bluuebunny/crossref_metadata_2025 huggingface dataset:
Computerized features of spatial interplay of tumor-infiltrating lymphocytes predict disease recurrence in p16+ oropharyngeal squamous cell carcinoma: A multisite validation study.
Authors: Corredor Germán , Lu Cheng , Koyuncu Can , Bera Kaustav , Toro Paula , Fu Pingfu , Koyfman Shlomo A. , Chute Deborah , Adelstein David J. , Thorstad Wade , Bishop Justin A. , Faraji Farhoud , Lewis James , Madabhushi Anant
Published: May 2020

6559

Background: While overall, patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis, subsets of patients experience disease recurrence (DR) and death despite aggressive multimodality treatment. Aside from routine staging criteria, there are no biomarkers of tumor behavior routinely employed in OPSCC to identify patients at higher risk of DR. In this study we sought to evaluate whether the interplay between tumor-infiltrating lymphocytes (TILs) & cancer cells, in both stromal and epithelial compartments from digitized H&E-stained slides, can predict DR in OPSCC patients. Methods: OPSCC resected specimens from 354 patients (66 with DR) were retrospectively collected from 3 different sites. 107 (16 DR) patients from site 1 formed the training set and 247 (50 DR) patients from sites 2 & 3 formed the independent validation cohort. Computerized algorithms automatically identified 4 types of nuclei (TILs & non-TILs in both stromal & epithelial regions), defined clusters for each nuclei type based on cell proximity, and used network graph concepts to capture measurements relating to the arrangement of these clusters. The top 10 features determined by a statistical selection method (LASSO) were used to train a Cox regression model that assigns a risk of DR to each patient on the training set. The median risk score was used as threshold for stratifying patients on the validation set into low and high-risk of DR. Survival analysis was used to evaluate the stratification given by the trained model. Results: Patients identified by the TIL interplay model as high risk for DR had statistically worse disease specific survival. Univariate analysis yielded an HR=2.49 (95% CI: 1.22-5.07, p=0.04) for site 2 and HR=3.62 (95% CI: 1.39-9.43, p=0.03) for site 3. Multivariate analysis controlling the effect of different clinical variables is shown in the attached table. Conclusions: We introduce a prognostic model based on the automated quantification of the interplay between tumor microenvironment cells that is able to help distinguish OPSCC patients with higher DR risk from those who will experience longer disease-free survival. [Table: see text]
Nivolumab (Nivo) and ipilimumab (Ipi) in combination with radiotherapy (RT) in high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Johnson Jennifer Maria , Bar Ad Voichita , Lorber Emily , Poller Dawn , Manukian Gregor , Luginbuhl Adam , Curry Joseph M. , Cognetti David M. , Keith Scott W. , Axelrod Rita Susan , Rodeck Ulrich , Harshyne Larry , Argiris Athanassios
Published: May 2020

6577

Background: Immune checkpoint inhibitors (ICI) are the standard of care in recurrent/metastatic SCCHN but their role in the curative therapy setting with RT is under study. We evaluated the novel approach of combining Nivo, a PD-1 inhibitor, and Ipi, a CTLA-4 inhibitor, in lieu of chemotherapy, with concurrent RT in pts with high-risk LA SCCHN. Methods: We enrolled newly diagnosed, chemotherapy eligible pts with AJCC 7th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, and larynx. HPV+ OP were T4, N2c or N3 OP. Nivo (3 mg/kg every 2 weeks IV x 17 doses) and Ipi (1 mg/kg every 6 weeks x 6 doses) were administered starting 2 weeks prior to the start of RT. RT was prescribed to a dose of 70 Gy delivered in 2 Gy/fraction/day using VMAT. The primary objective was safety of combination ICI with RT. Secondary objectives included 1-year progression-free survival (PFS), overall survival, and correlative studies. Results: 24 pts were enrolled; median age of 60 (range 48-77); 20 were male; 16 oropharynx (14 HPV+), 2 hypopharynx, and 6 larynx; AJCC 7th edition stage IVA (23), IVB (1). Grade 3 acute in-field adverse events (AEs) occurred in 17/24 (71%) of patients during concurrent ICI-RT (9 mucositis, 6 dysphagia, 5 dermatitis, 4 odynophagia, 1 dysphonia); there were no grade 4/5 AEs during ICI-RT. During ICI maintenance 5 pts developed in-field ulcerations at the primary site detected at an average of 3 months post RT; 1 of them died of bleeding due to erosion into the carotid artery with no evidence of active cancer; 4 additional pts developed in-field necrosis. 7 pts discontinued ICI treatment at > 3 months post-RT: 1 due to immune AE, 5 due to in-field ulcerations, 1 due to persistent mucositis without ulceration. 4 pts (17%) had grade 3 immune AEs: 1 elevation of lipase, 1 colitis, and 2 rash. There were no grade 4/5 immune AEs. The median follow-up is 16 months (range, 6.3-30.6). 21 of 24 pts (87.5%) are alive with no evidence of disease progression. 2 pts recurred at distant sites: 1 had a solitary lung lesion at 11 months and was treated with RT; 1 in mediastinal lymph nodes at 9 months and was treated with chemo-RT. Locoregional control remains at 100%. Conclusions: RT plus dual ICI combination was feasible and resulted in no locoregional relapses so far in 24 high-risk LA SCCHN pts. Longer follow-up is needed to fully assess PFS and locoregional control as well as post-treatment in-field ulceration/necrosis that may be attributed to the potent radiosensitizing effect of dual PD-1 and CTLA-4 blockade. Clinical trial information: NCT03162731 .
Cumulative incidence of financial hardship in metastatic colorectal cancer patients: Primary endpoint results for SWOG S1417CD.
Authors: Shankaran Veena , Unger Joseph M. , Darke Amy , Suga Jennifer Marie , Wade James Lloyd , Kourlas Peter , Chandana Sreenivasa R , O'Rourke Mark Allen , Satti Suma , Liggett Diane , Hershman Dawn L. , Ramsey Scott David
Published: May 2020

7010

Background: Despite evidence that rising cancer care costs are contributing to “financial toxicity” in cancer pts, no studies, to our knowledge, have prospectively assessed the financial impact of cancer diagnosis (dx) using both self-reported and objective financial measures. S1417CD, led by the SWOG Cancer Research Network and conducted in the NCI Community Oncology Research Program (NCORP), was the first national prospective cohort study to evaluate time-to-first evidence of major financial hardship (MFH) in pts with newly diagnosed mCRC. We present results of the primary endpoint analysis. Methods: Pts age ≥ 18 within 120 days of mCRC dx receiving systemic treatment completed surveys every 3 months (mo) for 12 mo. MFH was defined as ≥ 1 occurrence of self-reported increase in debt, new loans, selling home, refinancing home, or ≥ 20% income decline during the 12 mo study period. Cumulative incidence (CI) of MFH was estimated to account for competing risk of death. Additional endpoints, not reported here, included quality of life, caregiver strain, and changes in credit status over 12 mo. Results: In total, 380 pts (median age 59.9) across 126 clinic sites were enrolled, with 377 eligible and evaluable for the primary endpoint (reached 12 mo assessment, death, or MFH endpoint); complete data were available for 92% of pts as of Jan 23, 2020. Most pts were white (78%), male (61%), and insured (98%), with annual income ≤ $50,000 (56%). Cumulative incidence of MFH at 12 mo was 71.5% (95% CI: 65.9%-76.3%), with 24.6%, 52.4%, and 61.8% at 3, 6, and 9 mo. The dominant components of MFH were new debt (12-mo CI, 56.7%) and >20% decline in income (26.7%); 104 (41%) pts reported ≥ 2 elements of MFH. In a secondary analysis excluding new debt, 12 mo cumulative incidence of MFH was 42.9% (95% CI: 37.2%-48.5%), with 10.3%, 24.4%, and 31.9% at 3, 6, and 9 mo. Conclusions: In a national sample of mCRC pts on systemic tx, financial hardship, most commonly in the form of increased debt, accumulates progressively over time. Nearly 3 out of 4 pts experiencing MFH at 12 mo despite access to health insurance coverage. These findings underscore the need for clinic and policy solutions such as early financial navigation and elimination of cost sharing to protect pts from financial devastation as they continue with tx. Clinical trial information: NCI-2015-01885 . [Table: see text]
Geographic and demographic disparities in breast cancer outcomes: A population-based study.
Authors: Gosain Rohit , Abdou Yara , Gupta Medhavi , Sarma Maithreyi , Groman Adrienne , Gandhi Shipra
Published: May 2020

7028

Background: Breast cancer (BC) is one of the leading causes of cancer-related mortality worldwide, with over 2 million new cases diagnosed each year. Area of residence has been shown to affect survival, but its impact on BC is unknown. The purpose of this study is to address the potential disparities in BC outcomes between the urban area (UA) and rural area (RA). Methods: We obtained data based on BC patients’ (pts) area of residence; UA vs RA, using the Surveillance, Epidemiology, and End Results (SEER) database treated from 1975-2016. Different socio-demographic variables and tumor characteristics (cts) from both groups were analyzed. Disease specific survival (DSS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Multivariable analyses were conducted using Cox regression models. Results: A total of 99,339 and 872,742 pts were analyzed from RA and UA respectively. Pt cts, including age, sex, marital status, insurance status were similar across both RA and UA. There were a higher number of Black and Hispanic pts in the UA compared to RA. A total of 264,191 pts had receptor subtype data available. A slightly higher percentage of triple negative BC (TNBC) pts was seen in the RA compared to UA (13.5% v 12.7%) whereas UA had a higher percentage of HER2+ BC (18% v 17.3%). There were 95.4% early/locally advanced (stage I-III) and 4.6% metastatic pts. UA pts had significantly improved DSS and OS regardless of stage, grade or other tumor cts compared to RA pts. When stratified by receptor subtype, UA had significantly improved DSS and OS in hormone positive (HR+) (OS HR of 0.86; DSS HR of 0.87; p < 0.05) and HER2+ pts (OS HR of 0.87; DSS HR of 0.83; p < 0.05). However, there were no significant differences seen between UA and RA pts with TNBC. Conclusions: To our knowledge, this is the first study to report BC outcomes based on geographic disparities. Interestingly, HR+ and HER2+ UA pts had better outcomes than RA pts, whereas TNBC pts had similar survival regardless of residence area. Perhaps this disparity is partly due to the longer duration of treatment needed with hormonal therapy in the adjuvant setting making compliance an important factor to take into account in RA pts, in addition to complicated decision making with upcoming data in HER2 + cancer in the early stage setting. Access to healthcare, differences in surgical and systemic approaches of pt care, management of treatment-related toxicities and environmental factors are all potential factors that may affect outcomes in BC pts. Based on the above data, further studies are needed to further evaluate and reduce such disparities.
The impact of census-tract socioeconomic status on survival in stage III colon cancer.
Authors: Dhahri Amina , Kaplan Jori Lee , Ntiri Shana , Imanirad Iman , Felder Seth , Dineen Sean Patrick , Sanchez Julian , Dessureault Sophie , Carballido Estrella M. , Powers Benjamin
Published: May 2020

7032

Background: Socioeconomic status (SES) has been associated with worse outcomes in stage III colon cancer. However, these studies have used large geographic areas (zip codes or counties) as a proxy for SES which may bias results. To overcome this challenge, we used a national database with census-tract level SES to assess the impact on cancer-specific (CSS) and overall survival (OS). Methods: Using the SEER Census-Tract Dataset from 2004-2015, we identified 8th edition AJCC stage III colon adenocarcinoma patients who underwent curative-intent surgery and initiated adjuvant chemotherapy. The predictor variable was census-tract level SES, consisting of 7 variables such as income, housing, and education. SES was analyzed as quartiles. Statistical analysis included chi square tests for association and Kaplan-Meier and Cox regression for survival analysis. Results: We identified 27,222 patients who met inclusion criteria. Lower SES was associated with younger age, Black or Hispanic race/ethnicity, Medicaid or uninsured status, higher T stage, <12 lymph nodes examined and lower grade tumors. Median CSS was not reached; the 25th percentile CSS time was 54 months for the lowest SES (LSES) quartile and 80 months for the highest (HSES). Median OS was 113 months for LSES and not reached for HSES. The 5-year CSS rate was 72.4% for the LSES quartile compared to 78.9% in the HSES (p<0.001). The 5-year OS rate was 66.5% for LSES and 74.6% in the HSES (p<0.001). After adjusting for potential confounders (age, sex, race, insurance, pathologic T and N stage and grade), LSES was associated with increased cancer-specific death relative to the HSES (HR 1.22; 95% CI [1.114-1.327]) Conclusions: This is the first study to evaluate CSS and OS in a national cohort of stage III colon cancer patients using a granular, standardized measure of SES. Despite receipt of guideline-based treatment, low SES remained a predictor of increased cancer-specific mortality. These data suggest that investigating treatment barriers beyond adjuvant therapy is needed to address colon cancer survival disparities. [Table: see text]
A randomized controlled trial of a self-administered, online decision-aid (“Navya Patient Preference Tool”) to reduce decisional conflict in women with early breast cancer.
Authors: Joshi Shalaka P , Ramarajan Lakshmi , Deshpande Ojas , Fernandes Elizabeth , Vanmali Vaibhav , Hawaldar Rohini W , Kannan Sadhana , Parmar Vani , Nair Nita S. , Gupta Sudeep , Badwe Rajendra A.
Published: May 2020

7033

Background: Shared decision making to confront choices with clinical equipoise, has been the privilege of those patients with access to time intensive consults with oncologists. We conducted a randomized controlled trial for breast cancer patients to use an online, self-administered, out-of-the-medical-encounter decision aid (DA) to choose between breast conserving surgery (BCS) and mastectomy. Methods: Navya Patient Preference Tool (Navya PPT) is a multilingual DA based on adaptive conjoint analysis of tradeoffs between cost, adverse effects of radiation, and breast conservation. Prior analysis established high internal reliability and external validity of the Navya PPT. Eligible cT1/2, cN0 breast cancer patients planned for surgery were block randomized, in 1:1:1 ratio, to receive the research questionnaire (RQ) to measure decisional conflict on choice of surgery (control, arm 1), Navya PPT followed by RQ (experimental, arm 2) or Navya PPT followed by RQ administered with key male family member (experimental, arm 3). Groups were stratified with respect to age, socio-economic status (SES) and educational level. The study was powered to detect a decrease in Decisional Conflict Index (DCI) by 0.25 (β-0.8, two sided α- 0.01). Results: Between June 2017 and December 2019, 247/255 patients were randomized to arm 1 (83), arm 2 (84), and arm 3 (80). Median age was 48 years (IQR 23-76), and median pT size was .5 cm (0.5-6 cm). 59% of patients were middle or lower SES and 46.2% had ≤ 12th grade education. DCI was significantly reduced in arm 2 as compared with arm 1 (1.34 vs. 1.65, Cohen’s d 0.49 (± 0.31) p<0.05) as well as in arm 3 as compared with arm 1 (1.30 vs. 1.65, Cohen’s d 0.54 (± 0.31) p<0.05). 80% (± 6%) of patients underwent surgery of choice as determined by Navya PPT. BCS rate was similar in all three arms (85.2, 88.9 and 86.5% respectively (p=0.779). Conclusions: Online, self-administered, adaptive DAs used out of the medical encounter can reduce decisional conflict and increase access to shared decision making for every patient; especially in practices with low doctor to patient ratios. Clinical trial information: IEC/0116/1619/001 .
National estimates of substance use, substance use disorders, and treatment among adolescent and young adult cancer survivors.
Authors: Ji Xu , Cummings Janet , Mertens Ann C. , Wen Hefei , Effinger Karen Elizabeth
Published: May 2020

7042

Background: Adolescent and young adult (AYA) survivors of cancer are at an elevated risk of early-life morbidity and mortality due to the disease trajectory and treatment. Engagement in risk behaviors, including substance use, can exacerbate survivors’ vulnerabilities and place them at further risk for adverse health outcomes. This study provides national estimates of the prevalence of substance use and misuse, substance abuse or dependence (i.e., substance use disorders [SUD]), and receipt of treatment for SUD among AYA cancer survivors. Methods: We used 2015-2018 National Survey of Drug Use and Health data to identify a nationally-representative AYA sample (aged 12-34 years). Outcomes included past-year alcohol use, marijuana use, other illicit drug use, misuse of any prescription psychotherapeutic drugs (including opioid analgesics, stimulants, sedatives, or tranquilizers), and misuse of prescription opioid analgesics. Outcomes also assessed past-year SUD in aforementioned drug classes. Among those with SUD, we evaluated past-year receipt of SUD treatment. Multiple logistic regressions were estimated to compare outcomes between 846 AYAs who reported a cancer history and 142,870 AYAs who did not, adjusting for sociodemographic and need-related characteristics. Results: In bivariate analyses, AYAs with a cancer history were more likely than noncancer peers to use alcohol (78.6% vs. 63.4%; p< 0.001) and illicit drugs other than marijuana (11.2% vs. 7.8%; p= 0.02), misuse any prescription psychotherapeutic drugs (16.9% vs. 10.6%; p< 0.001) and prescription opioid analgesics (12.0% vs. 5.9%; p< 0.001), and have an illicit drug (other than marijuana) SUD (3.7% vs. 1.3%; p< 0.01) in the past year. In regression analyses, differences in past-year misuse of any prescription psychotherapeutic drug and prescription opioid analgesics persisted ( p= 0.02, p< 0.01, respectively). Among AYAs with SUD, those with a cancer history were more likely than noncancer peers to receive SUD treatment (21.0% vs. 8.1%; p= 0.01) in the past year; this difference persisted in regression analyses ( p= 0.03). Conclusions: AYAs with a cancer history had an elevated risk for misusing prescription psychotherapeutic medications, which was driven by misuse of prescription opioids; yet, only one in five AYAs with a cancer history and SUD received treatment. Our findings underscore the need for future interventions designed to reduce substance use and misuse and improve access to SUD treatment in AYA cancer survivors.
Neoadjuvant treatment with chemotherapy or chemoradiation in stage III non-small cell lung cancer: Analysis of the National Cancer Database.
Authors: Malapati Sindhu Janarthanam , Singh Sunny R K , Kumar Rohit , Hadid Tarik H.
Published: May 2020

7046

Background: Use of neoadjuvant chemotherapy (Neo-chemo) improves survival in locally advanced NSCLC. However, data regarding the benefit of adding radiation (Neo-CRT) is limited. Meta-analyses suggest that the use of Neo-CRT could lead to significant tumor downstaging but with increase in therapy-related mortality. Methods: Patients with resected stage III NSCLC were identified from the NCDB between 2010 and 2015. Patients were divided into two groups based on the type of neoadjuvant therapy received (Neo-chemo vs. Neo-CRT). Surgical and survival outcomes were compared. Kaplan-Meier method and log-rank test were used for survival analysis. Results: Of the 136,942 patients with stage III NSCLC, 15,804 patients had definitive surgery. Mean age was higher for those who received Neo-chemo (63.8 vs. 61.8 years, p<0.0001). Median overall survival (OS) for Neo-CRT was 49.8 months and for Neo-chemo was 53.6 months. After adjusting for treatment facility, age, gender, race, comorbidity index, insurance status, T and N stage, there was a 12% reduction in mortality with use of Neo-chemo compared to Neo-CRT (p=0.03, 95% confidence interval 0.78-0.98). 3 years OS for Neo-CRT and Neo-chemo was 51.1 and 54.3%, respectively. The 30-day operative mortality rate was slightly higher in the Neo-chemo group (4.6 vs. 3.2%, p=0.004) but 90-day mortality rates were similar (7.41% vs. 6.83%, p=0.37). Length of hospital stay for primary tumor resection was shorter for the Neo-chemo group (5 vs. 6 days, p<0.0001); however, there was no significant difference in 30-day readmission rates between the two groups (91.53% vs. 94.01%, p=0.09). Conclusions: In this study, neoadjuvant chemotherapy resulted in 12% lower mortality compared to neoadjuvant chemoradiation despite the notable increase in the rate of complete pathologic tumor and nodal response achieved with the addition of neoadjuvant radiation. There was no difference in R0 resection rates, postoperative mortality or readmissions between the two groups. [Table: see text]
Long-term financial outcomes and quality of life in partners of colorectal cancer survivors.
Authors: Veenstra Christine M , Abrahamse Paul , Morris Arden M. , Hawley Sarah T.
Published: May 2020

7048

Background: Many patients with colorectal cancer face financial toxicity, but little is known about financial outcomes among their partners. Moreover, virtually nothing is known about associations between partners’ quality of life and their financial outcomes. Methods: In 2019 we surveyed patients who, in 2014-18, underwent resection of Stage III colorectal cancer and were seen at a community oncology practice, an academic cancer center, or reported to Georgia SEER (current RR 46%). Patients gave a separate survey to their partner. 254 partners (68% RR) completed surveys. Partners were asked about financial impacts of the patient’s cancer. Partners’ quality of life (QOL) was measured with the PROMIS global health scale. Multivariable regression analyses of 3 partner-reported outcomes (1. Perception that their financial status is worse off, 2. Substantial worry about finances, 3. Debt related to patients’ cancer) were generated to assess associations between each outcome and key partner and patient variables, and associations between partners’ QOL and financial outcomes. Results: Among partners, 55% were < age 65, 64% female, 86% white, and 27% had < high school education. 61% were employed at time of patient’s diagnosis; 38% of those missed 7-30 days work and 13% missed > 1 month work due to the patient’s cancer. 66% patients were employed at diagnosis. Among those, 34% were no longer working at the time of survey. In 14% dyads only the patient was working at diagnosis and among those, 50% were no longer working at the time of survey. 32% partners reported their financial status is worse off, 36% reported substantial worry about finances, and 28% reported current debt, all due to the patient’s cancer. After adjustment for partner and patient variables, partners of patients further out from diagnosis and partners of patients who were working at diagnosis were more likely to report substantial worry. Partners < age 50, with 1 comorbid condition, and partners of patients who were working at diagnosis were more likely to report debt (all p < 0.05). Endorsing each of the 3 financial outcomes was associated with lower QOL among partners, after adjustment for partner and patient variables (all p < 0.01). Conclusions: Nearly 1/3 of partners of survivors of colorectal cancer reported long-term adverse financial outcomes due to the patient’s cancer. Partners of patients working at the time of diagnosis were more likely to report substantial worry and debt, perhaps because many patients who were working at diagnosis are no longer working in the survivorship period.
A personalized prediction model for hospital readmission risk for cancer patients.
Authors: Shreve Jacob Tyler , Lee Sarah , Felix Christina , Benish Shirley Rachel , Hilton Cameron Beau , Radakovich Nathan , Stevenson James , Montero Alberto J. , Nazha Aziz
Published: May 2020

7057

Background: Cancer patients (pts) are at high risk of unplanned hospital readmissions. Predicting which cancer patients are at higher risk of readmission would improve post-discharge follow-up/navigation, decrease cost, and improve pt outcomes. Methods: We conducted a retrospective cohort study of non-surgical cancer pts hospitalized at our center between 12/2014 to 7/2018. A machine learning algorithm was trained on 348 medical, sociodemographic and cancer-specific variables with a total of 1,801,944 data points. The cohort was randomly divided into training (80%) and validation (20%) subsets. Prediction performance was measured by area under the receiver operator characteristic curve (AUC). Results: A total of 5,178 hospitalizations were included, of which 45.1% were women, and 27.6% experienced an unplanned readmission within 30 days. The most frequently represented cancers were hematologic malignancies (30.5%), followed by GI (18.1%), lung (13.7%), and GU (10.9%). Significant variables that impacted the algorithm decision are ranked from the most to the least important, including: days from last admission; planned index chemotherapy admission; number of vascular access lines, drains, and airways in use; length of stay; cancer diagnosis; total ED visits in past 6 months; age; discharge lab values (sodium, albumin, alkaline phosphatase, bilirubin, platelets); number of prior admissions; and discharge disposition. The AUC for the validation subset was 0.80. To ease the translation of this model into the clinic, we developed a web application whereby users can supply the aforementioned variables to the model and receive a personalized prediction that highlights those variables most affecting a subject’s readmission risk status: www.Cancer-Readmission.com. Conclusions: A cancer-specific readmission risk model with high AUC for 30-days unplanned readmission has been developed. The model is embedded in a freely available web application that provides personalized, patient-specific predictions. Programs that integrate this model can identify cancer patients with a greater risk for unplanned hospital readmission, thus providing a personalized approach to prevent future unplanned readmissions.
The effect of cardiovascular disease on the association between immune-related adverse events and overall survival.
Authors: Oren Ohad , Molina Julian R.
Published: May 2020

7059

Background: Preliminary data suggests that immune-related adverse events (irAEs) are associated with lower all-cause mortality, presumably due to improved anti-tumor responses. Investigations of large cohorts are needed to establish better understanding of that association. Methods: We reviewed the Mayo Clinic database for all patients who received an immune checkpoint inhibitor (ICI). The primary outcome was all-cause mortality. Descriptive and uni-variate analyses were generated. Results: Between March, 2010 and July, 2019, 3,326 patients received an ICI. The most common irAEs were colitis (287, 8.6%), pneumonitis (238, 7.2%) and hepatitis (227, 6.9%). A total of 933 (28.1%) patients developed at least 1 irAE and 176 (5.3%) patients experienced 2 or more irAEs. Survival analysis demonstrated an association between the number of irAEs and all-cause mortality (log-rank, P < 0.0001), a relationship which was maintained for the 3 most common cancer types (lung, melanoma, renal) and for the individual ICI agents. In patients with lung cancer, colitis (P = 0.04) but not pneumonitis (P = 0.83) was associated with improved overall survival. No association between irEA and all-cause mortality was demonstrated in patients with history of stroke (log-rank, P = 0.12), peripheral artery disease (PAD) (log-rank, P = 0.68) and obesity (log-rank, P = 0.18). In an analysis of pre-ICI body-mass index (BMI), an association between irAE and lower overall mortality was shown in patients with BMI < 30 (log-rank, P < 0.001) and not in those with higher BMIs (log-rank, P = 0.09). The presence of stroke, PAD and obesity were associated with higher all-cause mortality in a survival analysis (P < 0.001). The irAE-mortality association was not modulated by the presence hypertension (log-rank, P < 0.0001), diabetes mellitus (log-rank, P < 0.0001), or heart failure (log-rank, P = 0.006). Conclusions: The development of any irAE is associated with higher overall survival. The presence of numerous cardiovascular disease states neutralizes that association, likely a result of competing causes of mortality although interaction with immune or inflammatory pathways is possible. In addition, pneumonitis is not associated with better overall survival in patients with lung cancer presumably due to compromise of already-tenuous respiratory status.
Linking insurance claims across time to characterize treatment, monitoring, and end-of-life care in metastatic breast cancer.
Authors: Caswell-Jin Jennifer Lee , Callahan Alison , Purington Natasha , Han Summer S. , Itakura Haruka , Sledge George W. , Shah Nigam , Kurian Allison W.
Published: May 2020

7063

Background: Treatment and monitoring options for metastatic breast cancer (MBC) are increasing, but little is known about patterns or predictors of their use. Insurance claims are potentially informative, but tracking patient care timelines using episodic claims data has been cumbersome. Methods: We used an advanced cohort engine, implementing a temporal query language, to link IBM Marketscan claims over time for > 125 million US individuals from 2007-2014. To select the most common MBC subtype (ER+, HER2-), our criteria were: ≥2 MBC ICD codes, ≥1 year of follow-up, and ≥1 CPT or medication code for endocrine therapy and 0 for HER2-targeted therapy. We defined aggressive MBC as ≥1 ICD code for visceral or central nervous system metastasis < 1 year after the first MBC code. Geographic area was defined by 9 Census-Bureau designated regions. End-of-record was used as a surrogate for death in a Cox regression. We used multivariate logistic regression to determine correlation of factors, including disease aggressiveness and geography, with treatment, monitoring, and end-of-life events. Results: 7,335 women met criteria for ER+, HER2- MBC, with median age 59. Nearly half (46%) had aggressive disease, which correlated with shorter survival (hazard ratio (HR) 1.5 [1.4-1.6], P < 0.001). Treatment: first-line was endocrine therapy for 64% versus chemotherapy for 36%. Monitoring: 79% were imaged mostly by CT versus 21% by PET-CT, with median between-scan interval of 81 days; 63% received CA 15-3 serum tumor markers. End-of-life: 10% had a hospice code, of whom 19% had an ICU stay and 34% chemotherapy in the prior 3 months. Correlates of care: Disease aggressiveness correlated with first-line chemotherapy (odds ratio (OR) 2.0 [1.8-2.2], P < 0.001), PET/CT (OR 1.6 [1.4-1.8], P < 0.001), more frequent scans (OR 2.3 [2.1-2.6], P < 0.001), and chemotherapy < 3 months pre-hospice (OR 1.2 [1.1-1.4], P < 0.001), but not with CA 15-3 monitoring or ICU stay. Disease aggressiveness did not vary by region (χ2 P = 0.8), but region was significantly associated with treatment, monitoring, and end-of-life care (P < 0.001). Conclusions: Approximately two-thirds of ER+, HER2- MBC patients receive first-line endocrine therapy and are monitored with CA 15-3 serum tumor markers; 10% had evidence of hospice use, a likely underestimate due to differential follow-up. MBC care patterns vary by geography while disease aggressiveness does not, suggesting that care is not optimally tailored to individuals. These insights from claims data can inform quality improvement for MBC care.
Effect of enasidenib (ENA) plus azacitidine (AZA) on complete remission and overall response versus AZA monotherapy in mutant-IDH2 (mIDH2) newly diagnosed acute myeloid leukemia (ND-AML).
Authors: Dinardo Courtney Denton , Schuh Andre C. , Stein Eytan M. , Montesinos Pau , Wei Andrew , De Botton Stephane , Zeidan Amer Methqal , Fathi Amir Tahmasb , Quek Lynn , Kantarjian Hagop M. , Frattini Mark G. , Lersch Frederik , Gong Jing , Franovic Aleksandra , Vyas Paresh , Dohner Hartmut
Published: May 2020

7501

Background: ENA and AZA each induce overall response rates (ORR) of ~30% and complete remission (CR) rates of ~20% in ND-AML. In vitro, combining ENA + AZA enhances cell differentiation. We report results of the phase II portion of an open-label, randomized phase I/II study of ENA + AZA (“E+A”) vs. AZA monotherapy (“A”) in patients (pts) with m IDH2 ND-AML (NCT02677922). Methods: Pts age ≥ 18 years ineligible for intensive chemotherapy, with ECOG PS ≤ 2 and intermediate- or poor-risk cytogenetics, were randomized 2:1 to E+A or A in 28-day (d) cycles. All pts received SC AZA 75 mg/m2/d x 7 d/cycle; pts randomized to E+A also received ENA 100 mg QD. The primary endpoint was ORR (CR, CR with incomplete recovery, partial remission, morphologic leukemia-free state). Other endpoints include duration of response (DOR), overall and event-free survival (OS, EFS), safety, and m IDH2 VAF. Results: 101 pts received E+A (n = 68) or A (n = 33). Median age was 75 years (57–85); most pts (83%) had intermediate-risk cytogenetics. 21 pts in the E+A arm and 1 in the A arm were ongoing at data cutoff (Aug 2019). Most common reason for discontinuation was disease progression (E+A 31%, A 52%). Median number Tx cycles was 10 (1–26) in the E+A arm and 6 (1–28) in the A arm. 7 pts (21%) in the A arm received subsequent Tx with ENA. ORR, CR rate and DOR were significantly improved with E+A vs. A (Table). Median OS was 22 mo in both arms (HR 0.99 [95%CI 0.52, 1.87]; P = 0.97). Median EFS was 17.2 and 10.8 mo in the E+A and A arms, respectively (HR 0.59 [95%CI 0.30, 1.17]; P = 0.13). Maximal m IDH2 VAF change from BL was –83.4% with E+A vs. –17.7% with A ( P < 0.01). No baseline co-mutation predicted primary resistance. Common Tx-related grade 3–4 AEs in the E+A arm were thrombocytopenia (37%), neutropenia (35%), anemia (19%), and febrile neutropenia (15%); these occurred in 19%, 22%, 22%, and 16% in the A arm. Grade 3–4 infections occurred in 18% of E+A pts and 31% of A pts. IDH differentiation syndrome occurred in 12 pts (18%) in the E+A arm. 5 E+A pts (7%) and 1 A pt (3%) died in the first 60 d. Conclusions: Combining ENA + AZA resulted in significantly improved response rates and durations, and was generally well-tolerated in older patients with m IDH2 ND-AML. The impact of subsequent Tx on OS/EFS and new translational data will be presented at the meeting. Clinical trial information: NCT02677922 . [Table: see text]
Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up.
Authors: Heuser Michael , Robak Tadeusz , Montesinos Pau , Leber Brian , Fiedler Walter M. , Pollyea Daniel Aaron , Brown Andrew , O'Connell Ashleigh , Ma Wendy , Chan Geoffrey , Cortes Jorge E.
Published: May 2020

7509

Background: In newly diagnosed AML or high-risk MDS, primary analysis of the randomized phase 2 BRIGHT AML 1003 trial (data cutoff Jan 2017) showed superior OS for GLAS+LDAC vs LDAC alone. The trial then continued to predefined completion 4 years from randomization of all patients (pts), reached in Mar 2019 and presented herein. Methods: Pts with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to GLAS+LDAC (n=88) or LDAC alone (n=44). For these groups, median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; median follow-up for survival 47.6 and 48.1 months; 4 (4.5%) and 1 pt (2.3%) completed ≥4 years’ follow-up. Results: Consistent with the primary findings (OS HR 0.51; 80% CI 0.39, 0.67 p=0.0004), GLAS+LDAC prolonged OS vs LDAC alone (table). Results were consistent in AML pts and cytogenetic risk/disease history subgroups (table), as were analyses by pt characteristics and baseline risk factors (not shown). Survival probability was 39.5% vs 9.5% at 1 year and 18.0% vs 2.4% at 2 years. GLAS+LDAC induced higher complete remission (CR) rates overall (16/88 vs 1/44; RR 8.12, 95% CI 1.05, 62.78, p=0.010) and across subgroups. Notably, fewer pts discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%) and alopecia (10.7%), with only 1 pt discontinuing due to dysgeusia. Conclusions: Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Clinical trial information: NCT01546038 . [Table: see text]
Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies.
Authors: Singh Abhay , Mrad Chebli , Faber Mark G , Hahn Theresa , Wang Eunice S. , Herr Megan , Thota Swapna
Published: May 2020

7516

Background: Data describing risks of tMDS/AML after targeted and immunotherapy (IO) agents are lacking. Melanoma (Mel) and renal cell carcinoma (RCC) are considered chemotherapy insensitive and have been treated with IO (interferon and interleukin) since the 1990s. In 2004, use of tyrosine kinase inhibitors (TKIs) began in non-small cell lung cancer (NSCLC) and expanded to RCC in 2005 and Mel trials in 2011. Checkpoint inhibitor (CPI) use began in 2011 for Mel, 2012 for NSCLC in trials and later for RCC. For multiple myeloma (MM), use of lenalidomide has been increasing since 2007. All these modern therapies have well described immunomodulatory functions. Methods: Using 17 population-based SEER cancer registries, we studied 565,149 patients diagnosed from 2000-2015 with Mel, RCC, NSCLC, or MM who survived ≥1 year and assessed risk of tMDS/AML across periods P1 (2000-2005), P2 (2006-2010) and P3 (2011-2015). Censoring occurred at 5 years of follow up to limit bias and assess risk alteration across approval and utilization periods of these modern therapies. Results: tMDS/AML risk was significantly elevated after RCC in P1 [standardized incidence ratio (SIR): 1.61, possibly from chemo exposure that was still prevalent to some extent in P1 period] and a downtrend noted in P2 (SIR: 1.11) and P3 (SIR: 0.60). tMDS/AML risk after Mel showed similar downtrend, not statistically significant. In contrast, risk for tMDS/AML after MM increased across all periods ( SIRs 4.51 > 5.05 > 5.23), and risk after NSCLC increased from P1 to P2 but decreased thereafter, pattern most pronounced in stage I-III NSCLC ( 1.64 > 3.15 > 1.92). Conclusions: Periods when TKI and CPI use became standard in Mel and RCC, we observed a decrease in tMDS/AML risk. Similar decrease in the most recent period for stage I-III NSCLC was observed, possibly due to progression of these earlier staged cancers resulting in receipt of TKIs and CPI for stage IV disease. tMDS/AML risk after MM increased contradicting the decline in risk previously reported in the literature. Discordance may be due to survival bias as MM patients are now living longer (SEER 5-yr survival in ‘00 was 35% and 53% in ‘15) with more time to develop tMDS/AML. Overall, aside from better efficacy and/or tolerability of modern therapies, another observed benefit was lower tMDS/AML risk. This risk was lower than general population in Mel/RCC, suggesting a possible protective effect of these therapies. SIR tables/graphs with updated SEER data (available 04/2020) with follow up through 2018 will be presented.
Glasdegib in combination with azacitidine (AZA) in patients (pts) with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML): Effects on marrow recovery and transfusion independence.
Authors: Zeidan Amer Methqal , Schuster Michael , Joris Magalie , Krauter Jurgen , Maertens Johan , Gyan Emmanuel , Kovacsovics Tibor , Verma Amit , Vyas Paresh , Wang Eunice S. , Ma Wendy , Zeremski Mirjana , Kudla Art , Chan Geoffrey , Sekeres Mikkael A.
Published: May 2020

7526

Background: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the USA in combination with low-dose cytarabine to treat pts with newly diagnosed AML unable to receive intensive chemotherapy due to comorbidities or age (≥75 years). Glasdegib + AZA showed promising remission rates and overall survival with a generally well-tolerated and manageable safety profile in an analysis of BRIGHT MDS & AML 1012 in pts with MDS, AML and CMML. Here we evaluate early hematopoietic recovery and transfusion independence with glasdegib + AZA in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m2/D on D1–7 q28D). Data cutoff: Sept 11, 2019. Results: Among pts with MDS (n=30; including 3 with CMML), median duration of treatment was 5.0 months (range, 0.4–15.5). Recovery of absolute neutrophil count (ANC), hemoglobin (Hb) and platelets at 2 thresholds started in cycle (Cyc) 1 (Table). Early platelet recovery correlated with response to treatment; 54% (7/13) of pts with platelets ≥100,000/µL at Cyc 2, D1 achieved complete or partial remission vs 0% (0/13) of pts with <100,000/µL, P=0.002. Start of Cyc 2 was delayed due to AEs in 8% (2/26) of pts. 54% (7/13) of evaluable pts transfusion dependent at baseline (BL) became transfusion independent. Among pts with AML (n=30), median duration of treatment was 5.0 months (range, 0.3–14.9). ANC, Hb and platelet recoveries started in Cyc 1 (Table). 9% (2/23) of pts had Cyc 2 dose delays due to AEs. 64% (9/14) of evaluable pts transfusion dependent at BL became transfusion independent. Clinical trial information: NCT02367456 . Conclusions: Glasdegib + AZA shows promising rates of survival with early marrow recovery in the up-front treatment of pts with MDS, AML and CMML ineligible for intensive chemotherapy. The association between early hematopoietic recovery and efficacy in the MDS cohort merits further study. [Table: see text]
Post-remission clonal hematopoiesis; Practical implications for measurable residual disease assessment in acute myeloid leukemia (AML).
Authors: Loghavi Sanam , Tanaka Tomoyuki , Furudate Ken , Wang Sa A , Takahashi Koichi
Published: May 2020

7529

Background: Clonal Hematopoiesis may persist following complete remission (CR) in patients with acute myeloid leukemia (AML) but does not necessarily indicate residual AML and may represent persistence of pre-leukemic stem cells. Post-remission CH identified by NGS has not been systemically studied in parallel with measurable residual disease (MRD) detection by flow cytometric immunophenotyping (FCI). Methods: We studied bone marrow sample from AML patients at baseline and CR by targeted deep NGS of 295 genes (median 403x depth) and compared the results to FCI. Measurable residual disease (MRD) detection by FCI was performed by comparing the phenotype at CR to baseline and by detection of leukemia associated immunophenotype (LAIP) and derivation from normal (DFN) (sensitivity: 0.1%). Post-CR CH was defined as presence of mutations originally detected in AML with variant allele frequency > 2.5%. FCI results were categorized into 4 groups: a) AML MRD negative by LAIP or DFN b) AML MRD+ (similar to baseline) c) AML MRD+ (different from baseline), d) Negative for AML MRD, but aberrant phenotype suggestive of pre-leukemic cells. We correlated FCI and NGS results. Results: 101 patients were included in the study. 45 (45%) had persistent post-CR clonal hematopoiesis; 23 (51%) had phenotypic alterations detected by FCI including AML MRD+ in 18 (40%) and pre-leukemic cells in 5 (10%). Among patient with no detectable mutations by NGS (n = 56; 55%), 14 (25%) had FCI aberrancies including AML MRD+ in 4 (7%) and pre-leukemic cells in 10 (18%). CH was significantly more common in samples with residual phenotypic aberrancies detected by FCI (p = 0.004). There was no significant correlation between FCI group d and persistent CH (p = 0.4). Persistent ASXL1 (p = 0.024, OR = 7.2 ) and RUNX1 (p = 0.016; OR = 17.3) mutations were significantly associated with FCI abnormalities. The correlation coefficient between FCI abnormalities and RUNX1 mutations inferred from a Bayesian network structure was 0.66. Conclusions: NGS and FCI are complementary in evaluating post treatment disease status in AML. Post CR-CH is associated with phenotypic abnormalities that either represent residual AML or pre-leukemic cells. The latter may not have the same prognostic implications as AML MRD; however, the association with outcome needs to be elucidated. Single cell DNA sequencing technologies may be helpful in more accurately deciphering the association of individual gene mutations and their contribution to phenotypic aberrations.
Health-related quality of life (HRQoL) in the phase III QUAZAR-AML-001 trial of CC-486 as maintenance therapy for patients with acute myeloid leukemia (AML) in first remission following induction chemotherapy (IC).
Authors: Roboz Gail J. , Dohner Hartmut , Pocock Christopher , Dombret Hervé , Ravandi Farhad , Jang Jun Ho , Selleslag Dominik , Mayer Jiri , Martens Uwe Marc , Liesveld Jane , del Castillo Teresa Bernal , Wang Ming-Chung , La Torre Ignazia , Skikne Barry , Kumar Keshava , Dong Qian , Braverman Julia , Abi Nehme Salem , Beach C. L. , Wei Andrew
Published: May 2020

7533

Background: Effective AML maintenance treatment (Tx) should decrease the risk of relapse and prolong survival without compromising HRQoL. In the placebo (PBO)-controlled phase III QUAZAR AML-001 trial (NCT01757535), CC-486, an oral hypomethylating agent, provided significant improvements in overall (OS) and relapse-free survival (RFS) in patients (pts) with AML in first remission following IC. Here we present pt-reported HRQoL outcomes from that study. Methods: Eligible pts were ≥ 55 yrs of age with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and in CR/CRi after IC ± consolidation. Pts were randomized 1:1 to CC-486 300 mg or PBO QD on days (d) 1–14 of 28d Tx cycles. HRQoL was assessed by FACIT-Fatigue scale and EQ-5D-3L health utility index, completed on d1 of each cycle and at end of Tx (EOT). Endpoints include Tx differences in mean changes from baseline (BL), and proportions of pts with clinically meaningful change from BL (improvement, no change, deterioration). Evaluable pts had an HRQoL assessment at BL and ≥ 1 post-BL visit. Stratified ANCOVA models included Tx and BL scores as covariates. Results: In all, 225/238 pts (95%) in the CC-486 arm were evaluable for FACIT-Fatigue and EQ-5D-3L, and 219/234 pts (94%) in the PBO arm were evaluable for FACIT-Fatigue and 217 (93%) for EQ-5D-3L. Pt characteristics were comparable between Tx arms. Most pts (61%) were 65-74 yrs of age. Median number of CC-486 Tx cycles was 12 and PBO cycles was 7. Compliance rates were > 95% at BL and remained high ( > 85%) at all post-BL visits except for EOT. At BL, pts in both Tx arms had comparable low levels of fatigue and generally good HRQoL relative to an age-matched general population. There were no meaningful differences between CC-486 and PBO in mean changes from BL in FACIT-Fatigue or EQ-5D-3L scores at any post-BL visit. There was no statistically significant difference between Tx arms in proportion of pts with a clinically meaningful deterioration in FACIT-Fatigue score at any post-BL visit except at cycle 29 (likely due to chance; no adjustment made for multiple testing), or in EQ-5D-3L at any visit. Median time to deterioration was not significantly different between CC-486 and PBO on the FACIT-Fatigue scale (41 vs 44 weeks, respectively; P = 0.70) or the EQ-5D-3L (200 vs 164 weeks; P = 0.63). Conclusions: HRQoL and low levels of fatigue were preserved with CC-486 maintenance Tx. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to PBO. Clinical trial information: NCT01757535 .