cancers treated between November 2011 and February 2018. Patients were identified from Foundation Medicine Company database and were linked to records at Maimonides. We evaluated if NGS was used to guide FDA-approved targeted therapy, potentially-useful targeted therapy not approved for the cancer type, or referral to a clinical trial. Results: 177 patients (lung ca = 119, colon ca = 58) were included. NGS identified 34 (28.6%) lung ca patients with driver mutations, (21 EGFR, 6 RET, 3 ALK, 2 MET amplification, 1 ROS1 and 1NTRK mutation), who were all given FDA-approved therapy. 70 (58.8%) patients had at least 1 target with an FDA-approved therapy for a different cancer; 89 (74.9%) had a mutation being studied in a clinical trial, and 48 patients were eligible for the NCI-MATCH trial. None received non-FDA-approved drugs and none was referred to clinical trials. In the colon cancer cohort, NGS identified alterations in KRAS (27), BRAF (5), ERBB2 mutation (2), ERBB2 amplification (1), MLH1 (1), MSH2 (1) and BRCA 2(1). Among them, one patient received BRAF inhibitors. 45 and 24 patients were eligible for phase I/II trials and NCI-MATCH trial respectively, and none was referred. Conclusions: NGS has a high efficiency of detecting driver mutations in lung cancer; but only reveals low frequencies of alterations otherwise not tested in colon cancer. The approach of prescribing un-approved targeted treatment based on theoretical mechanism of action was very uncommon, and the referral to clinical trials was rare in this community practice, both of which decreasing the utility value of NGS.
Out of pocket costs and financial toxicity experienced by patients in early phase clinical trials.
Authors: Huey Ryan , George Goldy , Phillips Penny , White Revenda , Fu Siqing , Janku Filip , Karp Daniel D. , Naing Aung , Piha-Paul Sarina Anne , Subbiah Vivek , Tsimberidou Apostolia Maria , Pant Shubham , Yap Timothy A , Rodon Ahnert Jordi , Meric-Bernstam Funda , Shih Ya-Chen T. , Hong David S.
Published: May 2019

e18383

Background: Clinical trials are an important therapeutic option for cancer patients. Although financial burden in cancer treatment is well-described, the financial burden associated with clinical trials is not well understood, especially for patients with lower socioeconomic status. Methods: We conducted a survey regarding economic burden and financial toxicity among cancer patients on Phase I clinical trials for at least 1 month. Financial Toxicity Score (FTS) was assessed using the validated COmprehensive Score for Financial Toxicity (COST) survey (scale 0-44, lower scores indicating worse financial toxicity). Patients also reported monthly out of pocket (OOP) medical and non-medical expenses. Results: Of 147 consecutive patients approached, 105 agreed to participate; median age = 60y; 62% female; 49% had annual income < $60K; 50% lived < 300 miles from the clinic; 34% required air travel; 41% had Medicare, 50% had employer sponsored insurance. Median FTS = 20, with interquartile range of 12.5. Median monthly OOP costs for non-medical expenses was $985, and for medical expenses was $475. Median total monthly OOP costs was $1695. Compared to patients in the highest quartile of FTS, a significantly lower % of patients in the lowest (worst) quartile of FTS had incomes > $60K (27% v. 77%, P < 0.001), and a significantly higher % were unemployed or not working outside the home (54% v. 12%, P = 0.001), and incurred higher than expected medical (39% vs. 12%, P = 0.025) and non-medical (64% vs. 15%, P = 0.003) expenses. Compared with patients for whom medical costs were not much higher than expected, a significantly higher % of patients with medical costs much higher than expected were non-White (77% v. 46%, P = 0.004) and unemployed/not working outside the home (46% v. 19%, P = 0.009). Conclusions: Among cancer patients participating on clinical trials, economic burden is high and financial toxicity is disproportionally higher in patients with lower income. OOP costs can be substantial and are often unexpected for patients.
Value appraisal of FDA approved cancer drugs over the past decade.
Authors: Huey Ryan , Anand Seerat , Rogers Jane , Dasari Arvind , Varadhachary Gauri Rajani , Gothwal Anirudh , Loree Jonathan M. , Ellis Lee M. , Overman Michael J. , Raghav Kanwal Pratap Singh
Published: May 2019

e18385

Background: Value based drug pricing is emerging as an imperative health care precept in recognition of the ever-increasing drug costs, especially in oncology. Though novel therapies are regularly approved based on benefit, they are often associated with physical and financial toxicities to patients. We aimed to assess the value of FDA approved oncology drugs defined as their expected clinical benefit compared to their toxicities and costs. Methods: We reviewed all new cancer drug approvals by the FDA from 7/2008-6/2018. Current analysis was restricted to approvals based on overall survival (OS) and progression-free survival (PFS). Data regarding approval indication, effect size, and toxicity were collected from FDA website and publications. Toxicity was estimated as adverse events ≥ grade 3 (or serious adverse events) as reported. Micromedex RED BOOK was used to estimate the total drug price using 2018 average wholesale prices. Price was estimated over 3 months to account for difference in drug regimens. Results: Among the 231 trials used by FDA for approvals in oncology, 115 had OS or PFS as their primary endpoint. Median patients per trial was 539. Of 79 trials with a PFS endpoint, the median HR was 0.50 (range: 0.15 - 0.91); median 3-month drug price was $45,903.72. Compared to the control arm, median toxicity for new drugs was 7% higher (range: -34.4 - 55%). Correlation of HR benefit to 3-month price was 0.06 (95% CI: -0.17 - 0.28, P = 0.61). Correlation of net toxicities to 3-month price was 0.01 (95% CI: -0.25 - 0.26, P = 0.94). Of 43 trials with an OS endpoint, the median HR was 0.72 (range: 0.37 - 0.94); median 3-month price was $43,523.46. Relative to control arm, median toxicity for new drugs was 4% higher (range: -34.4 - 45.8%). Correlation of HR benefit to 3-month price was 0.38 (95% CI: 0.08 - 0.62, P = 0.012). Correlation of net toxicities to 3-month price was -0.12 (95% CI: -0.45 - 0.24, P = 0.50). Conclusions: Drug approvals in oncology come with a high cost and drug prices have very little correlation with estimated benefit in outcomes and toxicities. As policies evolve to promote higher value in health care, attention should be paid to benefits of drugs in relation to pricing and using biomarker-based patient selection to maximize benefits and minimize toxicities.
Continuous intravenous infusion Rh-endostatin in combination with dacarbazine and cisplatin as the first-line therapy for metastatic melanoma.
Authors: Cui Chuanliang , LIAN BIN , Wang Xuan , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , Yan Xieqiao , Tang Bixia , Zhou LI , Guo Jun
Published: May 2019

e21007

Background: Immunotherapy and targeted therapy have dramatically improved the survival of advanced melanoma patients (pts), but they show relative lower efficacy in Asian pts especially in acral and mucosal subtypes. Rh-Endostatin (endostar) is a potent endogenous inhibitor of angiogenesis. Previous studies have indicated that endostar combined with dacarbazine (DTIC) was effective in the treatment of metastatic melanoma. To further improve the effectiveness, this study was designed to observe the efficacy and safety of continuous infusion (CIV) of endostar combined with DTIC and cisplatin as the first line therapy for advanced melanoma pts. Methods: Pts with treatment naive, ECOG 0/1, and unresectable stage IIIC or IV melanoma were enrolled. DTIC (250 mg/m2, intravenous infusion, day 1-5), cisplatin (75 mg/m2, intravenous infusion, separated in 3 days) and endostar (15 mg/m2, CIV, day 1-14) were administered in a 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was progression free survival (PFS). Secondary endpoints included disease control rate (DCR) and safety. Results: From January 2016 to May 2018, 64 pts were enrolled and 50 pts were evaluable. 26 pts were female. The median age was 50 years (range 28-71 years) old. 10/64 (15.6%) were primary mucosal and 21/64 (32.8%) were primary acral, 40 pts were at stage IV and 32% pts got BRAF mutation. At the last follow up of Dec 2018, 5 pts achieved partial response and 27 pts got stable disease. The objective response rate was 10%. The DCR was 64%. The median PFS was 6.0 months (95% CI 1.7-10.3 months). The median overall survival was not reached. The most common adverse events were nausea (56.25%), vomiting (31.25%) and leucopenia (29.7%). Grade 3-4 toxicity was few, one got intermittent palpitation and one got atrial fibrillation, which caused drug discontinuation and recovered to normal. Conclusions: Continuous infusion of endostar plus DTIC and cisplatin improved median PFS as the first line therapy for advanced melanoma. This combination therapy was well tolerated and might be recommended as the first line therapy for advanced melanoma. Clinical trial information: NCT03095079.
Immune related adverse events (irAE) of mono-, combination, and sequential therapy regimens of ipilimumab (IPI), nivolumab (NIV), and pembrolizumab (PEM) for advanced melanoma.
Authors: Almutairi Abdulaali , McBride Ali , Sundararajan Srinath , Abraham Ivo
Published: May 2019

e21011

Background: The immunotherapy agents IPI, NIV, and PEM have transformed the management of advanced melanoma but are associated with irAEs. We estimated the incidence of irAEs as observed in clinical trials of mono, combination , and sequential regimens of these agents in the advanced melanoma setting. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in USA, Europe, Australia, and Japan for phase 1-3 trials of IPI, NIV, and PEM in advanced melanoma. Random effect meta-analysis was utilized to estimate the incidence of irAEs (expressed as % with 95%CI) for all agents in mono-, combination, and sequential regimens. Results: 56 reports (32 published articles, 7 updates, 15 results published on clinicaltrials.gov and 2 regulatory documents) of 37 trials and relating unique and independent irAE data were included in the analysis. See Table. Conclusions: IPI mono had higher incidence rates of all grade and ≥ grade 3 hypophysitis and colitis but lower rates of all grade hypothyroidism, pneumonitis, and vitiligo than NIV or PEM mono. Combination and sequential regimens had higher irAE incidence rates compared to monotherapies except for grade ≥3 hypophysitis in PEM+IPI and NIV→IPI, and grade ≥3 vitiligo as well as all grade colitis and hypophysitis in IPI →NIV. Table. Incidence rates of select irAEs expressed as % with 95%CI (‡ all grade; * ≥ grade 3). [Table: see text]
Cyclooxygenase inhibitor use during checkpoint blockade immunotherapy and effect on time to progression for metastatic melanoma patients.
Authors: Wang Shang-Jui , Khullar Karishma , Yegya-Raman Nikhil , Kim Sinae , Silk Ann W. , Malhotra Jyoti , Gentile Michael A. , Mehnert Janice M. , Jabbour Salma K.
Published: May 2019

e21029

Background: In tumors, cyclooxygenase (COX) activity leads to biosynthesis of prostaglandin E2 which can inhibit T-cell and dendritic cell function, thereby allowing immune evasion. Preclinical models have shown therapeutic synergy between COX inhibitors (COXi) and anti-PD-1 inhibition (PD-1i) immunotherapy (IT). We hypothesized that patients (pts) treated with checkpoint blockade IT and concurrent COXi would have improved responses compared to those treated with IT and no COXi. Methods: We retrospectively analyzed 65 metastatic melanoma pts who received IT (PD-1i/PD-L1i/CTLA4i) between 5/2011-11/2017 on their 1st course of IT. Of these pts, 38.5% (N = 25) took concurrent COXi (aspirin, NSAIDs, or selective COX-2i) and 61.5% (N = 40) did not. We compared differences in baseline characteristics and time to progression (TTP) between IT-treated melanoma pts who did or did not receive COXi, using the Kaplan-Meier method and Cox regression. TTP was defined as time from IT start to progression of disease (POD) as determined by the treating physician based on CT or PET/CT scans, or last known alive. Results: Mean age was 66 yrs; male: 64.6%; BRAF mutant: 29.2%, ECOG 0/1/2: 60%/35.4%/4.6%; steroid use: 47.7% during IT; and prior non-checkpoint blockade IT: 13.8%. IT was stopped due to POD in 53.8% of pts, IT toxicity 6.2%, completed therapy 24.6%, and treatment holiday 15.4%. There were no significant differences in baseline characteristics between pts who did or did not receive COXi during IT, except for mean age (70 (COXi) versus 63 yrs (no COXi), p = 0.019). Pts that received COXi had longer TTP (median 245 days) vs without COXi (median 85 days, p = 0.0002). On multivariate analysis, COXi was associated with longer TTP (HR 0.34, p = 0.0004) after accounting for age, gender, steroid use, and ECOG PS ≥1. Immune-related toxicity was not significantly different with or without COXi (p = 0.73). Conclusions: Our findings suggest that in metastatic melanoma pts treated with IT, concurrent COXi use may result in a longer TTP, without increasing toxicity. These findings warrant further study to continue to augment outcomes for pts.
Specificity of markers CD44 and S100 for skin melanoma and nevi tissues.
Authors: Goroshinskaya Irina A. , Kit Oleg I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Pozdnyakova Viktoria V. , Shikhlyarova Alla I. , Akhmedova Amira A. , Khokhlova Olga V. , Neskubina Irina V. , Cheryarina Natalia D.
Published: May 2019

e21036

Background: The high metastatic potential of melanoma and the need for long-term patient monitoring causes the search for tumor markers of this malignant neoplasm. Our aim was a comparative analysis of levels of tumor-specific proteins CD44 and S100 and protein composition in melanocytic lesions of the skin. Methods: We studied 86 samples of cutaneous melanoma and nevus tissues, their perifocal tissues and resection line tissues obtained during tumor excision from 23 patients with cutaneous melanoma pT1-4N0-1M0 and 14 patients with nevi. Intact skin samples obtained from non-cancer patients during reconstructive plastic surgery were used as the comparison group. All patients gave their written informed consent. Levels of CD44 (BenderMedSystems, USA) and S100 (Fujirebio, Sweden) were determined by ELISA in 10% homogenates of all tissues; total protein levels were determined by standard spectrometry and fractional composition of proteins were studied by turbidimetric method. Statistical processing of results was performed using the Statistika 6.0 program with Student’s t-test for two independent groups. Results: Melanoma was characterized by a sharp increase in S100B levels, 28 and 7 times exceeding the levels in intact tissues and nevi. The level of CD44 in melanoma tissue was increased only by 2 times, in nevus tissue - by 48%. The ratio of albumin and gamma globulins in the tissue of melanoma and nevi was 79% and 29% lower than in healthy skin. A more than twofold increase in the gamma globulin fraction in the melanoma tumor tissue against a decrease in albumin and the absence of changes in other globulins, as well as a moderate but statistically significant increase in the gamma globulin fraction in nevi tissue, indicates that S100B and CD44 proteins belong to the gamma globulin fraction. Conclusions: A highly specific increase of S100 levels and a less specific increase of CD44 levels in supernatant liquid of melanoma tissue homogenates, together with the predominance of the gamma globulin fraction, allow considering such factors as a prognostically unfavorable sign of tumor progression, which can be important when choosing a personalized treatment strategy.
Response to PD-1 inhibition in early- and late-relapsing cutaneous melanoma.
Authors: Fitzgerald Kelly , Daud Adil
Published: May 2019

e21038

Background: Up to 45% of stage I-II melanomas will relapse within 5 years, and some relapses occur more than 10 years after surgical resection. Little is known about the differences in tumor characteristics, including immunogenicity, of early- vs. late-relapsing melanoma, or the implication of these differences in response to PD-1 inhibition. Methods: A retrospective cohort study was conducted to compare time from definitive treatment of localized melanoma to relapse with response to pembrolizumab. Patients with prior stage I-II melanoma who relapsed, and then treated with pembrolizumab, were included in the study. Time to relapse was compared with overall response rate. Results: Among the study population, 66 patients initially presented with early stage disease that relapsed within the study period. The median time to relapse was 5 years (range 0.5-33 years, interquartile range 7.25, Q1 = 2, Q2 = 9.25). 9 patients (14%) relapsed within 2 years of surgery; these patients had a higher overall response rate to pembrolizumab than late-relapsing patients with marginal significance (88% vs 50%, p = 0.056). The difference became less significant when patients who relapsed before or after 5 years (70% vs 47%, respectively, p = 0.20), and before or after 10 years (64% vs 45%, p = .31). Conclusions: Patients with early-relapsing melanoma had higher ORR to pembrolizumab than patients with late-relapsing disease, with early relapse defined as earlier than 2 years from definitive surgical intervention. Late relapsing tumors may harbor mechanisms of resistance to immune checkpoint inhibition.
Does the initial biopsy type affect clinically important outcomes in malignant melanoma? A meta-analysis.
Authors: Fayyaz Fatima , Shellenberger Richard A
Published: May 2019

e21041

Background: Malignant melanoma continues to have an increasing incidence worldwide without a decline in mortality, despite advances in treatment and early detection which have led to improved mortality outcomes for most malignancies. Early detection is particularly favorable for melanoma localized to the site of disease, which confers a five year survival rate of 98.4 %. Guidelines from the American Academy of Dermatology (AAD) give three acceptable options for the initial management of pigmented lesions suspicious for melanoma: elliptical excision, wide punch excision and a deep shave or saucerization. Methods: We performed a systematic review and meta-analysis to better define the evidence for differences between punch incisional and excisional biopsy with regard to clinically important outcomes in the evaluation of skin lesions suspicious for melanoma. These were melanoma specific mortality, all-cause mortality, Breslow tumor thickness, and melanoma recurrence. The comparison groups were punch incisional and excisional biopsy; there was insufficient data to include shave biopsies. Results: The result of pooling the studies that track melanoma specific mortality finds that there is a higher, but non-significant rate of death among those in the punch incisional group. The pooled risk ratio is 1.21, p = 0.153. The results of pooling the all-cause mortality studies also finds a higher, but non-significant, rate of death among the punch incisional group, RR = 1.03, p = 0.390. Pooling the two studies that examine Breslow thickness found that values in the punch incisional group are significantly lower, with a standardized mean difference of -0.17, p = 0.006. Finally, the pooled risk ratio for recurrence was not significant, RR = 1.161, p = 0.198. Conclusions: Until further data is available, there is no evidence to suggest a preferred diagnostic procedure in the initial evaluation of pigmented lesions suspected of cutaneous melanoma related to clinically important outcomes. To our knowledge, this is the first meta-analysis done on this important question regarding melanoma epidemiology and public health.
Melanoma nodal management in Ontario following ASCO/SSO guidelines.
Authors: Latosinsky Steven , Shariff Salimah , Allen Britney
Published: May 2019

e21054

Background:Methods:Results: Conclusions:The American Society of Clinical Oncology and Society of Surgical Oncology (ASCO/SSO) published a joint guideline in 2012 regarding indications for sentinel lymph node biopsy (SLNB) in cutaneous melanoma. The guideline supported completion lymph node dissection (CLND) for all patients with a positive SLNB. We examined the rates and predictors of SLNB and CLND for melanoma patients in Ontario (population 13.6 million) following guideline publication. Methods: We used the Ontario Cancer Registry (OCR) to identify cutaneous melanoma patients diagnosed in 2013. Patient records were linked to prospectively maintained health administrative databases to obtain details for each patient including surgical procedures. Results: We identified 3298 melanoma patients from Ontario in 2013 of which 1,973 (59.8%) could be analyzed. The majority, 1,227 (62.2%) had a local excision alone, while 746 (37.8%) had a SLNB. SLNB was performed on T1, T2, T3 and T4 primary melanomas in 13.9%, 67.8%, 62.6% and 47.2% of cases respectively. Receipt of a SLNB was positively associated with a younger age (< 80), higher T stage, and non-head and neck primary in multivariate analysis. Of the patients who received a SLNB 136 (18.2%) were found to be node positive. A CLND was performed in 82 (60.3%) of these patients. Conclusions: In Ontario only two-thirds of intermediate thickness melanomas (T2, T3) received a SLNB as recommended by the ASCO/SSO guidelines. Utilization was lower for head and neck patients and higher for younger (< 80 years) patients. Use of CLND for positive SLNB was also low relative to the guidelines.
Preliminary safety results of a phase II study investigating pembrolizumab in combination with postoperative intensity modulated radiotherapy (IMRT) in resected high risk cutaneous squamous cell cancer of the head and neck.
Authors: Koyfman Shlomo A. , Gastman Brian , Vidimos Allison T. , Joshi Nikhil Purushottam , Lucas Jennifer , Poblete-Lopez Christine , Vij Alok , Meine Jon , Burkey Brian B. , Ku Jamie , Lamarre Eric , Prendes Brandon , Scharpf Joseph , Billings Steven D , Samsa Julia , Robinson Shelley Beth , Adelstein David J. , Geiger Jessica Lyn
Published: May 2019

e21056

Background: High risk cutaneous squamous cell cancer of the head and neck (cSCC-HN) have suboptimal outcomes with surgery and postoperative radiation. We report preliminary safety outcomes of a phase II study (NCT03057613) exploring the safety and efficacy of the addition of Pembrolizumab to postoperative IMRT. Methods: Patients with cSCC-HN were eligible for this IRB approved study if they had resection of all gross disease and demonstrated (a) invasion of the skeleton or skull base; (b) node positive disease; (c) or a tumor > 2cm with ≥1 of the following risk factors: recurrent disease, perineural invasion, lymphovascular space invasion, poorly differentiated, positive margins, satellitosis or in-transit metastases. Immune competent pts and those with CLL were eligible. This study aimed to accrue 34 evaluable patients to assess a primary safety endpoint of dose limiting toxicity (DLT) defined as any grade ≥3 toxicity at least possibly related to the immunotherapy. Assuming toxicity of < 20% is acceptable and > 40% is unacceptable, if ≥11 of 34 (32%) patients experienced a DLT, the regimen would be considered unsafe. Results: Of 15 pts already enrolled on this study, 11 have completed the protocol treatment. There were no DLTs observed to date. Grade 2 immune related toxicity was seen in two patients, one with bullous pemphigoid and another with lymphopenia and peripheral neuropathy and weakness in his hands in the setting of a prior cervical spine injury. Both responded to steroids and recovered completely. Based on this initial cohort, the 95% confidence intervals (CI) on DLTs for the entire cohort is 0-28%. Using the most conservative CI of 28%, the likelihood of 11 of the remaining 23 patients experiencing a DLT is 3.4%. Assuming a CI of 20%, the risk is 0.3%. None of the 11 pts who have completed protocol therapy have experienced a recurrence. Conclusions: The addition of Pembrolizumab to postoperative IMRT in high risk cSCC-HN is safe and will be studied in a randomized phase III adjuvant study (Keynote 630). This phase II study will continue to enroll CLL patients to assess safety and efficacy signals in this unique higher risk population. Clinical trial information: NCT03057613.
Cancer Immune Control Dynamics (CICD): A clinical data driven model of systemic immunity.
Authors: Markovic Svetomir , Sprau Allan , McElroy Virginia , Nevala Wendy Kay , Leontovich Alexey , Frisch Harold
Published: May 2019

e21058

Background: Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This will lead to improvements in the efficacy of existing immune therapies (patient selection; drug combinations) and insight into new therapeutic targets that may significantly reduce the time to new therapeutics discoveries capable of meaningful clinical impacts. Methods: A systems analysis approach (Cancer Immune Control Dynamics, CICD) attempts to identify the differences between systemic immune homeostasis of healthy volunteers versus patients with metastatic malignant melanoma based on serial measurements of a set of conventional peripheral blood biomarkers of immune function (15 cell subsets and 35 cytokines) assessed daily over 7-10 days. The modeling strategy takes aerospace engineering control theory and system identification algorithms to analyze the state of an individual’s immune system based on the biomarkers’ dynamic non-linear oscillatory behaviors. The analysis framework builds on the classical predator-prey equations commonly used to model biological system dynamics. Tens of thousands of biologically possible biomarker interactions are modeled by a set of matrix equations that creates a system interaction model. CICD quantifies the system equations with biomarker values and solves it to measure the interactions. Results: Quantification of thousands of unique biomarker relationships per participant enables classification based on their immune profile rather than their clinical diagnosis and a basis for a visualization of a person’s immunity state. Conclusions: Results provide initial evidence that a model-based analysis of serially collected biomarker data can lead to biological insights into human immunity, of potential benefit in clinical decisions. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.
Nation-wide trends in mortality of patients with ocular and orbit melanoma: 2000 to 2014.
Authors: Forehand William , Gopishetty Swathi , Shahbandi Ashkan , Guddati Achuta Kumar
Published: May 2019

e21061

Background: Ocular and orbit melanoma is a rare subtype of melanoma for which outcomes have not been adequately reported. In this study we he have analyzed the incidence-based mortality trends of ocular and orbit melanoma over a 15 year period. Most ocular melanomas originate from the uvea and to a lesser extent from the conjunctiva. Primary orbital melanoma is exceedingly rare. The incidence of ocular melanoma has been stable for the past few decades but incidence-based mortality has not been studied over the past 15 years. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was utilized to query the incidence-based mortality for all patients diagnosed with ocular and orbit melanoma for the years 2000 to 2014. The results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander). Paired T-test was used to determine statistically significance difference between various subgroups (p < 0.05). Results: Incidence-based mortality has been the highest in Caucasian/White patients from 2000 to 2014 followed by African American/Black and Asian/Pacific Islander patients. American Indian/Alaskan native patients appear to have the least mortality. There was a statistically significant difference (p < 0.05) in mortality between Caucasian/White patients from 2000 to 2014 followed by African American/Black and Asian/Pacific Islander patients. The sample size for African American/Black and American Indian/Alaskan native patients was too low for discerning a meaningful trend in mortality. Overall it appears that Caucasian males and females have a far higher and worsening incidence-based mortality compared to other races. Conclusions: Ocular melanoma and orbit melanoma are rare entities which are predominantly seen in Caucasian/White patients. This study shows that the incidence-based-mortality has been worsening for these patients in the past two decades. These entities have poor prognosis and have not been studied extensively in immunotherapy trials. This study highlights the need for new clinical trials to help improve the mortality rates.