tbuckley/cabot-search huggingface dataset:
Phase II study of combination BCNU and temozolomide (TMZ) prior to radiotherapy in newly diagnosed anaplastic oligodendroglial tumors
Authors: O. L. Chinot, M. Sanson, M. Barrié, M. Fabbro, L. Taillandier, J. Honnorat, D. Figarella-Branger, K. Mokhtari, R. Guillevin, K. Hoang-Xuan
Journal: Journal of Clinical Oncology (2008)

2068 Background: Chemosensitivity of oligodendroglial tumors has been widely demonstrated also no standard treatment has been defined to date. Combination of BCNU and TMZ offers the potential advantage of combining the two most efficient drugs in high grade glioma, and have been described to overcome chemoresistance in part by depleting O-6 methylguanine-DNA methyl transferase (MGMT). Our objective was to assess the clinical activity of the combination of BCNU and TMZ administered prior to radiotherapy, and to determine the predictive value of 1p/19q codeletion and MGMT status on response for patients (pts) with newly diagnosed anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). Methods: To be eligible in this ongoing multicentric phase II study, pts must present a newly diagnosed AO or AOA, with measurable disease after initial surgery. Pts are given BCNU 150 mg/m2 on day 1 and TMZ 110 mg/m2 on day one to day 5 of every 42-day cycle, up to 6 cycles before radiotherapy unless progression. MRI is performed every two cycles. Primary endpoint is objective response rate (Macdonald criteria). Secondary endpoints include progression-free survival, overall survival and predictive value of response for 1p and 19q deletions and MGMT status. Results: To date, 36 pts have been enrolled out of a planned accrual of 50 pts. For interim analysis which included centralised review of histology (WHO 2007) and imaging of the first 23 patients, 21 pts are evaluable and meet inclusion criterias: median age is 55 years; median KPS is 80; histology (WHO 2007) is AO grade III (6 pts), AOA grade III (9 pts), AOA grade IV (6). Median PFS is 16 months [CI 2.6 - 29.4]. Response include CR: 2(10%) and PR: 5(24%), SD: 5(24%), PD: 9(43%). Responses (RC+RP) were of 3/6 (50%) in AO grade III, 3/9 (33%) in AOA grade III, and 1/6 (17%) in AOA grade IV. Toxicity is acceptable. Molecular analysis is in progress. Conclusions: Interim analysis of this phase II study suggests that BCNU and TMZ is active in anaplastic oligodendroglial tumors and confirms heterogeneity of this population. Impact of molecular markers will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Lilly Oncology, Schering-Plough
Prognostic value of metabolic tumor volume and total lesion glycolysis on preoperative <sup>18</sup>F-FDG PET/CT in patients with pancreatic cancer.
Authors: Jeong Won Lee, Chang Moo Kang, Sang Mi Lee, Jae-Hoon Lee, Jong Doo Lee
Journal: Journal of Clinical Oncology (2014)

190 Background: In this study, we aimed to assess the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured on 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT in pancreatic cancer patients who underwent resection with curative intent. Methods: Eighty-seven patients with pancreatic ductal adenocarcinoma who underwent 18 F-FDG PET/CT and subsequent surgical resection with curative intent with (30 patients) or without (57 patients) neoadjuvant therapy were retrospectively enrolled in this study. The maximum standardized uptake value (SUVmax), MTV, and TLG were measured on 18 F-FDG PET/CT in all patients. The prognostic significance of SUVmax, MTV, TLG, and tumor factors for predicting recurrence-free survival was evaluated by univariate and multivariate analyses. Results: Of the 87 patients enrolled, 57 (64%) experienced recurrence during the follow-up period, and the 1-year recurrence-free survival rate was 52%. Among the variables determined to be significant on univariate analysis including tumor size, pT stage, the presence of lymph node metastasis, SUVmax, MTV, and TLG, only tumor size, MTV, and TLG were significant prognostic factors on multivariate analysis (p &lt; 0.05). Patients with low MTV (71%) or TLG (74%) had significantly higher 1-year recurrence-free survival rates than those with high MTV (42%) or TLG (38%; p &lt; 0.05). In the 57 patients who did not undergo neoadjuvant treatment, MTV and TLG remained significant predictive factors for tumor recurrence, along with tumor size and SUVmax. Conclusions: MTV and TLG are independent prognostic factors for predicting recurrence in patients with pancreatic cancer. Thus, 18 F-FDG PET/CT can provide useful prognostic information for patients undergoing resection of pancreatic cancer with curative intent irrespective of neoadjuvant treatment.
Long-term efficacy and safety outcomes of the modified (simplified) combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as front-line therapy for unresectable or metastatic urothelial cancer (UC).
Authors: Andrea Necchi, Luigi Mariani, Patrizia Giannatempo, Daniele Raggi, Elena Farè, Giorgio Pizzocaro, Luigi Piva, Davide Biasoni, Tullio Torelli, Mario Catanzaro, Silvia Stagni, Angelo Milani, Alessandro M. Gianni, Filippo G. De Braud, Nicola Nicolai, Roberto Salvioni
Journal: Journal of Clinical Oncology (2013)

284 Background: MVAC and cisplatin-gemcitabine (CG) are the established standard of care for untreated patients (pts) with locally advanced-metastatic UC. CG is the preferred choice in most cases due to the better toxicity profile. Modifying MVAC by reducing side-effects may have the potential to improve efficacy. Methods: Data relative to unresectable T/N+/M+ pts entering sequential single-institution trials were collected. Chronologically, these changes to classic MVAC were provided: deletion of day 22 and administration of 25 mg/m 2 CDDP d2-5 (modified MVAC [mMVAC]); deletion of day 22 only, and deletion of days 15 and 22 in a 3-week schedule (simplified [s]MVAC1 and 2). 4-6 cycles were provided. Multivariable analysis was undertaken for recognized clinical variables. ITT analysis was applied. Results: From 09/86 to 04/12, 157 pts were treated (25 mMVAC, 72 sMVAC1, 60 sMVAC2). 84% had a bladder primary, 70% had distant metastases, 53% and 36% had nodal and visceral mets, respectively. 43.9% had a Bajorin score 1-2. 65.8% attained a complete (19.1%) or partial response (46.7%), 24.3% a stable disease, with no difference among regimens. After a median follow up of 87 mos (IQR 37-161), median (95% CI) PFS was 10.2 mos (8.4-10.8) and median OS was 19.5 mos (16.3-24.1). 2yr (95% CI) PFS and 5yr OS were 30.9% (23.8-40.1) and 25.3% (18.8-34.1). Responses were mainly seen in nodal mets (OR: 2.48, 95%CI, 1.12-5.54). Presence of visceral (HR: 2.42, 95%CI, 1.37-4.30), nodal mets (HR: 1.70, 95%CI, 1.07-2.69) and mMVAC regimen (HR: 1.73, 95%CI, 1.02-2.92) were negative prognostic factors for OS. G3-4 toxicities were similar among regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. 2 pts died for toxicity. Conclusions: Simplifying MVAC schedule may result in improved activity and efficacy while reducing toxicity. Though retrospective, the combined results of MVAC modification would claim a benefit over either classic/dose-dense MVAC or CG in terms of efficacy and safety. A reappraisal of the upfront management of advanced/metastatic UC is warranted.
Combination effects of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and individual chemotherapeutics in non-small cell lung cancer (NSCLC) cells with and without sensitizing-EGFR mutations.
Authors: C. Tsai, K. Chang, C. Chiu, S. Hsiao
Journal: Journal of Clinical Oncology (2011)

e18062 Background: NSCLC cells harboring sensitizing-EGFR mutations are supposed to be more sensitive to the combination of EGFR-TKI and chemotherapy than EGFR wild type cells. We tested this theory in NSCLC cell lines. Methods: Using the MTT assay and the classical isobole method, we examined the combination effects of six gefitinib (G)-containing doublets, namely, G/C (cisplatin), G/Gem (gemcitabine), G/Pem (pemetrexed), G/P (paclitaxel), G/D (docetaxel) and G/V (vinorelbine) in a panel of 15 (3 harboring sensitizing-EGFR mutations) chemonaive NSCLC cell lines, in a concomitant administration schedule. Results: In the whole group of cell lines, overall results showed marked antagonism (ant) of G/C, additivism (add) of G/Gem, marginal synergism (syn) of G/P, marked syn of G/Pem, G/D and G/V, with the mean values of combination index (mCIs) were 1.184 (95% confidence interval: 1.12-1.24, P=0.001), 1.027 (0.948-1.107, P=0.683), 0.911(0.833-0.989, P=0.078), 0.814 (0.7-0.92, P=0.011), 0.870 (0.78-0.96, P=0.017), and 0.899 (0.816-0.982, P=0.041), respectively. The mCIs of G/C, G/Gem, G/Pem, G/P, G/D and G/V of the 3 sensitizing mutants were 1.116 (ant), 1.110 (ant), 0.993 (add), 1.077 (ant), 1.067 (ant), and 1.082 (ant), respectively. In contrast, the mCIs of the other 12 cell lines were 1.201 (ant), 1.007 (add), 0.769 (syn), 0.869 (syn), 0.820 (syn), and 0.853 (syn), respectively. The combination effects of gefitinib and single chemotherapeutic agents that act through a variety of anti-cancer mechanisms showed consistent low degree antagonism (G/Pem, additivism) in the sensitizing-EGFR mutants. In contrast, the combination effects were marked ant (G/C), add (G/Gem), or obvious syn (G/Pem, G/P, G/D and G/V) in cells with no sensitizing mutations. Conclusions: Concomitantly treated NSCLC cells harboring sensitizing-EGFR mutations with EGFR-TKI and individual chemotherapeutics showed a broad spectrum of antagonism. We hypothesize that the gefitinib hypersensitivity and associated oncogenic shock of these mutant cells resulted in the broad spectrum of chemo-refractoriness.
Missing the mark? Prostate cancer upgrading by systematic biopsy over fusion biopsy.
Authors: Akhil Muthigi, Arvin Koruthu George, Amogh Iyer, Michael Kongnyuy, Meet Kadakia, Raju Chelluri, Francesca Mertan, Thomas P Frye, Amichai Kilchevsky, Abhinav Sidana, Spencer Krane, Daniel Su, Maria J Merino, Ismail B. Turkbey, Peter L. Choyke, Bradford J. Wood, Peter A. Pinto
Journal: Journal of Clinical Oncology (2016)

62 Background: Multiparametric MRI (mpMRI) and fusion biopsy (FBx) detect more high risk prostate cancer (CaP) and less low risk CaP than standard systematic biopsy (SBx). However, there remains a small subset of patients where SBx captures higher grade disease than FBx. We aim to identify potential reasons for failure of FBx biopsy in detection of clinically significant (CS) CaP. Methods: A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by FBx and SBx in the same session from 2007−2014. Patients upgraded to higher risk disease based on SBx results relative to FBx were identified. Independent re−review of MR imaging in this subset was conducted to identify potential proximity between MR targets and SBx region which revealed higher risk CaP. Univariate analysis was performed to determine association of patient, MRI, and pathologic characteristics with upgrading by SBx. Results: We identified 1003 total patients who underwent mpMRI and biopsy, of which 564 were found to have CaP (56.2%). Upgrading based on SBx occurred in 137/564 (24.3%) patients, of which only 55 (9.8%) were to intermediate (high volume 3+4) [N = 37, 6.5%] or high risk CaP ( ≥ 4+3) [N = 18, 3.2%]. 41 of 55 patients (75%) had a lesion identified by mpMRI with FBx in the same sextant in which SBx biopsy revealed intermediate or high risk CaP. On univariate analysis, higher prostate volume (48cc vs 42cc, p &lt; 0.001) and lower percent core involvement (20% vs. 58%, p &lt; 0.001) were associated with upgrading by SBx. Conclusions: MRI rarely misses CS CaP and FBx, if accurate, should reflect the true disease state. Most gleason upgrades by SBx were to low risk, low volume CaP. In patients upgraded by SBx to CS CaP, mpMRI identified a targetable lesion in proximity to the SBx sextant in a majority of patients. FBx failure may be related to suboptimal imaging or biopsy related inaccuracy including registration error, miscalculation of target location, or inadequate lesion sampling. Other possibilities include presence of tumor heterogeneity, multi−focality within the same sextant, or low volume disease. Future studies with biopsy mapping on MRI will provide insight into mechanisms of failure in patients with overlapping target and sextant sampling.
The impact of aspirin and statin usage on the likelihood of advanced neoplasia at colonoscopy following a positive FOB screening test.
Authors: David Mansouri, Donald C. Mcmillan, Emilia M Crighton, Paul G. Horgan
Journal: Journal of Clinical Oncology (2013)

346 Background: There is increasing evidence that non-steroidal anti-inflammatory drugs, in particular aspirin, and statins can reduce the incidence and progression of colorectal cancer. However, studies examining this relationship within colorectal cancer screening are limited. Therefore the aim of the present study was to assess the impact of aspirin and statins on an individual’s risk of advanced neoplasia in a colorectal cancer screening programme. Methods: A prospectively maintained database of all patients in the first round of screening (April 2009 to March 2011) in our geographical was analysed. Medication usage was recorded prospectively at pre-colonoscopy assessment. The outcome measure was advanced neoplasia, which was defined as cancer or an intermediate or high risk adenomata (&gt;2 polyps, or &gt; 1 polyp &gt;1cm). Results: 4,631 individuals underwent colonoscopy following a positive FOBt of which complete results were available for 4,188 (90%) pts. Overall, 657 (16%) were on aspirin, 880 (21%) were on statins and 537 (13%) were on both. Colorectal pathology was associated with a positive FOBt in 3,043 (73%) pts. Aspirin usage was associated with a reduced likelihood of colorectal pathology being identified (OR 0.79 (0.66-0.95) p=0.012). In the 3,043 pts in whom colorectal pathology was identified, advanced neoplasia was seen in 1,704 (56%) pts. Patients with advanced neoplasia were more likely to be older (OR 1.38 (1.19-1.59)) and male (OR 1.66 (1.43-1.94)) (both p&lt;0.001). In contrast, those on aspirin (OR 0.68(0.56-0.83)), statins (OR 0.65 (0.55-0.78)) or both (OR 0.69 (0.55-0.86)) were less likely to have advanced neoplasia at colonoscopy (all p&lt;0.001). On multivariate analysis, use of both aspirin and statins (OR 0.60 (0.48-0.75) p&lt;0.001) remained independently associated with less advanced neoplasia. Conclusions: In patients undergoing colonoscopy following a positive FOBt with documented evidence of statin or aspirin usage, advanced neoplasia was less likely to be found. This suggests that usage of these medications may have a chemopreventative effect within the context of screening for colorectal cancer.
Relationship of hypoxia signature with variant subgroup of clear cell renal cell carcinoma (ccRCC) and its association with clinical activity on tivozanib hydrochloride.
Authors: Murray Owen Robinson, Bin Feng, Richard Nicoletti, Anna Berkenblit, Andrew Louis Strahs, Brooke Esteves, Timothy Eisen, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

361 Background: TIVO-1, a randomized Phase III trial in first-line targeted therapy for patients (pts) with ccRCC, demonstrated significant improvement in progression-free survival (PFS) in pts receiving tivozanib hydrochloride (T) vs. sorafenib (S) (11.9 vs. 9.1 months [12.7 vs. 9.1 in treatment-naïve pts]). To further characterize molecular ccRCC subtypes and assess relationships between subtypes and vascular endothelial growth factor tyrosine kinase inhibitor activity, we characterized available molecularly annotated datasets from TIVO-1. Methods: Tumor subtypes were established using hierarchical clustering and evaluated in two microarray ccRCC datasets using gene set enrichment analysis with 51 signatures representing a set of molecular phenotypes. A 9-gene signature comprising genes associated with hypoxia-inducible factor (HIF) transcription was quantified by RT-PCR on all available (69/517) formalin-fixed, paraffin-embedded material from patients using a predefined classifier score and cutoff. Results: Hierachical clustering generated 3 distinct tumor classes. Molecular clusters defining HIF gene expression (low), endothelial cell content (low), extracellular matrix (low), proliferation (high) epithelial cell phenotype (high), and metabolism (high) were differentially expressed in cluster 3 tumors, which represented approximately 15% of the populations. Based on predefined analysis, the hypoxia signature was significantly associated with better PFS on T using a previously established classifier (Table). The hypoxia signature was not significantly associated with PFS on S. There was no significant correlation to single largest diameter for either agent. Conclusions: A novel molecular subtype of ccRCC is characterized by a distinct molecular profile and can be classified by a low hypoxia signature. This hypoxia gene signature may help identify T responders. This signature is seen in subsets of other solid tumors supporting the broad exploration of this candidate T response biomarker. Clinical trial information: NCT01030783. [Table: see text]
Risks of thromboembolic events among patients diagnosed with metastatic pancreatic ductal adenocarcinoma treated with chemotherapy.
Authors: Bela Bapat, Sharvari Bhurke, Edward Rosen, Michael Stokes, Tarun Bhagnani, Beth Nordstrom, Sara Zaknoen, Ammar Qadan
Journal: Journal of Clinical Oncology (2016)

380 Background: Clinical trials suggest that patients with metastatic pancreatic ductal adenocarcinoma (mPDA) are at a high risk of thromboembolic events (TEs) as a result of both disease and treatment. Real-world data on TE rates are limited for patients with mPDA. Methods: Using a retrospective cohort design, patients with mPDA aged ≥ 65 years and treated with chemotherapy during 2007-2012 were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients enrolled in Medicare parts A, B, and D were followed from the start of first-line chemotherapy (index date) to the earliest of disenrollment from Medicare, death, or 12/31/2012. The baseline (BL) period was defined as 12 months prior to the index date. The incidence of TEs was calculated as the number of events per 100 person-years (PY) of follow-up (F/U) among patients without a BL TE. Anticoagulant use during F/U was categorized as preventive (before first TE, if any) and treatment (on or after first TE date) among patients with no BL TE. Results: Of 1,308 patients meeting the selection criteria, the mean age was 74 years, and 56% were female. The prevalence of TEs during the study period (BL or F/U) was 58% (n = 755). Excluding the 427 patients (33%) with TEs during BL, 328/881 (37%) of patients had a first TE during F/U, for an incidence rate of 85/100PY, including 29/100PY arterial and 59/100PY venous events. In the full study cohort, only 467/1,308 (36%) had a claim for any anticoagulant during the study period, although inpatient anticoagulant use is likely under-reported. Among patients receiving anticoagulants, 287/467 (61%) received low molecular weight heparin (LMWH). Preventive anticoagulant use was observed in 74/881 (8%) of patients without a BL TE; anticoagulation treatment was observed for 159/328 (48%) patients with a first TE during F/U. Conclusions: Real-world mPDA patients face a significant risk of TEs both before and after starting chemotherapy. Although inpatient use of anticoagulants including LMWH is incomplete in this database, it is clear that use of anticoagulants for treatment, and for prevention, of TEs is sub-optimal.
Copy number differences in EGFR and other amplicons between primary colon tumors and paired lymph node metastasis.
Authors: Vassiliki Liana Tsikitis, David Larson, Christina Preece, Spyros Tsavaridis, Patricia Thompson
Journal: Journal of Clinical Oncology (2012)

498 Background: Prior study, demonstrating differential immunohistochemical EGFR expression between the primary colon cancer and the liver metastasis, suggested possible molecular differences between the two tumor sites. This questions the relevance of obtaining genomic information from the primary tumor to guide adjuvant treatment. In this study we examine whether there are genomic differences specific to metastatic nodes versus the paired colon primary samples. Methods: Using 30 primary and lymph node metastasis pairs (dissected for &gt;80% tumor from paraffin embedded tissue), we obtained a dataset of copy number derived from the Affymetrix Oncoscan Molecular Inversion Probe platform. Using the Nexus Copy Number software for processing, we used the default automatic segmentation of the copy number data with a threshold for calling copy number gains/losses of 2.3/1.7. Subsequently we applied the Wilcoxon signed-rank test in order to find regions showing copy number imbalance that differ between the paired nodes and tumors correcting for multiple comparisons by performing permutation-based estimation of the false discovery rate permuting the samples 100 times. Results: Using 40 ng of total DNA from paraffin embedded tumor from primary and tumor in positive nodes, we obtained high quality, genome wide copy number data. Using FDR &lt; 0.1, we identified four chromosomal segments that showed statistically significant increased likelihood of copy number gains in the primary tumor compared to the tumor-containing node. Thirty five percent of tumor-bearing lymph nodes were copy number normal at the EGFR locus whereas the corresponding primary tumor showed amplification at 7p11.2 (includes the EGFR gene). A similar pattern was observed for 8q24, 14q11.2, and 20q12-q13; regions associated with aggressive tumor behavior. Conclusions: Our results demonstrate four significant differences between the primary tumor and lymph node metastasis and in all cases the metastasis were copy number normal compared to the copy number gain observed in the primary tumor. These results support the importance to examine differences at the genome level between the metastatic tumor site and the primary.