tbuckley/cabot-search huggingface dataset:
Phase II trial of paclitaxel-topotecan-etoposide (PTE) followed by consolidation chemoradiotherapy for limited stage small cell lung cancer (LS-SCLC): CALGB 30002
Authors: A. A. Miller, J. A. Bogart, D. M. Watson, X. F. Wang, C. M. S. Rocha Lima, E. E. Vokes, M. R. Green
Journal: Journal of Clinical Oncology (2005)

7170 Background: We sought to exploit the sequence and schedule dependent synergistic effects of PTE in induction therapy for LS-SCLC. Methods: Patients with measurable disease, performance status (PS) 0–2, no prior therapy, and adequate organ function were eligible. P 110 mg/m2 iv day 1, T 1.5 mg/m2 po days 2–4, E 160 mg/m2 po days 5–7 q21 days with filgrastim x2 cycles was followed by chest irradiation to 70 Gy concurrent with carboplatin AUC=5 iv day 1 and E 100 mg/m2 days 1–3 q 21 days without filgrastim x3 cycles (5 chemotherapy cycles total). We aimed to determine the response rates to induction and overall therapy, overall and progression-free survival, and toxicity. The primary statistical endpoint was to differentiate between CR rates of 50% and 70% for the overall treatment program (>36 CRs/60 patients, α=0.046, β=0.063). Results: Between 6/01 and 1/03, 65 patients were enrolled (21 months median f/u) but 1 never started therapy and 1 was ineligible: male/female, 27/36; white/black/other/?, 58/3/1/1; median age 62 (range, 38–78); PS 0/1/2/?, 26/33/3/1. PTE induction resulted in 5 (8%) CR, 34 (54%) PR, and 14 (22%) SD. Best response to chemoradiotherapy was 27 (43%) CR, 26 (41%) PR, and 5 (8%) SD. The 95% confidence intervals (CI) were 31–56% for CR and 73–92% for CR plus PR. Median estimated survival is 16.6 months (CI, NA). Median progression-free survival is 10.8 months (CI, 9.3–14.8). Frequent (>20%) grade 3/4 toxicities over all therapy were: neutrophils 24%/54%; febrile neutropenia 21%/0%; hemoglobin 21%/3%; platelets 46%/3%; fatigue 21%/2%; dysphagia 29%/0%. One patient died of febrile neutropenia, one died of febrile neutropenia and typhlitis, and a Jehovah’s witness who declined transfusion for anemia died of cardiac ischemia. Conclusions: This treatment regimen has activity in LS-SCLC but did not meet our criteria to be investigated further. Adding a third drug to a non-platinum induction regimen does not appear beneficial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
A phase II study of celecoxib (C) with irinotecan (I), 5-fluorouracil (F), and leucovorin (L) in patients (pts) with advanced or metastatic colorectal cancer (CRC)
Authors: R. E. Sanborn, H. Lenz, D. G. Haller, A. B. Benson, T. Dragovich, C. Robles, M. McMahon, H. Li, M. Mori, N. Mattek, C. D. Blanke
Journal: Journal of Clinical Oncology (2006)

3588 Background: Expression of cyclooxygenase-2 (COX-2), present in most CRC, is associated with a worse prognosis. C, a selective COX-2 inhibitor, has inhibitory effects against CRC which appear at least additive with chemotherapy preclinically. A multi-institutional phase II trial was conducted to evaluate C plus standard IFL as first-line treatment for pts with incurable CRC. Methods: C 400mg po BID starting Day #1; I 125mg/m 2 iv weekly starting Day #15; F 500mg/m 2 iv bolus weekly starting Day #15; L 20mg/m 2 iv weekly bolus starting Day #15. Patients received IFL for 4 weeks followed by a two-week rest. C was continued during the rest. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint was response with planned sample size of 47 patients. Results: 47 pts were consented and treated. Evaluable pt characteristics: Male/female (no.) = 34/13; mean age = 59.7; ECOG PS 0/1/2 (no.) = 31/14/2; cancer stage locally-advanced/distant/unknown (no.) = 10/28/9. Due to concerns of risk of excess cardiovascular (CV) toxicity the protocol was amended halfway through enrollment to exclude pts with PS 2, and to require low-dose aspirin (ASA) for pts at high risk for CV events. Pre-and post-modification (mod) results are shown in the table . In general hematologic toxicity was moderate. Non-hematologic toxicity was mostly gastrointestinal, but 25% experienced cardiac or vascular toxicity (1 cardiac arrest, 1 MI, 1 CHF, 3 arrhythmias, 2 DVT, 2 CVA, 1 hyper- and 1 hypotension). All cardiac events occurred before modification of the protocol. There was 1 treatment-related death from cardiac arrest. Conclusions: C may be given safely with IFL chemotherapy, if pts are carefully selected. Addition of low-dose ASA may reduce cardiac toxicity. Post-mod TTP and survival for C plus IFL appear superior to historical results for IFL, but a phase III study would be required for confirmation. [Table: see text] [Table: see text]
Cost-effectiveness analysis of the addition of bevacizumab to first-line chemotherapy in metastatic colorectal cancer.
Authors: D. Villa, L. Hedden, S. Peacock, H. F. Kennecke
Journal: Journal of Clinical Oncology (2010)

3623 Background: The addition of bevacizumab (Bev) to either an irinotecan or oxaliplatin- based regimen in the systemic management of metastatic colorectal cancer is associated with a significant improvement in overall survival, but at the expense of a very high acquisition cost. We evaluated the cost-effectiveness of this combination using an era-to-era, population-based analysis. Methods: All patients with newly diagnosed metastatic colorectal cancer in 2003/04 (pre-Bev era) and 2006 (Bev era) referred to the British Columbia Cancer Agency were identified. Cost data are presented in the Table. An incremental cost-effectiveness analysis was constructed based on a Markov model that tracked major clinical and treatment events in the natural history of the disease. Probabilistic and one-way sensitivity analyses varying the median overall survival and median cost of treatment per patient were conducted to test the robustness of the model. Results: 943 patients were included: 611 from 2003/04 (pre-Bev era) and 332 from 2006 (Bev era). Median overall survival improved from 15.6 months in the pre-Bev era to 19.5 months in the Bev era (p=0.03). The weighted average cost of treatment per patient was $34,972 and $38,764 in the pre-Bev and Bev eras, respectively. In the Bev era, the cost of treatment resulted in an incremental cost-effectiveness ratio of $15,617/LYG, which translates into $62,468/QALY gained. Probabilistic sensitivity analyses produced an interquartile range of $38,900-$85,800/QALY, suggesting that the model is sensitive to the cost of systemic therapy. Conclusions: Even though Bev incurs in a high acquisition cost, it has also improved the cost-effectiveness of systemic therapy during the era in which it has been used. Expense Source Average cost per patient Pre-Bev (n=611) Bev (n=332) Diagnosis and staging StatsCan POHEM modeling $2115.38 $2115.38 Day surgery Ontario Case Costing Initiative $ 1,046.01 $ 1,136.00 Inpatient Ontario Case Costing Initiative $ 11,115.13 $ 14,718.00 Systemic Therapy BCCA provincial pharmacy database $ 20,672.62 $ 24,464.53 Radiation therapy BCCA radiation oncology database $ 3,843.40 $ 3,843.40 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, sanofi-aventis Roche, sanofi-aventis
Abstract 12881: Increased Stiffness of Aorta is Related to the Decreased Myocardial Flow Reserve Assessed by NH3 Myocardial Perfusion PET in Patients With Hemodialysis
Authors: Takeshi Yamamoto, Masafumi Yano, Kazuyoshi Suga, Masunori Matsuzaki
Journal: Circulation (2014)

Introduction:  In patients with compliant aorta, reflective wave from the peripheral artery arrives at the aortic root at diastolic phase. In patients with stiff aorta, reflective wave arrives earlier in the central aorta so that the diastolic pressure decreases. In this context, aortic stiffness may affect myocardial flow reserve. The patients with hemodialysis tend to have stiff aorta with calcifications. Here, we investigate the relation between myocardial flow reserve (MFR) assessed by NH3 myocardial perfusion PET and aortic stiffness in patients with hemodialysis.   Methods:  Forty-five patients with hemodialysis enrolled to this study. After 15 minutes rest, brachial-ankle pulse wave velocity (baPWV) was measured using BP-203 (Omron Japan). Patients who have significant decreased ABI (   Results:  Subjects with decreased MFR (   Conclusions:  In patient with hemodialysis, stiffness of aorta might be an important determinant of myocardial flow reserve.
Phase I trial of temozolomide plus O<sup>6</sup>-benzylguanine on three different 5-day temozolomide regimens for patients with progressive glioblastoma multiforme
Authors: J. A. Quinn, X. S. Jiang, J. N. Rich, A. Desjardins, J. J. Vredenburgh, D. A. Reardon, S. Gururangan, A. R. Walker, R. Birch, A. H. Friedman, H. S. Friedman
Journal: Journal of Clinical Oncology (2008)

2084 Background: We conducted a phase I clinical trial in patients with progressive glioblastoma multiforme (GBM). This trial was designed to define the maximum tolerated dose (MTD) of temozolomide administered for 5 consecutive days in combination with O6-benzylguanine (O6-BG). Methods: Three different dosing regimens of temozolomide were explored. On Schedule 1, patients received 200 mg/m2/day on day 1 and 25 mg/m2/day (dose escalations by 25 mg/m2/day) on days 2–5. On Schedule 2, patients received the same dose on all five days. On Schedule 3, patients received the same dosing schedule as Schedule 2 except the patients were supported with pegfilgrastim. The first dose levels for Schedule 2 and 3 were dependent on the MTD found in Schedule 1. O6-BG was administered both as a bolus infusion (120 mg/m2), over 1 hour on day 1 and repeated every 48 hours on days 3 and 5, and as a continuous infusion (30 mg/m2/day) on days 1–5. Temozolomide was administered orally within 60 minutes of the end of the first 1-hour infusion of O6-BG and then every 24 hours during the continuous infusion of O6-BG. Treatment cycles were 28 days in length. Results: On Schedule 1, 2, and 3 the MTD for temozolomide was found to be 50 mg/m2/day. A total of 28 of 29 patients were evaluable for toxicity with dose-limiting toxicities (DLTs) limited to myelosuppression. On Schedule 1, one patient experienced a DLT of grade 4 neutropenia at a temozolomide dose of 50 mg/m2/day, and two patients experienced a DLT of grade 4 thrombocytopenia-leukopenia and grade 4 neutropenia at a temozolomide dose of 75 mg/m2/day. On Schedule 2, two patients experienced a DLT of grade 4 thrombocytopenia-neutropenia, and grade 4 neutropenia at a temozolomide dose of 75 mg/m2/day. On Schedule 3, two patients experienced a DLT of grade 4 thrombocytopenia at a temozolomide dose of 75 mg/m2/day. One patient who had prior progression on temozolomide achieved a complete response while completing 12 cycles of temozolomide in combination with O6-BG. Conclusions: The MTD of temozolomide was found to be 50 mg/m2/day on all three dosing schedules. This study will provide the foundation for a phase II trial of temozolomide in combination with O6-BG in temozolomide-resistant malignant glioma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AOI Pharmaceuticals Keryx Biopharmaceuticals, Inc., Schering-Plough Keryx Biopharmaceuticals, Inc. Schering-Plough
Phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium.
Authors: M. I. Milowsky, A. M. Regazzi, I. R. Garcia-Grossman, A. Trout, A. Flaherty, S. Gerst, D. F. Bajorin
Journal: Journal of Clinical Oncology (2011)

245 Background: Second-line chemotherapy has limited activity in advanced TCC with a median progression free survival (PFS) of 2-3 months. We have previously demonstrated the overexpression of activated mTOR pathway markers in invasive TCC specimens (BJU Int. 2010 Jul 26). Everolimus selectively inhibits mTOR, a central regulator of cell growth, proliferation, survival, and angiogenesis. This trial was designed to assess the efficacy of everolimus in patients (pts) with advanced TCC. Methods: The primary objectives of this single-institution phase II trial of everolimus in pts with TCC who have failed prior chemotherapy are 1) to measure PFS as determined by RECIST and 2) to evaluate toxicity. Prior therapy is restricted to ≤ 4 chemotherapy drugs. Pts receive everolimus 10 mg oral daily continuously (1 cycle = 4 weeks). A Simon 2-stage design requires ≥13 of 23 pts to be progression free at 2 months to proceed to maximal accrual of 37. Results: 43 pts (31 M, 12 F) with a median age of 65 yrs (32-84) and median KPS of 90 (70-90) were enrolled between 02/16/2009 and 09/30/2010. Primary tumor sites include bladder (32 pts) and ureter/renal pelvis (11 pts). Prior therapy included 28 pts with 2 drugs, 13 with 3 and 2 with 4. 34 pts have visceral metastases including lung (21), liver (19), and bone (5), and 9 pts have lymph node only disease. 8 pts who received ≤ 1 cycle secondary to rapid progression or toxicity unrelated to everolimus were deemed inevaluable for PFS endpoint and were replaced. To date, 33 pts are evaluable for the primary PFS endpoint; 2 pts are too early for PFS assessment. 22 of 33 pts are progression-free at 2 months. The median PFS for 33 evaluable pts is 2.9 months (1.4-9). One partial response has been seen. The most common grade 3-4 toxicities at least possibly related to everolimus include: anemia (7), infection (6), hyperglycemia (5), lymphopenia (4), hypophosphatemia (4), fatigue (3), hyponatremia (3), mucositis (2), dehydration (2), renal (2) and liver (2). Conclusions: Everolimus has clinical activity in pts with advanced TCC. An ongoing analysis of pretreatment tumor tissue specimens for markers of activated mTOR pathway will be correlated with PFS. [Table: see text]
A multicenter, first-in-pediatrics phase I study of ridaforolimus (AP23573, MK-8669) in patients (pts) with refractory solid tumors.
Authors: L. Gore, T. M. Trippett, H. M. Katzenstein, J. L. Boklan, A. Narendaren, A. Smith, M. Macy, N. Narasimhan, C. D. Turner, M. L. Nieder
Journal: Journal of Clinical Oncology (2010)

9531 Background: The mTOR inhibitor ridaforolimus (R) has shown antitumor activity in adults with sarcomas and other malignancies. We implemented this phase I study to determine the maximum tolerated dose (MTD), biologic profile, and recommended phase II dose (RP2D) of R in children and adolescents. Methods: Pts ages 1-17 yrs, diagnosed with progressive or refractory malignant solid tumors were eligible. A standard 3+3 design was used and R was escalated in sequential dose levels: 8, 10, 13 and 16 mg/m2/day IV over 1 hour daily × 5 every other week in 28 day cycles. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected to evaluate the biologic properties of R. Results: 16 heavily pretreated pts median age 12 yr (range 2-16) with refractory sarcoma (9), brain tumors (6), and nephroblastoma (1) were enrolled; 15 were treated. Dose level 4 remains open; 1 pt is too early to evaluate. Related grade 3/4 toxicities seen in >10% of patients were myelosuppression, electrolyte disturbances, transaminitis, hyperglycemia, anorexia, nausea, vomiting, acidosis, and pain. A pt with metastatic desmoplastic small round cell tumor (DL1) achieved a >15% reduction in tumor size with resolution of ascites and pleural effusions for 15 months. Four pts with CNS tumors and 2 with sarcomas had SD as best response (median 2 cycles, range 1-14). Nine pts discontinued for PD, 1 for unrelated AE, 1 withdrew consent, and 3 pts remain on study. Median OS was 7.5 months. All pts had PK/PD samples collected. Mean day 5 t1/2 was 53 (SD±18) hrs. Phos-4EBP1 in PBMCs at 24 hours were decreased by ≥ 70% in 12 pts analyzed across all dose levels and was sustained in 9 pts. PD mirrors PK levels and shows target inhibition at all doses. Conclusions: IV Ridaforolimus is safe and well tolerated in pediatric pts. The trial is ongoing as the pediatric RP2D has not yet been determined despite exceeding the adult RP2D IV dose. PK and PD results are similar to those seen in adult trials and support use in children. Dose level Ridaforolimus (mg/m2) days 1-5 and 16-20 # of pts enrolled/treated Median # of cycles (range) # of DLTs Best response by RECIST 1 = 8 mg/m2 5/5 1 (1-14) 0 2 SD 2 = 10 mg/m2 4/4 3 (2-6) 0 2 SD 3 = 13 mg/m2 4/3 2 (2-5) 0 1 SD 4 = 16 mg/m2 3/3 2 (2) 0 1 SD Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad Pharmaceuticals Ariad Pharmaceuticals
Cinacalcet HCl controls secondary hyperparathyroidism (HPT) regardless of gender, race, age, and geography in patients with chronic kidney disease (CKD) receiving dialysis.
Authors: DW Coyne, Michel Jadoul, MH Stegman, H Azad, Joy, SF Mischel, N Pokroy, R Ouseph, R Gokal, HS Brink, KA Olson, MB Albizem, PS Klassen, GM Chertow
Journal: Journal of the American Society of Nephrology (2003)
Abstract 13474: PI3K{alpha} is Required for Recovery from Transient Cre/tamoxifen Induced Cardiotoxicity
Authors: Brent A McLean, Seyyed M Kazemi-Bajestani, Zamaneh Kassiri, Bart Vanhaesebroeck, Gavin Y Oudit
Journal: Circulation (2012)

Introduction: Tamoxifen activation of the Cre recombinase transgene is a commonly used model for tissue and time-specific gene deletion. Tamoxifen treatment combined with Cre causes a transient car...
Stemness signature of BMI1 and clinical outcome in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy
Authors: Y. Fujiwara, R. Yoshikawa, L. Tao, T. Tsujimura, M. Sasako
Journal: Journal of Clinical Oncology (2009)

4572 Background: The polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of hematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Our recent report has demonstrated that Gli-1 nuclear expression indicative of Hh signalling activation can predict very poorer prognosis of esophageal squamous cell carcinomas (ESCCs)(Br J Cancer 2008). As data were not available on the clinical role of BMI1 expression, we analyzed whether it could be also used to predict disease progression and prognosis in ESCC patients undergoing neoadjuvant chemoradiotherapy (CRT). Methods: BMI1, Gli-1, and p16 INK4A expressions were evaluated in 78 ESCC patients by immunohistochemical staining. All patients underwent preoperative chemoradiotherapy; 40 Gy irradiation plus FP (5- FU and CDDP) regimen. Results: In total, 24 out of 78 patients (30.8%) showed BMI1 positive expression. All Gli- 1 nuclear positive cancers expressed BMI1. There was no significant correlation between p16 INK4A expression and BMI1 expression. Overall survival (OS) was significantly correlated with the absence of BMI1 expression. The patients with BMI1-positive cancers showed significantly poorer prognoses than those without (mean disease-free survival (DFS) time 16.8 vs 71.2 months, P&lt;0.005; mean OS time 21.8 vs 76.6 months, P&lt;0.001). Conclusions: We demonstrated that BMI1 expression indicative of PcG protein chromatin silencing pathway activation was significantly correlated with esophageal cancer recurrence and poor prognosis after CRT, and that it was not inversely correlated with the presence of the downstream target p16 INK4A . These findings suggest that the stemness signature including components of Hh and PcG pathways might be involved in promoting cancer regrowth and progression after CRT, and is thus a potential prognostic biomarker and rational therapeutic target for attacking the “more aggressive” cancer cells causing recurrence. No significant financial relationships to disclose.
Neonax (AIO-PAK-0313): Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: A phase II study of the AIO Pancreatic Cancer Group.
Authors: Thomas Jens Ettrich, Andreas W. Berger, Rainer Muche, Manfred P. Lutz, Nicole Prasnikar, Waldemar Uhl, Andrea Tannapfel, Volker Heinemann, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2015)

TPS497 Background: Resectable pancreatic cancer still has an unfavourable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Recently, two phase III trials demonstrated for the first time, a substantial improvement in overall response, PFS and OS in patients with metastatic pancreatic cancer compared to standard gemcitabine (FOLFIRINOX and nab-paclitaxel/gemcitabine). The combination of nab-paclitaxel/gemcitabine has a more favourable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods: NEONAX is a study for patients (to be enrolled: n=166) with resectable ductal adenocarcinoma of the pancreas ≤ T3 in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) - tumor surgery - 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant only arm): tumor surgery - 6 cycles nab-paclitaxel/gemcitabine. NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 month with adjuvant gemcitabine). The randomization (1:1) is eminent to achieve two comparable patient groups. Primary objective is DFS at 18 months after randomization. Key secondary objectives are 3-year OS and DFS, progression during neoadjuvant therapy and QoL. In the perioperative group tumor tissue will be collected prior to and post-surgery and subjected to microdissection and exome sequencing of tumor tissue. Tumor regression will be assessed both in the perioperative and the adjuvant group, respectively. In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. Start of trial will be in IV/2014 in 20 high-volume centers for pancreatic surgery in Germany. Clinical trial information: NCT02047513. Clinical trial information: NCT02047513.