tbuckley/cabot-search huggingface dataset:
Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.
Authors: H. Gungor, A. Saleem, R. Agarwal, S. P. Blagden, A. Michael, E. A. Stronach, M. Chen, E. Pickford, N. R. Rama, Y. L. Lewis, S. C. Carme, C. Salinas, D. A. Smith, E. Krachey, A. Santiago-Walker, R. N. Gunn, M. El-Bahrawy, S. A. Babar, S. R. Morris, H. Gabra
Journal: Journal of Clinical Oncology (2011)

5064 Background: GSK795 is a potent, ATP-competitive, pan AKT inhibitor. The purpose of this study was to characterize the relationship between AKT inhibition by GSK795 and downstream effects in platinum resistant ovarian cancer pts. Methods: Pts with recurrent platinum-resistant ovarian cancer received 25, 50 or 75mg of oral GSK795 daily. Dynamic FDG-PET scans and paired tumor biopsies (PTB) were performed prior to first dose and at 2 and/or 4 weeks post treatment. Semi-quantitative (SUV) and quantitative (Ki, MRglu) PET PD parameters were derived. PTB were analyzed by immunohistochemistry (IHC) for PD marker expression. PK samples were obtained in parallel. Response was monitored by RECIST and CA125 criteria. Results: 12 pts have been treated on study: 4 at 25mg, 4 at 50mg and 4 at 75mg. After completion of the 2 or 4 week post-treatment PD assessment, all eligible pts underwent intra-subject dose escalation to 75mg. The most common drug-related adverse events (≥ 10%) were decreased appetite (18%) and vomiting (18%), all G1/2. Mean Cmax and AUC24 increased with increasing doses and increased 1.2-fold from Week 2 to Week 4 where 2 and 4 week doses were the same. Median Tmax was 4 h. Overall tumor FDG metabolism decreased in 71% of tumors with treatment, although inter- and intra-patient variability in tumor uptake measurements following therapy was seen. There was no clear temporal or dose-response effect in FDG uptake. IHC analysis of PTB from 5 pts dosed at either 50 or75mg indicated that pAKT levels increased in 2/2 pts dosed at 75mg, pPRAS40 levels decreased in 4/5 pts, and Ki67 levels decreased in 4/5 pts after treatment with GSK795. 8/12 pts had stable disease and 4/12 had progressive disease by RECIST criteria at week 4. Currently 4 pts are still on the study, 2 > 24 weeks, with tumor regressions of 26% and 11% and CA125 decreases of 70% and 58% respectively. Conclusions: A dose response relationship between changes in FDG-PET and GSK795 was not observed in pts dosed from 25 to 75mg daily. Evidence of AKT pathway inhibition was observed in PTB from pts dosed with 50 or 75mg GSK795. Clinical activity evidenced by tumor regressions and CA125 decreases was also observed.
Improving chemotherapy ordering process.
Authors: Jill Bryant
Journal: Journal of Clinical Oncology (2014)

213 Background: Chemotherapy ordering process can be unsafe and inefficient, putting patients at risk for medication errors. Documentation is essential in decreasing the incidence of errors with ordering and administration. The goal is to provide safe, efficient and quality care to oncology patients. Methods: The aim of the project was to decrease the number of deviations on the chemotherapy order forms by 50% within five months. Deviations identified were documentation inconsistency; checking of chemotherapy dosing at the provider level; and difficulty in updating the original order when changes were required. Large amount of time was spent in reconciling deviations. A multidisciplinary team collaborated on identifying root causes, such as, variances in completion of the forms, knowledge deficit of the ordering process, and staff accepting incomplete orders. Results: Order forms were reviewed and real time observations of the process were conducted. Data was collected on the types of deviations on the forms. The top three deviations were: 1. Lab values were not being completed within seven days; 2. Physician’s name and pager number were not provided; and 3. Order forms were missing the day of the chemotherapy cycle. Interventions included the education in entering complete and pertinent information on orders; institution of same day labs on day of visit; standardizing lab parameters; manual audits; and Nursing education regarding the acceptance of orders with deviations. Prior to intervention, 70% of the chemotherapy order forms had at least one deviation. At the five month evaluation, there was a reduction of 13%. Although a modest decrease, interventions continued. In follow-up, a random sample of orders was reviewed reflecting a reduction of 51%. Conclusions: Interventions continue with anticipation for further improvement in the chemotherapy ordering process. With decreasing the number of deviations, there will be an increase in safe, efficient and quality care for oncology patients. This project showed an initiative of improving a process to provide efficient care throughout the healthcare continuum. [Table: see text]
Phase II trial of combination topotecan and carboplatin chemotherapy in platinum-sensitive ovarian cancer
Authors: M. S. Shahin, P. Hanjani, S. Nolte
Journal: Journal of Clinical Oncology (2005)

5127 Background: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan (Hycamtin) administration schedule in combination with carboplatin in the management of platinum-sensitive recurrent ovarian cancer Methods: Patients with recurrent measurable ovarian cancer who had up to 2 prior regimen of chemotherapy for the management of their disease participating in this phase II trial received topotecan at a dose of 1.0 mg/m2/day x 3 days in combination with carboplatin (AUC=5) on day 3 every 21 days. Both dose escalation and reductions were permitted. Results: A total of 20 patients (mean age=63.2; range 34–84) were treated with this combination regimen. Thirteen patients had only one and 7 had 2 prior regimen of therapy in the past. A total of 110 cycles of chemotherapy was administered (range=2–10). Major toxicity included grade 3 (35%) and grade 4 (2.7%) neutropenia, grade 3 thrombocytopenia (11.8%), neutropenic fever (7.1%), and requirement for blood transfusion (30%). Dose escalation was possible in 14 (70%), and dose reduction was required in 3 (15%) patients. Bone marrow support with epoetin (30%), and filgrastim (30%) were utilized. Overall response rate was 75% (13 PR, 2 CR) and 25% demonstrated stable disease. Median progression free interval and overall survival was 27.1 and 46 weeks respectively. A carboplatin allergic reaction was encountered in 7 (35%) patients during the course of therapy, and successful desensitization was carried out in 5 patients. Conclusions: The 3-day topotecan schedule in combination with carboplatin appears to have moderate activity in recurrent ovarian cancer. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This combination is particularly attractive in patients who have prior chemotherapy related neuropathy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Survival differences in chronic myeloid leukemia by race in pre- and post-imatinib era.
Authors: R. Mandal, D. M. Bolt, B. K. Shah
Journal: Journal of Clinical Oncology (2011)

6555 Background: Since May 2001, imatinib mesylate has become the standard treatment for chronic myeloid leukemia (CML) but the survival pattern and the ethnic disparity are unknown. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database to compare survival rates in CML among Caucasians, African-Americans (AA), and other races, and also within each race to see survival differences from the pre- (1980-1997) to post-imatinib eras (2002-2005). We used Z-test in the SEER*Stat to compare the relative survival rates categorized by race, gender, and age groups (<50, > 50 years). The survival rates accompany standard errors and the number of individuals (n). Results: The 3-year relative survival rates among Caucasians, AA, and other races in pre-imatinib era were 47.5±0.7%, 47.7 ±2.1%, and 47.8±2.6% respectively, and in post-imatinib era 64.8±1%, 66.9±2.9%, and 68.9 ±3.2% respectively. The relative survival increased from the pre-to post-imatinib era for all ethnic groups but comparisons among these groups were not statistically significant when ages and genders were not categorized. In the post-imatinib era, 3-year relative survival rates among young (<50 years) Caucasians, AA, and other races were 86.7±1.3% (n=810), 79.1±3.5% (n=144), and 85.3±3.4% (n=119) respectively. The survival rates for young AA compared to young Caucasians were significantly lower (Z-value = -2.207, p=0.027). The corresponding survival rates among young AA women were significantly lower (Z-value = -2.575, p=0.010) than young Caucasian women, 78±5.5% (n=59) vs. 89.9±1.8% (n=319). From pre- to post-imatinib era, there was no significant increase in the survival rates for young AA women (64.6±4.5% vs. 78±5.5%, Z=1.701, p= 0.089). Conclusions: Young (<50 year) AA women with CML had lower relative survival rates compared to Caucasian women in the post-imatinib era, and survival increases from pre- to post-imatinib were not statistically significant in the former group. One possible explanation of this difference could be the selective imatinib resistance in young AA women.
A New Acute Monoblastic Leukemia Cell Line Expressing Vascular Endotelial Growth Factor (VEGF) -A and -D and VEGF Receptor-3 (Flt-4).
Authors: Dario Ferrero, Graziella Bellone, Valentina Giai, Anna Carbone, Patrizia Scaravaglio, Chiara Dellacasa, Milena Gilestro, Mario Boccadoro
Journal: Blood (2006)
The impact of zoledronic acid treatment on frequency of skeletal complications experienced and on followup duration post diagnosis of bone metastasis in lung cancer patients
Authors: H. T. Hatoum, S. Lin, A. Lipton, V. Barghout, N. Mody-Patel, M. R. Smith
Journal: Journal of Clinical Oncology (2008)

8106 Background: Lung cancer patients (pts) with bone metastasis are at high risk for skeletal complications (SCs). These SCs greatly compromise the patients’ quality of life, survival and add great expense to the health care system. Methods: PharMetrics integrated claims database of 80 health plans across the U.S was used to evaluate the impact of zoledronic acid (Zometa®, ZA) on SC rates, follow-up duration (from first bone metastasis diagnosis to last claim), and time from bone metastasis to first SC in ZA treated pts and non-bisphosphonate-treated pts (non-treated). Lung cancer patients who had first bone metastasis diagnosed from Jan 02 to Oct. 06 were included. Results: There were 2539 selected lung cancer pts, with 2174 non- treated, and 365 ZA treated. ZA treated pts were younger (57.14±8.97, mean± SD), had lower Charlson’s Comorbidity Index (CCI, 8.96±1.05) as compared with non-treated pts (59.61±10.42; 9.13±1.27). Unadjusted results demonstrated that ZA treated pts had lower mean SC (per month) of .11±.22, longer follow-up duration of 222.25±178.65 days (median, 189), and longer time to first SC of 163.85±147.13 days (median, 139) as compared to non-treated patients (.15±.32; 170.17±225.63, median 86; 116.40±191.74, median 41). Regression model on log of follow-up duration indicated that ZA users had 85.5% longer follow-up, 95% CI, 60.6% - 114.2%). Cox regression model with time to first SC as dependent variable found a significant effect for ZA treatment in delaying the occurrence of first SC (hazard ratio, HR, 0.62; 95% CI, 0.49–0.78) and a small but significant trend of attenuation of ZA protective effect over time (HR 1.003). Also, with negative binomial regression of SC count, with follow-up duration used as offset, ZA treated patients had significantly lower risk of SCs (OR, 0.727; 95% CI: 0.594–0.890) as compared to non-treated patients. All regression models were adjusted for age and CCI. Conclusions: Lung cancer pts treated with ZA had significantly reduced risk of SC by 30–40%, and increased followup duration by 85%. These findings support the clinical trial results of zoledronic acid in lung cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis
Exploration of the effect of treatment to progression with the VEGF signaling inhibitor cediranib (CED) plus chemotherapy (CT) on the results of the HORIZON (HZ) II trial in first-line metastatic colorectal cancer.
Authors: A. Fielding, P. M. Hoff, L. Pike, D. Wilson, J. D. Robertson
Journal: Journal of Clinical Oncology (2011)

e14052^ Background: The HZII trial (CED + FOLFOX [FF] or XELOX [X] vs placebo [PBO] + FF or X) met the co-primary endpoint of improved progression-free survival (PFS) with CED (hazard ratio [HR]=0.84), but not overall survival (HR=0.94). PFS results were similar to those of the N016966 trial (bevacizumab + FF4 or X vs PBO + FF4 or X; HR=0.83) in which treatment to progression was considered to affect outcome (Saltz et al 2008). The HZII protocol specified that patients (pts) should be treated to progression with CT + randomized treatment (RT), although individual components could be stopped for tolerability. This analysis assessed whether treatment to progression in HZII impacted PFS. Methods: Pts were randomized to CED or PBO, each with FF or X (per physician preference), and considered to be treated to progression if they received treatment to within 28 days of their disease progression date. Separate Cox proportional hazards models that included time-dependent covariate effects for the number of 5-FU/capecitabine cycles received were fitted for FF and X pts, and the treatment-effect PFS HRs (adjusted for amount of CT received to progression) assessed. Results: The proportion of pts treated to progression with RT was high in both arms (72% CED vs 81% PBO), but the proportion treated to progression with RT + fluoropyrimidine was lower in the CED vs PBO arm (42% vs 58%, respectively). Analysis by CT type showed more pts treated to progression with RT + oral capecitabine (48% CED vs 68% PBO) than RT + iv 5-FU (33% CED vs 45% PBO), but the difference between arms remained. The treatment-effect PFS HRs for pts receiving FF and X, adjusted for 5-FU/capecitabine cycles received, were 0.81 and 0.79, respectively. Conclusions: Treatment to progression with CT + CED may have a beneficial effect in colorectal cancer. Although the overall proportion of pts treated to progression with CED was high, adverse events probably affected the ability to maintain CT + CED to progression, which may have influenced overall outcome. As this analysis was not a randomized comparison, the magnitude of effect is difficult to quantify due to confounding factors.
Detection and prediction of carboplatin-related hypersensitivity reaction in patients with gynecologic cancer using basophil CD203c.
Authors: T. Iwamoto, A. Yuta, T. Tabata, H. Sugimoto, H. Hirai, S. Kojima, E. C. Gabazza, N. Sagawa, M. Okuda
Journal: Journal of Clinical Oncology (2011)

e19504 Background: Hypersensitivity reaction (HR) to carboplatin (CBDCA) restrains adequate therapy in cancer patients. Reliable in vitro test to detect and predict HR to carboplatin is not currently available. We hypothesized that CD203+ basophils are useful marker to predict carboplatin-related hypersensitivity. Methods: This is prospective case-control study that comprised 29 patients with gynecologic cancers that consulted our institution from October 2009 through September 2010. Among these patients, 11 had a history of CBDCA-related HR in the past 3-year, and 18 had no history and previously received intravenous CBDCA for more than 5 courses. Six of these 18 patients developed CBDCA-related HR during the study period. The number of CD203+ or CD63+ basophils after exposure to carboplatin was compared between patients with and without HR. Comparison of the expression of CD203c on basophils among groups classified by severity of anaphylaxis was also performed. Changes in the CD203c expression on basophils before and after anaphylaxis were assessed in 6 patients with CBDCA-related HR that occurred during the study period. Results: Test for basophil activation was performed in a total number of 116 samples. In patients with HR, the percentage of CD203c+ basophils (5.7% vs. 2.4%) and the mean fluorescence intensity (MFI) (12.1 vs. 0.8) of CD203c after exposure to (50 mg/ml) CBDCA for 30 min were significantly higher in patients with HR than in patients without HR. In addition, the median MFI (14.4) was markedly higher in patients with grade 4 anaphylaxis than in patients with grade 3 (MFI 1.6) and grade 1-2 anaphylaxis (MFI 0.6). Five patients that had grade 2-4 anaphylaxis during the study period showed increased percentage of CD203c+ basophils and/or increased MFI at HR onset, whereas one patient with grade 1 anaphylaxis did not. The expression of CD63 expression on basophils was found to be less sensitive than CD203c to predict CBDCA-related HR. Conclusions: The membrane CD203c expression on basophils may be a novel biomarker to predict severe CBDCA-related anaphylaxis in patients with gynecologic cancer.
5-fluorouracil related gene expression levels in primary colorectal cancer and corresponding liver metastases
Authors: H. Kuramochi, K. Hayashi, K. Uchida, D. Shimizu, D. Vallboehmer, S. J. Park, S. Miyakura, K. D. Danenberg, K. Takasaki, P. V. Danenberg
Journal: Journal of Clinical Oncology (2005)

3568 Background: The most commonly used chemotherapeutic drug for colorectal cancer (CRC) is 5-fluorouracil (5-FU). Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyl transpherase (OPRT) are involved in the metabolic pathway of 5-FU and have been shown in several studies to be associated with response to 5-FU-based therapies. Since liver metastases are the main cause of death for most of CRC patients, it is reasonable to expect that measurement of these gene expression levels in liver metastases would provide the best prediction of therapy benefit, but in most cases, only biopsies of the patient’s primary tumor are readily available for analysis. Our aim was to determine how TS, DPD, TP, and OPRT gene expression levels in primary CRC were related to those in liver metastases. Methods: Thirty-one pairs of primary CRC and corresponding liver metastases were analyzed. (18 males and 13 females: Median age 66 (range 45–85)). Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR (Taqman PCR). Results: No significant difference was seen between median mRNA expression levels of TS, DPD, TP, and OPRT in primary cancer and those in corresponding liver metastases (Median value: TS 1.48 vs. 1.43; p=0.92, DPD 0.19 vs.0.12; p=0.10, TP 1.20 vs. 0.98; p=0.39, OPRT 1.17 vs. 0.95; p=0.10, Wilcoxon signed rank test). When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs=0.52, p=0.0026, Spearman rank correlation coefficient). However, no correlation was seen between matched sets for DPD, TP, or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs=0.38, p=0.03) and liver metastases (rs=0.72, p<0.0001). Conclusions: A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP, and OPRT. No significant financial relationships to disclose.
Breast cancer in young women: Indian scenario.
Authors: Veda Padma Priya Selvakumar, Shubha Garg, Rajeev Kumar
Journal: Journal of Clinical Oncology (2015)

52 Background: Breast cancer in young women tends to be more advanced at presentation, more aggressive in nature with poorer survival. In this background we sought to study the clinicopathological profile of patients less than 40 years diagnosed with breast cancer at our institute. Methods: Out of the 1,330 patients who underwent surgery from December 2010 to December 2014 in the breast unit at our institute, 211 women were younger than 40. We retrospectively reviewed the clinic-pathological profile of these patients. SPSS 22 was used for statistical analysis and Kaplan Meier graphs plotted. Results: Mean age of patients was 35 years. The stage distribution was Stage 0: 2, Stage I: 9, Stage II: 81, Stage III: 95 and Stage 4: 2. 123 women underwent MRM and 85 breast conservation. On histopathological examination 202 were IDC, 1 ILC, 3 Mucinous Ca and 5 DCIS. 95(45 %) were Grade 3, 54 Grade 2 and 9 Grade 1. 55 patients were TNBC and 57 Her-2-neu positive. 57 underwent NACT while the rest underwent adjuvant chemotherapy, 170 received adjuvant radiation therapy and 122 adjuvant hormonal therapy. Overall survival is 98.9 % and DFS is 91.5 % at mean follow up of 17 months. Conclusions: In contrast to worldwide literature, around 15 % of women with breast cancer presenting to our institute were less than 40 years of age. They presented late with a higher stage, higher grade, and aggressive biology.
Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer (mCRC): Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial—Comparison of the efficacy of <i>KRAS</i> status.
Authors: Michio Nakamura, Satoshi Yuki, Masayoshi Dazai, Yoshimitsu Kobayashi, Takashi Kato, Hirohito Naruse, Mineo Kudo, Nobuaki Akakura, Yuh Sakata, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2013)

536 Background: Mutations of the KRAS gene were identified as a predictive marker in mCRC for anti-EGFR antibody. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab (BV) treatment in mCRC is independent of alterations in the KRAS status. We analized efficacy of BV combined irinotecan and S-1 (IRIS/Bev) in mCRC relative to KRAS status. Methods: In the retrospective analysis (n=53) of patients who participated in the Phase II trial of IRIS/Bev, additional statistical analyses were done with data from KRAS mutational analyses. In this trial, eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of &gt;20 years, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival (PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRASin terms of PFS and OS. All statistical tests were performed using SPSS. Results: The target number of 53 patients was enrolled as of March 2009. KRAS status was assessed in 43 patients (wild = 27, mutant = 16). Response rate was 63.0% with wild-type and 68.8% with mutant-type KRAS, that was not significant (p=0.752). The median Progression-free survival was 17.1 months with wild-type and 22.7 months with mutant-type KRAS, that was not significant (p=0.531). And median OS was 49.0 months with wild-type and 38.0 months with mutant-type KRAS, that was not significant(p=0.906) as well. Conclusions: IRIS/Bev provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Comparison of the efficacy of KRAS status is also planned in this study. Clinical trial information: NCT00569790.