bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-GD2 immunotherapy in adults with high-risk neuroblastoma (HR-NB): The Memorial Sloan Kettering Cancer Center (MSKCC) experience.
Authors: Suzuki Maya , Kushner Brian H. , Kramer Kim , Basu Ellen M. , Roberts Stephen S. , LaQuaglia Michael P , Cheung Nai-Kong V. , Modak Shakeel
Published: September 2018

10550

Background: The diagnosis of NB in adulthood is rare and little is known about its biology and clinical course. There is no established therapy for adult NB. Anti-GD2 immunotherapy is now standard in children with HR-NB but its use has not been reported in adults. Methods: After obtaining IRB waiver, records of all patients with adult-onset (≥18 years) NB seen at MSKCC between 1983 and 2015 were reviewed. Overall survival (OS) was tested by log-rank test. Cox-regression was used for multivariate analysis. Results: The subjects were 42 adults (median: 25; range18-71 years); 23 male and 19 female. Five, 1, 1 and 35 patients had INSS stage 1, 2, 3 and 4 disease, respectively. Genetic abnormalities included somatic ATRX (59%) and ALK mutations (43%) but not MYCN-amplification. 16 patients remain alive at a median follow-up of 5.3 years. OS for non-stage 4 patients was superior to stage 4 (median survival 14.6 vs 5.3 years; p < 0.05). However 5/7 patients with < stage 4 NB progressed to stage 4. Among 35 stage 4 patients, 4 achieved complete remission (CR) after induction chemotherapy and surgery, 11 underwent autologous stem cell transplant (ASCT) and 15 received multiple cycles of anti-GD2 antibodies 3F8 or hu3F8 without complications. In univariate analysis, patients ≤ 29 years old (n = 24) at diagnosis, those achieving CR, and those receiving anti-GD2 antibodies had superior OS (p < 0.05 for each). ASCT was not beneficial (p = 0.3 for ASCT vs no ASCT). For stage 4 patients, anti-GD2 immunotherapy was associated with favorable OS in multivariate analysis (95% CI of anti-GD2 antibody: 1.270 to 7.990). Conclusions: Adult-onset stage 4 NB demonstrates a high incidence of somatic mutations and is only partially chemosensitive. However, 3F8/hu3F8-based anti-GD2 immunotherapy appears to improve long-term survival and is well tolerated.
Neuroblastoma metastatic to the central nervous system: Survival analyses from the German Childhood Cancer Registry and the literature.
Authors: Berthold Frank , Hömberg Marc , Baadsgaard Ole
Published: September 2018

10555

Background: Therapeutic innovation has resulted in an overall decline in childhood neuroblastoma (NB) mortality; however, metastatic NB to the central nervous system (CNS NB), which has emerged as a sanctuary site for NB metastases, remains difficult to treat and is typically fatal. The objective of this study was to describe the natural course of CNS NB. Methods: Data were sourced from a custom query of the German Childhood Cancer Registry (GCCR) and from the literature. Survival statistics were prepared from a diverse, thus generalizable, pool of CNS NB patients. Data are presented as secondary event-free and overall survival (EFS and OS) after diagnosis of first CNS recurrence from initial high-risk NB. Results: The GCCR query identified 85 patients with CNS NB diagnosed from 1990–2010, including 57 with isolated CNS disease. The median (95% confidence) EFS and OS times were 2.6 (1.5–3.8) and 4.7 (2.1–7.2) months, respectively, for all CNS NB patients, and 2.8 (1.4–4.1) and 6.8 (2.1–11.5) months, respectively, for isolated CNS NB patients. Secondary OS at 12, 18, and 36 months was 29.4%, 18.8%, and 8.2%, respectively, for all CNS NB patients, and 35.1%, 22.8%, and 12.3%, respectively, for isolated CNS NB patients. Thirteen publications were selected with 83 patients treated from 1979–2013. In addition to an inclusive analysis, a restricted analysis was performed, excluding patients who did not receive therapy with curative intent, to assess survival after therapeutic intervention. Median OS (95% confidence) was 5.6 (3.0–8.0) and 8.7 (5.8–11.0) months in the inclusive and restricted analyses, respectively. The proportion of patients surviving 12, 18, and 36 months at reporting were 24%, 12%, and 3.6%, respectively, for the inclusive population, and 33%, 17%, and 5%, respectively, for the restricted population. Conclusions: An assessment of the natural course of CNS NB from two sources arrived at similar conclusions with respect to overall and long-term survival. In general, median secondary OS is < 6 months and < 10% of patients survive 36 months. The findings were consistent across geographic regions and have not changed appreciably in 4 decades.
Apatinib for patients with unresectable high-grade osteosarcoma progressing after standard chemotherapy: A multi-center retrospective study.
Authors: Yu Wenxi , Yu Xiuchun , Wu Sujia , Tang Lina , Zheng Shui'er , Zhou Yan , Huang Yujing , Qian Guowei , Li Hongtao , Zhang Jianjun , He Aina , Wang Yonggang , Hu Haiyan , Lin Feng , Shen Zan , Yao Yang
Published: September 2018

11031

Background: Prognosis for patients with relapsed/metastatic osteosarcoma is dismal and the optimal treatment strategy remains to be refined. Sorafenib and sorafenib plus everolimus are the only two second-line targeted therapies recommend by FDA. The median progression-free survival (PFS) was 4–5 months. In this study, the efficacy and safety of apatinib, another oral tyrosine kinase inhibitor targeting VEGFR-2, were evaluated in patients (pts) with inoperable high-grade osteosarcoma progressing after standard multidisciplinary treatment. Methods: This retrospective study reviewed the medical records of 26 pts with metastatic osteosarcoma who received apatinib at a dose of 500 mg qd or 250 mg bid after failure of standard treatment including doxorubicin, cisplatin, ifosfamide and high-dose methotrexate from Jul 2015 to Nov 2016. Results: Among all pts, 25 (96.2%) had pulmonary metastases and 4 (15.4%) had metastases in the bone (Table). Eleven pts achieved partial response, 10 stable disease and 5 progressive disease, yielding an objective response rate of 42.3% and a clinical benefit rate of 80.8%. Followed up to Dec 31 2016, the median PFS was 8 months (95%CI, 3.2–12.8 months), and the median overall survival (OS) was not reached. The 12-month PFS and OS rates were 22.5% (95%CI, 1.6%–58.1%) and 68.7% (95%CI, 37.5%–86.5%), respectively. Noteworthy, the 12-month PFS rate for patients treated with apatinib in the second-line setting was 51.3% (95%CI, 9.1%–83.1%). The most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (HFSR) (84.6%), hypertension (46.2%), and diarrhea (23.1%). Severe AEs included grade 3 HFSR (7.7%) and hypertension (3.8%). No unexpected AE was found. Conclusions: Apatinib was well tolerated and demonstrated activity as a second- or later-line treatment in patients with metastatic osteosarcoma, which deserves further investigations. [Table: see text]
Novel germline risk loci in familial melanoma (FM).
Authors: Kazlow Esther , Ferguson Robert , Simpson Danny , Martinez Carlos N. , Vogelsang Matjaz , Moran Una , Lee Yesung , Osman Iman , Polsky David , Kirchhoff Tomas
Published: September 2018

1535

Background: While about 10% of cutaneous melanoma (CM) clusters in families, known high-risk loci explain not more than 40% of expected inherited risk. Besides the most frequently mutated genes in FM (e.g. CDKN2A), it is estimated that the remaining 60% of FM susceptibility is due to the interaction of environment with specific pools of rare known loci and yet unknown high-risk genes. In our study, we report the discoveries of novel germline genetic risk factors in FM in a recently developed FM cohort at New York University Langone Medical Center (NYULMC) consisting of CM and multiple primary melanomas (MPM) of Ashkenazi Jewish (AJ) and non-AJ European ancestries. Methods: As part of an ongoing ascertainment of FM at NYULMC, we assessed the status of CDKN2A mutations using Sanger sequencing, examining the coding regions of 47 AJ FM families and 81 non-AJ FM kindreds. In high-risk mutation-negative families, we applied whole-exome sequencing (WXS) and an innovative hot-spot mutational analysis of non-coding regions to identify novel high-risk loci associated with FM susceptibility. Results: We found that frequencies of CDKN2A deleterious mutations in our FM cohort (13%) are comparable with observations from previous studies. We have also identified a specific CDKN2A coding mutation in FM kindreds of AJ ancestry, which is particularly interesting as CDKN2A mutations in AJ cohorts have been sparsely reported in prior studies. The WXS/targeted non-coding sequencing of mutation-negative families identified putatively deleterious mutations in regulatory regions in the vicinity of several novel loci, including SMAD4 and PAX8, co-segregating in FM kindreds. Conclusions: Our unique FM ascertainment, including > 50% AJ kindreds, provides an excellent platform for mapping high-risk genetic susceptibility in FM. Novel deleterious mutations identified in non-coding regulatory regions of SMAD4 and PAX8 genes, some with increased frequency in AJ families, suggest a need for a more thorough investigation of the non-coding genome using a founder FM population, as we propose here. As our ongoing ascertainment expands, we are pursuing validation of our observations through comprehensive sequencing efforts.
Effects of physical condition and body composition on cancer risk in a nationwide cohort of 31,158 men from Finland.
Authors: Sormunen Jorma Tauno Juhani , Arnold Melina , Soerjomataram Isabelle , Pukkala Eero
Published: September 2018

1565

Background: Regular physical activity seems to protect men from colorectal cancer and possibly also from prostate cancer. In the case of other cancers the evidence is adding up, and physical activity seems to have a small protective effect to its incidence. The aim of this study was to analyse the effects of physical condition (PC) in early adulthood on cancer incidence later in life. Methods: We collected data on general health, anthropometry and PC for 31,158 Finnish men born in 1958 from the time of their military service between the ages of 17 and 30 years. Using linkage with the Finnish Cancer Registry, all men were followed-up for cancer incidence up to 2014. Results: Overweight and obesity (body mass index (BMI) ≥ 25 kg/m2) were associated with an increased overall cancer risk [hazard ratio (HR): 1.08, 95% confidence interval (CI): 0.89-1.30] when compared to those with BMI < 25 kg/m2. Those with normal weight but bad PC had an increased risk of all cancers combined as compared to those with normal weight and good PC (HR 1.18, 95% CI: 1.01-1.38), which further increased in those who were also overweight (HR 1.30, 95% CI: 1.01-1.69). We noticed an increased overall cancer risk in men in who entered service with minor health problems (HR 1.46, 95% CI 1.19-1.80), when compared to those that were completely healthy. This was especially observed for advanced prostate cancer (HR: 3.35, 95% CI: 1.14-9.90). Increased HRs, yet statistically insignificant, were also seen for colorectal and other obesity-related cancers. Conclusions: Good PC at young age seems to protect men from cancer later in life. Early adulthood obesity, when combined with bad PC, seems to further increase cancer risk.
Anti-cancer effect among patients with familial Mediterranean fever: Outcome of 258,803 person-years analysis.
Authors: Brenner Ronen Mordechay
Published: September 2018

1566

Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease that causes recurrent serosal inflammation. The association between FMF and malignancy has not been previously described. We estimated cancer risk in a large single-institution cohort of FMF patients. Methods: The study cohort consisted of 8,534 FMF patients registered in the Israel National FMF Center at Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and stratified by age and gender. Standardized incidence ratios (SIR) for cancers were calculated. Results: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. Overall cancer risk among patients with FMF was significantly lower than that expected in the following gender and population groups, based on cancer incidence rates in those groups in the Israeli population: males of Jewish ethnicity SIR 0.66, CI 95% [0.55-0.77], p< 0.001; females of Jewish ethnicity SIR 0.75 CI 95% [0.64-0.86], p< 0.001; males of Arabic ethnicity SIR 0.34, CI 95% [0.07-0.99], p= 0.024. Conclusions: FMF patients have a significantly lower incidence of cancer than the general population. This pattern was demonstrated in two different ethnic populations, Jewish and Arabic. We speculate that the lower cancer incidence could be attributed to the direct physiological effect of FMF or to the anti-FMF treatment.
RNA-Seq analysis of glioma tumors to reveal targetable gene fusions.
Authors: Subramaniam Deepa Suresh , Xiu Joanne , Mehta Shwetal , Gatalica Zoran , Swensen Jeffrey , Sanai Nader , Heimberger Amy B.
Published: September 2018

2019

Background: Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. We aim to use RNA-sequencing to interrogate a large cohort of gliomas for targetable genetic fusions. Methods: Gliomas were profiled using the ArcherDx FusionPlex Assay at a CLIA-certified lab (Caris Life Sciences) and 52 gene targets were analyzed. Fusions with preserved kinase domains were investigated. Results: Among 404 gliomas tested, 39 (9.7%) presented potentially targetable fusions, of which 24/226 (11%) of glioblastoma (GBM), 5/42 (12%) of anaplastic astrocytoma (AA), 2/25 (8%) of grade II astrocytoma and 3 of 7 (43%) of pilocytic astrocytoma (PA) harbored targetable fusions. In GBMs, 1 of 15 (6.7%) IDH-mutated tumors had a fusion while 22 of 175 (12.6%) IDH-wild type tumors had fusions. 46 oligodendroglial tumors were profiled and no fusions were seen, which was lower than frequency of fusions in astrocytic tumors (34/300, p = 0.0236). The most frequent fusions seen involved FGFR3 (N = 12), including 10 FGFR3-TACC3 (1 AA, 6 GBM and 3 glioma NOS); 1 FGFR3-NBR1 (AA) and 1 FGFR3-BRAP (GBM). 11 fusions involving MET were seen, 10 in GBM and 1 in AA. The most common MET fusion was PTPRZ1-MET (1 in AA and 4 in GBM), followed by ST7-MET (N = 3, GBM), CAPZA2-Met (N = 2, GBM) and TPR-MET (N = 1, GBM). 8 NTRK fusions were seen; 1 involving NTRK1 (BCAN-NTRK1, PA), 6 NTRK2 (1 NOS1AP-NTRK2 in AA; GKAP1-NTRK2, KCTD8-NTRK2, TBC1D2-NTRK2 and SOSTM1-NTRK2, 1 each in GBM and 1 VCAN-NTRK2 in grade II astrocytoma) and 1 NTRK3 (EML4-NTRK3 in GBM). EGFR fusions (2 EGFR-SEPT14 and 1 EGFR-VWC2) were seen in 3 GBMs, BRAF in 3 (1 KIAA1549-BRAF, 1 LOC100093631-BRAF in PA and 1 ZSCAN23-BRAF in glioma NOS) and PDGFRA (RAB3IP-PDGFRA, in GBM) in 1. C11orf95-RELA fusions were seen in 2 of 3 grade III ependymomas but not in the 2 grade II ependymomas. Conclusions: We report targetable fusion genes involving NTRK, MET, EGFR, FGFR3, BRAF and PDGFRA including novel fusions that haven’t been previously described in gliomas (e.g., EGFR-VWC2; FGFR3-NBR1). Fusions were seen in over 10% of astrocytic tumors, while none was seen oligodendrogliomas. Identification of such kinase-associated fusion transcripts may allow us to exploit therapeutic opportunities with targeted therapies in gliomas.
Epidemiologic study of risk factors for meningioma in the Mayo Clinic Study of Aging.
Authors: Butts Alissa , Syrjanen Jeremy A. , Aakre Jeremiah , Brown Paul D. , Jack Clifford R. , Petersen Ronald C. , Roberts Rosebud O. , Cerhan Jane H
Published: September 2018

2067

Background: An estimated 2% of the general population has a meningioma (Vernooij et al. 2007), which accounts for about 36% of all primary intracranial tumors (Ostrom et al. 2015). The most established risk factors are older age and female gender. One small study identified gender but no other risk factors with meningioma (Krampla et al 2004). A larger study using the Iowa Women’s Health study data found lower levels of physical activity, greater body mass index (BMI), greater height and uterine fibroids were associated with meningioma (Johnson et al. 2011). We sought to replicate these findings and to identify additional risk factors related to meningioma in a large population-based sample. Methods: Study participants were enrolled in the Mayo Clinic Study of Aging (MCSA), a population-based sample of Olmsted County, Minnesota residents used to study prevalence, incidence, and risk-factors for Mild Cognitive Impairment and dementia and includes a variety of medical factors. Using a text search of radiologists’ notes of 2,402 MCSA individuals, mean age 77±8 years and scanned between 2004-2014.We identified 52 subjects who had at least one meningioma. We estimated the association of selected potential risk factors with presence of meningioma using odds ratios and 95% confidence intervals from logistic regression models adjusted for age and gender, which informed the multivariable models. Results: In the initial models, significant risk factors identified included BMI (as a continuous variable) (OR = 1.06 95%CI 1.01 to 1.12), taking NSAIDS (OR = 2.11, 95%CI 1.13 to 3.95), aspirin (OR = 1.90, 95%CI 1.04 to 3.46), and blood pressure lowering medication (OR = 2.06, 95%CI 1.07 to 3.99). Protective factors included male gender (OR = 0.51, 95%CI 0.29 to 0.90), coronary artery disease (CAD; OR = 0.46, 95%CI 0.22 to 0.97) and higher Beck Anxiety Inventory (BAI) total score (OR = 0.88, 95%CI 0.78 to 0.98). Simultaneous adjustment for these factors in a multivariable model did not attenuate these associations. Conclusions: Findings reveal gender and BMI as risk factors for meningioma. Additionally, certain medications such as NSAIDS and BP lowering medications warrant follow up as potential factors related to development of meningioma.
A phase I trial of TRC102 (methoxyamine HCl) with temozolomide (TMZ) in patients with solid tumors and lymphomas.
Authors: Meehan Robert S. , O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Collins Jerry M. , Anderson Larry , Zlott Jennifer , Juwara Lamin , Takebe Naoko , Piekarz Richard , Streicher Howard , Sharon Elad , Conley Barbara A. , Rubinstein Larry , Wilsker Deborah , Dull Angie B , Ferry-Galow Katherine V. , Kinders Robert J. , Parchment Ralph E. , Doroshow James H. , Chen Alice P.
Published: September 2018

2518

Background: TRC102 inhibits BER by binding to abasic sites and acting as a topo II poison to cause DNA strand breaks; it potentiates the activity of alkylating agents including TMZ in murine models. In xenograft studies, TRC102 efficiently enhanced the antitumor effect of TMZ regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA-methyltransferase, mismatch repair (MMR), or p53 status. This is the first report for the expansion phase (the escalation phase was reported previously (ASCO2016)). Methods: We conducted a phase 1 trial of TRC102with TMZ in patients (pts) with refractory solid tumors. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. TRC102 and TMZ were given orally days 1-5, in 28-day cycles. The pharmacokinetic and pharmacodynamic profile of TRC102 with TMZ was evaluated. Antitumor responses were determined using RECIST 1.1 criteria. The DNA damage response (DDR) markers γH2Ax, pNbs1, and Rad51 were evaluated in the expansion cohort at DL6, tested by previously described methods on paired tumor biopsies prior to and after the first course of therapy. Results: After the recommended Phase 2 Dose was defined as DL6 (TRC102 125mg, TMZ 150mg/m2 D1-5), 15 pts were accrued to the expansion cohort between 9/2015 to 11/2016. A total of 52 pts were enrolled (37 escalation, 15 expansion). Grade 3/4 adverse events included neutropenia (13%), anemia (the DLT;10%), thrombocytopenia (7%), hemolysis (5%) or hypophosphatemia (3%). 4 pts had a partial response (PR) (NSCLC, ovarian (2), and colon); 13 pts had stable disease (SD), 29 progressive disease (PD), and 6 were not evaluable; three pts remain on study. 11/14 paired biopsies were suitable for analysis. Rad51 signal was induced in 6/11pts. One patient showed γH2Ax and 2 showed pNbs1 induction. 4/5 colon cancer specimens had evidence of DDR marker induction. Conclusions: The combination of TRC 102/TMZ is active with 4 PRs and 13 SDs, and the side effect profile is manageable. DDR markers were induced in 4 of 5 paired colon biopsies indicating DNA damage following treatment. A phase 2 trial of patients with colon cancer, NSCLC, and granulosa cell ovarian cancer is accruing. Clinical trial information: NCT01851369.
Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU.
Authors: Ackland Stephen P. , Garg Madhu Bala , Ranson Marie , Jokela Rebecca , Brungs Daniel , Aghmesheh Morteza , Tafreshi Ali , Ranson Richard David , Parker Suzanne , De Souza Paul L. , Clingan Philip R.
Published: September 2018

2530

Background: Simultaneous administration of 5-fluorouracil (5FU) and leucovorin (LV) is generally not feasible as 5FU and LV are chemically incompatible (CaPO4 crystals), so the maximum possible interaction for benefit is not achieved. Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at pH 7, was developed to overcome this problem. Methods: Limited sampling PK was done with dose 1 and 6 in a standard 3+3 phase I trial of Deflexifol given in two schedules (46-h infusion Q2W or bolus weekly x6) with no intrapatient dose escalation, at doses shown in Table. Sample times were infusion: 0, 2, 46h; bolus: 0, 0.2, 0.4, 1, 24h. 5FU and dihydroFU were measured as per Ackland et al, Anal Biochem 1997. 5FU AUC, clearance (CLR) and t1/2 were estimated for each patient to assess PK variability and adequacy of dosing compared to previous reports. Results: 40 patients were treated (21 infusion, 19 bolus, median age 67, 19 M, 21 F). The MTD(bolus) was 575 mg/m2, with no DLT in infusion schedule to 3600 mg/m2. PK showed substantial inter-patient variability – CLR(bolus) 21-900 L/h, t1/2 0.11-0.52 h, with intra-patient dose 6 CLR = 54-117% of dose 1, and a trend to increased AUC (mg/L.h) with dose (Table). Infusion CLR and AUC estimates were highly variable (CLR range 2-1200), with many cases with insufficient data. Compared to historical data with 5FU alone, AUC was likely subtherapeutic until 475mg/m2 bolus and for many patients with infusion <3000mg/m2. Conclusions: 5FU PK with Deflexifol is similar to 5FU alone. No evidence of saturation of kinetics over this dose range was seen, or induction of metabolism with repeated dosing. In each schedule AUC data supports the clinical impression of reduced toxicity at the same dose of 5FU. Accurate estimation of infusion PK requires more than 2 timepoints. PK in a phase II study is planned. Clinical trial information: 044867. [Table: see text]
Association of liver metastases (LM) with survival in NSCLC patients treated with durvalumab (D) in two independent clinical trials.
Authors: Paz-Ares Luis G. , Shen Kui , Higgs Brandon W. , Morehouse Chris , Rizvi Naiyer A. , Segal Neil Howard , Jin Xiaoping , Zheng Yanan , Narwal Rajesh , Gupta Ashok Kumar , Dennis Phillip A. , Mukhopadhyay Pralay , Ranade Koustubh
Published: September 2018

3038

Background: Immunotherapies have improved survival in NSCLC but not all pts benefit. Besides baseline PDL1 expression, routinely measured clinical factors may predict clinical outcomes in immunotherapy trials. LM are associated with poor prognosis in melanoma and bladder cancer pts treated with anti-PD1/L1, respectively. We examined correlation between pretreatment LM and survival in D-treated NSCLC pts. Methods: CP1108/NCT01693562 and ATLANTIC/NCT02087423 were nonrandomized phase 1/2 and 2 trials, respectively, of D 10 mg/kg Q2W in advanced NSCLC. As of Oct 24/Jun 3 2016, 304/265 primarily pretreated pts were enrolled in CP1108/ATLANTIC Cohort 2. Cox proportional hazards analysis was conducted, first among LM+/− pts, then LM+/− and PDL1 high/low pts. Both models accounted for tumor stage, ECOG/WHO PS, histology, sex, age, smoking and PDL1 status. PDL1 high was defined as ≥25% tumor cells immunostained for PDL1 at any intensity. Results: LM absence was a positive independent predictor of OS and PFS in both trials. LM− and PDL1 high or low pts had improved OS and PFS vs PDL1 low/LM+; PDL1 high/LM+ pts had improved PFS vs PDL1 low/LM+. An independent tumor kinetic model indicated LM as a predictive covariate of rapid tumor growth in D-treated pts. Conclusions: LM are associated with shorter survival in D-treated NSCLC pts in 2 trials irrespective of PDL1 status. Clinical trial information: NCT02087423 and NCT01693562. [Table: see text]
A phase III trial (ZJBIO009): CMAB009 plus irinotecan versus irinotecan alone as second-line treatment after fluoropyrimidine and oxaliplatin failure in wild-type K-ras metastatic colorectal cancer patients.
Authors: Shi Yuankai , Li Jin , Xu Jianming , Cheng Ying , Liu Wei , Cheng Yigui , Bai Li , Zhang Yiping , He Xiaohui , Luo Yi , Liu Yunpeng , Yao Qiang , Li Yuhong , Qin Shukui , HU Xiaohua , Guo Yajun , Sun Yan
Published: September 2018

3513

Background: More efficient second line treatment regimen for mCRC is urgently needed. CMAB009, a recombinant human/mouse chimeric monoclonal antibody, is specifically targeting human epidermal growth factor receptor. This study aimed to determine clinical efficacy and safety of CMAB009 plus irinotecan compared with irinotecan alone in wild-type K-ras mCRC patients (pts). Methods: This is a open-label, randomized, phase 3 trial. Patients had histologically confirmed wild-type K-ras mCRC, who previous failure of 5-fuorouracil plus oxaliplatin more than 1 month of the last-dose enrolled in study. Pts were randomly assigned on a 2:1 to receive CMAB009 (initial 400mg/m2 on day 1, and then 250 mg/m2 weekly) plus irinotecan (180mg/m2, every 2 weeks) (A arm) or irinotecan alone (B arm). B arm pts could switch to CMAB009 sequential treatment (C arm) on diseas progression. The primary end point was overall response rate (ORR). The secondary endpoints were PFS, OS, DCR, and DOR (NCT01550055). Results: From May 2009 to December 2012, 512 pts were assigned from 38 sites. Efficacy evaluation could be in 501 pts, ORR were 33.2% (112/337) and 12.8% (21/164) in A arm and B arm ( p <0.0001). C arm had 115 pts, DCR was 63.5% (73/115). DOR in A arm and B arm were 210 days and 109 days ( p=0.001). In C arm, DOR was 148 days . Median PFS was significantly longer in A arm than B arm (169 days vs 95 days; p < 0.0001). In C arm, median PFS was 84 days. Median OS was 425 days in A arm and 401 days in B arm ( p=0.94). 96.2% (484/503) pts experienced at least one adverse event (AE). 55.3%(187/338) and 37.6%(62/165) patients in A arm and B arm had at least one grade ≥3 AE respectively. The most common AE included diarrhea, emesis, leucopenia, neutropenia and fatigue. Adding CMAB009 to irinotecan increased the risk of rash (66.6% vs 5.5%, p <0.001) and paronychia (9.8% vs 0,p < 0.001). Conclusions: CMAB009 plus irinotecan significantly increased ORR and prolonged PFS compared with irinotecan alone. CMAB009 plus Irinotecan were efficient and well tolerated, which could be considered as a standard second-line treatment choice in wild-type K-ras mCRC pts. Clinical trial information: NCT01550055.
Early tumor shrinkage (ETS) and depth of response (DpR) in wild-type (WT) RAS tumors from the phase III trial of panitumumab (pmab) plus best supportive care (BSC) versus BSC in chemorefractory metastatic colorectal cancer (mCRC).
Authors: Kim Tae Won , Elme Anneli , Park Joon Ho , Udrea Anghel Adrian , Manojlovic Nebojsa S. , Guan Xuesong , Jung A. Scott , Vrdoljak Eduard
Published: September 2018

3561

Background: Activating RAS mutation is a negative predictor of anti-EGFR therapy. In the final analysis of 20100007, the first phase 3 study to prospectively evaluate efficacy and safety of WT RAS ( KRAS and NRAS exons 2, 3, 4 ) mCRC, pmab + BSC continued to show improved survival (OS and PFS) and ORR. Recent data suggest that tumor burden reduction and ETS may contribute to improved OS. Previous studies have shown that pmab plus chemotherapy results in ETS, which correlates with OS benefit (Douillard et al, EJC, 2015; Rivera et al, JCO, 2015; Mansmann et al, JCO 2013). Here we report analyses of ETS and DpR and the effect on OS in patients (pts) with WT RAS mCRC treated with pmab monotherapy in the ‘0007 trial. Methods: Anti-EGFR naïve pts with WT KRAS exon 2 mCRC were randomized 1:1 to pmab + BSC or BSC. Pt tumors were further evaluated for RAS status, and DpR (percent tumor shrinkage at nadir or progression) and ETS (≥/< 0% or ≥/< 20% by week 8) were analyzed in WT RAS pts. OS and PFS were compared for each ETS group. Results: Of 377 pts with WT KRAS exon 2 mCRC, 270 were WT RAS (142 pmab + BSC, 128 BSC alone). In the pmab + BSC arm, 69.5% and 38.2% of pts had ≥0% and ≥20% ETS, respectively, and median (Q1, Q3) DpR was 16.9% (0%, 37.5%). OS was improved in pts with higher ETS (≥0% or ≥20%) compared with lower ETS (<0% or <20%; Table). Conclusions: In this post-hoc analysis, pmab monotherapy provided any ETS benefit (≥0%) in 69.5% of WT RAS mCRC pts, and ETS was associated with improved PFS and OS. Pmab should be considered both in combination and as monotherapy for its significant impact on OS and also for its ability for substantial ETS in pts with WT RAS mCRC. Validation is necessary to investigate the value and cutoff of ETS in a prospective study. Clinical trial information: NCT01412957. [Table: see text]
Neoadjuvant chemotherapy with mFOLFOXIRI alone for cT4 and fixed cT3 rectal cancer: Results from a single arm phase II study (FORTUNE).
Authors: Zhang Jianwei , Cai Yue , Hu Huabin , Chen Dianke , Xiao Jian , Ling Jiayu , Wenjing Wang , Lan Ping , Wang Lei , Huang Meijin , Wu Xiaojian , Kang Liang , Wang Jianping , Deng Yanhong
Published: September 2018

3607

Background: Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in locally advanced rectal cancer (LARC), it delays administration of systemic chemotherapy. About 30% of patients still developed distant metastases, which is the main obstacle for improving survival of LARC. Besides, preoperative radiation causes lots of concerns about anal and sexual functions. We aimed to explore the efficacy of preoperative chemotherapy with mFOLFOXIRI in LARC rather than consistent use of chemoradiotherapy. Methods: Patients with fixed cT3 or cT4 rectal cancer evaluated by pelvic MRI participated in this trial. All candidates were to receive 4-6 cycles of mFOLFOXIRI. MRI will be performed to assess clinical responses. Patients with stable/progressive disease were to have radiation before surgery, whereas responders were to have immediate total mesorectal excision (TME). Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX was recommended. The primary endpoint is the ratio of tumor downstaging to ypT0-2N0M0.The secondary endpoint included pathologic complete response rate, 3-year disease free survival rate and safety. Results: Between August 2014 and September 2016, 83 patients were enrolled and 80 participants had received TME. Three refused surgery after chemotherapy, because the tumor location is too low to perform sphincter-preserving operation. Of 80 patients completing at least 4 cycles of preoperative chemotherapy, two received short-term radiation before TME, and 10 patients underwent long-term chemoradiotherapy after MRI evaluation. The pCR rate of the whole group was 15 of 80 (18.8%) and the tumor downstaging rate was 43.8%. Among patients without chemoradiotherapy, the pCR rate and tumor downstaging were 14.3% and 41.4%, respectively. And the chemo-related toxicity was all tolerable. Conclusions: Neoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. The result was promising and further phase III study is warranted to validate this experience. Clinical trial information: NCT02217020.
Phase III study of individualized intraperitoneal/intravenous/oral chemotherapy compared with standard intravenous/oral chemotherapy in patients with advanced gastric cancer.
Authors: Yang Yang , Wei Jia , Du Juan , Yu Lixia , Qian Hanqing , Yang Yan , Qian Xiaoping , Liu Baorui
Published: September 2018

4021

Background: Tumor mRNA expression levels may have a promising role as potential predictive biomarkers for chemotherapy. Intraperitoneal (IP) chemotherapy provides sustained high local concentrations, and its efficacy has been shown in ovarian cancer and gastric cancer patients with peritoneal metastasis. We developed a regimen combining IP/intravenous(IV)/oral chemotherapy for the treatment of advanced gastric cancer patients with individualized chemotherapeutics according to mRNA expression. This multicenter phase III study evaluated the efficacy of individualized multi-route chemotherapy compared to standard systemic chemotherapy. Methods: Eligibility criteria included pathologically confirmed advanced gastric adenocarcinoma, and no prior chemotherapy. Patients were randomized 3:1 to an individualized arm (IN) and standard arm (ST). Randomization was stratified by center. Patients in individualized arm first underwent mRNA expression (BRCA1/TOPO1/TS) to choose sensltive chemotherapeutics from oxaliplatin/cisplatin/docetaxel/irinotecan/S-1 and then received individualized IP/IV/oral chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were response rate, progression-free survival (PFS), and safety. Results: Between April 2013 and December 2015, 231 patients were enrolled, and 218 patients were included in the efficacy analysis. Baseline patient characteristics were balanced between the two arms. The median OS for IN and ST were 16.3 and 14.1 months, respectively (adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.61-0.98, p < 0.05). The overall response rate was 44.0% in the IN arm, and 33.9% in the ST arm (p < 0.05). Both regimens were tolerable. Conclusions: The primary analysis showed the statistical superiority of the individualized multi-route regimen. It suggested clinical efficacy of this regimen in patients with advanced gastric cancer. Clinical trial information: ChiCTR-IPR-15006201.
The prognostic role of metastatic lymph node ratio-staging system in gastric cancer patients: Analysis of the National Cancer Database.
Authors: Naffouje Rand , Salti George I.
Published: September 2018

4044

Background: The NCCN recommends retrieval of at least 15 lymph nodes for adequate nodal staging in gastric cancer. There is an ongoing debate about the accuracy of the classification systems for nodal involvement based on the absolute number of positive nodes (AJCC-N) vs. the ratio of positive nodes (rN). In this study, we aim to assess the accuracy of each system in the prediction of 5-year survival using the National Cancer Data Base (NCDB) for gastric cancer. Methods: The database included 168,377 gastric cancer patients between 2004-2014. Patients who were approached with palliative intent, or had metastatic disease were excluded from the analysis. Only patients who had at least one regional node examined were included. A univariate and multivariate regression analysis were conducted to identify significant predictors of the 5-year survival among the perioperative patients’ characteristics. Bayesian Information Criterion (BIC) was used to compare the model fitting when the AJCC nodal staging is applied to that of the ratio nodal staging. Results: 48,126 patients were included in the final analysis. 23,102 (48%) patients had ≥15 nodes examined. The univariate and multivariate regression analysis identified age, male gender, Caucasian race, and presence of comorbidities as significant demographic predictors. TNM T-stage, N-stage, and rN-stage were significant predictors with worsening prognosis as the stage increases. Overall, BIC demonstrated that the model using rN had a better fit (rN = 30321 vs. AJCC-N = 30619). However, subgroup analysis showed that the AJCC-N functioned better when < 15 nodes were examined (rN = 17367 vs. AJCC-N = 17311), whereas rN functioned better when ≥15 nodes were collected (rN = 16776 vs. AJCC-N = 16831). Conclusions: Both AJCC-N and rN are valid systems for nodal staging in terms of survival prediction in gastric cancer. When at least 15 nodes are resected in line with the current NCCN guidelines, the rN staging system for nodal metastasis appears to function more accurately in survival prediction. It might be advisable to consider the ratio of positive lymph nodes when a large number of nodes are collected to avoid over-staging and stage migration.
Long term cardiac outcomes and anthracycline exposure in breast cancer survivors: A retrospective cohort data linkage and competing risks analysis.
Authors: Rust Kelly , Walker Jeremy , Stoker Richard , Wild Sarah , Henriksen Peter , Cameron David A. , Maclennan Marjory , Simpson Maighread , Lilley Christina , Hall Peter
Published: September 2018

553

Background: Anthracycline chemotherapy is used frequently in adjuvant breast cancer treatment but there is clinical trial evidence of cardiac toxicity. Attempts to quantify this risk in routine care have been limited by follow up time & confounding factors. The aim of this project was to exploit rich Scottish NHS datasets for this purpose. Methods: Patients treated surgically for stage I-III invasive breast cancer between 2000 & 2010 were identified from a local cancer database (Edinburgh Cancer Centre). Outcomes were captured by linkage to the Scottish Morbidity & death Records. Follow-up was until March 2016. The primary outcome was a cardiac event or cardiac death, identified from coding. Analysis used the Latouche approach (estimating cause-specific hazards & sub-distribution hazards) for the primary outcome & the competing risks of death from breast cancer & death from other causes. Results were adjusted for age, deprivation (SIMD), co-morbidity (Charlson), year of diagnosis, side of radiotherapy, cancer stage, grade, ER & HER 2 status. Results: 4080 patients were identified, 1658 received an anthracycline containing regime, 297 received non-anthracycline chemotherapy & 2125 received no chemotherapy. A total of 33946 women years were analysed. During median follow up of 8.2 years there were 448 cardiac events & 559 breast cancer deaths. After adjustments there was no association between anthracycline use & cardiac outcomes (HR 0.9, 95% CI 0.67-1.21). There was an increased risk of breast cancer death (HR 1.66, 95% CI 1.28-2.16).Age & Charlson score were associated with an increased cardiac risk. Stage & grade were statistically associated with breast cancer death. Conclusions: No increased risk of cardiac events was seen in women treated with anthracyclines, they can be safely used in carefully selected patients. This data suggests selection may be over-cautious, a lower threshold for treatment may lead to improved breast cancer outcomes. Rich routine health datasets & appropriate analysis methods make outcomes monitoring feasible in Scotland. Oncologists are skilled at assessing both cardiac risk factors & breast cancer risk.
Prediction of radiation therapy response in breast cancer patients.
Authors: Arora Divya , Hasan Salman , Jebakumar Deborah , Munoz Yolanda , Ford John , Ord Celine , Rao Arundhati , Deb Niloyjyoti
Published: September 2018

565

Background: While radiation portals are tailored to a patient’s unique anatomy and the selection of systemic agents routinely employs biomarker data, the selection of radiotherapy based on a patient’s tumor biology is not routinely utilized in breast cancer. The purpose of this study was to identify which genetic markers are possible predictors for local recurrence as a surrogate for radiation response. Methods: We identified 200 patients who received radiotherapy for breast cancer. Selected tumor markers included: Androgen receptor (AR), Hypoxia Inducible Factor 1-α (HIF-1), Phosphotidylinosotol-4,5-bisphosphate 3-kinase (PI3K), and Interleukin 13 (IL-13). Biomarkers were analyzed in terms of “extent” and “intensity” on a scale of 0-3 and scored by 2 separate pathologists. The primary endpoint of local recurrence (LR) & secondary endpoint of overall survival were analyzed using Kaplan-Meier survival curves, log-rank test for differences, and Cox regression models. Results: Median follow up was 7.98 years. At 5 years, the rate of LR was 92.6% and overall survival was 89.4%. On multivariate Cox regression analysis, a one unit increase in IL-13 extent increased the hazard of LR by 73%. A one unit decrease in AR extent increased the hazard of LR by 134%. The hazard of death increased 3.2 times for each unit increase in HIF1 extent. The hazard of death increased 1.5 times for each unit increase in PI3K extent. PI3K extent and intensity was increased, and AR extent and intensity was decreased in triple negative breast cancer (TNBC) (n = 68) vs non-TNBC (p < 0.0001). African Americans had a 4.2 times hazard of LR vs Caucasians. Conclusions: Expression of IL-13 was associated with a higher risk of LR; expression of AR was associated with decreased LR. These two markers may be instrumental in predicting radiation response. If this study is validated, cancers that express more IL-13 may require higher doses or targeted therapy. In contrast, those cancers expressing AR may not require as aggressive therapy. Lastly, PI3K and HIF1 α expression were significant predictors of worse overall survival. The clinical implications of these biologic markers are significant as they may help to guide biologically-driven, personalized breast cancer radiotherapy.
Relationship between out-of-pocket spending and drug value for oral oncolytics reimbursed by commercial insurers: 2007-2014.
Authors: Rotenstein Lisa , Dusetzina Stacie , Keating Nancy Lynn
Published: September 2018

6524

Background: With total and out-of-pocket (OOP) spending for oral oncolytics rising, there is increased interest in choosing oncology treatments based on their clinical value relative to cost. We sought to determine if OOP spending varied for higher versus lower-value oral oncology drugs reimbursed by commercial insurers. Methods: This was a retrospective analysis of commercial insurer prescription drug claims filed between 2007-2014 for 13 oral oncolytics approved before 2009. We calculated mean monthly OOP payments for each patient. We then categorized oral oncolytics by their overall and progression-free survival benefits for each FDA-approved indication, using evidence from published studies. We assessed the relationship of survival benefit with mean monthly OOP payment, adjusting for demographic and plan characteristics. Results: Our population included 44,109 patients ages 18-65 (mean age = 52.5 years, SD = 9.4 years) with a cancer diagnosis who filled 731,261 prescriptions. The most commonly represented oncolytics were imatinib (37.4% of fills) and lenalidomide (17.7% of fills). Approximately 57.6% of fills were for drug-indication pairs with an overall survival benefit of 5+ months. In adjusted analyses, there was no significant difference in mean monthly OOP payment between drugs without evidence of benefit and those with 0-5 months progression-free survival benefit or 5+ months of overall survival benefit (p > 0.05). Meanwhile, drugs with 5-10 months progression-free survival benefit or 0-5 months overall survival benefit had higher OOP payments than those without benefit (p < 0.01). Conclusions: OOP payments for oral oncolytics were not clearly related to indication-specific value. This suggests that despite increased attention to value- and indication-based drug pricing, cost-sharing for oral oncolytics does not currently reflect these goals.
Prevalence and estimated trend in chemotherapy use near death from population-based studies on cancer patients: A systematic review and meta-analysis.
Authors: Chou Pei-Chun , Chen Chen Hsiu , Liu Tsang-Wu , Tang Siew Tzuh
Published: September 2018

6590

Background: Chemotherapy (CMT) use near death, based on US national guidelines, is an indicator of aggressive treatment and poor quality of end-of-life (EOL) care. US law also decreased Medicare payments for outpatient CMT since 2005-2006. To evaluate the impact of US payment reform and guidelines on CMT use at EOL, we estimated and compared the overall prevalence of CMT use at EOL in the US and other countries as well as before and after 2007 in the US. Methods: Six databases were systematically searched to January 2017 for population-based studies of CMT use at EOL for patients in all cancer groups. Two reviewers independently extracted data.Overall CMT use prevalence was pooled by a random-effects model. Differences in prevalence of CMT use were compared by meta-regression between subgroups (US vs non-US countries; before and after 2007 in the US). Results: We identified 9 and 7 articles from the US and non-US countries, respectively. CMT was provided to 28.9% [95% confidence interval (CI) 26.2%-31.8%], 23.2% [95% CI 21.7%- 24.8%], 10.0% [95% CI 8.5%-11.8%], and 4.5% [95% CI 3.9%- 5.2%] of cancer patients in their last 6, 3, and 1 months as well as 14 days of life, respectively. CMT use in the last 6 months was more common in the US than in non-US countries (32.4% vs. 26.2%, p = 0.015) but similar to that of other countries in the last month (9.3% vs.11.2%, p = 0.179) and last 14 days (4.6% vs.5.6%, p = 0.683) of life. Prevalence of CMT use in the last 14 days of life in the US did not differ significantly before and after 2007 (5.1% vs. 5.2%, p = 0.967). Conclusions: Many cancer patients worldwide receive CMT at EOL, and the prevalence of CMT use in US patients’ last 14 days of life was virtually unchanged over time. Effective interventions should be developed and provided to offset the trend of continuing CMT use at EOL.
Prevalence and complications associated with off-label use of lenalidomide in older patients with myelodysplastic syndromes (MDS).
Authors: Brunner Andrew Mark , Weng Shicheng , Cronin Angel M. , Fathi Amir Tahmasb , Stone Richard M. , Graubert Timothy A. , Steensma David P. , Abel Gregory A.
Published: September 2018

7054

Background: Lenalidomide (LEN) is approved for patients with lower-risk MDS with del5q who are transfusion-dependent (TD). We aimed to assess the prevalence and complications associated with LEN use in non-TD older patients with MDS. Methods: Using the SEER-Medicare database we identified Medicare enrollees diagnosed with MDS from 2007-2011. Medicare part D claims were analyzed for evidence of LEN use. CPT, HCPCS, and ICD-9 codes were used to characterize TD MDS (claims for ≥ 2 RBC transfusions within 8 weeks prior to LEN), complications, and baseline risk per SEER-Medicare MDS Risk Score (SMMRS; Uno, Leuk Res 2014). Incident complications during LEN were noted if there were no prior claims for the same within a 1-yr look-back window. Results: Among 469 patients initiating LEN (median age 78 years), 77% received it first-line, and 23% after a hypomethylating agent. Among all, 19% had del5q, 37% had non-del5q MDS, and 44% no histology specified (MDS NOS). SMMRS risk was evenly distributed between low (36%), intermediate (30%), and high (34%). Only 42% of patients were TD at the time of first LEN prescription, and 26% had not been transfused within six months prior to LEN. Non-TD patients receiving LEN were more likely to have lower-risk disease (p = .004), and less likely to have pre-treatment thrombocytopenia (p = .005) or neutropenia (p = .003); they did not differ significantly in age (p = .85), documentation of del5q (p = .51), comorbidity (p = .65) or treatment center volume (p = .80). Median days on LEN for the non-TD was 121. Incident complications post-LEN among the non-TD are shown. Conclusions:These data suggest there is widespread off-label use of LEN in older patients with MDS, as many receive the drug who are not TD. Moreover, off-label exposure to LEN in these patients is associated with a sizable risk of incident complications, which is difficult to justify given they are already living free of transfusion dependence. [Table: see text]