bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of activating NOTCH1 mutations in adenoid cystic carcinoma with shorter progression-free survival to systemic therapy.
Authors: Ferrarotto Renata , Duran Alper H , Wei Wei , Carter Brett W. , El-Naggar Adel K. , Su Shirley Y , Bell Diana , Kies Merrill S. , William William N. , Glisson Bonnie S. , Godoy Myrna , Heymach John
Published: September 2018

6089

Background: We previously reported that activating NOTCH1 mutations occurs in approximately 20% of ACCs and drive a phenotype with solid histology, liver and bone metastases, poor prognosis, and potential responsiveness to Notch1 inhibitors; however the impact of NOTCH1mutations on responsiveness to systemic therapy in ACC is unknown. The aim of this study was to evaluate the ORR and median PFS (mPFS) to systemic therapy in patients with metastatic ACC according to their Notch1 status. Methods: We identified 20 ACC patients with measurable disease that underwent treatment at MDACC and had tumor molecular profile. A radiologist blinded to the patient’s NOTCH1status performed review of all images. Measurement of target lesions was captured by a quantitative imaging analysis tool for ORR assessment by RECIST 1.1. PFS was estimated by Kaplan-Meier method. Comparisons of PFS between groups were performed using log-rank test. P≤0.05 was considered statistically significant. Results: Out of 20 patients, 4 (20%) were NOTCH1 mutant. Notch1 pathway activation status by immunohistochemistry (NICD) was available for 15 patients, 10 were positive. The median number of therapy lines was 2 (range 1-6). Best ORR among 49 treatment plans across all lines of systemic therapy including chemotherapy (15), anti-EGFR (10), anti-VEGFR (11), and others (13) was PR in 2 (4%), SD in 29 (59%), and PD in 18 (37%). During first line treatment, patients with NOTCH1 mutations had significantly shorter mPFS compared to NOTCH1 wild-type (2.97 vs. 6.92 months, P = 0.02). The PFS rate at 3 months was 25% for NOTCH1mutants vs. 81% for wild-type. A trend towards shorter PFS was seen in NICD positive vs. negative (3.58 vs. 6.74 months, P = 0.2). Conclusions: NOTCH1 mutations in ACC are associated with shorter PFS during first-line treatment. Validation of these findings is warranted in larger patient cohorts.
Racial composition in trials supporting the U.S. approval of anti-cancer new molecular entities (NMEs): 2011- 2016.
Authors: Fashoyin-Aje Lola A. , Fernandes Laura L. , Lemery Steven , Keegan Patricia , Sridhara Rajeshwari , Bull Jonca C. , Pazdur Richard
Published: September 2018

6518

Background: In New Drug- and Biologics License Applications, clinical trials provide the primary safety and efficacy data upon which approval decisions are made. Low numbers of patients from racial groups that experience higher incidence and/or mortality from some cancers compared to the overall US population, may limit the generalizability of trial results. The Census estimates that the US population is 77.1%White, 13.3% Black/ African American (AA), 5.6% Asian, 1.2% American Indian/ Alaska Native (AIAN), and 0.2% Native Hawaiian/ Other Pacific Islander (NHPI). FDA conducted an analysis to compare the racial composition in trials supporting the approval of NMEs for the treatment of solid tumor malignancies. Methods: We reviewed the marketing applications of the 33 NMEs approved between 2011- 2016 to identify trials that provided the primary evidence of safety and efficacy. Results: A total of 29941 patients were enrolled. The table below illustrates enrollment by race (excluding Non-Hispanic, Hispanic, Other, Mixed Race & Missing) and approval year. Conclusions: The proportion of White patients enrolled in the US (88%) is higher than the proportion of Whites in the US population. However, the enrollment of AA and NHPI/AIAN patients is low and below the proportional representation of AA and NHPI/AIAN in the US. While enrollment targets may differ across cancer type and by race, the racial composition of patients enrolled in the trials that support the approval of cancer therapeutics should be reflective of the likely US patient population for whom these agents will be prescribed. The majority of Asian patients enrolled were from RoW while the majority of AA and NHPI/AIAN patients were enrolled from the US. Increasing the representation of racial minority patients in oncology trials will require targeted recruitment and enrollment of these patients in US sites. [Table: see text]
What does the general population think about chemotherapy shortages?
Authors: Frosch Zachary Ak , Cronin Angel M. , Joshua Gagne J. , Teschke Maxwell P. , Gray Stacy W. , Abel Gregory A.
Published: September 2018

6530

Background: Chemotherapy shortages have been increasingly recognized, and most oncologists report their patients have been at least intermittently affected. Despite their potential impact, little is known about the perspectives of the general population regarding shortages. Methods: In October 2016, we conducted a survey using the GfK KnowledgePanel, an online probability-based sample representative of adults in the United States. We assessed awareness of shortages, and provided vignettes in which a substitute chemotherapy drug had either a major or minor difference in side effects or effectiveness. We asked respondents whether they would want to be informed of a substitution, and, if the original drug were available elsewhere, would transfer care to receive it. We also asked if cancer centers were to publish drugs in shortage at their center, if such data would affect decisions about where to seek care. Analyses applied post-stratification sampling weights to draw national inferences. Results: Of 737 potential participants, 420 (57%) responded; 16% had heard of chemotherapy shortages. Respondents with a personal history of cancer were more likely to have heard of shortages (31% vs 14%, p = 0.03), as were those with greater education (p = 0.01) and those who reported more sources of health information (p = 0.01). Most desired to be informed about a chemotherapy substitution in the setting of both major (87%) and minor (83%) differences in side effects, as well as both major (87%) and minor (82%) differences in effectiveness. In contrast, only 61% reported they would transfer care if a substitute drug had major differences in side effects, and even fewer (40%) for minor differences. Similarly, 72% and 46% reported they would transfer care if a substitute had major or minor differences in effectiveness respectively. Finally, 57% reported that publically-reported shortage data would be a “big factor” in deciding where to be treated. Conclusions: Our data suggest that the general population is largely unaware of chemotherapy shortages. Moreover, in the setting of even minor changes in effectiveness or side effects, respondents wanted to be made aware of substitutions. With major differences, many would seek care elsewhere.
Enrollment of high-risk patients with diffuse large B-cell lymphoma in clinical trials.
Authors: Loh Kah Poh , Baran Andrea , Hu John , Casulo Carla , Barr Paul M. , Friedberg Jonathan W. , Reagan Patrick Michael
Published: September 2018

6536

Background: Contemporary precision medicine trials in DLBCL often require real-time central pathology review for enrollment. Central review may lead to treatment delays and prevent high risk patients (pts) with aggressive presentations from enrolling onto clinical trials. We explored reasons pts with DLBCL were not enrolled on trials and the implication of non-enrollment on trial design and interpretation. Methods: We retrospectively analyzed all pts with histologic diagnosis of DLBCL or HGBL from 4/14 to 6/16 at the University of Rochester. Therapeutic trials open during this time included 3 sponsored and 2 NCTN studies. The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS; time from start of treatment until progression/death or until the last date the patient was known to be progression free) and overall survival (OS). Results: 140 pts were identified; 22% enrolled on a trial. Reasons for non-enrollment included: 1) Protocol ineligibility (n=58); (2) Physician choice (n=24) and; 3) Patient choice (n=20). Reasons were unclear in 8 pts. Of the 24 pts who were not enrolled due to physician choice, 21 required urgent treatment secondary to symptoms or rapid progression. Compared to pts treated on trial, pts with rapid progression had higher risk clinical features (table). There was a trend towards a lower 1-year PFS rate in pts who required urgent treatment compared to those on trial (72.1% vs. 56.1%; p=0.08). There was no statistical difference in OS. Conclusions: At our institution, for patients with DLBCL meeting trial eligibility criteria, 42% required urgent chemotherapy and failed to enroll. Exclusion of these high risk patients in precision medicine trials has important implications in the interpretation and generalizability of clinical trials in DLBCL. In this curable malignancy, excluding high risk patients from trials limits the event rate, and associated power to demonstrate impact of novel therapies. [Table: see text]
A patient navigation program to enhance access to care for undeserved patients with a suspicion or diagnosis of cancer in Mexico City.
Authors: Bukowski Alexandra , Soto Perez De Celis Enrique , Ramos-López Wendy A , Rojo-Castillo Patricia , Sanchez- Gonzalez Jesus Armando , Sánchez-Gutiérrez Oscar , Viramontes-Aguilar Lorena , Davila-Davila Bernardo , Ahumada Tamayo Samuel , San Miguel Sandra , Alcalde-Castro Jacqueline , Goss Paul E. , Chavarri Guerra Yanin
Published: September 2018

6544

Background: High cancer mortality rates in developing nations are partially driven by advanced stages at diagnosis and limited access to care. In Mexico, the interval from problem identification to start of treatment can be up to 7 months, mostly due to healthcare system delays. We implemented a patient navigation (PN) program aimed at reducing time to referral to cancer centers for patients (pts) with a suspicion or a diagnosis of cancer seen at a public general hospital in Mexico City. Methods: Pts age > 18 seen at Hospital General Ajusco Medio in Mexico City who required referral to a cancer center were enrolled. Baseline demographic, economic and psychosocial data were collected. A Patient Navigator assisted pts with scheduling; paperwork; obtaining results in a timely manner; transportation; and with other cultural barriers. The goal of the PN program was for at least 70% of enrolled patients to obtain a specialized appointment at a cancer center within the first 3 months from enrollment. Results: 53 pts (median age 54, range 19-80; 51% female) were included between 01/16 and 12/16. 19% (n = 10) had breast/GYN, 19% (n = 10) GU, 19% (n = 10) endocrine, 19% GI (n = 10) and 14% (n = 13) other tumors. All the pts were uninsured, 59% (n = 30) had less than middle school education, 80% (n = 41) were unemployed and 96% (n = 49) had a monthly household income of < $360 USD. 54% (n = 28) reported deprivation in at least one basic living need (education, running water, toilet, electricity or flooring). The most commonly identified barriers to healthcare access were financial (73%, N = 37), lack of transportation (47%, N = 24), fear (37%, N = 19) and poor communication with healthcare workers (35%, N = 18). Mean time to referral was 11 days (range 0–46, SD 11.2) and mean time to cancer specialist appointment 26 days (range 1–94, SD 21.18). 92% of pts successfully obtained appointments at a cancer center in < 3 months. Conclusions: Compared with previously reported data, this PN program shortened time to referral to a cancer center for pts with a suspicion or diagnosis of cancer in Mexico City. PN represents a potential solution to overcome barriers to healthcare access for underserved pts with cancer in developing countries.
Minority patient reported attitudes regarding tissue donation and participation in cancer research.
Authors: Sohal Davendra , Raska Paola , Abraksia Samir , Wilson Sherry , Griggs Jennifer J. , Khorana Alok A.
Published: September 2018

6558

Background: Minority populations are underrepresented in biospecimen banks created for cancer research, which has implications for future therapeutic approaches. Patients’ reluctance to donate biospecimens is perceived to be a potential barrier but is poorly studied. We present interim analyses of a survey to assess attitudes in a patient cohort comprised of racial/ethnic minorities. Methods: Patients filled out a validated 23-item survey [ J Cancer Educ, 2014. 29: p. 580-7] for this prospective cohort study approved by the Cleveland Clinic IRB. Surveys were provided in the outpatient oncology clinic of a Cleveland Clinic community hospital. Eligibility requirements included tissue diagnosis of any solid tumor malignancy in non-curative setting; age ≥ 18 years, ECOG PS 0-2, self-reported race/ethnicity as any other than non-Hispanic White, undergoing cancer therapy in the next 30 days. Data are presented for the first 90 patients surveyed in 2015-2016. Results: Median age was 69 years (range, 35-92). Only 24 (27%, 1 missing) had been asked to donate samples in the past; of those, 20 (83%) had donated. The majority (n = 60, 67%) were willing to donate samples. A higher proportion (75%) responded as being likely to donate samples if they learned more about the research and reasons for sample donation. A smaller proportion was likely to donate samples if they received money (30%) or health services (40%) in return. Many (55-73%) disagreed with negative statements such as, “I will be treated as a guinea pig,” and only (3-4%) disagreed with trust statements such as, “I trust sample banks/medical researchers/procedures.” However, 42% endorsed being “concerned that something like the Tuskegee study could happen again.” Conclusions: The majority of racial and ethnic minority patients in this study were willing to donate biospecimens for research, with an even greater likelihood of participation if appropriate rationales were provided. While systemic mistrust persists, the vast majority trusted medical researchers and procedures. Our findings suggest that underrepresentation of minorities in cancer biospecimen repositories, not likely attributable to patient reluctance, must be addressed to achieve health equity.
The Affordable Care Act Dependent Coverage Expansion (ACA-DCE): Disparities in impact in young adult oncology patients.
Authors: Alvarez Elysia Marie , Keegan Theresa , Johnston Emily E. , Haile Robert , Sanders Lee , Wise Paul , Saynina Olga , Chamberlain Lisa J
Published: September 2018

6561

Background: Private health insurance is associated with improved outcomes in cancer patients. We know little, however, about the impact of the ACA-DCE, which extended private insurance to young adults (up to age 26) beginning in 2010, on the insurance status of young adults with cancer. This study sought to determine the effect of the ACA-DCE on having private insurance coverage among hospitalized young adult oncology patients. Methods: We performed a retrospective, population-based analysis of hospitalized young adult oncology patients (22-30 years-old) in California during 2006-2014 (n = 11,062) using the Office of Statewide Health Planning and Development database. Multivariable regression analyses examined the social and clinical predictors of having private insurance. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CIs). A difference-in-difference analysis examined the influence of the ACA-DCE on insurance coverage by race/ethnicity and zip code federal poverty level. Results: Multivariable regression demonstrated patients of black and Hispanic race/ethnicity were less likely to have private insurance both before and after the ACA-DCE, compared to non-Hispanic white patients. Younger age (22-25 years) was associated with having private insurance after the ACA-DCE implementation (OR 1.18, CI 1.05-1.33; reference, 27-30 years). In the difference-in-difference analysis, private insurance increased among non-Hispanic whites aged 22-25 living in medium- (2006-2009: 64.6% versus (vs) 2011-2014: 69.1%; p = 0.003) and high-income zip codes (80.4% vs 82%; p = 0.043) and among Asian patients aged 22-25 living in high-income zip codes (73.2 vs 85.7%; p = 0.022). Private insurance decreased for all Hispanic patients aged 22-25 between the two time periods. Conclusions: The ACA-DCE provision was an important first step in increasing coverage, but it was not universal and generated disparity in coverage as gains occurred for non-Hispanic white and Asian patients living in higher income zip codes. This policy change was shown to increase coverage for a traditionally underinsured population and attention should now focus on those remaining uninsured.
Feasibility of wearable physical activity monitors in cancer patients (PAMCaP).
Authors: Beg Muhammad Shaalan , Stewart Tyler , Gupta Arjun , Dong Ying , Rahimi Zain , Paul Tony , Crane Kimberli , Rethorst Chad
Published: September 2018

6577

Background: Wearable physical activity monitors (PAMs) provide a degree of functional assessment not possible with prior clinical instruments. Subjective assessments of functional status are prone to inaccuracy and current objective assessment techniques are limited to the research setting. The relevance of physical activity monitors (PAMs) to measure functional status in cancer patients is unclear. The feasibility of using these devices in cancer patients is not known. Methods: This is a prospective pilot trial of a commercially available PAM in cancer patients. Patients with Eastern Cooperative Group performance status (ECOG PS) 0-2 receiving systemic therapy at an NCI Designated Comprehensive Cancer Center were enrolled. (NCT02583815). The primary objective was to determine feasibility of PAM use, defined as device use of more than 50% of the study observation period. Secondary objectives were to correlate PAM-reported measures: median, minimum and maximum steps/day, minutes of activity/day, (light/ fairly active/ very active); with 1) clinician assessed ECOG PS and 2) quality of life tool scores (FACT-G, QIDS, PQSI and BFI). Patient experience with wearable PAMs was assessed at the end of study. Results: We enrolled 32 patients: median age = 56 years (range 23-72), female = 67%, and white = 78%. Most patients had gastrointestinal (52%) and breast (19%) primaries. Clinician assessed PS was ECOG 0 in 56%, 1 in 37% and 2 in 7%. Majority of patients (81%) met the primary end point. Mean PAM measured steps for ECOG 0 was 5911 steps/d, ECOG 1 was 1890 steps/d and ECOG 2 was 845 steps/d (p = 0.002). Minimum steps/day correlated with BFI (r = -0.56, p < .01), FACT-G (r = 0.45, p 0.01) and QIDS (no vs mild vs moderate depression, p 0.01). Patients reported a positive experience with the devices (74%). Conclusions: Wearable PAMs are a feasible tool to measure physical activity in cancer patients receiving systemic therapy. PAM derived measures correlate with clinician assessments of performance status. Future work should develop methods to systematically incorporate PAMs in oncology clinical trials and practice. Clinical trial information: NCT02583815.
Possible mechanisms of serotonin and aprepitant actions in chemotherapy induced nausea and vomiting (CINV): Insights into the mechanisms of serotonin and aprepitant actions in CINV—According to recent multi-institutional double-blind randomized clinical research on the AC regimen.
Authors: Tsuneizumi Michiko , Saito Mitsue , Ogata Hideaki , Kutomi Goro , Hosoya Keiko , Kawai Yuko , Matsuoka Joe
Published: September 2018

6587

Background: One of our interests has been whether palonosetron(P) would be superior to granisetron(G) when administering triplet antiemetic therapy for the prevention of CINV, since a prior trial demonstrated P to be superior to G for controlling CINV induced by highly emetogenic chemotherapy (HEC) in doublet therapy. In this study(TTT; trial for antiemetic therapy), we assessed the efficacies of P and G for use as triplet antiemetic therapy for AC, by monitoring CINV, focusing complete response (CR; no vomiting and no rescue medicine) in the delayed phase. The primary endpoint of TTT was a CR during the delayed phase with 5-HT3ra plus dexamethasone and aprepitant administration for AC.　The purpose of gaining insights into the possible mechanism of action of aprepitant and P was to obtain ideas for the next strategy against CINV. Methods: Between 2012 and 2015, 491 breast cancer receiving AC were recruited from 11 institutions, and randomly assigned to either single-dose P(0.75mg) or G(40μg/kg) prior to AC on day 1, both with dexamethasone (9.9 mg) and aprepitant (125mg) on day 1 followed by additional doses (80mg) on days 2 and 3. Age, institution and habitual alcohol intake were used as stratification factors. The primary endpoint was a CR. Results: All 491 patients were included in efficacy analyses: 246 patients in the group P and 245 in the group G. The difference in CR during the delayed phase, i.e. 24 hrs after the administration of AC, did not reach statistical significance, however, there was a remarkable difference between 48 and 72 hrs in the day-to-day analysis(p < 0.02). Conclusions: P showed better efficacy in controlling CINV between 48 to 72 hours after AC, than G as triplet antiemetic therapy for AC. We can reasonably speculate that the influence of serotonin has two peaks (0-24 hrs and 48-72 hrs). For controlling CINV in the delayed phase, not only an NK1 receptor antagonist but also administering a 5-HT3ra with long life should be considered until 72 hrs after HEC. Clinical trial information: UMIN 000007882.
Identifying determinants of quality of life in patients undergoing systemic therapy for solid tumors.
Authors: Lin Frank Po-Yen , Martin Chloe , Kocbek Simon , Joshua Anthony M. , Dear Rachel Fitz-Gerald , Lim Elgene , Chantrill Lorraine A. , Chin Venessa T. , Epstein Richard J
Published: September 2018

6596

Background: Knowing which factors compromise quality of life (QoL) in patients undergoing cancer treatments can help oncologists provide more effective care. To identify these factors, we conducted a single-centered cross-sectional study examining the relationships between patient-reported QoL, adverse events (AE), and treatment characteristics. Methods: Consecutive patients attending an outpatient chemotherapy unit completed two questionnaires (EORTC QLQ-C30 and National Cancer Institute PRO-CTCAE) per visit to identify factors contributing to the lowest global QoL score [QLQ-C30 QL2, range 0 (worst)–100 (best)] over a 6-week period. QL2 was correlated to each PRO-CTCAE item and treatment characteristic (tumor type, drug class, number of cycles, and treatment intent) using multiple regression, adjusted for age, sex, and use of concurrent radiotherapy. To determine whether QoL can be reliably modeled by machine learning, ten algorithms were compared for performance in classifying patients into dichotomized QL2 subgroups. Results: One hundred and fifteen of 130 patients (157/244 visits) completed up to 6 sets of questionnaires (median QL2: 67, IQR: 50–83). No difference was found between QL2 and treatment characteristics (at α Bonferroni=5×10-4). However, QL2 was significantly associated with AE in gastrointestinal, respiratory, attention, pain, sleep/wake, and mood categories. Using AE as covariates, support vector machine with radial basis kernel was the best at classifying patients into QoL groups (mean bootstrapped area under ROC curve 0.812, 95% CI 0.700–0.925). Conclusions: Patient-reported QoL is associated with multiple AE, but not with characteristics of systemic therapy. Machine learning analysis suggests that a combined AE analysis may reliably characterize a patient’s QoL. [Table: see text]
Are surrogate endpoints unbiased metrics compared to hazard ratio for death? An evaluation of clinical benefit scores (CBS) in the American Society of Clinical Oncology (ASCO) value framework.
Authors: Qureshi Mahin Iqbal , Cheung Matthew C. , Cheng Sierra , Jiang Di Maria , McDonald Erica , Arciero Vanessa Sarah , Ezeife Doreen Anuli , Chambers Alexandra , Sabarre Kelley-Anne , Chan Kelvin K.
Published: September 2018

6600

Background: Clinical benefit scores (CBS) are a key element of the American Society of Clinical Oncology (ASCO) value framework's Net Health Benefit valuation of cancer therapies. CBS are assigned based on a hierarchy of efficacy endpoints, from hazard ratio for death (HR OS), to median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, other endpoints in the hierarchy are used as "surrogates" to calculate CBS via their scaling factors. We aim to examine whether surrogate-derived CBS offer unbiased scoring of clinical benefit compared to HR OS-derived CBS. Methods: CBS for advanced-disease settings were computed for randomized clinical trials (RCTs) of oncology drug approvals by the Food and Drug Administration, European Medicines Agency, and Health Canada, between 2006 and August 2015. Spearman's correlation assessed association between CBS derived from surrogates and HR OS. Mean bias (surrogate-derived CBS minus HR OS-derived CBS) evaluated the tendency for surrogate-derived CBS to over- or under- estimate clinical benefit. Mean absolute error (MAE), a measure of average deviation, assessed precision of surrogate-derived CBS in relation to HR OS-derived CBS. Results: Scored RCTs (n=104) yielded 69, 93, 88, and 89 paired CBS between HR OS and mOS, HR PFS, mPFS, and RR, respectively. See table for results. Restricting to RCTs reporting all endpoints (n=59) and RCTs without OS as primary endpoint (n=68) showed similar results. Conclusions: Findings suggest HR PFS-, mPFS-, and RR-derived CBS are poor "surrogates" as they are imprecise and weakly correlated to HR OS-derived CBS. HR PFS and particularly mPFS exhibit bias to overestimate CBS. [Table: see text]
Delivery of meaningful cancer care: Evaluating benefit and cost of cancer therapies using ASCO and ESMO frameworks.
Authors: Del Paggio Joseph , Sullivan Richard , Schrag Deborah , Hopman Wilma M , Azariah Biju , Pramesh C S. , Tannock Ian , Booth Christopher M.
Published: September 2018

6609

Background: ASCO and ESMO have developed frameworks to evaluate the benefit of cancer therapies. Here, we apply the frameworks to a cohort of contemporary randomized controlled trials (RCTs) to explore agreement and to evaluate the relationship between treatment benefit and cost. Methods: Characteristic and outcome data from RCTs evaluating systemic therapies in non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer (CRC), and pancreatic cancer published and cited in PubMed between 2011-2015 were abstracted. Trial endpoints were evaluated using ASCO and ESMO frameworks. Cohen’s kappa statistic was calculated to determine agreement between the two frameworks, using the median ASCO score as a benefit threshold. Differences in monthly drug cost between RCT experimental and control arms were derived from 2016 average wholesale prices. Analyses included Pearson chi-square tests, Fisher’s Exact tests, independent samples t-tests, and Pearson correlation to assess the association between continuous variables. Results: Fifty percent (136/271) of published RCTs favoured the experimental arm; scoring rubrics were applicable to 109 RCTs (39% NSCLC, 33% breast, 23% CRC, 5% pancreas). ASCO scores ranged from 2 to 72; median score was 25. Thirty seven percent (40/109) of RCTs met benefit thresholds using the ESMO framework. Agreement between frameworks was fair at best (κ = 0.28, p = 0.002). When stratified by treatment intent (19 curative, 90 palliative RCTs), agreement remained poor (κ = 0.23, p = 0.115; κ = 0.34, p < 0.001). Major differences leading to limited agreement includes the relative weights each framework places on HR, endpoints, and toxicity/QOL analysis. Smaller RCT sample size was the only trial characteristic associated with higher ASCO scores (p = 0.015). Among the 100 RCTs for whom drug costing data were available, there was no association between ASCO benefit score and monthly drug costs (r = -0.12, p = 0.22); those meeting ESMO thresholds had a lower mean drug cost than those who did not (p = 0.046). Conclusions: There is only fair correlation between ASCO and ESMO clinical benefit frameworks. Drug costs are not associated with ESMO/ASCO measures of magnitude of clinical benefit.
Cost of surveillance imaging in head and neck cancer patients treated with definitive radiotherapy.
Authors: Ng Sweet Ping , Jomaa Mona K , Pollard Courtney , Ayoub Zeina , Mohamed Abdallah , Garden Adam S. , Berends Joel , Gunn Gary Brandon , Frank Steven J. , Skinner Heath Devin , Phan Jack , Rosenthal David Ira , Morrison William H. , Johnson Jason Michael , Sturgis Erich M. , Lai Stephen Yenzen , Fuller Clifton David
Published: September 2018

6610

Background: The goal of surveillance is to detect potentially salvageable recurrence, allowing early salvage treatment and thereby improving clinical outcomes. Currently, there is limited data on the optimal frequency of imaging for head and neck cancer patients treated with definitive radiotherapy. This study aims to evaluate the cost-effectiveness of surveillance imaging in this group of patients. Methods: Eligible patients included those with a demonstrable disease free interval (≥ 1 follow up scan without evidence of disease and a subsequent visit/scan) treated between 2000-2010. Age, tumor site and stage, induction chemotherapy use, dose/ fractionation, mode of detection of recurrence, salvage therapy, number and modality of scans were recorded. Deaths from disease recurrence or from other causes were also recorded. Imaging costs were calculated based on the 2016 Medicare fee schedule. Results: 1508 patients were included. Mean age was 55.8 years (range: 17-87). Median overall survival was 99 months (range: 6-199). Mean imaging follow up period was 70 months. 190 (12.6%) patients had disease recurrence – 107 locoregional (LR) and 83 distant. 119 (62.6%) of the relapsed group were symptomatic and/or had an adverse clinical finding associated with recurrence. 80.4% of LR relapses presented with a clinical finding, while 60.2% of distant relapses were detected via imaging alone in asymptomatic patients. There was no difference between the successful salvage rates and overall survival between those with relapses detected clinically or via imaging alone. 70% of relapses occurred within the first 2 years post-treatment. In those who relapsed after 2 years, the median time to relapse was 51 months (2 LR and 11 distant relapses). After 2 years, the average cost for detecting a salvageable recurrence for image-detected group was $741 447.41, and the cost for preventing 1 recurrence-related death for image-detected disease was $889 736.89. The number of scans required to detect a salvageable recurrence in an asymptomatic patient after 2 years was 3512. Conclusions: Surveillance imaging in asymptomatic patients without clinically suspicious findings beyond 2 years requires judicious consideration.
Economic impact of immune checkpoint inhibitor therapy in Brazil and strategies to improve access.
Authors: Aguiar Pedro Nazareth , De Mello Ramon Andrade , Tadokoro Hakaru , Lopes Gilberto
Published: September 2018

6612

Background: Immunotherapy was elected by ASCO as the most important advance in Oncology for the last 2 consecutive years. Nevertheless, the costs of immune checkpoint inhibitors is a limitation to their incorporation in several countries, including Brazil. The objective of this study is to estimate the economic impact of immunotherapy and make suggestions in order to improve the access for patients who benefit the most from treatment. Methods: We assessed Brazilian cancer epidemiology data and the international literature to estimate the number of eligible patients each year. The authors estimated the economic impact according to the medication acquisition costs converted to US dollars. The median duration of the treatment was based upon the clinical trials. Results: We assessed 3 different agents (and one combo) for 7 indications. The results are summarized in the table below. Conclusions: The current cost of immune checkpoint inhibitors is prohibitive in the public health system in Brazil. While the country’s GDP per capita is 78% lower than that of the US, immune checkpoint inhibitors have similar prices in both. Biomarker selection, posology, and lower cost drugs help decrease the total economic impact of therapy. Price discrimination and volume discounts would help improve access. Further studies and discussion with all stakeholders is needed to identify patients who would benefit the most and to implement strategies to increase access to these potentially life-saving therapies. [Table: see text]
Access and price of cancer drugs: What is happening in France?
Authors: Grande Mathilde , Fernandez Judith , Putzolu Jade , Stanel Sorin , Galbraith Margaret , Belorgey Chantal , Albin Nicolas , Guillevin Loic , d'Andon Anne
Published: September 2018

6623

Background: The French National Authority for Health (HAS) is responsible for health technology assessment (HTA), providing opinion on drugs for reimbursement and pricing purposes. For all indications with a positive opinion for reimbursement, HAS assesses the clinical added value (CAV) on a 5-point scale for pricing negotiations based on clinical data. A major to moderate CAV leads to the highest prices, a minor CAV leads to a higher price than the comparator, and no CAV leads to lower price than the cheapest comparator. Countries increasingly face the policy challenge of harnessing the benefits of cancer drugs while managing healthcare budgets. In this context, we aimed to analyze cancer drugs assessment by HAS. Methods: a retrospective and descriptive analysis comparing all new hematology/oncology cancer indications versus all others new indications assessed by HAS between 2010 and 2015 has been conducted. Results: 87 cancer indications (60 drugs) have been evaluated, representing 17% (87/510) of all new drugs indications assessed by HAS. Almost all cancer indications (92%) obtained a favorable opinion for reimbursement. Seven (8%) had an unfavorable opinion versus 20% in other therapeutic areas. However, 5 of these 7 indications were related to a drug included on the list of reimbursed drugs for another indication and consequently drugs are available. Overall, only 2 drugs were not reimbursed: nintedanib in non small cell lung cancer and tegafur/gimeracil/oteracil in gastric cancer (no impact on survival and lack of results transposability). Of the 80 indications with a favorable opinion, 20 had a major to moderate CAV (25%), 32 a minor CAV (40%) and 28 have no CAV (35%). Major to moderate CAV are mostly composed of hematology drugs (12, 60%). The proportion of major to moderate CAV assessment is higher in oncology than in other therapeutic areas (66% vs. 30%). Conclusions: France benefits from a universal healthcare system offering wide coverage and large access to drugs. Almost all of the new hematology/oncology cancer drugs assessed had a favorable opinion and are fully reimbursed (100%) by health insurance. A high proportion (66%) of CAV is recognized in oncology. Nevertheless, the over DRG list can inadvertently limit access to these new cancer drugs.
Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF).
Authors: Mesa Ruben A. , Kiladjian Jean-Jacques , Catalano John V. , Devos Timothy , Egyed Miklos , Hellman Andrzei , McLornan Donal , Shimoda Kazuya , Winton Elliott F. , Deng Wei , Dubowy Ronald L. , Maltzman Julia D. , Cervantes Francisco , Gotlib Jason R.
Published: September 2018

7000

Background: MMB, an oral JAKi, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion (Tx) requirements in patients (pts) with MF. This study was designed to test non-inferiority of MMB vs RUX in splenic volume reduction and Sx amelioration, and superiority in Tx requirement, in JAKi naïve MF pts. Methods: Eligibility: MF, IPSS high risk, Int-2, or symptomatic Int-1; palpable spleen ≥5cm; platelets ≥ 50 K/μl, and no Gr ≥2 peripheral neuropathy (PN). Stratification by Tx dependency and platelets (<100, 100-200 and >200 K/μl). Pts were randomized 1:1 to 24 wks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all pts could receive open label MMB. Assessments: spleen volume by MRI, and pt reported Sx using a daily eDiary of modified MPN-SAF Total Sx Score (TSS). Primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 wks. Secondary endpoints, evaluated sequentially at 24 wks, were rates of TSS response (≥50% reduction from baseline), RBC Tx independence (TI), RBC Tx dependence (TD) and of RBC Tx . Results: 175 of 215 (81%) and 201 of 217 (93%) pts randomized to MMB and RUX, respectively, completed the 24 wk DB phase. Efficacy results are shown in Table. Most common Gr ≥3 AEs in the DB phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Gr ≥3 infections occurred in 7% of MMB and 3% of RUX pts. Treatment emergent PN occurred in 22 (10%) of MMB (all Gr ≤2) and 10 (5%) of RUX (9 Gr ≤2, 1 Gr 3) pts in DB phase, none discontinuing study drug for PN. Overall, AEs led to study drug D/C in 13% of MMB and 6% of RUX pts in DB phase. Conclusions: In pts with JAKi naive MF, 24 weeks of MMB is non-inferior to RUX for spleen response but not for symptom response. MMB treatment is associated with a reduced transfusion requirement. NCT01969838. [Table: see text]
Distinct patterns of somatic mutation clearance and association with clinical outcome in patients with AML.
Authors: Takahashi Koichi , Wang Feng , Patel Keyur , Bueso-Ramos Carlos E. , Issa Ghayas C. , Song Xingzhi , Zhang Jianhua , Tippen Samantha , Little Latasha , Gumbs Curtis , Ravandi Farhad , Kadia Tapan M. , Daver Naval Guastad , Dinardo Courtney Denton , Konopleva Marina , Andreeff Michael , Cortes Jorge E. , Jabbour Elias , Futreal Andrew , Kantarjian Hagop M.
Published: September 2018

7005

Background: Persistence of somatic mutations at the time of complete remission (CR) was associated with poor outcome in patients (pts) with AML. Methods: We studied 95 pts with AML who were treated with frontline induction and subsequently achieved CR. We sequenced pre-treatment and CR bone marrow samples by targeted capture sequencing of 295 genes (median 280x coverage). We defined 3 levels of mutation clearance (MC) based on variant allele frequency (VAF): MC2.5, persistent mutation with VAF<2.5%; MC1.0, persistent mutation with VAF<1%; and complete mutation clearance (CMC). Results: In the pre-treatment samples, we detected 597 mutations in 78 genes in 87 (92%) patients. In the matching CR samples, 62 (10%) and 82 (14%) mutations persisted at VAF≥2.5% and ≥1%, respectively, which corresponded to 43 (49%), 34 (39%), and 30 (34%) patients achieving MC2.5, MC1.0 and CMC, respectively. Table 1 shows the differential patterns of MC based on the mutations and pathways. Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and splicing pathways had low rate of MC, whereas mutations in transcription factors or receptor tyrosine kinase (RTK) had high rate of MC. Pts who achieved MC1.0 (median 31.2 vs. 12.5 months, P = 0.04) or CMC (median 31.2 vs. 12.5 months, P = 0.049) had significantly better relapse-free survival (RFS). Conclusions: Somatic mutations associated with CHIP, DNA methylation, and splicing pathways persisted frequently in CR samples suggesting preleukemic origin. Pts with deeper MC had significantly better RFS. Somatic mutation clearance may help risk prediction of AML. [Table: see text]
An antibody derived from a cured AML patient to identify a unique epitope on CD43 (CD43s) as a novel target for acute myeloid leukemia and myelodysplastic syndrome.
Authors: Hazenberg Mette D. , Gillissen Marijn , De Jong Greta , Yasuda Etsuko , Levie Sophie , Wagner Koen , Bakker Arjen , Kedde Martijn , Hensbergen Paul , Villaudy Julien , Van Helden Pauline , Spits Hergen
Published: September 2018

7009

Background: Immunotherapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is hampered by the lack of tumor-specific targets. Methods: We took advantage of the tumor-immunotherapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) and searched the B cell repertoire of a patient with a lasting and potent graft versus AML response for AML-specific antibodies. Results: We identified a donor-derived B cell clone that produced an IgG1 antibody, AT1413, that specifically interacted with AML cell lines, with the patient’s autologous AML blasts, but not with lymphocytes or with cells from liver, colon, skin and other tissues. AT1413 recognized a unique, not previously described, sialylated epitope on CD43 (CD43s). CD43s is overexpressed on all types of AML and MDS, as illustrated by its reactivity with freshly isolated blasts of each of more than 60 randomly selected AML and MDS patients in our clinic, representing all WHO 2008 AML and MDS classes. AT1413 induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) of target cells in vitro. To investigate the effect of AT1413 in vivowe first generated mice populated with human effector cells (NK cells, CTL and myeloid cells) by injecting human hematopoietic stem cells into new born immunodeficient mice. After establishment of a human immune system in these mice we inoculated luciferase labeled AML cells via tail vein injection. Following engraftment of the tumor we dosed the mice biweekly with AT1413 or a control antibody. We observed strongly reduced numbers of AML cells in AT1413- but not in control antibody treated mice. Importantly, AT1413 treatment was tolerated well and did not affect numbers of non-malignant human myeloid cell in these mice. Conclusions: We have obtained an antibody from a cured AML patient which recognizes a unique sialylated epitope on CD43 (CD43s) that is selectively over-expressed on all WHO 2008 types of AML and MDS. This antibody was able to eliminate AML cells in vivo and therefore has high therapeutic potential.
Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML to reduce risk of relapse.
Authors: Boddu Prajwal , Jorgensen Jeffrey L. , Kantarjian Hagop M. , Borthakur Gautam , Kadia Tapan M. , Daver Naval Guastad , Alvarado Yesid , Pemmaraju Naveen , Bose Prithviraj , Naqvi Kiran , Yilmaz Musa , Pierce Sherry , Brandt Mark , Dinardo Courtney Denton , Jabbour Elias , Garcia-Manero Guillermo , Cortes Jorge E. , Ravandi Farhad
Published: September 2018

7018

Background: Persistence of minimal residual disease (MRD) post therapy is a powerful predictor of outcome in patients with AML treated with traditional cytarabine and anthracycline based regimens. The clinical relevance of MRD in the context of hypomethylating agents has not been evaluated extensively. Methods: Among 194 patients with AML treated with single agent azacytidine, decitabine, or gaudecitabine, 116 (median age 76, range 60 - 92) had MRD analysis performed on bone marrow specimens obtained at time of assessment of response or thereafter; among them 69 (59%) achieved either morphologic complete remission (CR) or CR with incomplete recovery of platelets (CRp) or counts (CRi), and 61 (53%) had evaluable MRD data; MRD was assessed using an 8-color flow panel, with a detection sensitivity of 0.01%. Results: Median cycles to achieving response was 2 (range, 1-6). Sixty one patients had evaluable MRD data at the time of response, of whom 19 (28%) became MRD negative (-). This was associated with a reduced cumulative risk of relapse (p = 0.012) but did not translate to an improved relapse-free survival (RFS; p = 0.17) or overall survival (OS; p = 0.79) due to high frequency of non-relapse deaths (attributable to comorbidities and infections) in the MRD- group. Patients who achieved a MRD- state at the time of achieving response had a higher mortality [5/8 (62%)] when compared with those who achieved a MRD- state in subsequent cycles [1/13 (7.6%); p = 0.01], resulting in an inferior OS (6.2 months (mo) vs 20 mo, p = 0.012). Similarly, achieving negative MRD at CR and at any time up to 3 months post response was not associated with improved RFS or OS despite a lower cumulative risk of relapse (p = 0.045). There was no impact of MRD, on OS, whether the MRD- state was achieved after 1st, 3rd or 6thcycle of therapy. Association between depth of MRD response at time of remission and RFS was borderline significant (p = 0.08). On multivariate analysis, response (CR vs CRi/CRp), but not a negative MRD, was predictive for RFS or OS. Conclusions: In this cohort of older AML patients treated with hypomethylating agents, achieving a MRD- state was associated with a reduced risk of relapse but not improved RFS or OS.
A Bayesian randomized phase II study of guadecitabine (SGI-110) based regimens comparing guadecitabine 5 days (SGI5), 10 days (SGI10), 5 days + idarubicin (SGI5 + Ida), 5 days + cladribine (SGI5 + Clad), in untreated patients ≥ 70 years with acute myeloid leukemia (AML).
Authors: Naqvi Kiran , Nogueras-Gonzalez Graciela M. , Cheung Cora M. , Pemmaraju Naveen , Jabbour Elias , Garcia-Manero Guillermo , Dinardo Courtney Denton , Ohanian Maro , Jain Nitin , Takahashi Koichi , Alvarado Yesid , Konopleva Marina , Huang Xuelin , Cortes Jorge E. , Kantarjian Hagop M.
Published: September 2018

7019

Background: Guadecitabine is a next generation hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. This allows prolonged exposure of leukemia cells to its active metabolite, decitabine. We aimed to compare the efficacy and safety profile of guadecitabine in untreated ≥ 70 years AML patients. Methods: Untreated patients ≥ 70 years with AML were randomized in a phase 2 Bayesian design in one of the 4 arms: guadecitabine 60mg/m2/daily x 5 (SGI5), guadecitabine 60mg/m2/daily x 10 (SGI10), SGI5 + Ida (6mg/m2/daily x 2), or SGI5 + Clad (3mg/m2/daily x 5). The Bayesian design evaluated response and toxicities simultaneously. Primary objective was complete remission (CR) rate and remission duration. Survival was estimated using the Kaplan-Meier method. Results: Between June 2014 and Nov 2016, we treated 34 patients: 8 in SGI5; 9 in SGI10; 8 in SGI5 + Ida and 9 in SGI5 + Clad. Median age was 75 years. 38% had complex karyotype. Median follow-up was 8.3 months. Overall response rate (ORR= CR + CRi) was 53%, shown in the table below. Median remission duration was 7.4 months. 4 week mortality was 3%. Median survival is 13.1 months. A trend for superior survival was observed with SGI5 + Ida (median survival not reached; p=0.22). Common G3/4 toxicity included febrile neutropenia (48%), thrombocytopenia (26%), leukopenia (22%) and anemia (11%). Conclusions: Guadecitabine is clinically active and safe as single agent and in combination in elderly patients with untreated AML. A separate previously reported multicenter study showed no difference between SGI5 vs SGI10 in 103 treatment naïve elderly AML patients (Kantarjian et al. Blood 2015 126:458). CR and ORR were lower with SGI5 + Clad. Based on these findings, the study continues now comparing SGI5 vs SGI5 + Ida. [Table: see text]