bluuebunny/crossref_metadata_2025 huggingface dataset:
The spectrum of genomic alterations in young adult non-small cell lung cancer (NSCLC).
Authors: Oxnard Geoffrey R. , Heng Jennifer C. , Mach Stacy L. , Lo Peter C. , Butaney Mohit , Jackman David Michael , Janne Pasi A.
Published: March 2020

8077

Background: Identification of targetable genomic alterations in patients (pts) with NSCLC can have a profound impact on treatment and clinical outcomes. Given the complexity and cost of comprehensive genomic testing, clinical characteristics enriching for targetable genomic alterations are of interest. We hypothesized that young adults with NSCLC would have a higher prevalence of targetable genomics alterations compared to the general NSCLC population. Methods: An institutional database of pts with NSCLC was reviewed in an IRB-approved fashion to identify subjects with age < 40 at diagnosis. Clinical characteristics and risk factors were reviewed. Tumor genotyping for alterations in EGFR, KRAS, ALK, BRAF, HER2, and ROS1was pursued as part of an institution-wide genomics protocol. Targeted next-generation sequencing (NGS) of wild-type cases is underway. Results: From 2032 subjects with NSCLC, we identified 70 diagnosed at an age < 40 (3.4%). Pt characteristics: median age 35 (range 20-39); 63% never-smokers, 33% with ≥10 pack-years; 74% adeno, 9% squam, 14% undifferentiated, 3% neuroendocrine; 19% had a family history of lung cancer; 61% stage IV at diagnosis. Median survival from date of advanced disease was 15.8 months. Genotyping was performed on 51 pts with adeno or undifferentiated histology: 14 with EGFR mutations (27%), 5 with KRAS mutations (10%), 8 with ALK rearrangements (16%), 0 with BRAF mutations, 1 with a HER2 insertion (2%), 1 with a ROS1 rearrangement (2%). Compared to a reference prevalence from the Lung Cancer Mutation Consortium (Kris et al, ASCO, 2011), KRAS mutations were less common (p=0.01) and ALK rearrangements were more common (p<0.01). NGS of 2 cases to date has identified one pt with a novel 21 base-pair insertion mutation in FGFR2, not present in germline tissue. Conclusions: 47% (CI: 33%-60%) of pts diagnosed with NSCLC under age 40 harbor a targetable alteration in EGFR, ALK, HER2, or ROS1. These patients may be enriched for targetable genotypes and deserving of a unique treatment approach, and additionally represent an attractive population for genomic discovery.Supported in part by the Bonnie J. Addario Lung Cancer Foundation and the Conquer Cancer Foundation of ASCO.
Erlotinib after initial platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR) wild-type (WT) non-small cell lung cancer (NSCLC): Results of a combined patient-level analysis of the BR.21 and SATURN trials.
Authors: Osarogiagbon Raymond U , Cappuzzo Federico , Ciuleanu Tudor-Eliade , Leon Larry
Published: March 2020

8080

Background: Two double-blind, prospective, randomized, placebo-controlled trials demonstrated survival benefit in unselected populations with advanced NSCLC in the 2nd/3rd line (BR.21) and maintenance setting (SATURN). The efficacy of erlotinib in patients with EGFR WT NSCLC has been questioned. We examined the impact of erlotinib vs placebo in confirmed EGFR WT patients in both studies. Methods: Combined re-analysis of progression-free survival (PFS) (from date of randomization to investigator-assessed progression or death from any cause), and overall survival (OS) (from date of randomization to death from any cause) in patients with known WT EGFR. PFS and OS were estimated by Kaplan-Meier curves and compared by 2-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Sensitivity analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations. Results: 74% of the BR.21 population (n=150) and 89% of the SATURN population (n=388) with known EGFR mutation status had WT EGFR. PFS and OS for individual and combined analyses are shown (Table). Adjusting for non-randomized therapy after study therapy discontinuation, HR for OS was 0.74 (0.61–0.91); p<0.01. Baseline characteristics were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR WT data. Erlotinib benefit was sustained in all clinical subsets. Conclusions: Erlotinib provided a consistent and significant improvement in survival for patients with EGFR WT NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating EGFR mutations. [Table: see text]
Prediction of survival outcomes in NSCLC using a new PRO index from the LCSS (Lung Cancer Symptom Scale): Results of a 622-patient prospective trial.
Authors: Gralla Richard J. , Hollen Patricia J , Thongprasert Sumitra , Kim Hoon-Kyo , Hsia Te-Chun , Yuankai Shi , Kohn Nina , Lesser Martin
Published: March 2020

8087

Background: Accurate and easy prediction of survival at the onset of treatment for all patients is required for appropriate trial design and personalization of patient (pt) monitoring. No pt reported factor is routinely used for these purposes, as performance status (PS) is not pt rated. Methods: This prospective study, the AP-QL lung trial, enlisted 622 pts receiving initial docetaxel-based chemotherapy (80% with cisplatin or carboplatin) and correlated patient reported outcomes (PROs) from an electronic version of the LCSS (eLCSS-QL) every 3 weeks with survival outcomes. The eLCSS-QL requires < 3 minutes. Results: Baseline PROs and survival data were available for 96% of pts. Pts: 70% male; 65% adenoca; medians: KPS = 90; ECOG = 1 (27% ECOG 0); Stages: IV (72%), IIIB (28%). Survival: 12.8 months median; 52%, 1 year. Survival results were analyzed for differences for those living less than or greater than the median for each NSCLC symptom and LCSS global factor. For symptoms such as pain, dyspnea, or appetite, survival differences above and below the median varied from 2.5 to 4 months. Unlike individual symptoms which are found only in subsets of pts, LCSS pt-reported global items (symptom distress, activity level, and quality of life) each apply to all pts. Median survival differences above (positive factor) or below (negative factor) medians for each global item varied by 4 months (p < 0.003). An index was created using the number of negative factors, 0 to 3, based on survival less than the median for each of these 3 factors (Table). Conclusions: Several large and highly significant survival differences can be predicted by this simple LCSS HRQL-PRO Index, if assessed prior to chemotherapy. This index identifies more accurate survival differences than PS, can assist better trial design and analysis, and can aid in personalizing patient monitoring based on individual likelihood of risk and benefit. The results illustrate the strong correlations of PROs with survival. [Table: see text]
Phase I and pharmacodynamic study of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Gerber David E. , Skelton Rachael , Dong Ying , Loudat Laurin , Dowell Jonathan , Boothman David A. , Sarode Venetia , Zhang Wei , Xie Yang , Gazdar Adi , Frenkel Eugene P. , Schiller Joan H.
Published: March 2020

8088^

Background: Preclinical studies have demonstrated anti-tumor efficacy of the combination of the HDAC inhibitor romidepsin plus erlotinib in NSCLC models insensitive to erlotinib monotherapy (eg, KRAS mutation, EGFR resistance mutation, EGFR wild type). Methods: This phase I study evaluated safety, pharmacodynamics, and preliminary activity of romidepsin (8-10 mg/m2) given IV days 1, 8, and 15 every 28 days plus erlotinib 150 mg PO daily in previously treated advanced NSCLC. In Cycle 1, erlotinib was initiated on Day 3, permitting pharmacodynamic analysis of romidepsin alone and in combination. Results: As of January 31, 2013, 15 patients (pts) have been treated: median age 60 years; 7 F, 8 M; all former or current smokers; 6 had prior erlotinib exposure; 8 adenocarcinoma, 6 squamous, 1 large cell; 5 EGFR wild type 1 KRAS mutation, 9 unknown mutation status. Most common related AEs regardless of grade were nausea (87%), vomiting (73%), fatigue (60%), diarrhea and rash (both 53%), and decreased appetite (47%). Grade 3-4 AEs (all grade 3) included nausea and vomiting (both 20%); decreased appetite, diarrhea, fatigue (each 13%). Dose-limiting nausea and vomiting occurred at romidepsin 10 mg/m2 level despite aggressive antiemetic prophylaxis and treatment. At romidepsin 8 mg/m2, related grade 3 AEs included fatigue (n=1) and diarrhea (n=1), with no grade 3 nausea or vomiting. 9 pts were evaluable by RECIST; best response SD (n=6), PD (n=3). Median PFS was 3.3 months (range 1.4-16.5 months). At romidepsin 8 mg/m2, PFS range 2.0-16.5 months. At both dose levels, romidepsin inhibited HDAC activity and increased histone H3 and H4 acetylation status in peripheral blood mononuclear cells. Romidepsin also inhibited EGFR phosphorylation and, in 60% of pts, MAPK phosphorylation in skin biopsies. Conclusions: Romidepsin 8 mg/m2 plus erlotinib appears well tolerated, has encouraging evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population. Further studies are underway. Clinical trial information: NCT01302808.
First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.
Authors: Goldman Jonathan Wade , Rosen Lee S. , Algazi Alain Patrick , Turner Patricia Kellie , Wacheck Volker , Tuttle Jay , Wooldridge James E , Banck Michaela S.
Published: March 2020

8093

Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.
Canadian ALK (CALK): A pan-Canadian multicenter study to optimize and standardize ALK immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for ALK gene rearrangements.
Authors: Tsao Ming Sound , Craddock Kenneth , Brandao Guilherme , Xu Zhaolin , Greer Wenda , Yatabe Yasushi , Ionescu Diana , Jung Sungmi , Carter Ronald F , Karsan Aly , Bojarski Anna , Sekhon Harmanjatinder S. , Bigras Gilbert , Deschenes Jean , Albadine Roula , Pintilie Melania , Cutz Jean-Claude , Tran-Thanh Danh , Torlakovic Emina , Couture Christian
Published: March 2020

8096

Background: ALK gene rearrangement (ALK+) has been found in 3-5% of advanced non-small cell lung cancer patients. FISH is considered the “gold standard” for identification of ALK+ tumors, but its cost-effectiveness and adoption as a screening assay has been debated. Recent reports suggested that ALK IHC may serve as an alternative screening or possibly a diagnostic method. In this context, CALK was initiated to assess the feasibility of implementing ALK IHC and/or FISH assays across Canadian hospitals. Methods: FISH-confirmed 22 ALK+ and 6 ALK- tumors were used as study samples. Unstained sections and scanned images of HE-stained slides from each tumor block were distributed to participating centres. IHC protocols with best signal to noise ratio using the 5A4 (Novocastra) or ALK-1 (Dako) antibodies were developed for various auto-stainers and implemented to suit the existing conditions of the participating centres. A common FISH protocol using the ALK break-apart probe (Abbott Molecular, Chicago, IL) was developed based on published reports. H-score was used to assess IHC. FISH signals were scored in 100 tumor cells/case by 2-3 pre-trained persons. A second round IHC study using newly distributed slides was completed by 8 centres. Results: Independent IHC scores from 12 centres and FISH scores from 11 centres were collected and analysed. The intraclass correlation coefficients (ICC) between centres for IHC and FISH were 0.84 and 0.68, respectively. Following the analysis of initial IHC results, a second round study resulted in improved ICC of 0.94. One of 23 tumors revealed IHC-/FISH+ discrepancy, with the FISH revealing unusual signal configurations that suggested an atypical rearrangement. However, the sensitivity and specificity of FISH results across centres using the 15 aberrant signals cut-off ranged from 86.7-100% and 100%, respectively. Conclusions: Standardization across multiple centres for ALK testing by IHC and FISH can be achieved. IHC detected all FISH+ ALK tumors, except for one discrepant case with atypical FISH finding of unknown clinical implication. The study was supported by a Pfizer Canada grant.
High-dose erlotinib for refractory leptomeningeal metastases (LM) after failure of standard dose EGFR-TKIs.
Authors: Kawamura Takahisa , Hata Akito , Otoshi Takehiro , Fujimoto Daichi , Tamai Koji , Takeshita Jumpei , Matsumoto Takeshi , Monden Kazuya , Nagata Kazuma , Otsuka Kyoko , Nakagawa Atsushi , Tachikawa Ryo , Otsuka Kojiro , Kaji Reiko , Fujita Shiro , Katakami Nobuyuki , Tomii Keisuke
Published: March 2020

8098

Background: EGFR-TKIs, gefitinib and erlotinib can demonstrate dramatic and durable response in patients with EGFR-mutant non-small cell lung cancer. Approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM) after initial response to EGFR-TKIs. Pharmacokinetic failure due to insufficient penetration of EGFR-TKIs is suggested as a cause of CNS failure. Therefore, high-dose EGFR-TKIs are considered reasonable therapeutic options for refractory CNS metastases after failure of standard dose EGFR-TKIs, but there is little present evidence of high-dose EGFR-TKI’s efficacy and tolerability. Methods: Between 2007 and 2012, we screened 279 patients harboring EGFR sensitive mutations, and identified 31 patients with LM. Ten of 31 patients received high-dose erlotinib, and the other 21 underwent only standard dose EGFR-TKIs (gefitinib and/or erlotinib). In these 10 patients, erlotinib was administered at 200 mg on alternating days (n=2), 300 mg on alternating days (n=6), 300 mg every 3 days (n=1), or 600 mg every 4 days (n=1). We retrospectively investigated the efficacy and tolerability of high-dose erlotinib. Additionally, survivals from the diagnosis of LM to death were compared in patients with or without high-dose erlotinib. Results: Regarding high-dose erlotinib, five of 10 patients were radiologically evaluable, and partial response was observed in 60% (3/5), stable disease in 20% (1/5), and progressive diasease 20% (1/5). Median time to CNS progression was 3.4 months (range, 0.3-6.6 months). Improvement of neurological symptoms was observed in 9 (90%) of 10 patients. No severe adverse events (≥ grade 3) associated with high-dose erlotinib were confirmed. Median survival from the diagnosis of LM in patients with high-dose erlotinib was 6.5 months (95% CI: 2.5-12.3 months), and that in those without was 5.8 months (95% CI: 1.1-7.8 months) (p =0.51). Conclusions: The efficacy and tolerability of high-dose erlotinib were suggested for refractory LM. It can be a therapeutic option in patients after failure of standard dose erlotinib. Optimal dose and schedule are unclear, and further investigations are warranted.
A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.
Authors: Tan Daniel Shao-Weng , Lim Kiat Hon , Tai Wai Meng , Ahmad Aziah , Pan Summer , Ng Quan Sing , Ang Mei-Kim , Gogna Apoorva , Ng Yuen Li , Tan Bien Soo , Lee Haur Yueh , Krisna Sakktee Sai , Lau Dawn PX , Zhong Liz , Iyer Gopal , Chowbay Balram , Lim Alvin ST , Takano Angela , Lim Wan-Teck , Tan Eng-Huat
Published: March 2020

8107

Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline & d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority >3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax (>25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.
Impact of crizotinib on patient-reported symptoms and quality of life (QOL) compared with single-agent chemotherapy in a phase III study of advanced ALK+ non-small cell lung cancer (NSCLC).
Authors: Hirsh Vera , Blackhall Fiona Helen , Kim Dong-Wan , Besse Benjamin , Nokihara Hiroshi , Han Ji-Youn , Tassell Vanessa Roberts , Reisman Arlene , Iyer Shrividya , Shaw Alice Tsang
Published: March 2020

8108

Background: PROFILE 1007 compared the efficacy and safety of the ALK inhibitor crizotinib (N=172) with that of standard-of-care chemotherapy (pemetrexed [PEM; N=99] or docetaxel [DOC; N=72]) in patients with advanced ALK+ NSCLC. The primary endpoint was progression-free survival. The main objective of our present post-hoc analyses was to compare patient-reported outcomes in the crizotinib arm with those of the DOC and PEM subgroups in the chemotherapy arm. Methods: Patient-reported outcomes were assessed at baseline, on day 1 of each cycle, and at the end of treatment using EORTC QLQ-C30 and lung cancer module QLQ-LC13. Higher scores (range 0−100) indicate higher symptom severity or better functioning/QOL. Time to deterioration (TTD) was defined as time from randomization to the earliest time with a ≥10-point increase from baseline for pain in chest, dyspnea, or cough and was compared between groups using an unstratified log-rank test. Repeated measures mixed-effects analyses were performed to compare change from baseline scores, with no adjustment for multiple comparisons. Results: Completion rates at baseline were ≥90% in each group and scores were well balanced. Crizotinib treatment was associated with a significantly longer TTD compared with PEM (median, 5.6 vs. 1.9 mo; HR, 0.66; 95% CI, 0.48−0.92; P=0.013) or DOC (median, 5.6 vs. 0.9 mo; HR, 0.37; 95% CI, 0.26−0.54; P<0.0001). A significantly greater improvement from baseline was observed with crizotinib compared with either the PEM or DOC subgroups for global QOL (P<0.01), cough (P<0.001), dyspnea (P<0.0001), pain in arm or shoulder (P<0.0001), pain in chest (P<0.0001), pain in other parts (P<0.01), fatigue (P<0.05), insomnia (P<0.05), and pain (P<0.0001). A significantly greater improvement was also observed with crizotinib compared with DOC for functioning (P<0.05), alopecia (P<0.0001), and hemoptysis (P<0.0001). Conclusions: Crizotinib treatment showed a significantly greater improvement from baseline in key patient-reported lung cancer symptoms and global QOL compared with DOC and PEM, in addition to improved efficacy previously reported. Clinical trial information: NCT00932893.
Phase II double-blind placebo-controlled study of armodafinil for brain radiation induced fatigue.
Authors: Shaw Edward G. , Case Doug , Bryant David , Grisell David , Lesser Glenn , Monitto Drew C. , Naughton Michelle Joy , Rapp Stephen R. , Savona Steven R. , Shah Sunjay , Chan Michael D
Published: March 2020

9505

Background: Armodafinil (ARM), the R-enantiomer of modafinil, is FDA approved for narcolepsy, shift work disorder, and treated sleep-apnea, and has also been shown to reduce fatigue/improve cognitive function in cancer patients. This phase II study estimated the efficacy and toxicity of ARM in primary brain tumor (PBT) patients receiving brain radiation therapy (RT) to determine whether a larger phase III study would be warranted. Methods: Eligibility criteria – adult, PBT, total RT dose >45Gy, KPS>60, no severe headaches, and concurrent chemotherapy allowed. Patients were assessed at baseline, end of RT, then 4 weeks after end RT with the Brief Fatigue Inventory (BFI), Epworth Sleep Scale (ESS), FACT, and FACT brain and FACIT fatigue subscales. Patients were randomized to receive ARM 150mg/day during RT and for 4 weeks after RT or placebo (PLAC). Results: 54 patients enrolled between 9/10-12/12; 26 to ARM, 28 to placebo PLAC. Median age 59; 59% female; 95% White; 41% KPS 90-100, 59% KPS 60-80; 74% malignant glioma, 26% low-grade glioma/benign histology. 83% patients had concurrent chemotherapy. For all randomized patients, there were no statistically significant differences in outcome between ARM and PLAC groups at end-RT vs. baseline or 4 weeks post RT vs. baseline. For patients who had more baseline fatigue (fatigue subscale score <median), ARM-treated patients had significantly/suggestively better outcomes at end-RT vs. baseline compared to PLAC-treated patients: less fatigue (BFI p=0.056, fatigue subscale p=0.0295), less sleepiness (ESS p=0.1034), and better QOL (FACT p=0.0001). Incidence of grade 2/3 toxicities was the same between the two treatment groups: 7% anxiety, 7% nausea, 18% headaches, and 20% insomnia. There were no grade 4 or 5 toxicities. Conclusions: In irradiated PBT patients, fatigue, sleepiness, and reduced QOL occurring at the end of brain RT was less with ARM in those patients who were more fatigued at baseline. Toxicity was minimal. These data support conducting a larger phase III study. Analysis of cognitive function data is ongoing. Support - NIH/NCI grant 2U10 CA 81851 and Teva Pharmaceuticals. Clinical trial information: 95709.
Predictive factors for chemotherapy feasibility in elderly patients with solid tumor: Results of GERCOR old prospective multicenter study.
Authors: Carola Elisabeth , Chibaudel Benoist , Trager Stephanie , Bengrine-Lefèvre Leïla , Chuzel Joelle , Seitz Jean Francois , Dion Patrick , Artru Pascal , Aissat Nasredine , Sarlon Emmanuelle , Woerth Florence , Gauthier Mélanie , Bonnetain Franck , de Gramont Aimery ,   GERCOR
Published: March 2020

9511

Background: One quarter of patients with cancer are 75 year old and over. Previous studies suggested that geriatric parameters improved survival in elderly patients with solid advanced cancer and chemotherapy severe toxicity. A simplified scale would be helpful for oncologist to predict chemotherapy feasibility. The aim was to identify geriatric predictors of chemotherapy feasibility in chemo-naïve elderly patients. Methods: We conducted a prospective multicenter cohort study (NCT00664911). Inclusion criteria were: ≥ 75 years, solid tumor, able to receive at least 2/3 of the standard dose at the first course of treatment. Ten geriatric parameters were recorded at baseline by the oncologist: 1-three words test, 2-date and address for cognitive function, 3-Instrumental Activities of Daily Living (IADL), 4- monopodal stand-up test, 5-hospitalization during the previous year, 6-number of medicines taken for comorbidities, 7-creatinine clearance, 8-albumin serum level, 9-self-rated depressive mood question and 10-presence of a caregiver. The main outcome was chemotherapy feasibility defined by the ability to receive at least 3 months of the planned therapy. Multivariate logistic regression was used. Results: 576 patients were included in 49 centers from 2008 to 2012, 516 (89.6%) were eligible for analysis. Mean age was 81 years, 50.6% had colorectal cancer, 69.5% advanced stage and 83.6% had performance status 0-1. Chemotherapy feasibility was observed in 298 (57.8%) patients. Grade 3-4 toxicity was observed in 26.2% of patients. In multivariate analysis albuminemia < 30g/l (adjusted OR =2.34 CI95% [1.43-3.83]) and depressive mood (adjusted OR=1.55 CI95% [1.02-2.35]) were significantly associated with chemotherapy unfeasibility whereas others geriatrics parameters were not. Conclusions: Albuminemia and self rated depressive mood status were independently predictive for chemotherapy feasibility in elderly patients with solid tumor. Unexpectedly others geriatrics parameters were not independent predictors. Clinical trial information: NCT00664911.
Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC).
Authors: Hesketh Paul Joseph , Rossi Giorgia , Rizzi Giada , Palmas Marco , Alyasova Anna , Drobner Igor , Gralla Richard J.
Published: March 2020

9512

Background: Further progress in preventing CINV will require the introduction of novel agents providing maximal convenience and with efficacy for nausea as well as vomiting. NEPA is a single dose combination of NETU, a novel NK1 receptor antagonist (RA) and PALO, a pharmacologically distinct 5-HT3RA. This study was designed to determine the proper dose of NETU to combine with PALO. Methods: This was a randomized, double-blind, parallel group study in chemotherapy-naïve patients (pts) undergoing cisplatin-based HEC. Four study arms compared 3 oral doses of NEPA (NETU 100, 200, 300mg + PALO 0.50 mg) with oral PALO 0.50 mg, all given on day 1. All pts received oral dexamethasone (DEX) days 1-4. An exploratory aprepitant (APREP) + ondansetron/DEX arm was included. The primary endpoint was complete response (CR: no emesis, no rescue) in the overall (0-120h) phase. Results: 694 pts were enrolled with comparable characteristics across groups: males (57%), median age 55. Common cancers: lung (27%), head and neck (21%). Median cisplatin dose: 75 mg/m2. All NEPA groups showed superior CR rates compared with PALO during the overall and delayed phases, with NEPA300also superior to PALO during the acute phase. NEPA300was also superior to PALO during all phases for no emesis, no significant nausea and complete protection with incremental benefits over lower NEPA doses. AEs were comparable across groups with no dose-response. The % of pts developing ECG changes was comparable across groups. Conclusions: Each NEPA dose resulted in superior CR rates compared with PALO. NEPA300was the best dose studied, with an advantage over lower doses for all efficacy endpoints (including nausea). NEPA doses were well tolerated with similar safety profiles to PALO and APREP. NEPA combined with DEX is superior to PALO plus DEX in prevention of CINV following HEC. [Table: see text]
Caregivers’ perception of advanced cancer patients’ quality of death: Impact on caregiver suicidal ideation in bereavement.
Authors: Abbott Caroline H , Prigerson Holly Gwen , Maciejewski Paul K
Published: March 2020

9522

Background: Evidence suggests that patients’ quality of life (QOL) at the end of life (EOL), i.e., patients’ quality of death, may affect the health and well-being of informal family caregivers. Here we examine the relationship between family caregivers’ perception of patients’ QOL at the EOL and caregiver suicidal ideation in bereavement. Methods: Our analysis was based on data from a sub-sample of family caregivers (N=112) from the Coping with Cancer Study, an NCI-funded multicenter prospective cohort investigation of advanced cancer patients and their caregivers enrolled September 2002 – February 2008. Caregiver baseline suicidal ideation was assessed using the Yale Evaluation of Suicidality (YES) Scale a median of 4.1 months pre-loss; caregivers’ perception of patients’ overall distress in the last week of life was assessed a median of 1.9 months post-loss; and caregiver suicidal ideation in bereavement was assessed using the YES a median of 6.5 months post-loss. Suicidal ideation was defined as a positive screen on the YES. Multiple logistic regression analysis examined the effect of caregivers’ perception of patients’ quality of death on bereaved caregiver suicidal ideation, adjusting for caregivers’ baseline suicidal ideation and potential demographic confounds. Results: Caregivers’ perception of patients’ overall distress at the EOL was significantly related to caregivers’ suicidal ideation post-loss (AOR=1.26, p=0.022) adjusting for caregivers’ baseline suicidal ideation, relationship to patient, and years of education. Conclusions: The more caregivers’ perceive their loved ones’ quality of death to be poor, the more they are at risk for suicidal ideation in bereavement. Improving QOL at the EOL will not only benefit patients but also protect caregivers from suicidal ideation.
Preliminary results of RTOG 0831, a randomized, double-blinded, placebo-controlled trial of tadalafil in the prevention of erectile dysfunction in patients treated with radiotherapy for prostate cancer.
Authors: Bruner Deborah , Pugh Stephanie L. , Pisansky Thomas Michael , Greenberg Richard Evan , Pervez Nadeem , Reed Daniel R. , Rosenthal Seth A , Mowat Rex B. , Raben Adam , Buyyounouski Mark K. , Kachnic Lisa A.
Published: March 2020

9525

Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.
Risk perceptions in localized breast cancer (BC).
Authors: Kumar Pallavi , Sepucha Karen , Chang Yuchiao , Belkora Jeffrey , Lee Clara N , Partridge Ann H. , Feibelmann Sandra , Moy Beverly
Published: March 2020

9534

Background: Risk perceptions (RP) play an important role in decision making in localized BC. Little is known about RP in the context of adjuvant (adj) therapy decisions. We examined the accuracy of estimate of absolute benefit of adj therapy among patients (pts) with localized BC and sought to identify determinants of accurate RP. Methods: A cross-sectional survey was conducted in localized (Stage I-III) BC pts within 3 months after surgery at 4 U.S. cancer centers. Pts completed the Decision Quality Instrument, which includes items on BC knowledge, numerical estimates of benefit of adj therapy, and communication with providers. We analyzed pts with Stage I/II and calculated objective estimates of benefit of adj therapy using Adjuvant! Online. Based on published data, an estimate that was +/- 5% of the calculated risk was considered correct. We used multivariable (MV) regression to identify determinants of accuracy including tumor stage, age, adj treatment, education, total knowledge score, and decision involvement. Results: 192/249 (77.1%) pts completed the survey; analyses were limited to 166 pts stage I/II with complete risk estimate data. Mean age was 56.4 years (SD 12.1), 83% of respondents were white, and 58.5% were college graduates. 56.3% had stage I and 43.7% had stage II disease. Most (95.6%) had some type of adj therapy, either endocrine therapy only (43.2%), chemotherapy only (15.3%), or both (32%). On average, pts estimated the absolute benefit of adj therapy to be 31.8% (SD24.9), and this varied by stage (28.4 and 35.9 for stage I and II, p=0.06). The overall estimate for this sample from Adjuvant! Online was 11.8% (SD 7.67) and this varied by stage (8.6/16.0 for stage I/II respectively, p<0.001). Few pts (18.1%) had accurate estimates and the majority (68.3%) overestimated the benefit. In MV logistic regression analysis, only BC knowledge score was associated with accurate estimate of benefit (OR 1.36 95%CI 1.04, 1.8). No other factors were significantly associated with accuracy. Conclusions: Pts with localized BC overestimated the absolute benefit of adj therapy by an average of 20 percentage points. Some pts may be taking on risks of adj therapy without accurate knowledge of the benefits, calling into question whether these decisions are truly informed.
Comparison of toxicity experienced by elderly (E) and younger (Y) patients in breast cancer (BC) clinical trials.
Authors: Mariano Caroline Joy , Francl Mia Ivy , Lim Howard John , Pope Janice , Wong Linda , Lohrisch Caroline A.
Published: March 2020

9542

Background: E patients (pts), age 65 and older, form a large percent of BC pts, but are under-represented in trials, due to actual/perceived frail health, or actual/perceived greater potential toxicity from therapy (rx). With ethics approval, we examined whether E pts had more toxicity than Y pts (< 65 years) in clinical trials. Methods: All BC phase II and III drug trials open from 1999 to 2012 at British Columbia Cancer Agency Vancouver Center were reviewed, excluding trials with only premenopausal pts. Adverse events (AE) were captured from case report forms and charts. The primary endpoint was meaningful toxicity (MTOX), defined as any grade 3 or 4 AE; any AE with dose delay or reduction; or premature discontinuation of rx. Frequencies of MTOX were compared using chi-square tests, means were compared with T-tests. Results: Among 46 trials enrolling 799 pts, rx types were chemotherapy ([CT], 18% of pts), hormone ([HT] 40%), skeletal ([ST] 14%), targeted ([T] 14%]) and CT + T (14%). Pts were 19% E (age range 65-84) and 81% Y (age range 25-64). E pts were more likely to enroll in HT and ST trials; Y pts were evenly distributed among all rx types. Toxicity data (Table) was available for 778 pts (97%). Conclusions: In non CT trials, E and Y pts had similar frequency and number of MTOX. Few E (5%) enrolled in CT trials, but with no more MTOX than Y pts. Discontinuation of rx was equal in E and Y, considering all rx types. Appropriate selection of E pts by eligibility criteria, self selection, and/or clinician assessment allows safe participation of E pts in BC trials. Fear of increased MTOX should not exclude fit E pts from trial participation. [Table: see text]
Local tumor control and survival outcomes of percutaneous radiofrequency ablation plus post-ablation chemotherapy for lung tumors in nonsurgical patients: A meta-analysis.
Authors: Andrew Peter , Jerat Sandra , Valdes Mario , Lee-Ying Richard M. , O'Connor Stephen
Published: March 2020

9550

Background: Local recurrence is a frequent outcome post radiofrequency ablation (RFA) for local control of lung tumors. We sought to examine local tumor control and survival benefits of RFA plus post-ablation chemotherapy versus RFA alone for management of lung tumors in non-surgical patients. Methods: Search strategy: MEDLINE, the Cochrane Library, and EMBASE databases from January 2000 to December 2012. Inclusion criteria: RFA +/- post-ablation chemotherapy in non-surgical patients with solid lung tumors. Exclusion criteria: Post-RFA radiation therapy, biologics, brachytherapy, or other ablation modalities. Outcomes: Local tumor progression (LTP), overall survival (OS), and disease-free survival (DFS) at 12 month follow-up. Statistical analysis: Fixed effect analyses, bias assessment, and sensitivity analyses (BioStat Inc., NJ, USA). Results: RFA plus post-ablation chemotherapy group: 11 clinical studies, 684 patients (mean age 64 years [range 50 to 74]; 434 men, ECOG ≤2), ablation of 1,314 lung tumors, with a 4:1 ratio being <3cm versus ≥3cm in diameter, and a 1:4 ratio being primary versus metastatic. RFA alone group: 38 clinical studies, 1,874 patients (mean age 65 years [range 49 to 75]; 1,041 men, ECOG ≤2), ablation of 2,604 lung tumors, with a 2.1:1 ratio being <3cm versus ≥3cm in diameter, and a 1:1 ratio being primary versus metastatic. RFA plus post-ablation chemotherapy versus RFA alone: LTP of 15% over median follow-up of 31 months [range 12 to 59]) versus 19% over median follow-up of 21 months [range 12 to 29]); OR 0.73 (95% CI: 0.61-0.86, p<0.05) at 12 month follow-up. OS was 89% versus 78%, respectively, at 12 month follow-up; OR 1.52 (95% CI: 1.16-2.00, p=0.003). DFS was 90% versus 82%, respectively, at 12 month follow-up; OR 3.18 (95% CI: 2.04-4.96, p<0.05). Sensitivity analyses were robust, publication bias relatively narrow, and heterogeneity within acceptable limits; Q statistic<21; p>0.13 for all outcomes. Conclusions: This meta-analysis reveals that RFA plus post-ablation chemotherapy of lung tumors yields improved outcomes in terms of LTP, OS, and DFS compared with RFA alone.
Gender differences in comprehensive geriatric assessment (CGA): Results from the IN-GHO registry.
Authors: Honecker Friedemann , Bokemeyer Carsten , Kallischnigg Gerd , Huschens Susanne , Wedding Ulrich ,   on behalf of the IN-GHO Advisory Board
Published: March 2020

9553

Background: Elderly cancer patients (pts) are a heterogeneous population. As chronological age does not provide sufficient information on individual limitations and resources, a CGA helps to describe the heterogeneity in a structured way. Assessment instruments might be sensitive to gender differences. We therefore analyzed the IN-GHO registry for gender associated differences in results of CGA. Methods: The internet based IN-GHO registry prospectively collects data of elderly cancer pts from > 100 centres in Germany and Austria. Data from 1,580 pts aged 70+ years were analyzed comparing results between female (n=883) and male (n=697) pts by Chi-square or Mann-Whitney U test. Analyses included results from CGA, physicians´ rating (fit vs. compromised vs. frail) and pts´ self rating of fitness for treatment (Likert scale 1 = very fit to 6 = very unfit), type (combination vs. monotherapy vs. no), and dosage (full vs. adapted) of treatment. Results: Mean age was 76.7 years (range 70-97), 71.5% had a solid tumor, and 28.5% a hematological malignancy. Mean age was slightly but significantly higher in women than in men (76.9 vs. 76.4; p=0.02), reflected in a higher number of pts. aged 80+ (26.5% vs. 21.1%; p=0.013). No gender differences were observed in physicians´ rating and pts´ self rating of fitness for therapy, or in type or dosage of treatment. Furthermore, no gender associated differences were noted in Karnofsky-Performance-Scale, comorbidity (Charlson-Comorbidity-Score), polypharmacy, and cognition (Mini-Mental-Status-Examination). Gender associated differences, however, were noted in body mass index (more women in categories <19 and >35), mean ADL (91.7 vs. 93.4, p=0.03), mean IADL (6.9 vs. 6.7 (p=0.049), and timed-up-and-go test (< 10 seconds 36.1% vs. 43.6%, p=0.005). The main differences between women and men in ADL and IADL scores were noted in the item bathing (ADL) and food preparation, housekeeping, and laundry (IADL). Conclusions: The internet based registry is a valuable tool to gain data on prognostic factors, treatment, and outcome in old cancer pts. In several items of CGA, significant differences exist between women and men.
A prospective study examining PROs and other geriatric outcomes in older adults with prostate cancer undergoing chemotherapy.
Authors: Manokumar Tharsika , Aziz Salman , Rizvi Faraz , Breunis Henriette , Joshua Anthony Michael , Tannock Ian , Alibhai Shabbir M.H.
Published: March 2020

9555

Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy improves disease control and survival in older men (age 65+) based on large clinical trials. Its effects, though, on more frail elderly men are not well understood and chemotherapy may negatively impact frailty, daily function, physical performance, and quality of life (QOL), particularly outside the clinical trial setting. Methods: Men aged 65+ with mCRPC starting first-line chemotherapy were enrolled in this prospective observational pilot study. Physical function was assessed with the timed up and go (TUG) test, timed chair stands, and grip strength. Frailty was evaluated using the Vulnerable Elders Survey (VES-13) questionnaire in addition to functional status (OARS-IADL), social activities limitations and social support (MOS measures). Patients completed the FACT-P and FACT-G to measure prostate-specific QOL and general QOL, respectively. Assessments were completed before each cycle of chemotherapy. Pre-post within-group comparisons were done using student’s T-tests and linear regression. Results: 25 patients (mean age 75) receiving Docetaxel + Prednisone were enrolled, 3 of whom died and 2 dropped out. Both general and prostate-specific QOL improved over a median of 6 cycles. Patients’ instrumental activities of daily living (IADL) scores remained stable. On average, grip strength was stable and lower extremity function improved on both the TUG and Timed Chair Stands. At baseline, 13 of 25 patients (52%) were frail (VES score 3+). Of the patients that completed chemotherapy, 40% were frail. Conclusions: Contrary to our hypotheses, QOL did not decline in this frail elderly cohort, IADL function remained stable, and physical function remained stable or improved during first-line chemotherapy. Frailty also did not increase at the end of treatment as hypothesized. Older men with mCRPC appear to tolerate first-line chemotherapy fairly well in terms of QOL and geriatric domains.
Outcomes of severe sepsis in very elderly (age >80 years) patients with metastatic cancer.
Authors: Touqir Zahra , Shaheen Shagufta , Upadhyay Shivanck , Marak Creticus Petrov , Kumar Gagan , Guddati Achuta Kumar
Published: March 2020

9558

Background: With better treatment and prolonged life expectancy of cancer patients, more elderly patients with metastatic cancer are being treated aggressively for sepsis. There has been philosophical debate about how aggressive the treatment should be for very elderly patients with metastatic disease admitted to intensive care unit with severe sepsis. The data with regards to the outcome of severe sepsis in those above 80 years with metastatic disease is very limited. Methods: Using the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample 2007-2008, patients older than 80 years, discharged with severe sepsis were identified using ICD-9-CM codes. Those with metastatic disease were identified using ICD-9-CM codes 196-199. The outcomes studied were mortality and discharge disposition. We also examined the rates of invasive mechanical ventilation, blood transfusion, use of central venous catheter, tracheostomy and dialysis. The outcomes were compared to those who did not have cancer. Chi square test was used to compare the variables. Significance was defined as p value <0.05. Results: There were 458,443 discharges with severe sepsis in patients aged ≥80 years. Of these 3.3% had metastatic disease. The in-hospital mortality was significantly higher in those with metastatic disease (43.7% vs. 33.3%, p<0.001). The discharge disposition of the very elderly is shown in the Table. The rates of invasive mechanical ventilation, tracheostomy, use of central venous lines and dialysis were similar in both the groups. Blood transfusions were observed to be higher in metastatic group. Conclusions: Resource utilization in elderly with severe sepsis is similar regardless of the presence of metastatic disease. However, the mortality is significantly higher in those with metastatic disease. Of the survivors, only a fraction reaches home with independent functioning. Involvement of palliative care services at an early stage and addressing code status promptly during the beginning of each hospitalization may help relieve resource and financial burden to health care providers. [Table: see text]