tbuckley/cabot-search huggingface dataset:
The safety and tolerability of veliparib (V) plus capecitabine (C) and radiation (RT) in subjects with locally advanced rectal cancer (LARC): Results of a phase 1b study.
Authors: Brian G. Czito, Mary Frances Mulcahy, Dustin A. Deming, Houman Vaghefi, Gayle S. Jameson, Angela Deluca, Hao Xiong, Wijith Munasinghe, Matthew W. Dudley, Philip Komarnitsky, Kyle D. Holen, Michael Michael
Journal: Journal of Clinical Oncology (2015)

579 Background: Patients (pts) with LARC treated with neoadjuvant C/RT and then surgery have low rates of pathologic complete response (ypCR) and significant relapse rates. V is a potent, orally bioavailable PARP inhibitor that has been shown to enhance the efficacy of chemotherapy and RT in preclinical models. This study sought to establish the recommended phase 2 dose (RPTD), as well as to assess safety, pharmacokinetics (PK), and preliminary activity of V + RT/C in pts with LARC. Methods: Pts with stage II-III rectal cancer received RT (50.4Gy/1.8Gy/fraction) with C (825 mg/m 2 BID) five days per week (W) for 5.5W. Dosing of V (BID, 20mg-400mg) continued from W1D2 to 2 days past RT. Pts underwent surgery 5-10W following RT. Assessments included identification of RPTD with the Exposure Adjusted Continual Reassessment Method, adverse events (AEs), PK, and pathological response (ypCR and tumor downstaging rates). Results: As of August 5, 2014, 30 pts have been enrolled, 24/6 male/female, median age 58 yrs; 1 pt discontinued due to an AE. The most common treatment-emergent AEs possibly or probably related to V (&gt;15% pts, n &gt;4) were nausea (40%), fatigue (37%), diarrhea (30%), vomiting (20%), and dysgeusia (17%). One grade 3/4 event each of anemia and lymphopenia and 2 grade 3/4 events of diarrhea were deemed at least possibly related to V. Two dose limiting toxicities (DLTs) occurred: 1 at 70 mg BID V (radiation skin injury requiring dose interruption); 1 at 400 mg BID (nausea and vomiting requiring discontinuation). The RPTD is 400 mg BID of V in combination with RT/C. PK results from 16 pts suggest that V PK was approximately dose proportional when administered with RT/C and that V had no effect on the PK of C. To date, 18/25 (72%) pts have been downstaged post-surgery; with 7/25 (28%) achieving ypCR. Conclusions: V at 400 mg in combination with RT/C has an acceptable safety profile. 72% of 25 evaluable patients had tumor downstaging post-surgery, including 28% with ypCR. Dose escalation of V resulted in approximately dose-proportional increases in the V PK with no clear effect on C PK. Clinical trial information: NCT01589419.
The extent of lymphadenectomy and overall survival depend on the timing of radiotherapy for rectal cancer.
Authors: M. N. Le, B. A. Mailey, W. Lee, M. P. Duldulao, J. Garcia-Aguilar, J. Kim
Journal: Journal of Clinical Oncology (2011)

540 Background: Accurate staging and local disease control depend on the extent of lymphadenectomy (LAD) in rectal cancer. Previous studies suggest that lymph node (LN) number varies with neoadjuvant therapies. Our objectives were to measure the impact of timing of radiotherapy on extent of LAD and to determine the prognostic role of LN number in rectal cancer. Methods: Patients undergoing curative-intent surgery for rectal adenocarcinoma (1988-2006) in Los Angeles County were identified from the Cancer Surveillance Program. Patients were grouped according to radiotherapy timing (neoadjuvant, adjuvant, or none). To measure prognostic significance, an optimal cutoff was assessed for patients with N0 disease by dichotomizing LN numbers from 3-7. Results: Query of the registry identified 6,358 patients. Of these, 20% (n = 1,280), 25% (n = 1,573), and 55% (n = 3,545) received neoadjuvant, adjuvant, and no radiotherapy, respectively. There was no difference in LN number in patients with and without radiotherapy (7 vs. 8 LNs, p = NS). However, within the radiotherapy cohort, there was significantly lower LNs in the neoadjuvant group (5 vs. 9 LNs, respectively; p &lt; 0.001). Survival differences favored the groups with higher LN number. The optimal LN cutoff with no survival difference was 7 in the adjuvant radiotherapy group; there was no optimal cutoff for neoadjuvant therapy patients. Conclusions: From our population-based cohort, we observed that patients receiving neoadjuvant radiotherapy had decreased LN retrieval and that LN number was non-prognostic. In contrast, the extent of LAD is a prognostic factor for overall survival in patients receiving adjuvant radiotherapy. [Table: see text] No significant financial relationships to disclose.
A novel potential biomarker to monitor treatment response in gastric cancer.
Authors: Maria J. Maturana, Marcelo Garrido, Lidia Medina, Milenko Slako, Ricardo Funke, Francisco Acevedo, Claudia Giraldo, Marianela Sanchez, Cesar Munoz, Alejandro Corvalan
Journal: Journal of Clinical Oncology (2012)

55 Background: Gastric cancer (GC) is the second leading cause of death from cancer worldwide. No clinical useful biomarkers that detect early gastric cancer and have prognostic/predictive value are available. DNA methylation of promoter region of Reprimo (RPRM), a p53-dependent G2 arrest mediator candidate gene, has been postulated as a potential biomarker for early diagnosis of GC (Clin Cancer Res. 2008;14:6264-9). Since RPRM has been found methylated in more than &gt;90% of GC cases, we evaluate RPRM as a biomarker for monitoring response to treatment. Methods: We enrolled 28 patients with GC. Staging classification was carried out by AJCC system and evaluation of clinical response by RECIST criteria. DNA was obtained from plasma/serum by Proteinase K/quiagen and bisulfite converted by EZ DNA Methlyation Direct Kit (Zymo Research). Absolute quantification of DNA Methylation in serum/plasma of RPRM was performed by MethyLight technology. The IRB of PUC approved this study. All patients gave informed consent. Results: Among 28 patients with histological diagnoses of GC, average age was 64 y.o.(38-81 y.o.), male/female ratio 1.3/1, number of cases stage I 2, stage II 4, stage III 8, stage IV 13 and In situ or with preneoplastic lesions 3 patients. 13 patients underwent total gastrectomy and 19 cases received standard chemotherapy (CHM), 6 of them on a neoadjuvancy basis. At initial diagnoses, RPRM was detected in 67,8% (19/28) of patients (X 1049,7 copies per mL[49-11991]). 79% of patients had an objective response with one patient developing a complete response. In cases with clinical response, and at least two detections of RPRM, agreement was 81% with RPRM levels. At the end of study, one third of the patients finally died of gastric cancer. Interestingly, the average initial level of RPRM was higher on those with a fatal outcome (1822 vs 483 copies per mL). The two highest levels were seen on patients who developed a rapid progressive disease and died within months of diagnosis. Conclusions: RPRM could be a potential biomarker to monitor treatment-response in GC. Levels of RPRM may anticipate clinical progression. All these findings should be evaluated in a large, prospective clinical trial.
Insurance Reform in a Voluntary System: Implications for the Sick, the Well, and Universal Health Care
Authors: American College of Physicians*
Journal: Annals of Internal Medicine (1996)

In the absence of universal coverage, carefully designed insurance reforms can make health insurance in the individual and small-group markets more affordable for those who need it most--the sick--and more secure for all subscribers. In this position paper, the American College of Physicians calls for specific strong reforms at both the state and federal levels. Substantial reform of the insurance marketplace is a necessary step toward achieving universal coverage. It should reflect the view that providing quality health care is in the best interests of the community and that health care financing should be a community responsibility.
The utilization of chemotherapy and radiation at the end of life in individuals with metastatic non-small cell lung cancer.
Authors: Mark J. Stavas, Sara F. Martin, Sharon E. Phillips, Stephanie Mabry Perkins, Eric T. Shinohara
Journal: Journal of Clinical Oncology (2015)

143 Background: Advancements in the diagnosis and treatment of metastatic non-small cell lung cancer (NSCLC) have contributed to improved quality of life and survival. However, these successes are matched with rising healthcare costs and a growing debate over the appropriate utilization of medical resources near the end of life. To date, the majority of utilization studies report outcomes based on single institution or Medicare models. This may lead to significant bias due to individual physician preferences, narrow age groups or single payer systems. The purpose of this study is to analyze the broader trends and variables impacting the use of chemotherapy (CHT) and radiation (XRT) in the final months of life. Methods: The Florida Cancer Data System (FCDS) was used to evaluate patients with Stage IV (M1) NCLC from 1995 to 2010. Logistic Regression was used to determine the association between insurance types, census-based socioeconomic status (SES) and demographic variables with XRT received or CHT received. Results: 48,858 patients were identified within the FCDS and eligible for this study. The median age was 69 years. The median survival was 4.8 months. The overall use of XRT decreased between 1995 and 2010 from 52% to 37%, while the use of CHT increased from 35% to 49%. The utilization of treatment during the final 60, 30 and 14 days of death was 28%, 13% and 5% respectively for XRT, and 18%, 8% and 4% for CHT. Neither insurance status (OR, 0.852; 95% CI, 0.721 -1.174) nor poverty status (OR, 1.026; 95% CI, 0.950 -1.109) was predictive for XRT received. Those classified as low SES (OR, 0.685, 95% CI, 0.633-0.741) or not insured (OR, 0.678, 95% CI, 0.572-0.804) were less likely to receive CHT. Older-unmarried-females were less likely to receive CHT and XRT compared to their younger-married-male counterparts. Conclusions: When examining a broader demographic and insurance mix, the utilization of XRT and CHT in the final 30 and 14 days of death remain low at 13% and 5% for radiation and 8% and 4% for chemotherapy consistent with previously reported studies. Younger-married-males were more likely to receive palliative treatments. Insurance and SES did not influence the delivery of XRT while they did impact the use of CHT.
The effect of the CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of ZD6474 in healthy subjects
Authors: R. Smith, S. Oliver, P. Ghahramani, S. Kennedy, E. Gilmore, T. Duvauchelle, T. Hammett
Journal: Journal of Clinical Oncology (2005)

3124 Background: ZD6474 selectively targets two key pathways in tumor growth by inhibiting VEGF receptor-2 and EGFR tyrosine kinase activity. ZD6474 is orally active and shows antitumor activity in a range of human tumor xenografts. Because the CYP3A4 isoenzyme is likely to contribute to the metabolism of ZD6474, this study assessed the effect of itraconazole (IT), a potent inhibitor of CYP3A4, on the pharmacokinetics (PK) of ZD6474. Methods: Sixteen healthy male volunteers (mean age 30.2 years, range 20–44) were enrolled in a randomized, open-label, two-period, cross-over study. Subjects were randomized into two groups of eight. One group received 24 daily doses of IT (200 mg, days 1–24) plus a single oral dose of ZD6474 (300 mg, day 4), and the other received a single oral dose of ZD6474. After a 3-month washout period, subjects were crossed-over to receive the alternative regimen. Blood sampling for PK was performed regularly throughout the study. Subjects were also assessed for tolerability, including ECG monitoring. Results: Compared with ZD6474 alone, IT treatment increased ZD6474 AUC0–504 by 9% (90% CI: 1.01–1.18). This increase was statistically significant, but was not considered to be clinically relevant. There was also a trend for an increased t1/2 of ZD6474 in the presence of IT (mean 235.5 h, CV 19.39%) compared with ZD6474 alone (mean 209.2 h, CV 25.86%). Cmax was not significantly different between treatments (mean difference -4%; 90% CI: 0.83–1.11). Tmax was similar for ZD6474 alone (median 5 h, range 3–7) vs ZD6474 with IT (median 5 h, range 3–12). ZD6474 in the presence and absence of IT was well tolerated in this study. Conclusions: The increase in ZD6474 AUC0–504 during administration of IT, a potent CYP3A4 inhibitor, is a relatively minor PK interaction. This increase was considered to be due to a reduction in the systemic clearance of ZD6474 (indicated by the trend for an increased t1/2) caused by IT-mediated inhibition of CYP3A4, rather than because of a change in bioavailability. ZD6474 was well tolerated in this population and its concomitant use with CYP3A4 inhibitors is not expected to result in a PK interaction. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Outcomes of multimodality therapy for gallbladder cancer in the United States (US): Analysis of the National Cancer Data Base (NCDB).
Authors: Fatima Hamid, Hammad Shafqat, Kalyan Mantripragada, Thomas Guerrero, Ponnandai Somasundar, Adam J. Olszewski
Journal: Journal of Clinical Oncology (2016)

313 Background: Management of gallbladder cancer (GBCA) is largely based on small observational studies, and it is unknown how various treatment modalities are applied in the community. The objective of this study was to describe the utilization of surgery (S), chemotherapy (Ct) and chemoradiation (CRT), and associated overall survival (OS) in the US. Methods: We selected adult patients (pts) with GBCA diagnosed in 2004-2012 from the NCDB—a population-wide registry capturing &gt; 70% of incident cancers in the US. We identified pts undergoing S, Ct and concurrent CRT. We assumed adjuvant (Adj) therapy if it was started within 4 months (mo) of S. Stage was grouped as: T1-T3N0, node-positive (N+), T4 (N0 or N+) or metastatic (M1). OS was calculated from diagnosis, with 95% confidence intervals (CI). Results: We identified 22,574 GBCA pts. Median age was 71 years. There were 69% women, 71% white non-Hispanic, 10% white Hispanic, 14% black and 4% Asian pts. Distribution of stage groups was: in situ, 4%; T1N0, 8%; T2N0, 16%; T3N0, 13%; N+, 14%; T4, 3%; M1, 38%; unknown, 4%. Most non-metastatic pts underwent S, but only a minority received Adj Ct or CRT (Table). Among M1 and T4 pts, 44% received Ct, but 29% got no cancer-directed therapy. Median OS for M+ or T4 pts was 4 and 7 mo, respectively. It was 8 and 11 mo, respectively, if Ct was given. Conclusions: These OS estimates provide realistic prognosis for GBCA pts treated with various modalities in the US. Adj therapy is rarely delivered in locally advanced (T3N0 or T1-3N+) GBCA. Survival in T4 and M1 GBCA remains poor even with palliative Ct. Novel therapeutic approaches for GBCA of all stages are needed. [Table: see text]
Trends in utilization of oncology drugs for Medicare fee-for-service beneficiaries from 2002 through 2009.
Authors: K. B. Tong, N. Coustier, A. Layton
Journal: Journal of Clinical Oncology (2011)

e16625 Background: Medicare expenditures and the use of oncology drugs have increased over time. Shahinian, VB, et al (NEJM 2010) determined that changes in Medicare reimbursement policy in 2004 and 2005 were associated with reductions in the use of androgen deprivation therapy. The objective of this study is to evaluate trends in the use of oncology drugs from 2002 through 2009 both before and after changes in Medicare reimbursement policies. Methods: All data were obtained from the Physician/Supplier Procedure Summary (PSPS) Master File from the Centers for Medicare & Medicaid Services (CMS). This PSPS file includes 100% of all Part B carrier claims. The file is arrayed by carrier, pricing locality, Healthcare Common Procedure Coding (HCPC), modifiers, specialty, type of service and place of service. Data are reported for total submitted services and charges and allowed services and charges. Oncology drugs administered and billed in the physician office setting are included in the PSPS file. Oncology drugs administered in other settings of care (e.g., hospital inpatient and outpatient), as well as drugs paid for under Medicare Part D (Prescription Drug Coverage) are not included. Results: Allowed charges for oncology drugs (HCPC codes J9000 through J9999) under Part B increased 28% from US $3.2B in 2002 to US $4.0B in 2009 (3.6% compounded annual growth rate). In 2002, Leuprolide Acetate had the highest allowed charge ($680 million). In 2009, the highest allowed charges were for Rituximab ($844 million; indications including non oncology) followed by Bevacizumab ($774 million). Total allowed charges slowed to 1.6% in 2004 and negative 9.4% in 2005 before rising again in 2006 through 2009 (p<0.01). Conclusions: Increases in Medicare Part B expenditures for physician administered oncology drugs from 2002 through 2009 were in line with overall increased in health care costs. However, year to year changes in allowed charges may have been affected by the aging of the population, cancer prevalence, introduction of new technologies, generic competition, changes in reimbursement policies, and other factors.
Use of preoperative C-reactive protein to improve predictive accuracy in clear cell renal cell carcinoma.
Authors: Stephan Kruck, Felix K. Chun, Axel S. Merseburger, Hossein Tezval, Marcus Scharpf, Kathrin Kasprzyk, David Schilling, Karl-Dietrich Sievert, Arnulf Stenzl, Jens Bedke
Journal: Journal of Clinical Oncology (2013)

474 Background: White blood cell count (WBC) and C-reactive protein (CRP) are reliable biomarkers in clear cell renal cell carcinoma (ccRCC). Nevertheless, accepted cut-offs values for risk stratifications are missing. This study re-evaluated the prognostic and predictive significance of preoperatively WBC and CRP that independently predicts patient prognosis and to determine optimal cut-off values for CRP. Methods: 327 patients with surgery for ccRCC were retrospectively evaluated from 1996 to 2005. Cox-proportional hazard models were used, adjusted for the effects of tumor stage, tumor size, Fuhrman grade, and Karnofsky-Index; and to evaluate the prognostic significance of WBC and CRP; and to identify cut-off values. Identified cut-offs were correlated with clinico-pathological parameters and used to estimate cancer-speciﬁc survival (CSS). To prove any additional predictive accuracy of the identified cut-off it was compared to a clinico-pathological base model using Harrell c-index. Results: In univariable analyses WBC was a significant prognostic marker at a concentration of 9.5/µl (HR: 1.83) and 11.0/µl (HR: 2.09) and supported a CRP value of 0.25 mg/dL (HR: 6.47, p &lt; 0.001) and 0.5mg/dL (HR: 7.15, p &lt; 0.001) as potential cut-off values. If adjusted by the multivariable models WBC showed no clear breakpoint, but a CRP-value of 0.25mg/dL (HR: 2.80, p = 0.027) proved to be optimal. Reduced CSS was proven for CRP 0.25 mg/dL (median: 69.9 vs. 92.3 months). Median follow-up was 57.5 months with 72 (22%) tumor related deaths. The final model built by the addition of CRP 0.25mg/dL did not improve predictive accuracy (c-index = 0.877) than compared to the clinico-pathological base model (c-index =0.881) which included TNM-stage, grading and Karnofsky-Index. Conclusions: Multivariable analyses revealed an optimal breakpoint of CRP at a value of 0.25mg/dL best to stratify patients at risk of cancer-specific mortality, but CRP 0.25mg/dL added no additional information in the prediction model. Therefore we cannot recommend to measure CRP as the traditional parameters of TNM-stage, grading and Karnofsky-Index were already of high predictive accuracy.
Prognostic impact of primary tumor site location in metastatic colorectal cancer (mCRC).
Authors: Ignacio Matos, Carolina Ortiz, Elena Elez, Guillem Argiles, Julieta Grasselli, Teresa Macarulla, Jaume Capdevila, Maria Alsina, Tamara Sauri, Cinta Hierro, Helena Verdaguer, Enrique Sanz-Garcia, Ana Maria Martinez, Eloy Espin, Cristina Dopazo, Stefania Landolfi, Paolo Nuciforo, Ana Vivancos, Rodrigo Dienstmann, Josep Tabernero
Journal: Journal of Clinical Oncology (2016)

578 Background: CRC site is associated with differences in key molecular features that may impact survival in the metastatic (met) setting. We assessed the magnitude of outcome differences in a non-clinical trial scenario and explored how rectum cancer (RC) compares with right- and left-sided (RS and LS) colon tumors. Methods: Retrospective analysis of clinicopathological and molecular data from all mCRC patients (pts) treated at VHIO from January 2010 to June 2015. Targeted mutation (mut) profiling of driver oncogenes was performed by mass spectrometry (MassARRAY, Sequenom) or with next generation sequencing (Amplicon MiSeq, Illumina). Survival after relapse (SAR) was defined as time from diagnosis of met disease to death. Tumor site was categorized as RS (cecum, ascending, hepatic flexure, and transverse), LS (splenic flexure, descending, and sigmoid) or RC. We performed Cox proportional hazards models and adjusted for covariates including number and location of met sites, surgical resection of met lesions, and KRAS, BRAF and PIK3CA mut. Results: From 686 pts analyzed, primary site was RS/LS/RC in 29.4%/43.4%/27.2%, respectively. Pts with LS tumors were less likely to have ≥ 2 met sites (32%/20%/29%; p = 0.01). Lung metastases were more common in RC pts (20%/15%/36%; p &lt; 0.001), peritoneal metastasis in pts with RS tumors (28%/14%/5%, p &lt; 0.001). Surgical resection of any met disease was performed less frequently in pts with RS tumors (28%/46%/41%; p &lt; 0.001). KRAS mut (59%/45%/44%), BRAF V600E mut (9%/5%/3%) and PIK3CAmut (25%/14%/11%) were more prevalent in RS tumors. In the overall population with survival data (n = 606, 424 events), SAR was significantly lower in pts with RS tumors (31/46/46 months; RS vs. LS HR = 1.54 [1.2-2.0], p &lt; 0.001; rectum vs. left HR = 1.0 [0.7-1.3], p = 0.83). For comparison, worse SAR was also seen in the subset of pts (n = 337; 276 events) not eligible for surgical resection of met disease (26/31/35 months; right vs. left HR = 1.60 [1.2-2.2], p = 0.004; rectum vs. left HR = 0.9 [0.6-1.2], p = 0.42). Conclusions: The worse SAR of pts diagnosed with right-sided CRC tumors cannot be explained only by their distinctive met pattern or mutation profile of common oncogenes. Left-sided and rectum tumors have similar outcomes.
Time-Dependent Effect of Non-Hodgkin’s Lymphoma Grade on Disease Free Survival (DSF) of Relapsed/Refractory Patients Treated with High-Dose Chemotherapy (HDC) Plus Autologous Hematopoietic Stem Cell Transplant (AHSCT).
Authors: Pingfu Fu, Willem J. Van Heeckeren, Punit D. Wadhwa, David J. Bajor, Richard J. Creger, Brenda W. Cooper, Mary J. Laughlin, Hillard M. Lazarus, Stanton L. Gerson, Omer N. Koc
Journal: Blood (2004)