tbuckley/cabot-search huggingface dataset:
Oral vinorelbine in the treatment of advanced breast cancer
Authors: R. Bartsch, U. Pluschnig, C. Wenzel, D. Hussian, G. J. Locker, R. Mader, C. C. Zielinski, G. G. Steger
Journal: Journal of Clinical Oncology (2004)

626 Background: Oral vinorelbine (OV) is a new formulation of well known iv vinorelbine (V). We evaluated the effect of this drug in patients (pts) with advanced breast cancer (ABC) as first line chemotherapy (CT) or beyond first line alone or in combination with trastuzumab (T). Methods: 53 pts (median age: 60 years, range : 38–83) suffering from ABC were treated with OV. 1st line: 24 (45.3%), 2nd line: 18 (34%), 3rd line: 9 (17%), 4th line 1 (1.9%), 5th line: 1 (1.9%). 26 pts underwent prior adjuvant CT (49%), and 34 (64.2%) received prior hormone therapy. Her2-Status was evaluated in all pts. Those positive received a combination of OV and T. 23 pts (43.4%) had bones/soft tissue metastases, 9 (17%) had visceral metastases and 21 (39.6%) had both. The effect of OV was evaluated with CT-scans after three months (m), and treatment was continued until progression. OV was administered at a dose of 60 mg/m2 on day 1 and 8, q 21 days. Results: 25 pts in the OV group are now available for response. We observed a partial response (PR) in 6 pts (24%), stable disease ≥ 3 m (SD) in 11 pts (44%) and 8 pts (32%) showed primary progression (PD), resulting in a clinical benefit rate of 68%. 6 pts in the OV+T group are now available for response. CR and PR were each observed in 1 patient (16.7%), SD ≥ 3 m in 3 pts (50%) and 1 patient showed PD (16.7%). 6/53 pts (11.3%) were switched from V to OV because of pts preference. Median time of treatment until this switch was 3 m, (r1–10). Median time of observation is 5 m (r 3–12). In those pts who did not show a progression to date, time of treatment is median 7.5 m (r 5–12). In those showing progression after primary disease control, median time to progression is 6 m (r 3–9). OV was generally well tolerated. The main toxicities are nausea (N) and neutropenia (NP). IVo NP was found in 1.9% of our pts, IIIo in 9.4%, Io and IIo combined in 9.5%. We did not find any IVo N, however IIIo N was seen in 3.8%. No other IIIo or IVo toxicities were reported. There were no treatment-related deaths. Conclusions: OV appears to be an effective drug at the dose and schedule chosen. It is well tolerated and the oral formulation is a big advantage for the patients as well as for the nursing staff. Further evaluation in randomized trials appears to be warranted. No significant financial relationships to disclose.
Sunitinib objective response (OR) in metastatic renal cell carcinoma (mRCC): Analysis of 1,059 patients treated on clinical trials.
Authors: Ana M. Molina, Jingbo Zhang, Xun Lin, Liviu Niculescu, Beata Korytowsky, Ewa Matczak, Robin Wiltshire, Robert John Motzer
Journal: Journal of Clinical Oncology (2012)

4542 Background: Sunitinib achieves robust OR and improved progression-free survival (PFS) in mRCC patients (N Engl J Med 2007;356:115). A retrospective analysis was performed to characterize the OR rate with sunitinib treatment (Tx) and OR-associated patient features and survival. Methods: Data from six phase II and III trials were pooled from 1,059 patients who received sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the 1st- (n=783; 74%) and 2nd-line (n=276; 26%) Tx settings. Median PFS and overall survival (OS) were estimated by the Brookmeyer and Crowley method, and compared between responders and nonresponders, and early and late responders (response ≤ and &gt;12 weeks, respectively), by a log-rank test. Baseline characteristics were compared by Fisher-exact Test, T-Test, or Wilcoxon Rank-sum Test. Results: Of 1,059 patients, 398 (38%) had a confirmed investigator-assessed OR by RECIST (including 12 with a complete response), of whom 105 (26%), 243 (61%), 314 (79%), and 342 (86%) had a response by 6, 12, 18, and 24 weeks, respectively. Median (range) time to tumor response (TTR) in all patients was 10.6 (2.7–94.4) weeks, which was similar in the 1st- and 2nd-line Tx settings. Responders had better baseline ECOG scores, more favorable risk factor classification based on published MSKCC data, a longer interval since initial diagnosis, more prior nephrectomy, and less presence of baseline bone metastases (all p&lt;0.05). Early responders had more lung metastases (p&lt;0.01). Median PFS (16.3 vs. 5.3 months) and OS (40.1 vs. 14.5 months) were significantly longer in responders vs. nonresponders (both p&lt;0.001), with similar results regardless of 1st- or 2nd-line Tx setting. Median OS did not differ between early and late responders (p=0.1438). Conclusions: OR was achieved in 38% of 1,059 mRCC patients treated with sunitinib and was predicted by favorable pretreatment prognostic factors. Patients with OR had longer PFS and OS. Median TTR was 10.6 weeks, and characteristics and outcome of early and late responders were similar, except for higher frequency of lung metastases among early responders.
Chemopredictive assay for patients with primary brain tumors.
Authors: Pier Paolo Claudio, Jagan Valluri, Sarah E Mathis, Anthony Alberico, Thomas Alberico, James Denvir, Gerrit A. Kimmey, Mark Jeffrey Mogul, Rajesh Sehgal, Aneel A. Chowdhary, Mohammad Mozayen, Maria R. B. Tria Tirona, Laurie Beth Matt, Gerald Oakley, Krista L Denning, Thomas Dougherty
Journal: Journal of Clinical Oncology (2013)

2089 Background: Cancer stem-like cells (CSLCs) in primary brain tumors can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for personalized anticancer treatments. Methods: We have developed an ex vivo ChemoID assay designed to predict the sensitivity and resistance of CSLCs and bulk of tumor cells of a given patient's solid tumor to a variety of chemotherapy agents by measuring the percentage of cell death. In a retrospective study of five patients with malignancies of the central nervous system, we assessed the correlation between the results of the ChemoID assay and clinical response. Two anaplastic WHO grade-III ependymomas, two IDH-1 negative WHO grade 4 glioblastomas, and one medulloblastoma were tested. Tumors were classified as responsive (50-100% cell kill), intermediately responsive (30-50% cell kill), and nonresponsive (0-30% cell kill) to chemotherapy. Treatment selection was blinded to assay results. MRI and CT scan determined response to therapy. Results: The ChemoID assay performed on the tumor bulk produced a correct prediction in 4 out of 5 cases (p = 0.4, Fisher's Exact Test; PPV = 75%, NPV = 100%) when compared to the drugs received. The same assay performed on the CSLCs produced a correct prediction in all 5 cases (p = 0.1, Fisher's Exact Test; PPV=NPV=100%). Conclusions: An assay such as ChemoID that measures cell death of CSLCs and bulk of tumor cells appears to be beneficial in selecting specific standard chemotherapy agents ex vivo for patients with malignancies of the central nervous system.
Gastrointestinal stromal tumors: Institute of Oncology—Dr. “Luis Razetti” experience, Caracas, Venezuela.
Authors: Luis Chirinos, Maria Belen Fuentes, Maria Angelina Perez, Gustavo Gotera, Jesus Felipe Parra, Cristina Garcia Sebastian
Journal: Journal of Clinical Oncology (2013)

e21512 Background: Gastrointestinal Stromal Tumors are a heterogeneous group of tumors with clinical features and specific genetic alterations, which represent 1-3% of all gastrointestinal cancers. Imatinib, is the standard treatment in advanced and localized disease, and has demonstrated benefit in overall survival, progression free survival and disease free survival. Methods: The primary end point was to evaluate overall survival in patients with locally advanced, metastatic and early stage GIST treated with Imatinib; secondary end points were to evaluate disease-free survival and progression free survival. We included 34 patients with GIST treated between January 2005 and December 2011. Results: The most affected gender was male (55.88%), the average age was 51-60 years (26.47%), and most had localized disease at diagnosis (73.52%), mainly in the stomach (52.94%). As for the primary treatment, 25 underwent surgery (73.5%), applying adjuvant Imatinib in 18 patients (75%).The OS and DFS was higher in patients with localized disease compared with age (p = 0.0001 respectively). Regarding the use of adjuvant Imatinib, it produced clinical benefit in DFS and OS of 50 and 60 months respectively, regardless of risk. In patients with advanced or metastatic disease Imatinib was associated with higher PFS (p = 0.055) and OS (p = 0.1120). Relapses occurred in 24% of patients regardless of risk and the use of Imatinib. Conclusions: In our study we concluded that radical surgery and the use of Imatinib in GIST patients produce important clinical benefits which translate into higher survival rates.
Assessment of metabolism, excretion and pharmacokinetics of a single dose of [14C]-ZD6126 in patients with solid malignant tumors
Authors: M. Scurr, I. Judson, C. Brock, A. O'Donnell, S. Tan, E. A. Partridge, R. A. D'Souza, D. W. Roberts
Journal: Journal of Clinical Oncology (2004)

3083 Background: ZD6126 is a novel vascular-targeting agent that causes disruption of the microtubular network responsible for maintaining the shape of immature, proliferating endothelial cells in tumor vasculature. This leads to selective vessel occlusion and extensive tumor necrosis. Methods: A Phase I excretion balance study of ZD6126 has been conducted in 6 patients (47–56 yrs) with solid tumors refractory to standard therapies, a WHO performance status of 0–2 and a life expectancy of ≥12 weeks. Those with significant cardiac, hematopoietic, hepatic or renal dysfunction were excluded. Patients received a single 10 min infusion of 40 mg/m2 [14C]-ZD6126 (70 μCi; 2.6 MBq) on day 1 of a 28-day cycle. Urine and feces were collected continuously for the first 8 days and blood samples were collected on days 1 and 2. Subsequent treatment comprised a single i.v. infusion of ZD6126 (56 mg/m2). Results: Pharmacokinetic analysis showed that Cmax for plasma ZD6126 was observed 5 min into the 10 min infusion. Concentrations declined rapidly and were non-quantifiable by 1 hour. The Cmax of the active metabolite (ZD6126 phenol) was 1398 ± 364.8 ng/ml at the end of infusion; concentrations were non-quantifiable at 48 hours. An AUC of 1533 ± 556.6 ng.h/ml and t1/2of 2.913 ± 1.11 hours was determined. At 5 min, levels of radioactivity were 3 x ZD6126 phenol concentrations; this increased to 13 x at 24 hours. Recovery of radioactivity was excellent (93.3 ± 2.6%, n=5), with 38.4 ± 13.6% recovered in urine and 54.9 ± 13.8% in feces. Conclusions: ZD6126 is rapidly hydrolyzed to the active metabolite, ZD6126 phenol. The concentration of ZD6126 phenol in the plasma was lower than that of radioactivity at all times, indicating the presence of circulating metabolites. The dose was eliminated in the urine and feces, with the majority in the feces, showing the importance of biliary excretion. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Valproic acid and hydralazine-modulated gemcitabine and cisplatin followed by doxorubicin in advanced hepatocellular carcinoma: A phase II study.
Authors: Jin-Hwang Liu, Yao-Chung Liu, Chien-Wei Su, Che-Chuan Loong
Journal: Journal of Clinical Oncology (2015)

e15119 Background: Histone deacetylation inhibitors (HDACi) were found to accelerate degradation of Sae2 required for double strand DNA break repair. Valproic acid and hydrazaline as HDACis may possibly abort DNA repair in tumor cells and promote chemotherapy efficacy. Methods: This is an open, single arm, Simon 2-stage phase II trial with overall survival (OS) as the primary end for patients with advanced hepatocellular carcinoma (HCC). The treatment protocol is valproic acid (VA) and hydrazaline (HZ)-modulated gemcitabine and cisplatin (GCGG) as the first chemotherapy, followed by doxorubicin and dacarbazine (DoxDTIC) as the 2nd after failing GCGG. The trial advanced to stage 2 if > 8 in 25 patients survived at 6.5 months in 1st stage. The treatment would be deemed effective if 26/60 patients survived at 6.5 months. Eligible patients had advanced HCC, Child Pugh A/ B(7) and performance status < or = 1; were chemonaive; failed or were not suitable for local ablation. Patients were treated with oral VA 200 mg thrice/ day and HZ 12.5 mg twice/ day. The GCGG chemotherapy were given with intravenous (IV) gemcitabine 800 mg/m2 on D 1, 8, and 15; cisplatin 70 mg/ m2, D1 in a 28-day cycle, adjusted with renal function and the DoxDTIC with IV doxorubicin 45 mg/m2 and dacarbazine 450 mg/ m2on D1 in a 21-day cycle. Results: Thirty-one eligible patients were enrolled. Ten patients failed or were intolerant to previous sorafenib. All patients received GCGG but only 26 could receive DoxDTIC treatment. In the 1st stage, 21 out of the 25 patients survived at 6.5 months, and 26 out of 31 pateints reached an OS of > 6.5 months. The median OS was 17.5 months (95% CI: 8.3-26.7). Drug related toxicities included cytopenias, fatigue and liver dysfunction. Neutropenia and thrombocytopenia were the dose-limiting factors. The response rate (RR) of VA and HZ-modulated GCGG was 8/31 (25.8%) while VA and HZ-modulated DoxDTIC had RR of 5/26 (19.2%). RR of VA and HZ-modulated of either GCGG or DoxDTIC was13/31 (42%). Conclusions: The VA and HZ-modulated chemotherapy with less than the usual chemotherapy dose has shown an encouraging effective survival benefit with manageable toxicities in advanced HCCs. Clinical trial information: VGHIRB 97-06-05.
Phase 2 trial of trastuzumab and/or everolimus in hormone-resistant HER2-negative metastatic breast cancer.
Authors: Amelia Bruce Zelnak, Elisavet Paplomata, Sujatha Murali, Geetha D. Vallabhaneni, Virginia G. Kaklamani, Xiaoxian Li, Yuan Liu, Ruth O'Regan
Journal: Journal of Clinical Oncology (2014)

576^ Background: Increased signaling through growth factor receptor pathways, including HER2, has been demonstrated to play a role in resistance to endocrine therapy. Efficacy of inhibiting HER2 and mTOR in HER2-negative, hormone-resistant breast cancer has been previously demonstrated. We evaluated the ability of inhibition of HER2 with trastuzumab (TRAST) and/or mTOR with everolimus (EVER) to reverse resistance to endocrine therapy in patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (MBC). Methods: Eligibility included HR-positive, HER2-negative (IHC 1+ or 2+ and/or FISH negative) MBC on metastatic biopsy and documented progression within 6-months of starting an endocrine agent in the metastatic setting. Patients continued on the endocrine agent they had experienced disease progression on and were randomized to receive TRAST (8mg followed by 6mg every 3-weeks) or EVER 10mg daily. At disease progression the other agent (TRAST or EVER) was added. Biopsies of metastatic lesions were obtained prior to study entry where possible. Results: To date 38 patients have been randomized to TRAST (n = 13) or EVER (n = 22), 3 patients not evaluable. All patients continued the endocrine agent on which they had most recently experienced disease progression. The median PFS is 1.5 (95% CI 1.5 to 4) and 6 (95%CI 4 to 15) months (mos.) for patients initially randomized to TRAST and EVER respectively. At disease progression 13 patients in the TRAST arm received EVER and 5 in the EVER arm received TRAST. The overall PFS for this group is 5.5 (95% CI 3 to 8) mos: 7 (95% CI 3 to 13) mos. for patients in the TRAST arm who then received EVER; and 4 (95% CI 1.5 to 7) mos. for patients in the EVER arm who received TRAST. There were no unexpected toxicities though 2 patients were taken off study for decreases in ejection fraction. Metastatic biopsies are available for 57% of patients. Conclusions: This trial demonstrates the efficacy of inhibiting mTOR alone or in combination with HER2 in patients with hormone-resistant HER2-negative breast cancer, suggesting that inhibition of this growth factor pathway may restore sensitivity to endocrine therapy. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340.
A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy.
Authors: Susan Halabi, Chen-Yen Lin, Eric Jay Small, Andrew J. Armstrong, Ellen B. Kaplan, Daniel Peter Petrylak, Cora N. Sternberg, Liji Shen, Stephane Oudard, Johann Sebastian De Bono, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2013)

5011 Background: Although several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC, this work sought to develop and validate a prognostic model to predict OS in men who had progressed following first-line chemotherapy, and were receiving second line chemotherapy. Methods: Data from a phase III trial of cabazitaxel plus prednisone compared to mitoxantrone plus prednisone in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC data was randomly split into training (n=507) and testing (n=248) sets. A separate data set consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone (SPARC trial), was used as a second testing set for external validation. Adaptive Lasso selected nine baseline prognostic factors of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (&lt;-1.25) and high (≥-1.25) risk groups in the two testing sets. The model was assessed on the testing sets for its predictive accuracy using area under the curve (AUC). Results: The 9 prognostic variables in the final model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. The median OS in the TROPIC testing set were 11 and 16 months in the high and low risks, respectively, with a hazard ratio (HR) 2.3 (p-value&lt;0.0001). The median OS in SPARC were 11 and 20 months in the high and low risk groups, respectively (HR=2.0, p&lt;0.0001). The AUC for this model was 0.73 (95 CI 0.68-0.72) and 0.70 (95 CI 0.72-0.74) on the two testing sets (TROPIC, and SPARC), respectively. Conclusions: A prognostic model of OS in the post-docetaxel second line chemotherapy mCRPC setting was developed and externally validated. This model can be used to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.
Effect of demographic factors and histology on stage IV non-small cell lung cancer (NSCLC): A National Cancer Database review.
Authors: Brody Slostad, Jessica Gries, Apar Kishor Ganti, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2015)

6558 Background: Demographic characteristics, especially race and insurance status, affect the incidence of lung cancer diagnosed at Stage IV1. This is the largest epidemiological study to determine patient features associated with the development of Stage IV NSCLC. Methods: A population-based study using the National Cancer Database (2000-2012), which contains 70% of all cancer diagnoses in the U.S. from 1658 ACS Accredited-Hospitals. Demographic groups of NSCLC presenting with Stage IV were compared to the entire cohort of NSCLC patients using the Chi square test. Results: Of all NSCLC patients (N=2,956,237), 36% were Stage IV at presentation. Uninsured (52%), aged 40-49 (47%), Medicaid recipients (46%), aged 50-59 (42%), Hispanic (41%) and Black (41%) patients presented with more Stage IV at diagnosis. Medicare recipients (34%) presented with less Stage IV. Adenocarcinoma (AC) and Squamous Cell (SQ) presented with 43% and 25% Stage IV disease at diagnosis, respectively. Uninsured AC (60%) patients had the most frequent Stage IV disease at diagnosis. Conclusions: AC presents much more frequently than SQ as Stage IV. In particular, uninsured AC patients have the most frequent Stage IV presentation. Similar to a previous NCDB study, this study, which includes 5 times as many lung cancer patients as the previous study, shows uninsured, Medicaid, Hispanic and Black NSCLC patients present with more Stage IV disease (Halpern MT, et al. (2008) Association of insurance status and ethnicity with cancer stage at diagnosis for 12 cancer sites: a retrospective analysis. Lancet Oncol 9:222-232.). Conversely, Medicare patients present with less Stage IV disease. Stage IV NSCLC * = p<.001. % Stage IV Race/ Ethnicity* Hispanic 41 Black 41 White 35 Gender* Male 38 Female 35 Distance Traveled (miles)* <5 39 5 to 9 37 10 to 24 36 25 to 49 34 50 to 99 32 >=100 32 Insurance* None 52 AC 60 SQ 38 Medicaid 46 Private 38 Other Gov't 37 Medicare 34 % Without HS Degree* > 23% 38 15-22.9% 37 11-14.9% 36 6-10.9% 35 <6% 35 Household Income*(per year) < $36,000 37 $36,000 - 43,999 36 $44,000 - 52,999 36 $53,000 - 68,999 36 > $69,000 36 Comorbidity* None 39 One 33 2+ 34 Age* 40-49 47 50-59 42 60-69 37 70-79 33 80-89 33 Overall % Stage IV 36
Molecular and metabolic differences of treatment responders versus non-responders in a phase 0 clinical trial of metformin in endometrial cancer.
Authors: Dario R. Roque, Kevin M. Schuler, Brooke S. Rambally, Brante Sampey, Ruth Everett, Dhiren Thakker, Paola A. Gehrig, Siobhan O'Connor, Liza Makowski, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2015)

e22259 Background: In a phase 0 clinical trial of metformin in endometrial cancer (EC) patients, we previously reported that metformin decreased proliferation in the tumors of the majority of patients enrolled. We aimed to determine molecular and metabolic differences between responders and non-responders to metformin treatment. Methods: Obese women with endometrioid EC were enrolled. Patients took metformin (850 mg QD) for 1-4 wks prior to surgical staging. Tissue microarrays (triplicate cores) were constructed from formalin-fixed, paraffin-embedded endometrial biopsy and hysterectomy specimens before and after metformin treatment. Expression of the metformin transporters (PMAT, MATE1, MATE2), phosphorylated (p)-insulin-like growth factor 1 receptor (IGF1R), p-insulin receptor substrate-1 (IRS1), LKB1 and PTEN were evaluated by immunohistochemistry. Global, untargeted metabolomics was performed on serum of EC patients prior to metformin treatment, using combined GC-MS and LC-MS/MS techniques. Results: Of 20 patients enrolled, 13 (65%) responded to metformin as defined by a significant decrease in Ki-67 staining. In responders, metformin decreased expression of PMAT (66%, p = 0.0019), MATE2 (26%, p = 0.0017), p-IGF1R (24%, p = 0.035), LKB1 (36%, p = 0.0015) and PTEN (80%, p = 0.033) but was not associated with changes in MATE1 or p-IRS1. In non-responders, metformin treatment was not associated with any changes in these molecular targets. Pre-treatment MATE2 expression approached significance in predicting response to metformin (p = 0.0625). Metabolomic profiling revealed that responders had higher pre-metformin treatment levels of amino acids, dipeptides, glycolytic intermediates, arachidonic acid, monohydroxy fatty acids and lysolipids when compared to non-responders (p < 0.05). Conclusions: Treatment response to metformin was associated with decreased expression of PMAT and MATE2 and metabolically relevant proteins associated with obesity and EC. Baseline metabolic differences were found between responders and non-responders to metformin that may serve as biomarkers for ongoing clinical trials of metformin in this obesity-driven disease.
Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group
Authors: Mareike Rasche, Beate Lerius, Ursula Creutzig, Martin Zimmermann, C. Michel Zwaan, Dirk Reinhardt
Journal: Blood (2016)