tbuckley/cabot-search huggingface dataset:
Retrospective claims database cost analysis of second-line sorafenib (SR) or sunitinib (SR) therapy in treatment of patients (pts) with renal cell carcinoma (RCC).
Authors: E. Moyneur, T. B. Dorff, V. Barghout, S. Meyers, J. Hu, D. I. Quinn
Journal: Journal of Clinical Oncology (2010)

e16521 Background: Authors have shown that 1st-year medical costs of SR were less than SU in initial treatment of RCC pts and that baseline comorbidities were similar. Case series data suggest RCC control is common when either SR or SU is used sequentially. We investigated direct medical costs associated with each sequence. Methods: We conducted a retrospective U.S. claims-based analysis using MarketScan covering all U.S. census regions and >18 million lives annually from 2002 to 2009. Pts with ≥2 RCC claims (ICD9 189.0 and 198.0), continuous health care coverage, ≥1 switch from SR to SU or SU to SR, and >180 days' coverage before switch date were included. Observation period began with 1st-line therapy ≤12 mo before switch and ended ≤12 mo after switch. Second-line therapy (switch) ended with next dispensing of SR, SU, bevacizumab, or temsirolimus; disenrollment; death; or study end (3/31/09). A person-time approach was used. Limitations include physician coding and lack of disease staging. Results: At time of switch, the only significant differences between SU>SR (n=153) and SR>SU (n=119) groups were longer health plan enrolment in SR>SU group (12.4 vs 8.8 mo; p<0.0001) and higher prevalence of anemia in SU>SR group (52.9% vs 32.8%, p<0.001). Demographics, prior tumor removal, and/or shrinkage procedures were similar between groups. Univariate incremental total per member per month (PMPM) medical cost for SU>SR pts was $1639 (p=0.0003) more than SR>SU pts, representing yearly cost savings of $19,668 in RCC pts initially treated with SR. Conclusions: This retrospective claims database analysis suggests statistically significantly lower costs in RCC pts initially treated with SR, the difference mainly attributable to outpatient costs. These data mandate cost analyses as part of prospective trials of sequencing in RCC. Univariate analysis from ≤12 mo of 1st-line therapy to ≤12 mo of 2nd-line therapy Mean weighted costs PMPM, $ SU>SR SR>SU Incremental cost of receiving SU first P value Total medical cost 9,159 7,520 1,639 0.0003 Outpatient 3,400 2,148 1,252 <0.0001 Inpatient 1,755 1,582 173 0.6179 Pharmacy 4,004 3,790 214 0.1077 Pt-mo (n) 1,571 1,730 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche Bayer Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche Bayer, Genentech
A multicenter phase II study of cisplatin (C), gemcitabine (G), and bevacizumab (B) as first-line chemotherapy for metastatic urothelial carcinoma (UC): Hoosier Oncology Group GU-0475
Authors: N. M. Hahn, W. M. Stadler, R. T. Zon, D. M. Waterhouse, J. Picus, S. R. Nattam, C. S. Johnson, S. M. Perkins, M. J. Waddell, C. J. Sweeney
Journal: Journal of Clinical Oncology (2009)

5018 Background: Despite CG therapy, most metastatic UC patients die from their disease. Novel approaches are needed. Combining anti-angiogenic therapy with chemotherapy has improved outcomes in other malignancies, offering hope for similar improvements in UC patients. Methods: Metastatic or unresectable chemonaive UC patients (pts) with an ECOG performance status of 0–1 received C 70 mg/m 2 iv d1, G 1,000–1,250 mg/m 2 iv d1, 8, and B 15 mg/kg iv d1 on a q21d cycle for up to 8 cycles. Gemcitabine was reduced to 1,000 mg/m 2 iv d1, 8 for all subsequent pts after 7 thromboembolic events were noted in the first 17 pts. The primary endpoint was progression free survival (PFS). The trial was designed to detect a 33% improvement in PFS from 7.5 months with traditional CG therapy to 11.25 months with CGB. Results: By December 2008, 45 pts were enrolled, with 43 evaluable for toxicity, 36 for response. Demographics include: 33 (77%) male, 10 (23%) female; median age 66 (Range: 41 - 78); 26 (60%) and 17 (40%) ECOG 0/1; 19 (44%) and 24 (56%) lymph node only / visceral metastases. PFS will be evaluated in May 2009 when all pts will have more than 6 month follow-up data. 14 (33%) and 6 (14%) pts experienced grade 3 or 4 hematologic toxicity (4 pts - thrombocytopenia, 2 pts - neutropenic fever). Grade 3 or 4 nonhematologic toxicity was observed in 24 (56%) and 9 (21%) pts (DVT/PE - 9 pts, CNS hemorrhage/proteinuria/hypertension - 1 pt each) Best RECIST response was: complete response 6 pts (17%, 95% CI 6–33%), partial response 18 pts (50%, 95% CI 33–67%); with overall response rate of 67% (95% CI 51–82%). Stable disease lasting at least 12 weeks was observed in 10 pts (28%, 95% CI 14–45%) and progressive disease in 2 pts (5%, 95% CI 1–19%). Conclusions: CGB demonstrates significant clinical activity in the first-line treatment of metastatic UC patients at the expense of considerable toxicity. The durability of disease control will be determined by assessment of PFS. A phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to platinum-based doublets is planned in this population. [Table: see text]
Use of a novel biomarker HE4 for monitoring patients with epithelial ovarian cancer
Authors: J. Allard, E. Somers, R. Theil, R. G. Moore
Journal: Journal of Clinical Oncology (2008)

5535 Background: The serum biomarker CA125 is effectively used for monitoring response to therapy and monitoring for recurrent disease in patients with epithelial ovarian cancer (EOC). However, CA 125 is not elevated in approximately 20% of patients. The novel tumor marker HE4 has been shown to be elevated in the majority of EOC patients as well as in patients that do not express CA125. The object of this study was to determine the concordance between HE4 and CA125 in patients being followed with EOC. Methods: This was a retrospective study utilizing serum samples obtained from an IRB approved serum bank. Serial samples from patients either undergoing treatment for EOC or being monitored for recurrence were obtained. Clinical status of the patients was assessed through serial CA125 and CT imaging with documentation of regression or progression of disease or absence of disease over time. Serum CA125 and HE4 levels were measured using the Architect CA 125II assay and the HE4 EIA assay. Serial changes in the serum CA125 and HE4 levels were compared to the documented clinical status using a cutoff of 25%. Concordance between HE4 and CA125 was determined and the performance of CA125 and HE4 was compared directly using a non-inferiority approach. Results: A total of 434 serial samples from 80 patients either undergoing treatment for EOC or being monitored for recurrence were obtained. Longitudinal analysis of the serum sample sets showed that changes in HE4 values were not inferior to changes in CA125 values in accordance with clinical status (p=0.039). CA125 correlated with clinical status in 78.8% (63/80) and HE4 correlated in 76.2% (61/80). In patients where CA125 did not correlate with clinical status, HE4 correlated in 23.5% (4/17). In patients where HE4 did not correlate with clinical status, CA125 correlated in 31.6% (6/19). In consideration of all cases either CA125 or HE4 correlated with clinical status for 83.8% (67/80). Conclusions: HE4 is a valuable biomarker for the majority of patients with EOC and behaves in concordance with CA125 in patients with EOC. As well, HE4 is a valuable marker for the management of some patients where CA125 is not of clincal utility. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Fujirebio Diagnostics, Inc Fujirebio Diagnostics, Inc, Thiel Statistical Consultants Fujirebio Diagnostics, Inc Fujirebio Diagnostics, Inc
Leukemia Initiating Cells In Acute Lymphoblastic Leukemia Are Characterized By Low Metabolic Activity and Enriched In Early Cell Cycle
Authors: Luca Trentin, Manon Queudeville, Sarah M Eckhoff, Manuel Herrmann, Simone Miller, Sandra Lutz, Nabiul Hasan, Klaus-Michael Debatin, Lueder H Meyer
Journal: Blood (2013)
High-resolution methylome analysis of renal cell carcinoma and identification of aberrant epigenetic changes in gene bodies.
Authors: C. Y. Hu, D. Mohtat, Y. Yu, T. Bhagat, C. J. Heuck, K. Ware, A. Hakimi, R. Ghavamian, J. Pullman, K. Susztak, A. Verma
Journal: Journal of Clinical Oncology (2011)

e15000 Background: Metastatic renal cell carcinoma (RCC) has a very poor prognosis with limited therapeutic options. Despite this, there have been very few global genetic and epigenetic studies of RCC. DNA methylation is an epigenetic change that has been extensively studied in cancer, but most studies have focused on changes in promoters and CpG islands. We utilized a novel high resolution, high throughput assay, the HELP (HpaII tiny fragment enrichment by ligation-mediated PCR) assay, to determine DNA methylation in RCC. The HELP assay examines CpG methylation at 1.3 million loci in the genome, including promoters, gene bodies and intergenic regions, making it the most comprehensive study of the RCC methylome available. Methods: We performed the HELP assay on 13 clear cell RCC and 13 control samples. The HELP assay compares restriction enzyme digestion with a methylation-sensitive enzyme (HpaII) to a methylation-insensitive enzyme (MspI) at CCGG sequences in the genome. These digestion fragments are amplified by PCR, fluorescently labeled, and co-hybridized onto a custom microarray. Methylation can be determined at each loci by comparison of the HpaII to MspI signal. Results: Unsupervised clustering showed that the RCC samples were epigenetically distinct and clustered completely separately from controls. Next, we determined common epigenetic alterations in all samples of RCC and observed that these tumors are characterized by a dramatic hypermethylation of a large number of loci in the gene bodies when compared to controls. Ingenuity pathway analysis of genes that were methylated and underexpressed in RCC revealed the TGFβ1 pathway to be the dominant pathway affected by epigenetic silencing, while cell death and cancer were two major biological functions influenced by epigenetic methylation. Conclusions: The HELP assay revealed widespread novel epigenetic changes and identified differentially regulated genes in RCC. This is the first study of DNA methylation changes in gene bodies in RCC. We hope to correlate methylation profiles with clinical response to uncover novel signatures of prognosis in RCC and identify new therapeutic targets within its epigenome.
Hereditary Retinoblastoma: Host Resistance and Second Primary Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: E Matsunaga
Journal: JNCI Journal of the National Cancer Institute (1980)

Data for 26 cases of nonradiogenic osteosarcomas that developed in patients with retinoblastoma and in their close relatives were collected from the literature and analyzed. The distribution of unaffected and unilaterally and bilaterally affected cases of retinoblastoma agreed with the expectation that risk to osteosarcoma did not differ by the phenotypes of the gene carriers. This finding indicated not only that increased risk to second primary tumors was a pleiotropic effect of the retinoblastoma gene but also that host resistance to the gene effects was tissue-specific. The risk of gene carriers to nonradiogenic osteosarcoma was estimated at 1.2%, and the relative risk was estimated at 230. Liability of the gene carriers to osteosarcoma could be regarded as a multifactorial threshold character, and heritability was estimated at 71%. Results of analyses of ages at diagnosis suggested that nonradiogenic osteosarcoma developed slightly earlier in carriers of the retinoblastoma gene than in children not carrying the gene. These findings are discussed in the light of the host resistance model in which genes involved in tissue resistance must be suppressors to an error in differentiation (presumably a crucial event in malignant transformation) and radiogenic osteosarcoma in gene carriers is ascribed to the accumulation of induced mutations in that suppressor system.
Filgrastim as an Alternative to Donor Leukocyte Infusion for Relapse After Allogeneic Stem-Cell Transplantation
Authors: Michael R. Bishop, Stefano R. Tarantolo, Z. Steven Pavletic, James C. Lynch, Mary E. Morris, Diane Zacharias, James O. Armitage, Anne Kessinger
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. PATIENTS AND METHODS: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. RESULTS: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively. CONCLUSION: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT.
Low expressions of surfactant-associated protein (SP-A) in cancer tissues or in normal bronchial epithelial cells by immuno-histochemistry predict interstitial lung diseases (ILDs) induced by gefitinib in patients with advanced non-small cell lung cancer (NSCLC)
Authors: K. Tamura, I. Okamoto, T. Kurata, T. Satoh, K. Nakagawa, M. Fukuoka
Journal: Journal of Clinical Oncology (2005)

7188 Background: Gefitinib, an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is an effective treatment for patients with non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) induced by gefitinib has been reported as a severe adverse effect, and the incidence of the ILD is likely much higher in Asia than in western countries. We have previously reported that frequency and mortality rate of ILD in Japan were 3.5% and 1.6%, respectively (Proc. Am. Soc. Clin. Oncol. 23, Abs.7064, 2004.) Although, predictive clinical backgrounds of ILD by multivariate analysis were male, current/former smoker or hypoxia before the treatment of gefitinib, biological predictive marker is little known. EGF stimulates surfactant-associated protein A (SP-A) synthesis in fetal lung tissue through ligand binding to EGFR. Tyrosine kinase inhibitor or anti-sense against EGFR decreases expression of SP-A in vivo, or in vitro. Methods: We determined SP-A protein expression levels in cancer tissues or in normal bronchial epithelial cells by immuno-histochemistry using a specific antibody in paraffin embedded specimens from NSCLC patients before the treatment of gefitinib. We have retrospectively reviewed each 10 patients who have incidence of ILD or no incidence of ILD, receiving equally gefitinib at a dose of 250 mg once daily. Results: SP-A expression in cancer tissues was not detectable in Pt with ILD (0/10) in contrast with 50% (5/10. All five have above +2 exp. Level.) in Pt with non-ILD (p<0.05). SP-A expression in normal bronchial epithelial cells was 20% reactive (2/10. Both have +1 exp. Level.) in Pt with ILD, on the other hand, 80% (8/10). in Pt with non-ILD (p<0.05). Thus, low expressions of SP-A were associated with the incidence of ILD induced by gefitinib. EGFR expression in tumor or normal alveolar epithelium was not correlated with incidence of ILD. Conclusions: SP-A expression levels in cancer tissue or in normal bronchial cell before the treatment of gefitinib are potent biomarkers to predict ILD. No significant financial relationships to disclose.
Phase Ib study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI with or without bevacizumab (BV) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).
Authors: A. D. Baron, C. L. O'Bryant, Y. Choi, S. Royer-Joo, C. C. Portera
Journal: Journal of Clinical Oncology (2011)

532 Background: Drozitumab is a monoclonal antibody that triggers tumor cell apoptosis by selective agonistic interaction with the Apo2 ligand/TNF-related apoptosis-inducing ligand death receptor 5. This study assessed the safety of drozitumab combined with two standard IRI- containing regimens in previously treated mCRC pts. Methods: Multicenter, open-label, dose-escalation study with treatment until disease progression or treatment intolerance. For CET+IRI regimen (Cohorts 1-4), a 21-day cycle (cy) = drozitumab on Day 1 at escalating doses of 1, 4, 10, or 15mg/kg, IRI on Day 1, and CET on Days 1, 8, and 15. For FOLFIRI (Cohort 5), a 14-day cy = drozitumab on Day 1 given as a 10 mg/kg loading dose followed by 7 mg/kg in continuing cys, with FOLFIRI (plus BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 doses of drozitumab (29 days for CET+IRI; 28 days for FOLFIRI). Adverse events (AE) were recorded through all cys. Response was assessed by RECIST. Results: 14 pts received a median of 6.5 cys (range 2-21) of drozitumab with CET+IRI and 6 pts received a median of 12 cys (range 3-21) of drozitumab with FOLFIRI. No DLTs occurred at the time of dose escalation. The most frequent AEs were diarrhea (85%), fatigue (80%), nausea (80%), alopecia (70%), neutropenia (70%), and decreased appetite (50%). Most of the toxicities were grades 1-2. The most frequent grade ≥3 AEs were neutropenia (60%), diarrhea (15%), hypokalemia (15%), and leukopenia (15%). Two pts discontinued due to AEs: 1 grade 2 fatigue, 1 grade 3 pyrexia. Among the 20 total pts, best responses included 3 partial responses (2 confirmed, 1 unconfirmed), 12 stable disease and 5 progressive disease. The study enrollment was stopped early by the sponsor for reasons unrelated to safety or efficacy. Conclusions: The addition of drozitumab to two standard second-line IRI-containing regimens (CET+IRI or FOLFIRI ± BV) was well tolerated in mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses suggest no adverse interactions between drozitumab and the chemotherapy evaluated in this study. [Table: see text]
Relationship between dose, exposure, and antitumoral activity of sorafenib in melanoma.
Authors: N. Pécuchet, M. Avril, D. Kerob, B. Billemont, B. Blanchet, P. Herait, I. Gorin, M. Viguier, C. Lebbé, F. Goldwasser
Journal: Journal of Clinical Oncology (2010)

8582 Background: Interpatient variability in sorafenib (SOR) bioavailability and too-early treatment discontinuation might account for poor efficacy results of SOR in melanoma. A cohort of poor prognosis patients (pts) received dose-escalated SOR. Methods: In absence of limiting toxicity, dose was escalated every 2 weeks. Plasma SOR measurement is routinely made in our institution allowing retrospective pharmacokinetics analysis. A total of 163 plasma samples were assessed by HPLC with UV detection method and analyzed using nonlinear mixed-effects modeling. Results: 28 pts/24 evaluable for response. Median (M) age 57 (31-80), PS≥ 2: 28%. Primary: cutaneous (75%), choroid (11%), other (14%). 89% AJCC stage IV M1c, >2 sites: 71%; lung, liver and brain mets in 57%, 61%, and 32% of pts. LDH>N: 54%; Previous chemotherapy: 93%; M higher tolerable dose of SOR: 800 mg BID (range: 200-4000 mg), M treatment duration: 2.6 months (0.4-11.8). Overall response rate was 21%: 1 (4%) complete and 4 (17%) partial responses, 11 (46%) stable, and 8 (33%) progressive disease. M TTP: 3 months. M overall survival: 9.4 months (50% censored at the time of analysis). 2 groups are of interest: 1) SOR responders (5 pts): M PFS was 6 months (3-8) and M survival was 11.3 months (9.6-18.7). 2) 11 pts with initial overall PD but at least one responding site and consequently receiving increasing dose of SOR: M PFS: 6 months (0.7-8), M survival: 9.6 months (2.6-15.3). M survival in pts with brain mets: 5.4 (2.6-15.4) months. Relation between dose and AUC was infra-proportional. There was a trend for higher rate of disease progression in pts with SOR AUC below the mean AUC of the population: 45.5% versus 27.3%. Conclusions: Dose-individualization with PK-monitoring might prevent under-exposure to fixed-dose SOR, benefit to pts with dissociated response, and account for these PFS and OS results. Dose BID Median AUC mg/L.h Pts Samples 200 29.5 1 1 400 48.4 4 4 800 57.6 25 74 1,200 85.6 13 26 1,600 73.3 13 27 2,000 105.0 6 6 2,400 75.0 3 11 2,800 138.9 2 3 3,200 97.9 1 3 4,000 49.0 1 1 4,400 70.1 1 4 5,200 52.3 1 3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Bayer, Novartis, Pfizer Amgen, Bayer, Novartis, Pfizer