bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemoprevention of cancer with metformin: A meta-analysis.
Authors: Gandini Sara , Heckman-Stoddard Brandy M. , Puntoni Matteo , Dunn Barbara k , Ford Leslie , Bonanni Bernardo , Szabo Eva , De Censi Andrea
Published: March 2020

1516

Background: Previous meta-analyses have shown that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiological studies. Here we update the meta-analyses of observational studies with a focus on confounders and biases. Methods: We identified 47 articles published between 1966 to August 2012 that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. Results: The analysis is based on a total of 32,647 cancer events and 1,198 cancer deaths. Cancer incidence was reduced by 34% (SRR=0.66, 95%CI: 0.42-1.03) in subjects taking metformin compared with other antidiabetic medications. Cancer mortality was reduced by 49% (SRR=0.51, 95%CI: 0.30-0.86). The SRR estimates for liver (SRR=0.40, 95%CI: 0.20-0.80) and lung cancer incidence (SRR=0.87, 95%CI: 0.83-0.93) were significant. Adjustment for BMI and exclusion of studies with time-related biases showed a significant reduction in cancer incidence of 26% (95%CI: 1% to 45%) or 10% (95%CI: 9% to 11%), respectively (Table). Breast cancer was significantly reduced by 24% (95%CI: 7% to 38%) in BMI-adjusted studies and the reduction remains significant in prospective studies and in studies without time-related biases. Conclusions: Metformin is a promising agent for cancer prevention, although it may not benefit all populations equally. Clinical trials are needed to determine if the observations seen in diabetic populations apply to pre-diabetic or non-diabetic populations and to optimize the benefit/risk ratio. [Table: see text]
Second malignant neoplasms (SMN) in Cowden syndrome patients with underlying germline PTEN mutations.
Authors: Ngeow Joanne YY , Mester Jessica , Mahdi Haider , Yehia Lamis , Barnholtz-Sloan Jill , Eng Charis
Published: March 2020

1527

Background: Cowden syndrome (CS) patients with underlying germline PTEN mutations are at significantly increased risks of breast, thyroid, endometrial and renal cancers. Current estimates of lifetime cancer risks do not provide the majority of patients who present after their first cancer a meaningful gauge of their risk of a SMN. Quantification of the risk of a SMN will allow patients to be better informed and provide clinicians a much needed guide to finally address patients’ question of “how likely am I to have a second cancer and will it likely be the same primary?” Methods: We conducted a 5-year, multi-center prospective study of CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Patients’ records were reviewed for prior history of invasive cancers. Invasive SMNs were confirmed by pathology reports or physician reports where possible. All metastatic disease, synchronous primary cancer at the same site and non-melanoma skin cancers were excluded. Incidences of SMNs were compared between patients with pathogenic PTEN mutations (PTENmut+) and wildtype PTEN (PTENwt). Standardized incidence ratios (SIR), cumulative incidences and excess absolute risks for SMNs were calculated comparing against SEER-derived data. Results: Of 2,792 CS/CS-like patients who present with 1 or more cancers, there were 100 (4%) PTENmut+patients. Compared with PTENwt CS/CS-like patients with SMNs (223/2039; 11%), PTENmut+cases (42/100; 42%) were more likely to develop SMNs (p<0.0001). PTENmut+ cases were also younger at median age of SMN diagnosis (48yrs vs 54 yrs; p=0.30). PTENmut+ patients were 56-fold more likely to develop any SMN compared with the general population (95%CI 41-55); corresponding to an excess absolute risk of 731/10000 person years. Breast cancer was the most common SMN encountered in PTENmut+CS/CS-like patients (SIR 73; 95%CI 45-122) followed by endometrial (SIR 44; 95% CI 18-92), renal (SIR 47; 95% CI 15-113) and thyroid cancers (SIR 222; 95% CI 37-734). Conclusions: Our study shows that PTENmut+CS/CS-like patients are significantly more likely to present with a SMN compared to PTENwt CS/CS-like patients and the general population, and should be advised and surveillanced accordingly.
Effect of smoking on survival from non-small cell lung cancer.
Authors: Bhatt Vijaya Raj , Loberiza Fausto R. , Ganti Apar Kishor
Published: March 2020

1570

Background: Although a well-established risk factor for lung cancer, the impact of smoking on the survival of non-small cell lung cancer (NSCLC) is not well-known. This study evaluated the effects of tobacco exposure on outcomes from NSCLC. Methods: We performed a retrospective analysis of Veteran’s Affairs Comprehensive Cancer Registry of NSCLC patients diagnosed between 1995 and 2009. Data abstracted included age, gender, family history, stage at diagnosis, histology, tumor grade, smoking history, other exposures, treatment received and overall survival (OS). Smoking status was categorized as never-smoker, past-smoker and current-smoker based on the self-reported history at diagnosis. Multivariate analysis was performed using SAS version 10.2. Results: The study population (n=61,440) comprised predominantly of males (98%), of which Caucasians (81%) formed the majority. The median age at diagnosis within this cohort was 68 years (range: 22-108 years) and median follow-up was 6 months (range: <1 – 161 months). Squamous cell carcinoma (35%) and adenocarcinoma (30%) were the most common histologies. The majority (71%) presented with stage III or IV disease. Positive family history was identified in one-third. Current smokers were diagnosed with NSCLC at a younger age (65 yrs) compared to never-smokers (71 yrs) and past-smokers (72 yrs) (p<0.001). After adjusting for age at diagnosis, grade, histology, family history and treatment, current-smokers (n=34613) [Hazard ratio (HR) 1.059; 95% CI, 1.012-1.108], but not past-smokers (n=23864) (HR 1.008; 95% CI, 0.962-1.056), had worse OS for Stage III and IV NSCLC, compared to never-smokers (n=2963). Smoking status was not prognostic in stage I and II NSCLC. Conclusions: Current smokers were 6 years younger than never-smokers at diagnosis of NSCLC. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on OS was modest, at least in males. Therefore, primary prevention of smoking cessation is more likely to be meaningful than efforts on smoking cessation after the diagnosis of NSCLC.
The impact of body mass index on survival in stage 3 and 4 lung cancer.
Authors: Wong Kit Man , Cuffe Sinead , Coate Linda E. , Espin-Garcia Osvaldo , Boyd Kevin , Feld Ronald , Leighl Natasha B. , Shepherd Frances A. , Xu Wei , Liu Geoffrey
Published: March 2020

1579

Background: Obesity is an adverse prognostic factor in several cancers, including colorectal, breast, endometrial and prostate. Studies on body mass index (BMI) and lung cancer outcomes are lacking. Understanding the clinical impact of body weight is important given the high prevalence of obesity globally. We retrospectively evaluated the BMI at diagnosis and its effects on survival in stage 3/4 lung cancer patients. Methods: 1,121 patients with stage 3/4 lung cancer were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) were generated by Cox regression for each BMI (kg/m2) category (underweight: <18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese: ≥30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen. Results: In this cohort (n=1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p=0.002) and stage 3A disease (p=0.001); underweight patients were more likely current smokers (p<0.001). OS was significantly decreased with age ≥65, males, PS 2-3, stage 4, and lack of systemic therapy (p<0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMI≥18.5, being underweight was associated with poorer OS (aHR 1.33, 95% CI 1.01-1.77, p=0.045), but not progression-free survival (aHR 1.12, 95% CI 0.86-1.46, p=0.414). The magnitude of this association was greatest in those aged <65 (aHR 1.57, 95% CI 1.11-2.22, p=0.011). Conclusions: Underweight patients with stage 3/4 lung cancer, especially if aged <65, have significantly poorer OS. Lower BMI was mostly observed in current smokers, while above normal BMI was seen in stage 3A. Unlike other cancers, obesity does not increase mortality in this population. The inverse BMI-survival relationship in lung cancer requires further study.
Comparison of adenocarcinoma (ACA) and squamous cell carcinoma (SCC) of the uterine cervix: A population-based epidemiologic study of 60,000 women in Brazil.
Authors: Rodrigues Angelica Noguelra , Thuler Luiz Claudio Santos , Bergmann Anke , Aguiar Suzana Sales de , Ferreira Carlos Gil Moreira
Published: March 2020

1587

Background: Most cancers of the uterine cervix are SCC, but the relative and absolute incidence of ACA has risen in recent years, particularly in younger patients, and ACA now accounts for about 20% of invasive cervical cancers in screened populations worldwide. However, the developing world, with sub-optimally screened women, accounts for more than 80% of incident cervical cancers. Our objective was to compare epidemiological, clinical characteristics, and treatment outcome of ACA with those of SCC of the cervix, with respect to ethnic group, age and stage at diagnosis, and pattern of response to first treatment in a sub-optimally screened population. Methods: Data of cervical cancer patients with SCC and ACA (adenosquamous + adenocarcinoma) treated from 2000 through 2009 were obtained from the Brazilian Hospital Cancer Register databases. Summary odds ratios and chi-square tests were estimated. Results: A total of 60,883 patients were analyzed: 54,425 (89.4%) cases of SCC, and 6,458 (10.6%) of ACA. Compared to ACA, the SCC cohort were younger (49.37 x 51.83 years, p<0.001), more frequently black (58.1% x 49.2%, p<0.001), presented higher degree of illiteracy (22.7 x 16.1%, p<0.001), and alcohol (13 x 9.8%, p<0.001) and tobacco dependence (41.5 x 31%, p<0.001). Tumor stage at the time of diagnosis was also significantly different (p<0.01). Considering prognostic factors, in both subtypes, more than 60% of the patients were stage II or inferior and ACA was associated with a significantly increased risk of inadequate response after the first course of treatment (crude OR=1.14 CI95%=1.07-1.21; adjusted OR=0.94 CI95%=0.87-1.01) and of death (crude OR=1.26 CI95%=1.15-1.38; adjusted OR=1.1 CI95%=1.00-1.23). Conclusions: Differences between ACA and SCC were found in age at diagnosis, extent of disease and ethnic distribution. In spite of these differences, the inadequate response to treatment seems to be mainly the result of more advanced stage, rather than cell type. Screening strategies with higher sensitivity are necessary, and irrespectively of histological subtype, quality of treatment must be improved in developing countries.
The incidence, risk factors and prognostic implications of venous thromboembolism in Asian patients with non-small cell lung cancer.
Authors: Lee Yun-Gyoo , Kim Inho , Lee Eunyoung , Bang Soo-Mee , Kang Chang Hyun , Kim Young Tae , Kim Hak Jae , Wu Hong-Gyun , Kim Young Whan , Kim Tae Min , Lee Keun-Wook , Lee Se-Hoon , Kim Dong-Wan , Heo Dae Seog
Published: March 2020

1590

Background: The goal of this study was to describe the incidence, risk factors and prognostic implications of venous thromboembolism (VTE) in Asian patients with non-small cell lung cancer (NSCLC). The association between specific gene mutations and the risk of VTE was also evaluated. Methods: A total of 1998 consecutive patients with NSCLC were enrolled and analyzed retrospectively. To minimize potential confounding, we used propensity score-matching to compare overall survival between patients with and without VTE. Results: The 6-month and 2-year cumulative incidences of VTE were 4.2% and 6.4%, respectively. The risk of VTE increased 2.45-fold with each advancing stage in NSCLC (common hazard ratio [HR] 2.45; 95% CI 1.96–3.05; P<0.001). In multivariate analyses, the effects of therapeutic variables including surgery, chemotherapy, and radiotherapy on the development of VTE were modified by NSCLC stage. Therefore, we calculated stratum-specific HRs by performing stratified analyses for each stage. The independent predictors of VTE were advanced age, pneumonectomy (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in localized NSCLC and no surgery (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in locally advanced NSCLC. Adenocarcinoma histology (vs. squamous cell carcinoma) was the only independent risk factor for increased risk of VTE in metastatic NSCLC. EGFR mutation was independently associated with a 47% lower risk of VTE in adenocarcinoma compared to wild type (HR 0.53; 95% CI 0.29–0.99; P=0.045). Among both the entire and propensity score-matched cohorts, a significant survival difference was observed between patients with and without VTE in localized NSCLC, but not in locally advanced or metastatic NSCLC. The strong association we observed between VTE and the increased rate of recurrence (risk ratio 2.0; 95% CI 1.28–3.12; P=0.009) can explain the significant difference in survival in localized NSCLC. Conclusions: Approximately 6.4% of Asian patients with NSCLC developed VTE during a 2-year period. The association between VTE and decreased survival was limited to localized NSCLC.
A retrospective study on the role of diabetes and metformin in colorectal cancer disease progression.
Authors: Ramjeesingh Ravi , Orr Christine , Richardson Lyndsay , Hammad Nazik
Published: March 2020

1593

Background: Recent studies have suggested a potential epidemiological role for diabetes as an independent risk factor for the development of colorectal cancer (CRC). These studies have furthermore suggested patients with diabetes who develop colorectal cancer have an increased mortality. Methods: To identify a potential correlation between CRC and diabetes, we are performing a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from January 2005 to December 2011. 1,300 colorectal cancer patient charts have been identified through Ontario Cancer Registry Data based on confirmed ICD-10 diagnosis codes and the variables of 200 random patients have been extracted into our database thus far. The final analysis will be completed April 2013. Results: Preliminary analysis of the database has indicated that the average age of patients with CRC was 69 years with 55% being women. The incidence of diabetes in our CRC population was 19%, double the rate of diabetes in the general population in Canada. As expected, the rate of co-morbidities excluding diabetes was higher in the diabetic group (92.9% vs 69.3%; p=0.004). When we looked at the diabetic population specifically, the rate of death was not significantly different compared to the non-diabetic population (13.2% vs 12.7%, p=0.94), however those with diabetes presented with later-stage (stage 2/3/4) disease (92.1% versus 88.6%). The average number of days from the time of diagnosis to death in the diabetic group (200 days) was half compared to the non-diabetic group (420 days, p=0.014). However, there was no statistical difference in the percentage of progression, number of different metastatic sites or the burden of metastatic disease amongst the two populations. A subgroup analysis of diabetic patients on metformin illustrated that the death rate (p=0.06), rate of progression (33% vs 20%) and those presenting with later stage disease was higher in patients not on metformin compared to those on the drug. Conclusions: Our preliminary work suggests diabetics with CRC may have a worst prognosis however taking metformin may have a positive impact on prognosis.
Survival after cancer diagnosis among patients with higher income and education in Israel, a country with highly appreciated health service.
Authors: Rottenberg Yakir , Zick Aviad , Peretz Tamar
Published: March 2020

1598

Background: In recent years, the 5 year survival following cancer diagnosis is about two thirds. Among patients with various chronic diseases, improved survival is known to be associated with higher income and education. The aim of the current study is to assess the influence of income and education on survival following cancer diagnosis in Israel. Methods: Retrospective cohort study, using baseline measurement from the 1995 census conducted by the Central Bureau of Statistics in Israel. Cancer data were obtained from the Israel Cancer Registry. Cox proportional hazards ratios were calculated for mortality among cancer patients and adjusted for age, sex, religious, income and education years. The first model excluded cancers associated with early detection (breast, prostate, colorectal and cervix), and a second model excluded also lung cancer in order to control for smoking which is common in lower socioeconomic status. Results: A total of 3,712 cases of cancer and 1,252 deaths were reported during the study period. Higher income (HR=0.985 per 1000NIS, approximately 330$ in 1995's value, p=0.016) and education (HR=0.957 per year of education, p<0.001) were associated with decreased risk of death after cancer diagnosis. Jews had better prognosis than non-Jews following cancer diagnosis (HR=0.62, p<0.001), while males (HR=1.54, p<0.001) and age (HR=1.036 per year, p<0.001) had been associated with worse prognosis. The association between higher income and education was not changed in a model which excluded lung cancer. Conclusions: Higher income and education are associated with improved survival after cancer diagnosis. In the light of current study, further studies are needed to depict the variation in cancer incidence, stage at diagnosis and treatment disparities related to socioeconomic variables.
Effect of statin and metformin on survival in veterans (V) with B-cell lymphoproliferative disorders (BLD).
Authors: Srinivas Shanthi , Gonzalez Melanie L. , Khan Sunniya , Gandhi Arpita , Crump Barbara , McPherson Monica , Paz-Querubin Emma R , Chang Victor T , Kasimis Basil
Published: March 2020

1602

Background: The incidence of BLD has been increasing in V. As many V are on statin and metformin for comorbid conditions, we evaluated the impact of their use on survival. Methods: In an IRB-approved protocol, we reviewed the records of 332 V diagnosed with BLD from January 1997 to Dec 2011 for demographics, height(H),weight(W), BMI,statin and metformin use, clinical and laboratory data and ECOG PS. Comorbidity was assessed using the Charlson Comorbidity Index (CCI),Kaplan-Feinstein Index (KFI) and Cumulative Illness Rating Scale (CIRS). Cox regression analysis was performed using SAS v 9.2. Results: There were 332 V with a median (M) age of 70 years (27-94). The M for H 70 inches (58-78), W 183lbs (99-356.5) and BMI 26.7 kg/m2 (15.54 -48.45). The M for hemoglobin(Hgb) 12.8 g/dl (7.3-17.4), albumin 3.9(1.2-5.4), lactate dehydrogenase( LDH) 183 IU/L (85-1905), beta 2-microglobulin 2.6 mg/dl (0.8-39) . The M for CCI was 4.7 (0.8-12), KFI 2 (0-3), CIRS15 3 (0-6), CIRS16 6(0 -14), CIRS17 1.9(0-6), CIRS18 0(0-3), CIRS19 0(0-3). M survival was 1297days(4-7468).The number of V receiving statin was 167 (51%) and metformin 46 (14%). Statin use was a predictor of survival by both univariate and multivariate analysis but metformin was a predictor only by univariate analysis. Conclusions: Statin use was an independent and significant predictor of survival in this group of V with BLD and needs to be validated in a larger group of patients. [Table: see text]
Identification of the occult tumor in cancer of unknown primary (CUP): A priority based on histology.
Authors: Kim Chong Sung , Hannouf Malek Bassam , Brackstone Muriel , Winquist Eric , Zaric Gregory S
Published: March 2020

1605

Background: The poor prognosis of cancer of unknown primary (CUP) patients is likely to improve with knowledge of the primary site. CUP patients form a diverse clinicopathological group; however, there remains doubt as CUP may indeed represent a unique clinical classification. Methods: We used the Ontario Cancer Registry to identify all patients diagnosed with cancer from January 2000 to December 2005. We linked these patients with the Canadian Institute of Health Information Same Day Surgery and Discharge Abstract Database to identify those who were initially diagnosed with a metastatic tumour. Information on clinical and pathological characteristics including age, gender, primary tumour site, histology, and second primary were available from the Ontario Cancer Registry. We stratified results according to primary tumour site and histology. Five-year survival data were available for all patients and were obtained from the Ontario Cancer Registry. Results: Of 52,619 patients diagnosed with metastatic tumour at the time of their initial cancer diagnosis, 4,866 (9.2%) patients were diagnosed with CUP and 47,753 (90.8%) patients were diagnosed with metastasis of known primary. The 5-year Kaplan-Meier estimate of CUP overall survival (OS) differed significantly with patients diagnosed with metastasis of known primary (median OS= 1.0 versus 10.4 months, respectively, log–rank test p<0.0001). In subgroup analyses, the 5-year OS of CUP patients with adenocarcinoma (n=1,389, median OS=1.83) was significantly worse when compared to metastatic adenocarcinoma of known primary (log-rank test p<0.0001). An identical result was obtained with CUP patients of undifferentiated histology (n=3,230). The 5-year OS of CUP patients with squamous cell carcinoma (n=247, median OS=18.5) did not differ significantly with those of other squamous cell carcinoma groups of known primary (log-rank test p>0.56). Conclusions: Although CUP patients as a whole have a poor prognosis compared to other metastatic patients of known primary, distinct subsets of CUP patients have similar prognosis. These data suggest that an intensive diagnostic approach for identification of the primary is not justified for all CUP patients.
Optimizing the identification of anaplastic oligodendroglioma patients that benefit from adjuvant PCV chemotherapy using the Illumina platform: A further report from EORTC study 26951.
Authors: Van Den Bent Martin J. , Erdem Lale , Gorlia Thierry , Taphoorn Martin JB , Kros Johan M , Wesseling Pieter , Allgeier Anouk , Dubbink Hendrikus J , Idbaih Ahmed , Sanson Marc , French Pim ,   EORTC Brain Tumor Group
Published: March 2020

2011

Background: Adjuvant PCV chemotherapy improves overall survival (OS) in 1p/19q co-deleted grade 3 gliomas. Analyses of EORTC 26951 and RTOG 9402 suggest that other molecularly defined subsets of grade III tumors benefit as well. We previously identified a CpG-Island Hypermethylated Phenotype (CIMP+) as a candidate biomarker. This was further explored in a larger series using snap frozen (SF) or formalin fixed paraffin embedded (FFPE) tumor material, and compared to the value of 1p/19q, IDH1/2 and MGMT status. Methods: Methylation profiles were assessed using the Infinium HumanMethylation 27 or 450 BeadChip (Illumina). MGMT promoter methylation was re-assessed with a logistic regression model (MGMT-STP27) using probes cg1243587 and cg12981137 of the platform as described (Bady et al, Acta Neuropathol 2012;124:547-60). These probes correspond to area’s of the promoter correlated to MGMT protein expression. Previously, MGMT promoter methylation had been assessed using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA). Results: Methylation profiling was conducted in 115 patients. CIMP status correlation between FFPE and SF was excellent (R2 0.96). In multivariate analysis, 1p/19q co-deletion and CIMP status were independent prognostic factors. Although 1p/19q status and IDH mutational status identify subgroups with more benefit of PCV chemotherapy, tests for interaction remain negative (p 0.25 and 0.33 respectively); MGMTstatus (MS-MLPA) had no impact (p = 0.70). However, CIMP status was of borderline predictive significance (p= 0.07), and MGMT-STP27 was of statistical significance (p = 0.003; HR unmethylated 1.61, 95% CI [0.71, 3.66], HR methylated 0.37, 95% CI 0.23, 0.61]. Conclusions: CIMP status and MGMT promoter methylation assessed with Illumina HumanMethylation BeadChips appear the most informative tests for identifying grade III glioma patients benefitting from the addition of PCV to RT. Validation in an independent dataset is required. Clinical trial information: NCT00002840.
The Stupp regimen preceded by early post-surgery temozolomide versus the Stupp regimen alone in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM).
Authors: Zhou LF , Yao Yu , Yang Shuyuan , Yang Xuejun , Wang Xiang , Zhang Xiang , Zhang Liwei , Lu Yicheng , Chen Zhong-ping , Zhang Jianmin , Qi Songtao , Wang Renzhi , You Chao , Mao Ying , Wang Jisheng , Chen Juxiang , Yang Qun-ying , Shen Hong , Li Zhiyong , WB Ma
Published: March 2020

2022

Background: In treatment of newly diagnosed GBM with the Stupp chemo-radiotherapy regimen, following by adjuvant chemotherapy, patients were treated with temozolomide (TMZ) & combined radiotherapy 4-5 weeks after surgery. In the interval between surgery and chemo-radiotherapy, it is not known whether additional TMZ treatment will improve efficacy or safety. This trial evaluated the safety and efficacy of the Stupp regimen + early post-surgery TMZ chemotherapy in the treatment of patients with newly diagnosed GBM. Methods: The trial was a multi-center, randomized open-label study. 99 newly diagnosed GBM patients were enrolled and randomly assigned to the Stupp regimen + early post-surgery TMZ chemotherapy arm (experimental group, n = 52) or to Stupp regimen alone (control group, n = 47). Fourteen days after surgery, the patients in experiment group recieved TMZ orally at 75mg/m2/day for 14 days. The primary endpoint of the study was the overall survival (OS). The secondary endpoints included the progression-free survival (PFS), objective tumor assessment and adverse events (AEs). Results: The median OS time was 17.58 months (95% CI: 15.18 – 23.03 months) in the experiment group and 13.17 months (95% CI: 11.14 – 18.76 months) in the control group (log-rank test, p = 0.021). There is no significantly difference in the median PFS between experiment group and control group (8.74 months, 95% CI: 6.41-14.85 months vs 10.38 months, 95% CI: 8.18-15.44 months, p = 0.695). No statistically significant difference was detected as regards to the objective tumor assessments. There is no significance in OS or PFS between MGMT positive and MGMT negative groups. TMZ treatment was well tolerated in the study. AE types and rates were generally similar between the two groups. There were 22 SAEs in this study, with only 1 SAE (lung infection) in Stupp regimen group was possibly drug-related. Conclusions: The addition of early post-surgery TMZ chemotherapy to the Stupp regimen for newly diagnosed GBM resulted in a statistically significant survival benefit with minimal additional toxicity. Clinical trial information: NCT00686725.
A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.
Authors: Gerstner Elizabeth Robins , Levine Mike , Ye Xiaobu , Mikkelsen Tom , Nabors Louis B. , Olson Jeffrey J. , Kaley Thomas Joseph , Wen Patrick Y. , Batchelor Tracy , Grossman Stuart A.
Published: March 2020

2054

Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.
Methotrexate, rituximab, and temozolomide in CNS lymphoma: The Mayo Clinic experience.
Authors: Gupta Vinay , Wolf Robert C. , Johnston Patrick B.
Published: March 2020

2058

Background: We present a tertiary center experience with high-dose methotrexate, rituximab and temozolomide (MRT) chemotherapy in both primary and secondary CNS lymphoma. Methods: A retrospective analysis was performed for a total of 27 patients (20 male, 7 female) who underwent treatment at Mayo Clinic, Rochester between November 2010 and October 2012. The median age was 63 years (range 23-73). Of these, 12 patients were diagnosed with primary CNS lymphoma, while 15 patients had secondary CNS lymphoma. All patients received at least 1 cycle of MRT. The most common histological subtype was diffuse large cell lymphoma (23 of 27 patients). Other histological subtypes were high grade lymphoma (2 patients), Burkitt’s lymphoma (1 patient) and Mantle cell lymphoma (1 patient). Results: Of 26 patients, who underwent imaging studies for response assessment after MRT, 14 patients achieved complete response (CR), 4 patients achieved partial response (PR), 2 patients had stable disease, while 6 patients had evidence of disease progression. Overall, the median number of chemotherapy cycles with MRT was 3 (range 1-6). For patients, who achieved CR, the median number of MRT cycles was 4 (range 2-6). MRT was well tolerated. Of 27 patients, who underwent their entire treatment at Mayo Clinic, grade 3 or higher treatment related toxicity were noted to be as follows – neutropenia (9/27), thrombocytopenia (4/27), anemia (7/29), and transaminitis (10/27). 16 of 27 patients proceeded to high dose chemotherapy and autologous stem cell transplant. Out of 16 patients, 14 received BCNU/Thiotepa as conditioning regimen, while 2 patients underwent BEAM conditioning. All 16 patients who underwent transplantation remain in CR at this time. Of the remaining 11 patients, 4 are being planned for autologous transplantation, 2 received and responded to salvage chemotherapy, while 5 patients died of progressive disease. Conclusions: Overall, the MRT regimen was well tolerated. Overall response rate was noted to be 67% (18 of 27 patients) and achieved CR in 54% patients (14 of 26 patients). Patients who underwent autologous stem cell transplantation as consolidation therapy continue to do well at a median followup of 12.5 months (range 2-20 months).
Prophylactic anticonvulsants in patients (pts) with primary brain tumor (PBT): Have we really agreed to a consensus?
Authors: De Oliveira Julia Andrade , De Santana Iuri Amorim , Caires Inacelli Queiroz de Souza , Caires-Lima Rafael , Miranda Vanessa Costa , Protásio Bruno Mendonça , Rocha Lucila Soares Da Silva , Braga Henrique Faria , Mencarini Ana Cristina Malacarne , Teixeira Manoel Jacobsen , Martins Castro Luiz Henrique , Feher Olavo
Published: March 2020

2060

Background: Routine prophylactic antiepileptic drugs (AED) use to prevent seizures in PBT seizure-naïve pts is not supported by current guidelines. However, the best management of prophylactic AED started in the perioperative setting is still unclear. Additionally, AED can have serious side effects, might have a negative impact on cognition and may present significant drug interactions. Little is known about actual current practice patterns regarding prophylactic AED in PBT. In this report we investigated prophylactic AED use in a tertiary care institution. Methods: We reviewed medical files of 260 consecutive patients, registered in our center between 2008 and 2012, focusing on prophylactic AED use. Collected data included: patient demographics, starting date, AED type, and indication. A descriptive analysis was performed with SPSS IBM version 20.0. Results: Median age was 44.5 years (11 - 83). Most pts had an ECOG PS ≤ 1 (76.4%). Overall, AED were used by 218 pts. Most common agents were: phenytoin (68.8%), carbamazepine (27.1%) and phenobarbital (16.1%). Among 141 seizure-naïve pts, 99 (70.2%) received AED as primary prophylaxis (PP). Only 14 pts (14.1%) had the drug eventually discontinued, in a median time of 5.9 months (1.1 – 76.8m). AED were used as PP in 60% of pts with low-grade gliomas, 73.3% with anaplastic gliomas and 93.9% with glioblastomas. Twenty-seven pts (27.3%) on PP presented seizures, generally associated with tumor progression. For most of them a new anticonvulsant was added for seizure control. Of the 42 seizure-naïve pts who did not receive prophylactic AED, only two presented seizures during or within the first week post-radiotherapy. Conclusions: In our study population, prophylactic AED use in PBT was extremely high (70.2% of seizure-naive pts). Postoperatively, AED were discontinued in a small minority of pts, and even so, only after a prolonged period of time. Very few seizures occurred in pts not receiving prophylactic AED. Our results suggest that practice patterns regarding prophylactic AED in PBT still contradict established guidelines.
Prognostic factors and outcome of atypical and anaplastic meningioma with and without radiation.
Authors: Yoon Hannah , Helenowski Irene B. , Perumal Karthikeyan , Marymont MaryAnne H. , Chandler James , Bendok Bernard R. , Rosenow Joshua M. , Mehta Minesh P.
Published: March 2020

2083

Background: We evaluated outcome and prognostic factors for high grade meningioma (G2-3) and the role of early post-operative radiotherapy (RT). Methods: From 2000 to 2010, 136 patients were diagnosed with G2-3 meningioma at Northwestern: 124 with atypical (G2) and 12 with anaplastic (G3) meningioma. All were treated with or without RT after initial or subsequent resection. The primary endpoint was progression-free survival (PFS). Results: 21 patients received adjuvant RT, and 115 did not. Median PFS for G2 with and without RT was 68 vs.89 mos. Median PFS for G3 with and without RT was not reached=nr (mean 5) vs.60 mos (mean 35). Median PFS for Simpson G1-3 with and without RT was 18 vs.96 mos. Median PFS for Simpson G4 with and without RT was nr (mean 55) vs.59 mos (mean 44). For median follow-up of 33 mos for Simpson G1-3 and 29 mos for G4, recurrence rate for Simpson G1-3 with and without RT was 40 vs.6%, and for Simpson G4 with and without RT, 9 vs.31%. 3-yr OS for G2 with and without RT was 93 vs.94%. 3-yr OS for G3 with and without RT was 80 vs.80%. In multivariate analysis, G3 histology and Simpson grade were predictive for relapse, while brain invasion, mitoses, adjuvant RT, and location of tumor were not. For those who received adjuvant RT, mean dose of external beam radiation (EBRT) in 2 patients was 58 Gy, while mean dose of stereotactic radiosurgery (SRS) in 15 patients was 15 Gy. 51% EBRT patients recurred, while 22% SRS patients recurred (p = 0.45). Median PFS with EBRT was 43 vs.51 mos for SRS (p = 0.34). Patients were maldistributed between the with and without RT arms in terms of brain invasion, extent of resection, and G3 histology. Conclusions: Patients who received RT had lower PFS compared to those who did not; survival was comparable. This may be due to inherent selection bias for patients with more aggressive disease getting adjuvant RT. Our study may be underpowered to determine the true role of RT in G2-3 meningioma. Patients with subtotal resection, Simpson G4, who received RT had fewer recurrences and higher PFS compared to those who did not. 3-yr OS was equivalent in both G2 and G3 tumors with and without RT. G3 histology and Simpson grade were predictive for relapse while brain invasion, mitoses, adjuvant RT, and location of tumor were not.
Resectable central nervous system (CNS) metastases from colorectal cancer (CRC): Patient characteristics, outcome, and molecular correlations between primary tumor and metastases.
Authors: Bellini Elisa , Airoldi Mario , Francia di Celle Paola , Mariani Sara , Ruda Roberta , Soffietti Riccardo
Published: March 2020

2084

Background: Aim of this study is to describe clinical characteristics and outcome of CRC patients with CNS metastases undergone to surgical resection, and report preliminary data on the comparison between molecular aspects of primary tumor and metastasis. Methods: Thirty-two pts (17 males, 15 females) with a median age of 65 yrs (range 38-80 yrs) with brain metastases from colon (23 pts, 72%) or rectum (9 pts; 28% ) adenocarcinoma (G1 in 3 pts, 9%; G2 in 12 pts, 37%; G3 in 17 pts, 53%) underwent total surgical resection. Primary tumor TNM was: T2 in 1 pt (3%), T3 in 22 pts (69%) and T4 in 9 pts (28 %); no patient had N0 status , 10 pts had N1 lesions (31%) and 22 pts had N2 (69%) lesions; 25 pts were M0 (78%) while 7 (22%) were M1. Results: One patient had neurological symptoms as first manifestation of CRC; the other cases had metachronous metastases in the SNC after a median of 35.5 months (range 4-96). The CNS location was cerebellum in 15 pts (47 %), frontal lobe in 9 pts (28 %), spinal cord in 5 pts (16% ), parietal lobe in 2 pts (6%) and occipital lobe in 1 pt (3%). Perioperative mortality was 3%. Ten pts (31%) received post-operative whole-brain radiotherapy. Six patient (19%) had local recurrence. Primary cancers harbored a K-RAS mutation in 13 cases (41%) and a BRAF mutation in 1 case (3%). Preliminary data in 20 pts indicate a 100% mutation concordance between primary tumor and CNS metastases. Conclusions: Resectable CNS metastases from CRC adenocarcinoma were seen after a median of 3 yrs originating from T3-4 N1-2 M0-1 lesions. The preferential locations in the CNS were cerebellum and frontal lobe, being spinal metastases relatively frequent. The total resection was feasible with a good long-term local control ; the whole-brain irradiation given to one third of cases could have contributed to local control. Almost all pts died of extranervous metastases. There was a concordance of KRAS and BRAF mutation in primary and CNS lesions.
Phase I study of safety and pharmacokinetics (PK) of GDC-0917, an antagonist of inhibitor of apoptosis (IAP) proteins in patients (Pts) with refractory solid tumors or lymphoma.
Authors: Tolcher Anthony W. , Papadopoulos Kyriakos P. , Patnaik Amita , Fairbrother Wayne J. , Wong Harvey , Budha Nageshwar R. , Darbonne Walter C. , Peale Franklin V. , Mamounas Michael J. , Royer-Joo Stephanie , Yu Ron , Portera Chia C. , Bendell Johanna C. , Burris Howard A. , Infante Jeffrey R.
Published: March 2020

2503

Background: GDCE0917 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing IAP proteins. Preclinical studies demonstrated antitumor efficacy of GDC-0917 alone or in combination with chemotherapeutic agents. Methods: Oral GDC-0917 was given on Day (d) 1 followed by 2d off and a 2-week (w) on/ 1w off treatment (tx) schedule (21d cycle) starting d4. A modified continual reassessment method was used for dose escalation. Dose-limiting toxicity (DLT, assessed d1-24), PK, adverse events (AEs), pharmacodynamics (PD), and clinical activity were evaluated. Results: 42 pts of age 36-86 (median 60.5) were enrolled in 11 cohorts (5-600 mg) and received 1-15 cycles (median 2) of GDC-0917. One DLT, Grade (G) 3 fatigue, was observed at 450 mg. The maximum tolerated dose was not determined although plasma concentrations of preclinically defined IC90 were reached. The most frequent AEs were diarrhea, fatigue and nausea (26.2% each), vomiting (23.8%), and constipation (19%). The most frequent AEs reported as tx-related were mostly G1-2 and included fatigue and nausea (21.4% each), vomiting (14.3%), rash (11.9%) and pruritus (9.5%). AEs reported as tx-related that were ≥ G3 in > 1 pt were elevated AST and ALT (2 pts, at 450 and 600 mg). AEs reported as tx-related that resulted in tx discontinuation were G3 fatigue, G2 QTc prolongation, G2 drug hypersensitivity, G2 pneumonitis (1 pt each), and G3 pruritus/G2 rash (same pt). GDC-0917 peak concentrations were observed 2-3h post dosing. Exposure was dose-proportional with a mean plasma elimination t1/2of 4-8h and no apparent accumulation at steady state. Rapid down-modulation of cIAP1 was observed in PBMCs at all dose levels. Evaluation of tumor biopsies demonstrated decreases in cIAP1 (2 pts total, at 40 and 200 mg) and increases in activated caspase-3 and cPARP (1 pt at 200 mg). Two pts (4.8%) had a complete response (both unconfirmed, ovarian Ca and MALT lymphoma [PET]); 4 pts (9.5%) had stable disease for ≥ 3 months. Conclusions: GDC-0917 had a favorable safety, PK and PD profile in pts with advanced malignancies. These encouraging results support further clinical evaluation of this agent. Clinical trial information: NCT01226277.
A phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients.
Authors: Amaravadi Ravi K. , Senzer Neil N. , Martin Lainie P. , Schilder Russell J. , LoRusso Patricia , Papadopoulos Kyriakos P. , Weng David Edward , Graham Martin , Adjei Alex A.
Published: March 2020

2504

Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs with excellent tolerability, drug exposure, target suppression and apoptotic pathway activation in clinical studies. Preclinical studies demonstrate potent anti-tumor synergy when B is combined with TNFa-inducing chemotherapies (CT). Methods: Escalating doses of B were combined with CT in a 5-arm 3+3 phase 1 study for adults (pts) with relapsed/refractory solid tumors to determine maximum tolerated dose (MTD), pharmacokinetics (PK), and efficacy to identify indications for further studies. The arms included carboplatin/paclitaxel (CP), irinotecan (I), docetaxel (D), gemcitabine (G), and liposomal doxorubicin (LD). Results: 124 pts were treated with B at doses of 2.8 to 47 mg/m2. The MTD of B for each arm was CP (47 mg/m2); I (22 mg/m2); D (47 mg/m2). The proposed G regimen could not be administered in heavily pretreated pts and B could not be evaluated for dose escalation; this arm was discontinued and no dose-limiting toxicities (DLT) occurred. LD drug shortage prevented dose escalation for B > 35mg/m2 (MTD not reached). B did not limit CT administration for CP, I, D, LD, supporting tolerable combination of B with CT. B-associated toxicity of Bell’s palsy (Grade 2) was considered a DLT and noted at higher dose levels for I, D, and LD, but not CP. This unusual reversible toxicity occurred during cycle 1 in 7 pts. Six of these pts continued therapy without recurrence. PK studies demonstrated no effect of B on CT. Except for CP, CT did not change the PK of B. CP increased plasma PK for B, possibly due to OATP1B3 transporter effects, but without increased B toxicities. 11 pts had a partial response, 61 pts had stable disease (>2 cycles, median 4.6 mo) and 37 pts had progressive disease as their best response, with clinical benefit (CR+PR+SD) of 58%. Conclusions: B can be combined with excellent tolerability with multiple CT at standard dosing. B plus CT demonstrated clinical benefit in many tumor types. Notable clinical activity occurred with I + B in pts who had failed prior I. These results support planning for further clinical studies of the I + B, and support the hypothesis for TNFa-mediated I + B synergy. Clinical trial information: NCT01188499.
Final results of the phase I trial of niraparib (MK4827), a poly(ADP)ribose polymerase (PARP) inhibitor incorporating proof of concept biomarker studies and expansion cohorts involving BRCA1/2 mutation carriers, sporadic ovarian, and castration resistant prostate cancer (CRPC).
Authors: Michie Caroline Ogilvie , Sandhu Shahneen Kaur , Schelman William R. , Molife L Rhoda , Wilding George , Omlin Aurelius Gabriel , Kansra Vikram , Brooks David G. , Martell Robert E. , Kaye Stanley B. , De Bono Johann Sebastian , Wenham Robert Michael
Published: March 2020

2513

Background: Niraparib(N) is an oral, potent PARP1/2 inhibitor that induces synthetic lethality in BRCA1/2 deficient tumors. PARP is also implicated in transcription regulated by the androgen receptor (AR) and rearranged ETS genes; key targets in CRPC. Methods: Dose-escalation was enriched for BRCA1/2mutation carriers (BRCA-MCs). Two MTD expansion cohorts were undertaken in patients (pts) with sporadic high grade serous ovarian cancer (HGSOC) and CRPC. In CRPC pts, archival tissue and circulating tumor cells (CTC) were analyzed for PTEN deletion and ETS gene rearrangements. Results: 100 pts [ovary (49), CRPC (23), breast (12) others (16)], received N at 10 dose levels: 30mg to 400mg daily (od), continuously. Grade (G) 4 thrombocytopenia was dose limiting at 400mg od; MTD was established at 300mg od. Drug-related toxicities were G1-2 reversible anemia (48%), fatigue (42%), nausea (42%), thrombocytopenia (35%), anorexia (27%), neutropenia (24%), constipation (23%), and vomiting (20%). PKs were dose proportional with a mean elimination t1/2of 40 hours. Peripheral blood mononuclear cells had >50% PARP inhibition from 80 mg od. gH2AX foci formation, a marker of DNA damage, was seen in CTCs. Antitumor activity occurred from 60mg od with RECIST and/or CA125 partial responses (PR) in 9/20 (45%) BRCA-MC ovarian cancer pts and 2/4 (50%) BRCA-MC breast cancer pts. Platinum-sensitive vs resistant BRCA-MC HGSOC response rate was 60% vs 33% with median time for responding pts of 429 and 340 days, respectively. In sporadic HGSOC, there were 2/3 PRs in platinum-sensitive pts, and 3/20 PRs plus 4/20 stable disease (SD) >16 weeks in platinum resistant pts. In CRPC, symptomatic benefit and SD >6 months (median 9 months) was seen in 9/21 (43%) pts treated at MTD. CTC declines of >30% (median 80%; range 36%-92%) were observed in 7/10 (70%) pts with evaluable CTC counts (≥5 cells/ 7.5mL blood). Conclusions: Niraparib was well tolerated and has promising antitumor activity in BRCA-MCs, sporadic HGSOC and CRPC. Clinical trial information: NCT0074902.