tbuckley/cabot-search huggingface dataset:
Phase I study of temsirolimus (Tem) and pazopanib (Paz) in solid tumors with emphasis on renal cell carcinoma (RCC).
Authors: T. J. Semrad, C. Eddings, M. P. Dutia, S. Christensen, D. Lau, P. Lara
Journal: Journal of Clinical Oncology (2011)

e15113 Background: Phase III trials have shown that either inhibition of VEGFR- (Paz) or mTOR-signaling (Tem) can improve outcomes in patients (pts) with advanced RCC. To investigate the hypothesis that simultaneous “vertical inhibition” of VEGFR and mTOR pathways is feasible and results in enhanced efficacy, we conducted a phase I trial of Tem plus Paz to determine the maximum tolerated dose (MTD), safety, and recommended phase II dose. Methods: Pts with advanced solid tumors (emphasis on RCC), PS 0-2, no prior mTOR inhibitor or Paz, and acceptable end-organ function were eligible. A typical 3 + 3 design was used starting at dose level (DL) 1 with de-escalation to DL -2 if DL 1 was not well tolerated. Dose limiting toxicity (DLT) was defined as attributable grade 3 (Gr3) or higher non-hematologic adverse events (AEs) in cycle 1. MTD was defined as the maximum dose level at which less than 2 pts experienced DLT. Cycle length was 28 days. Results: Eight pts were enrolled. Median age was 57 years; 38% had RCC. One pt at DL1 was not evaluable due to treatment deviation in cycle 1 (see Table). At DL1, 2 pts had 4 DLTs (Gr3 anorexia, fatigue, hyponatremia, hypophosphatemia). After reduction to DL-2, 1 of 3 pts had DLT (Gr3 fatigue). The 1st pt in DL-2 expansion had Gr3 hypophosphatemia. Attributable Gr3+ AEs: hypophosphatemia (2 pts); neutropenia (2 pts); anorexia, hyperglycemia, hypokalemia, hyponatremia, mucositis and proteinuria (1 pt each). Gr2 nausea, elevated alk phos and rash were seen in at least 2 pts. Four of 6 pts evaluable for response had tumor reduction (not meeting RECIST response) including 2 with RCC and 1 with adrenal cancer. Conclusions: Tem plus Paz was not feasible in this population due to Gr3 fatigue and electrolyte disturbances. This and other trials of combined mTOR inhibitor and VEGFR-TKI therapy confirm that although active, this strategy is associated with unacceptable toxicity. Patient Dose Level Tem (mg IV weekly) Paz (mg/day) DLTs 1 1 15 400 None 2 1 15 400 Anorexia 3 1 15 400 Not evaluable 4 1 15 400 Fatigue, hyponatremia,hypophosphatemia 5 -2 10 200 Fatigue 6 -2 10 200 None 7 -2 10 200 None 8 -2 10 200 Hypophosphatemia
Changes in adjuvant endocrine therapy over one year among postmenopausal women with early-stage breast cancer initiating aromatase inhibitors.
Authors: Danielle Lindsay LaMorte, Katherine E. Hartmann, Vandana Gupta Abramson, Ingrid A. Mayer, Nancy Walker Peacock, David Cella, Liana Desharnais Castel
Journal: Journal of Clinical Oncology (2012)

11 Background: Aromatase inhibitors (AIs) are standard of care for adjuvant endocrine therapy (AET) to prevent recurrence of early stage breast cancer in postmenopausal women. Previous AET adherence research has focused on the 25-96% adherence observed with, but more information is needed about AI adherence, especially regarding the role of arthralgia (joint pain or stiffness) in AET changes. Our objective was to understand AET changes within a year of AI initiation. Methods: We examined AET switching (either to another AI or to tamoxifen), overall changes in AET (including switching and temporary or permanent discontinuation), and physician- and patient-reported arthralgia, using data abstracted from medical records and self-administered surveys among 93 patients initiating AI. We conducted Chi-square and Wilcoxon univariate analyses. Results: Anastrazole was initially prescribed to 64 patients (69%), letrozole to 28 patients (30%), and exemestane to 1 patient. A year after AI initiation, 64 patients (69%) had no change in AET. Among the 29 patients (31%) who had an AET change, 14 switched to at least one other AI, 11 switched to tamoxifen, 9 temporarily discontinued AET, and 7 entirely discontinued AET (categories not mutually exclusive). Average time to first AET switch was 182.7 days. Average number of AET switches was 1.4. Arthralgia was the most common reason for AET changes, noted in the records of 19 patients (66% of those who changed AET). Patients who changed AET reported more severe arthralgia (median pain from 0-10 among 8 joint groups =1.4, interquartile range [IQR]=0.3-2.6) at week 12 than those who did not (median=0.3, IQR=0-1.1), p=0.03. A higher proportion (46%) of the 28 patients who initiated with letrozole changed AET due to arthralgia, compared with 20% of the 64 patients who initiated with anastrazole (p=0.01). Conclusions: A substantial proportion of women initiating AI change AET over one year. Arthralgia appears to play a key role in AET changes, particularly for letrozole as compared with anastrazole. More longitudinal patient-reported arthralgia data are needed to guide clinical decision making about AI initiation and AET changes.
Feasibility of screening hospitalized cancer patients for palliative care.
Authors: Paul A. Glare, Mary K. Plakovic, Anna Schloms, Barbara Egan, Leonard Saltz, David Paul Kelsen
Journal: Journal of Clinical Oncology (2012)

9094 Background: The National Comprehensive Cancer Network Palliative Care (PC) Guideline recommends screening all oncology patients for PC needs, and to call a PC consult when referral criteria are met. There are no data on the feasibility or impact of this approach. The aim of this pilot study was to assess the feasibility of PC screening in patients admitted to a comprehensive cancer center (CCC). Methods: Design: Observational study. From 11/1/10 to 1/31/11, floor nurses screened all patients the day after admission under the two teams (“Team A” and “Team B”) of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center. Team A patients were also evaluated by the referral criteria. Endpoints: Patients screened ‘positive’ if they had advanced disease and any of the clinical situations nominated in the Guideline. The referral criteria triggered PC consults in Team A patients; clinical judgment triggered Team B consults. Outcomes: Screening rates, nursing satisfaction survey, clinical and operational metrics. Results: Ninety percent (229 of 254) of admissions were screened. Both Teams’ patients were seriously ill (see Table), and it was no surprise that 63% (145 of 229) screened positive. Survey respondents (response rate 50%) rated screening as simple, quick and helpful, although nurses scored the extent of disease wrong in 16%. Sixty eight percent (55 of 780) of Team A patients who screened positive met the referral criteria. This generated more consults on Team A, but the effect on key outcomes was not significant (n.s.). Conclusions: Screening for PC was feasible in this setting, but is a challenging concept in terms of reliability, validity and timing. The value to a CCC of increasing PC access via referral criteria needs evaluation in well-designed trials. [Table: see text]
A phase I safety and pharmacokinetic (PK) study of <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) for patients (pts) with advanced pancreatic cancer (APC) who have cholestatic hyperbilirubinemia (CH) secondary to bile duct obstruction.
Authors: Hanno Riess, Volker Kunzmann, Philip Agop Philip, Thomas Seufferlein, Desmond Micahel Thomas McGovern, Peng Chen, Alfredo Romano, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2016)

TPS474 Background: In pts with APC, the distal common bile duct is frequently obstructed, which can lead to elevated bilirubin levels. Normalization of bilirubin by stenting can take weeks, so treatment options that could be initiated in pts with elevated bilirubin are desirable. In a phase III trial of pts with metastatic PC, nab-P + Gem demonstrated superior efficacy vs Gem alone for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio, 0.72; P &lt; 0.001). This study will be the first to analyze safety and PK profiles of nab-P + Gem in pts with APC and CH secondary to bile duct obstruction. Methods: Treatment-naive pts (≈ 12 to 40) with APC, Karnofsky performance status ≥ 70, and CH due to bile duct obstruction are eligible. Pts with a biliary stent must have 2 stable (within 20% of each other) bilirubin readings within 48 to 72 hours of each other taken between 5 and 21 days after stenting. Exclusion criteria consist of brain metastases, any other active malignancy, infection requiring systemic therapy, a history of myocardial infarction, or current use of medications known to be strong inducers of CYP3A4 and CYP2C8. Pts will enter 1 of 2 cohorts based on bilirubin level: cohort 1, &gt; 1.5 to 3 × upper limit of normal (ULN), or cohort 2, &gt; 3 to 5 × ULN. Cohort 2 will proceed only after review of safety and PK data from cohort 1 by a safety monitoring committee (SMC) and a decision has been made to proceed. The starting doses are nab-P 100 mg/m 2 and Gem 800 mg/m 2 for cohort 1 and nab-P 75 mg/m 2 and Gem 600 mg/m 2 for cohort 2. Treatment will be administered on days 1, 8, and 15 of each 28-day cycle. Doses in each cohort will be modified according to tolerability as determined by the SMC. The primary endpoints are determination of maximum tolerated dose for each cohort and PK profile. Secondary endpoints include investigator-assessed objective response rate, progression-free survival, OS, PK profile of Gem, and safety. The exploratory endpoint is change in serum CA19-9 level from baseline. Enrollment is ongoing. ClinicalTrials.gov: NCT02267707. Clinical trial information: NCT02267707.
Phase I/II study with trabedersen (AP 12009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma.
Authors: H. Oettle, A. Hilbig, T. Seufferlein, A. Tsianakas, T. Luger, R. M. Schmid, G. von Wichert, E. Endlicher, C. Garbe, K. K. Kaehler, A. Hauschild, A. Enk, P. Kiessling, S. Schmaus, H. Heinrichs, K. Schlingensiepen
Journal: Journal of Clinical Oncology (2011)

2513 Background: TGF-β2 regulates key cancer mechanisms, particularly immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized, active-controlled Phase IIb study in high-grade glioma patients showed a clear survival benefit for trabedersen over standard chemotherapy. This study evaluates the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors. Methods: This open label, multicenter, Phase I/II study enrolled 33 patients with advanced pancreatic carcinoma (PanCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) into the dose-escalation part of the study. Patients were treated in cohorts with i.v. trabedersen monotherapy as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. In the Phase II-part of the study further PanCa and melanoma patients were treated with the 4d on, 10d off schedule with a dose of 140 mg/m2/d. The median overall survival of PanCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached (12.9 months as of Dec 2010). One PanCa patient had a complete response of liver metastases and is still alive after 61 months (status Oct 2010). Further promising efficacy data from the dose-escalation are: one patient with metastatic and DTIC-resistant melanoma who is still alive 19.7 months after start of treatment (status Dec 2010); 3 other patients with stage IV melanoma, treated 3rd or 4th-line with trabedersen, who survived for 11.4, 13.8, and 18.6 months. Conclusions: Trabedersen showed excellent safety and encouraging survival results. The evaluation of 14 melanoma patients treated with the 4d on, 10d off-140 mg/m2/d regimen is ongoing. A randomized, active-controlled study in PanCA patients is in preparation.
Does first-line treatment impact the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients?
Authors: C. Daniel Mullins, Andinet Woldemichael, Zhiyuan Zheng, Ebere Onukwugha, Brian S. Seal, Nader Hanna
Journal: Journal of Clinical Oncology (2014)

585 Background: Randomized clinical trials for second line treatment (Tx2) of metastatic colon cancer (mCC) often have strict inclusion/exclusion criteria regarding prior treatment, yet in the real world there is significant variation. This study aims to determine whether cost effectiveness estimates of Tx2 for elderly mCC patients varies by the regimen they received in first-line treatment (Tx1). Methods: We identified 3,211 elderly (age 66+) mCC patients in the SEER-Medicare dataset who received NCCN recommended Tx1 between 2003 and 2009. Patients were categorized by Tx1 based on a previously published algorithm as fluorouracil and leucovorin (5-FU/LV), irinotecan (IRI), oxaliplatin (OX), or “other,” which included IROX or biologics without OX or IRI. Separate 5-year incremental cost-effectiveness of Tx2 were calculated for each Tx1. Approximately 1% of patients with outlier costs were excluded. Patients enrolled in HMOs, lost Part A and/or B, and died of causes other than colon cancer are censored. We adjusted for censoring using the Inverse Probability Weighting (IPW) method. Costs were inflation-adjusted to 2009 dollars using the national monthly medical price index. Results: Among patients who received Tx1, 34% (n=1,090) received 5FU, 17% (n=530) received IRI, 46% (n=1,481) received OX, and 3% (n=110) received other (IROX or Biologics) regimens; 44.5% (n=1,440) proceeded to Tx2. Compared to those who do not receive Tx2, patients who received Tx2 following IROX or Biologics, IRI and 5FU in Tx1 live 292 (se = 4), 224 (se = 2), and 191 (se = 2) days longer and incur added costs of $49,096 (se = $7,137), $83,784 (se = $12,322), and $91,686 (se = $10,312), respectively. Recipients of OX in Tx1 did not receive a survival benefit from Tx2, despite additional costs of $46,849 (se = $10,468). Conclusions: The real-world survival benefit of Tx2 for elderly mCC patients in SEER-Medicare varied based on Tx1 from potential harm to a mean of 292 days of incremental survival. Similarly, the costs and cost effectiveness of Tx2 varied by Tx1. These results underscore the importance of considering prior treatment when evaluating the benefit of subsequent treatment for elderly mCC patients.
Multidisciplinary effect of adding docetaxel and mitomycin-C to low-dose multidrug therapy for cholangiocarcinoma.
Authors: H. Bruckner, A. Hirschfeld, S. Buddaraju, J. Stega, M. Jahan, M. E. Schwartz
Journal: Journal of Clinical Oncology (2011)

e14546 Background: Multidrug chemotherapy improves rates and quality of response in cholangiocarcinoma.It also delays progression and appears to improve survival for the, unresectable and recurrent, high-risk patients (ICACT Bruckner, H et al Paris 2004). This is analogous to experience with treatment for pancreatic cancer (Bruckner, H. et. al ASCO 2008). Methods: Chemotherapy with gemcitabine, 5-flourouracil, irinotecan, leucovorin, oxaliplatin (GFLIOx) and GFLIOx+ docetaxel, mitomycin-C (GFLIO-TXT±MMC) was used sequentially for 50 patients in order to produce opportunities for resection, debulking surgery, TACE and Yittrium 90. Analysis excluded ideal patients with either less than 5cm or well differentiated primary tumors. Prior oversight, safety, eligibility and consent procedures were employed in these ongoing retrospective analysis. Results: GFLIOx produced a 50% rate of benefit for six months or more and 19.5 months median overall survival. In sequence, on progression addition of both TXT and MMC produced a 90% rate of benefit, all for 6 months or more in duration and a median survival of 10 months from time of first addition. Chemotherapy sometimes eradicated bulky lymph node disease of bile duct and gallbladder origin and produced opportunities for multi-modality care. There were no hospitalizations for febrile nutropenia or bleeding due to thrombocytopenia. Treatment was well tolerated up to age 80 years. Final review of additional patients, patient characteristics, and impact on surgery will be available in April 2011. Conclusions: These findings satisfy our criteria for continued use, including median survival greater than one year and high quality, sometimes rapid, second-line responses. Findings also support testing these low dose combinations in both neoadjuvant and classic adjuvant settings. It is feasible to produce multidisciplinary opportunities and multi-year, treatment-free survivors with "palliative" low dose treatments for recurrent and unresectable disease. Secondary benefits include reduced cost and adverse events, compared to high dose standard therapy.
Phase II trial of topotecan, cisplatin, and bevacizumab for recurrent or persistent cervical cancer.
Authors: Israel Zighelboim, Jason D. Wright, Feng Gao, Ashley Stephens Case, L. Stewart Massad, David Gardner Mutch, Matthew A. Powell, Premal H. Thaker, Eric Lawernce Eisenhauer, David E. Cohn, Fidel A. Valea, Angeles Alvarez Secord, Lynne T. Lippmann, Janet Sue Rader
Journal: Journal of Clinical Oncology (2012)

5101 Background: The prognosis associated with recurrent or persistent cervical cancer is exceedingly poor. GOG-179 demonstrated a survival benefit with the combination of cisplatin and topotecan compared to single-agent cisplatin, with the former showing median PFS of 4.6 months, median OS of 9.4 months, and a 27% objective response rate. The role of angiogenesis in cervical carcinogenesis and progression has been well documented. We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with incurable carcinoma of the cervix. Methods: Patients with histologically proven measurable recurrent or persistent cervical carcinoma not amenable to curative intent treatment were eligible. No prior chemotherapy for recurrence was allowed. Cisplatin 50 mg/m 2 day 1, topotecan 0.75 mg/m 2 days 1, 2 and 3 and bevacizumab 15 mg/kg day 1 were prescribed in a 21-day cycle. Cytokine support was allowed at physician discretion. The primary endpoint was 6-month PFS. Additionally, objective clinical response and toxicity were evaluated. Accrual goal (N=27) was based on a 50% improvement goal in 6-month PFS in relation to GOG-179 (40% to 60%), with a one-sided 0.10 significance and 80% power. Results: 27 eligible patients received a median of 3 treatment cycles (range, 1-19). All patients received radiotherapy as part of their first line treatment. Median follow-up was 8.5 months (1.2-32.9). The 6-month PFS was 59% (95%CI: 38.0-74.7). Among 26 RECIST-evaluable patients, objective response rates were (%; 95%CI): 1 CR (4%; 1-19.6), 7 PR (27%; 11.6-47.8), 11 SD (42%; 23.4-63.1) and 7 PD (27%; 11.6-47.8). Median OS was 9.8 months (95%CI: 7.7-20.6) and median PFS was 7.1 months (95%CI: 2.0-12.1). Grade 3-4 hematologic toxicity occurred in 96% of patients (thrombocytopenia 93% leukopenia 70%, anemia 70%, neutropenia 59%). Other grade 3-4 toxicities were also common (metabolic 48%, pain 37%, genitourinary 30%, constitutional 22% and gastrointestinal 19%). Conclusions: The addition of bevacizumab totopotecan and cisplatin results in a highly active but toxic regimen. Future efforts should focus on identification of predictive biomarkers and treatment modifications to minimize toxicity.
Safety and Efficacy of Turoctocog Alfa in Prevention and on-Demand Treatment of Bleeding Episodes in Patients with Hemophilia A
Authors: Dragana Janic, Irina Matytsina, Mudi Misgav, Johannes Oldenburg, Margareth C Ozelo, Michael Recht, Lars Korsholm, Aleksandar Savic, Elena Santagostino
Journal: Blood (2016)
Prognosis model for overall survival in locally advanced unresecable pancreatic carcinoma: An ancillary study of the LAP 07 trial.
Authors: Dewi Vernerey, Pascal Hammel, Sophie Paget-Bailly, Florence Huguet, Jean Luc Van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Malcolm J. Moore, Thierry André, Laurent Mineur, Benoist Chibaudel, Christophe Louvet, Franck Bonnetain
Journal: Journal of Clinical Oncology (2015)

235 Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial and complex. Better discrimination for Overall Survival (OS) is needed to improve therapeutic decisions. We address this issue, with the largest Phase III cohort of LAPC, by establishing the first prognosis model for OS with the full spectrum of parameters currently available at diagnosis. Methods: We enrolled 442 LAPC patients recruited in LAP07, an international multicenter randomized phase III trial (NCT00634725). 30 baseline variables among demographic, cancer history, clinical, biological and radiological parameters were evaluated in univariate and multivariate analyses as prognostic factors for OS. The predictive value of the final model was evaluated with Harrell’s C index. This analysis was repeated 1,000 times with the use of bootstrap sample to derive 95%CI for the C. A prognostic score and nomogramm were then developed based on the identified prognostic factors in the final model. Results: Independent prognostic factors identified in multivariate analysis (n=370) for OS were: Age (HR= 1.01; 95%CI 1.00 - 1.03; p=0.0418), Pain (HR= 1.36 ; 95%CI 1.08 - 1.71; p=0.0094), Albumin (HR= 0.96; 95%CI 0.94 - 0.98; p=0.0001), and RECIST size (HR= 1.01; 95%CI 1.00 - 1.02; p=0.0033), Harrell’s C-statistic for the final model was 0.60 (95% bootstrap CI 0.56 0.63). A prognostic score between 0 and 4 was then calculated for each patient, based on the previous model. Three risk-groups for death could be identified: lower risk (n=17; median OS time = 18.8 months; group of reference); intermediate risk (n=166 ;median OS time = 13.4 months; HR=1.7); higher risk (n=187 ; median OS time = 11.8 months; HR=2.1); p = 0.0101 by the global log rank test. A score and nomogramm were also developped with the addition of CA19.9 information. Conclusions: Our results highlighted 4 OS’s independent pronostic factors among a broad spectrum of parameters at time of diagnosis. We identified 3 groups with different OS’s prognosis profile. The determination of this simple prognostic score allows risk stratification that may help guiding clinical management of patients and the design for future clinical trials.