bluuebunny/crossref_metadata_2025_split huggingface dataset:
Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION primary analysis.
Authors: Poveda Andres , Lheureux Stephanie , Colombo Nicoletta , Cibula David , Lindemann Kristina , Weberpals Johanne I , Bjurberg Maria , Oaknin Ana , Sikorska Magdalena , Gonzalez Martin Antonio , Madry Radoslaw , Rubio María Jesus , Ledermann Jonathan A. , Davidson Richard , Blakeley Christopher , Bennett James , Brown Jessica , Skof Erik 
Published: June 2021

5545 Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including non-BRCAm pts. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 prior lines of platinum-based chemotherapy (PBC), we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and were in complete response (CR) or partial response (PR) to PBC. Pts received maintenance olaparib (tablets; 300 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS (modified RECIST v1.1). Secondary endpoints included PFS by homologous recombination deficiency (HRD) and somatic BRCA mutation (sBRCAm) status determined by central Myriad tumor and germline testing; and time to first subsequent treatment (TFST). The primary analysis was planned for 18 months (mo) after the last patient was enrolled. Results: 279 pts were enrolled from 17 countries (mean age: 64 years); 253 pts (90.7%) were confirmed non-gBRCAm. At data cut-off (Oct 2, 2020), median PFS was 9.2 mo (95% CI 7.6–10.9), with 210 PFS events (75.3% maturity). 65.3%, 38.5% and 24.3% of pts were progression-free (PF) at 6, 12 and 18 mo, respectively. The Table shows PFS in key subgroups. Median TFST was 13.9 mo (95% CI 11.5–16.4). Median exposure to olaparib was 9.4 mo (range 0.0–31.9). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 29.0% of pts and serious TEAEs in 19.7% of pts. TEAEs led to dose interruption, dose reduction and treatment discontinuation in 47.0%, 22.6% and 7.5% of pts, respectively. Conclusions: Our findings support the use of olaparib maintenance therapy in non-gBRCAm PSR OC pts, consistent with our interim analysis and previous trials in this setting. Clinical trial information: NCT03402841. [Table: see text]
Does time to completion of radiation treatment in locally advanced vulvar cancer impact survival?
Authors: Nguyen Nancy T. , Zhao Xiao , Ponzini Matthew , Wilson Machelle , Leiserowitz Gary S. , Brooks Rebecca A. 
Published: June 2021

5593 Background: Although well established in cervical cancer, it is unclear whether time from initiation to completion of radiation therapy for vulvar cancer affects survival outcomes. We seek to assess if completion of radiation, either alone (RT) or as concurrent chemoradiation (CRT), within a planned timeframe in locally advanced squamous cell vulvar cancer impacts overall survival (OS). Methods: Women 18 years or older with FIGO stage II to IVA vulvar cancer who received external beam RT or CRT as part of their initial treatment course were identified from the National Cancer Database from 2004-2017. Patients with non-squamous cell carcinoma histology or who received systemic cytotoxic therapies as primary treatment were excluded. Patients who received less than 20 fractions of radiation were also excluded. Time to radiation completion was the number of days from the initiation to completion of radiation. The delay of radiation completion was calculated as the difference between the actual time to radiation completion and predicted duration of radiation. Types of treatment (RT and CRT) were both stratified into groups based on the delay of radiation completion, less than 7 days or greater than 7 days. Chi-square, Fisher Exact ANOVA and Kruskal-Wallis tests were used for analysis. Kaplan-Meier curves with log-rank tests were fit for univariate time-to-event analysis. Multivariable Cox proportional hazard models were fit to assess effects after controlling for confounding. Results: There were 2378 patients identified for analysis (n = 856 RT and n = 1522 CRT). Median age was 67 (IQR 56-78) and the CRT group was younger (p < 0.0001) than the RT group. The majority were white (88.35%) with advanced FIGO stage III or IVA (72.29 %) disease. Median dose of total radiation was 5720 cGy (IQR 5040-6300) with higher doses observed in the greater than 7 days delay group versus less than 7 days, (p < 0.0001). Median follow up was 27.2 (IQR 11.8-57.9) months. For both cohorts, completion of treatment with delay less than 7 days resulted in significant improvement in median survival when compared to treatment completion delay of more than 7 days: RT (Median OS 34.9 versus 21.6 months, p < 0.01) and CRT (58 versus 41.3 months, p < 0.01). On multivariate subset analysis, both completion of CRT and RT were associated with improved OS when treatment was completed with less than 7 days delay vs greater than 7 days delay, CRT (HR 0.869 [95%CI 0.758-0.997]), RT (HR 0.820 [95%CI 0.698-0.964]). Advanced FIGO stage IVA was associated with the greatest increase in hazard of death, (HR 1.758 [95%CI 1.516-2.039]), compared to FIGO stage II. Conclusions: Completion of radiation with less than 7 days delay is associated with improved overall survival, which is independent of concurrent chemotherapy. These findings suggest that strategies to minimize delays in radiation treatment are crucial in treating locally advanced vulvar cancer.
Impact of clinical trial enrollment on episode costs in the Oncology Care Model (OCM).
Authors: Young Garrett , Bilbrey Larry Edward , Arrowsmith Edward , Blakely L. Johnetta , Daniel Davey B. , Yue Andrew , Chaudhry Basit Iqbal , Spigel David R. , Lyss Aaron J. , Dickson Natalie R. , Fox John , Schleicher Stephen Matthew , Schwartzberg Lee S. 
Published: June 2021

6513 Background: Clinical trials are critical for improving outcomes for patients with cancer. However, there is some concern from health insurers that clinical trial participation can increase total cost of care for cancer patients. We investigated the impact of clinical trial participation on total costs paid by Medicare during the OCM program in a large community-based practice. Methods: Tennessee Oncology (TO) is a community oncology practice comprising over 90 oncologists across 30 sites of care. We linked TO trial data and electronic medical record data with OCM data for episodes of care from 2016-2018. To assess the impact of trial participation on total cost relative to routine care, we created matched comparator groups for each OCM episode based on cancer type, metastatic status, number of comorbidities, performance status, and age. Patients with breast cancer receiving hormone therapy only were excluded. Absolute and percent cost differences between groups were calculated for episodes that had a comparator group size of five or greater. Differences in total cost for trial episodes were compared to non-trial episodes, and significance was assessed using the Mann–Whitney U test. We also studied the impact of trial participation on receipt of active treatment in the last 14 days of life (TxEOL), hospice use, and hospitalizations. Results: During the study period, 8,026 completed OCM episodes met study criteria. Patients were enrolled in a clinical trial for 459 of these episodes. On average, episodes during which patients were on trial cost $5,973 less than matched non-trial episodes (Table), independent of early versus late-phase trial. Most savings resulted from decreased drug costs. There were no differences in rates of TxEOL (15% vs. 14% p=1.0), rates of hospitalizations (31% vs. 30% p=0.54), or hospice use (52% vs. 62% p=0.08) between trial and non-trial episodes. Median difference from comparator group average cost was significantly lower for clinical trial episodes (-18% vs. -6%, p<0.01). Conclusions: In the community setting, total costs paid by Medicare for patients participating in clinical trials during OCM episodes were lower than costs for similar patients receiving routine care. Clinical trial participation did not adversely impact end-of-life care or likelihood of hospitalization. These findings suggest that patient participation in clinical trials does not increase total cost of care nor enhance financial risk to payers.[Table: see text]
Bone modifying agents in veterans with castration-resistant prostate cancer.
Authors: Bauman Jordan , Kumbier Kyle , Burns Jennifer A. , Sparks Jordan , Tsao Phoebe A. , Skolarus Ted A. , Shahinian Vahakn B. , Caram Megan Veresh 
Published: June 2021

6582 Background: Skeletal related events (SREs) are a known complication for the 80% of men with metastatic prostate cancer who have bone metastases. Previous studies have demonstrated that bone modifying agents (BMAs) such as zoledronic acid and denosumab reduce SREs in men with metastatic castration-resistant prostate cancer who have bone metastases and are now recommended by national guidelines. We sought to investigate factors associated with use of BMAs in Veterans with CRPC across the Veterans Health Administration (VA). Methods: Using the VA Corporate Data Warehouse, consisting of aggregated medical record data from 130 facilities, we used an algorithm previously published to identify men with a diagnosis of castration-resistant prostate cancer (CRPC) based on rising prostate specific antigen (PSA) levels while on androgen deprivation therapy and who received systemic treatment for CRPC with one of the commonly used therapies: abiraterone, enzalutamide, docetaxel, ketoconazole between 2010 and 2017. To account for clustering among facilities, we used a multilevel multivariable logistic regression to determine the association of patient and disease-specific variables on the odds of a patient receiving a BMA after they started treatment for CRPC. Results: Of 4,998 patients with CRPC in our cohort, 2223 (44%) received either zoledronic acid or denosumab at some point after they were initiated on treatment for CRPC. After adjusting for other variables and accounting for a facility, the odds of receiving a BMA decreased by 3% for every additional year of age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.96-0.98), and decreased significantly with increasing comorbid conditions (OR 0.94, 95% CI 0.72-0.98 for Charlson Comorbidity Index [CCI] of 1; OR 0.69, 95% CI 0.59-0.81 for CCI 2+). Patients who were Black had 25% lower odds of receiving a BMA than patients who were White (OR 0.75, 95% CI 0.65-0.87). PSA at time of CRPC treatment start had a small but not significant effect on receipt of a BMA (OR 1.04, 95% CI 1.00-1.08) for every unit increase of PSA on the log scale. PSA doubling time was not associated with receipt of a BMA. The presence of a diagnosis code for bone metastases was far lower than expected in this cohort of patients with CRPC (40.7%), and thus was not included in the model. We did not expect the presence of bone metastases to vary significantly among the other independent variables. Conclusions: Despite most patients with CRPC historically having bone metastases, less than half of patients with CRPC received a BMA. Patients who are older, had more comorbidities, or were Black were less likely to receive a BMA after starting treatment for CRPC. Understanding factors that lead to different patterns of treatment can guide initiatives toward more guideline-concordant care.
Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.
Authors: Hamadeh Issam , Jacobs Ryan , Hu Bei , Moyo Tamara Kay , Soni Amy , Park Steven I. , Patel Jai Narendra , Steuerwald Nury , Ghosh Nilanjan 
Published: June 2021

7526 Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]
Post-transplant lymphoproliferative disorder in kidney transplant patients: A multicenter report.
Authors: Chong Elise A. , Tsai Daniel E. , Hughes Mitchell E. , Lim Mary Ann C , Besharatian Behdad D. , El Kassiss Yvonne , Bloom Roy , Jagadeesh Deepa 
Published: June 2021

7564 Background: Post-Transplant Lymphoproliferative Disorder (PTLD) is a complication of transplantation that often arises due to reactivation of the Epstein-Bar Virus (EBV). Given the rarity of this disease, a full understanding of its presentation and optimal therapies has yet to be determined. Methods: A multicenter retrospective analysis was performed utilizing data from kidney transplant patients (pts) who developed PTLD at the Hospital of the University of Pennsylvania and the Cleveland Clinic. The association between categorical variables and clinical response were assessed via Fisher’s exact testing. Results: 117 pts had diagnoses of PTLD after kidney transplantation. The median age at PTLD diagnosis was 52 yrs (range 17-89 yrs), and the median time from transplantation to diagnosis was 3.6 yrs (range: 7 days-36 yrs). Pt characteristics included: 84% Caucasian, 57% male, and 11% combined kidney and pancreas transplant patients. 68% pts had received unrelated donor transplants; 41% had prior rejection episodes. PTLD histology was 72% monomorphic and 28% polymorphic. Polymorphic PTLD was more likely to be EBV+ than monomorphic PTLD (81% vs. 54%, p = 0.05). At diagnosis, immunosuppression included: steroids (95%), mycophenolate (44%), azathioprine (40%), sirolimus (30%), cyclosporine (46%), and/or tacrolimus (45%). Common PTLD symptoms included fever (34%), pain (38%), weight loss (30%), fatigue (30%), and/or mass (26%). The most common sites of involvement were lymph nodes (64%), kidney allograft (22%), and/or GI tract (17%). At diagnosis, 61% of patients’ tumors were EBV+ and 59% of patients had elevated serum LDH. Overall, the majority of pts responded to first-line PTLD therapy, with 61% CR and 14% PR. Reduction of immunosuppression (RI) alone (36% of pts) led to 48% CR and 12% PR; RI with rituximab (16%) led to 47% CR and 7% PR; and RI with chemotherapy (14%) resulted in 58% CR and 42% PR. Patients treated with RI as well as resection (n = 18) of their limited stage disease had better outcomes (p = 0.05). Overall survival for all patients was 10.7 years (95%CI: 5.2-13 years). PTLD patients < 40 yrs were more likely to achieve CR after first line therapy (p < 0.001), have allograft involvement (p = 0.003), and have a polymorphic histology (p = 0.002). Allograft involvement tended to occur sooner after transplant (p = 0.001) and was more likely to present with allograft failure (p = 0.007). PTLD with allograft involvement had better response to first therapy than regular PTLD (p = 0.007) and often responded well to complete resection and RI. Conclusions: Pts with PTLD may achieve a CR through different initial therapies. Younger patients and those able to undergo complete resection of disease and RI had better prognoses. Allograft involvement by PTLD carries a good prognosis and should be identified and treated differently from other presentations.
PIT-2: A multicenter phase II trail of S-1 plus cisplatin with concurrent radiotherapy followed by surgery in stage IIIA (N2) lung squamous cell carcinoma.
Authors: Takamochi Kazuya , Tsuboi Masahiro , Okada Morihito , Niho Seiji , Ishikura Satoshi , Oyamada Shunsuke , Yamaguchi Takuhiro , Tanaka Fumihiro , Yoshino Ichiro , Tsuchida Masanori , Shiono Satoshi , Oizumi Hiroyuki , Okumura Norihito , Haruki Tomohiro , Suzuki Kenji 
Published: June 2021

8543 Background: A multicenter phase II study, PIT-2 (Personized Induction Therapy-2), was performed to investigate the efficacy and safety of S-1 plus cisplatin and concurrent thoracic radiation therapy (TRT) followed by surgery in patients with stage IIIA (N2) lung squamous cell carcinoma (LSCC). To date, no clinical trials on the use of induction therapy prior to surgery have focused solely on the treatment of N2 LSCC. Methods: Eligible patients were 20 to 75 years old and had stage IIIA (pathologically proven N2) LSCC, performance status of 0-1, and no prior treatment. The patients received induction therapy consisting of three cycles of S-1 and cisplatin plus concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at 40 mg/m2 twice per day, on days 1 through 14 along with an intravenous infusion of cisplatin (60 mg/m2) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, pathological complete remission (pCR) rate, feasibility, and toxicity. Results: Of the 45 patients registered between December 2013 and September 2018, 43 received induction therapy. Of the 43 patients, 39 (91%) underwent surgery (25 lobectomies, 10 bilobectomies, three pneumonectomies, and one wedge resection). The complete resection rate was 95% (37/39). Median follow-up time was 35.7 months. The 2-year PFS and OS rates were 67% (90% CI: 54-78%) and 70% (95% CI: 53-81%), respectively. The ORR and pCR rates were 86% (37/43, 95% CI: 76-96%) and 39% (15/39, 95% CI: 23-54%), respectively. Grade (G) 3 or 4 toxicities during the induction therapy in 43 patients included neutropenia (40%), anemia (9%), thrombocytopenia (7%), and hyponatremia (7%). Severe surgical complications in 39 patients included G3/4 pneumonia (5%), G3 bronchopleural fistula (5%), and G3 pleural effusion (5%). No G3/4 intraoperative adverse events occurred. There was no 30-day postoperative mortality and one 90-day postoperative mortality in a patient who underwent right pneumonectomy and developed pneumonia after discharge. Conclusions: Induction therapy using S-1 plus cisplatin and concurrent TRT followed by surgery is a promising treatment for patients with stage IIIA (N2) LSCC. Clinical trial information: 000012413.
Genomic landscape of malignnant mesothelioma by site and histology.
Authors: Adib Elio , Akl Elie , Nassar Amin , El Zarif Talal , Abou Alaiwi Sarah , Kwiatkowski David J. 
Published: June 2021

8559 Background: Malignnant mesothelioma (MM) is a highly lethal tumor that can develop in the pleura, the peritoneum, the pericardium or the testes. While the genomic features of pleural MM have been well-described overall, less is known about the distribution of genetic alterations (GAs) according to histology. In addition, few reports comparing genetic features according to disease site are available. Methods: We identified patients with pleural or peritoneal mesothelioma with mutational analysis through the GENIE registry. Patient tumor genetic data were provided by Memorial Sloan-Kettering Cancer Center (MSK)-IMPACT and Dana-Farber Cancer Institute (DFCI)-Oncopanel NGS initiatives. Patients with more than one sequenced sample were excluded. We limited our analysis to genes common to all versions of both panels and that were significantly mutated in the TCGA mesothelioma cohort. Mutation and copy number variant (CNV), collectively called GAs, were determined, and were compared using the Fisher’s Exact test and Kruskal-Wallis Test. Comparisons were made both by disease site (pleural vs. peritoneal) and histology for the pleural samples (epithelioid vs. biphasic vs. sarcomatoid). Nominal p-values were obtained, and FDR correction was employed (q<0.1). Results: We identified 439 patients with MM in the GENIE registry who fit the inclusion criteria. The median age was 70.5 years for pleural MM and 60 years for peritoneal MM (Wilcoxon-rank sum test p-value = 3e-9). 72% of patients were male. CDKN2A/CDKN2B GAs (97% and 100% being deletions in CDKN2A and CDKN2B respectively), a described prognostic marker in MM, were more common in pleural than in peritoneal MM. Among pleural MMs, tumors of epithelioid histology had less NF2 GAs than biphasic or sarcomatoid tumors, whereas sarcomatoid tumors had the lowest frequency of BAP1 GAs (Table). Conclusions: Malignnant mesotheliomas of different disease sites and/or histologies display distinct patterns of GAs. These findings may contribute in part to differences in response to treatment and survival among these subsets of MM.[Table: see text]