tbuckley/cabot-search huggingface dataset:
Safety of bevacizumab in patients with metastases to the central nervous system
Authors: U. P. Rohr, S. Augustus, S. F. Lasserre, P. Compton, J. Huang
Journal: Journal of Clinical Oncology (2009)

2007 Background:. The background rate of CNS hemorrhage (CH) in cancer patients with brain metastases not receiving bevacizumab (BV) treatment is 5%-29%, depending on tumor type. Patients with CNS metastases were routinely excluded from most BV late-stage clinical trials, following the occurrence of CH in one hepatocellular carcinoma patient with occult CNS metastasis in a BV phase I trial. In this particular tumour type, up to 87.5% has been reported as a background rate of CH without BV use. Available safety information in BV-treated patients with CNS metastases has been reviewed to determine whether the exclusion of these patients from trials is still justified. Methods: A retrospective exploratory analysis was conducted using safety data from three datasets: A.) 13 randomized controlled phase II or III trials (RCTs); B.) Two ongoing open-label trials MO19391 (ATHENA) and MO19390 (SAIL). While patients with known CNS metastases, based on imaging or clinical signs and symptoms, were excluded from trial in A and B datasets, patients who were found to have CNS lesions had either unrecognized CNS metastases at study entry or had developed these during the trial.; C.) 2 ongoing open-label studies AVF3752g and AVF3671g in patients with NSCLC, where inclusion of patients with treated CNS metastases was allowed. Incidence of CH in patients with brain metastases was quantified in each dataset. Results: A.) In 13 RCTs, with a total of 8443 patients with locally advanced, unresectable, or metastatic breast, renal, pancreatic, colorectal cancer, or NSCLC, brain metastases were identified in 187 patients (91 in BV-arms and 96 in control arm). Three of 91 (3.29%) BV-treated patients developed grade 4 CH, and one in 96 patients in the control arm (1.04%) developed grade 5 CH; B.) In open-label studies no CH was reported in 68 patients with CNS metastases, out of 3,252 patients enrolled. C.) In two studies in patients with treated CNS metastases, one subject in 83 (1.2%) BV treated patients developed a grade 2 CH. Conclusions: In this retrospective review, the rates of CH in BV-treated patients with CNS metastases is low, and appears consistent with historical rates of CH in these patient populations. Ongoing trials are expected to provide additional data regarding the risk of CH in patients with primary and metastatic CNS tumors. [Table: see text]
Neoadjuvant therapy for stage II-III breast cancer with weekly nab-paclitaxel, every-three-week carboplatin, and targeted agents: Interim dose delivery and toxicity data.
Authors: T. Rizack, M. M. Abu-Khalaf, R. D. Legare, R. Strenger, M. A. Fenton, B. J. Sakr, T. A. Kennedy, L. Harris, W. M. Sikov
Journal: Journal of Clinical Oncology (2010)

e11010 Background: To evaluate the efficacy and safety of neoadjuvant weekly (w) nanoparticle albumin-bound paclitaxel (Abraxane, NP) and every-3-week (q3wk) carboplatin (Cb) with either bevacizumab (Avastin, B) or trastuzumab (Herceptin, T). Methods: Patients (pts) with biopsy-confirmed clinical stage IIA-IIIC invasive breast cancer receive wNP 100 mg/m2, Cb AUC 6 q3wk, and either B 10 mg/kg q2wk × 12 wks (HER2-) or T 2 mg/kg qwk × 18 wks (HER2+). wNP is skipped for absolute neutrophil count (ANC) <800 or platelets (plts) <50,000 and reduced by 20% for ANC<100 or febrile neutropenia (FN). wNP and Cb are delayed for ANC <800 or plts <75,000 and Cb is reduced by 25% for plts <25,000 or a 2-week delay for low plts. Results: 43 pts have enrolled; 29 have completed wNP/Cb + B or T. Dose delivery data are tabulated below (Table). wNP doses were skipped for ANC<800 (33/426 planned doses), most often on day 15 of the 3-week cycle, low plts (6), and elevated ALT (5) and reduced for neutropenia (5 pts), ALT and mucositis (1 pt each). Grade 3-4 toxicities include ANC (in 21 of 29 pts) but only one episode of FN, plts (10), anemia (7), elevated ALT (3), nausea, diarrhea, and hypokalemia (1 each). No grade ≥ 2 neuropathy, thromboembolic events or significant reductions in LVEF have been reported. Serious adverse events have been limited to 2 pts hospitalized: one for mucositis, nausea, and vomiting and one for port infection and cellulitis. Two HER2- pts hemorrhaged following port insertion on the same day they started B. One HER2- pt had postmastectomy wound breakdown and necrosis requiring re-operation. Conclusions: The wNP/Cb regimen is reasonably well tolerated, though the frequency of doses skipped for low ANC and treatment delays for low plts have been higher than expected. Dose modification criteria will be amended to reduce the likelihood of treatment interruptions. Stratum (n) wNP Cb Doses delivered % planned doses # with dose red Doses delivered % planned doses # with dose red # with delay HER2- (16) 11 (4-12)/12 84.9% 5/16 4 (2-4) of 4 95.3% 1/16 8/16 HER2+ (13) 18 (13-18)/18 93.2% 2/13 6 (5-6) of 6 96.2% 4/13 7*/13 * 4 pts required 2 Cb delays. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abraxis BioScience
Phase I/II study of MDV3100 in patients (pts) with progressive castration-resistant prostate cancer (CRPC)
Authors: H. I. Scher, T. M. Beer, C. S. Higano, D. C. Danila, B. Montgomery, J. Shelkey, M. Hirmand, D. Hung, C. Sawyers
Journal: Journal of Clinical Oncology (2008)

5006 Background: CRPC is characterized by persistent, high level androgen receptor (AR) expression and remains AR-dependent in model systems. MDV3100 is a novel small molecule AR antagonist selected for its ability to overcome resistance to conventional antiandrogens in the setting of increased AR expression. Unlike bicalutamide, MDV3100 inhibits AR function by blocking nuclear translocation, DNA binding, and has no agonist activity when AR is overexpressed. A first-in-man, multi-center Phase I/II dose-escalation study was started in July 2007 to assess safety and pharmacokinetics (PK), and to evaluate antitumor effects including changes in prostate-specific antigen (PSA). Methods: MDV3100 was administered orally, once daily, to pts with CRPC. Three pts were enrolled per dose-escalation cohort starting at 30 mg. Once the safety of a dose was established, enrollment was expanded for that dose beginning at the 60 mg cohort. Results: To date, a total of 39 pts have been enrolled. Tabular summary of enrolled pts is as follows: MDV3100 has been well-tolerated to date, with no significant adverse events. PK are linear with dose with a half-life of approximately one week. In the 30 mg cohort, 3 of 3 Pts had PSA declines of 44% to 87% from baseline for 19+ weeks, and at 60 mg, 3 of 3 pts declines of 74% to 96% for 14+ weeks. None of the 6 showed evidence of clinical or radiographic progression. Overall 13 of 14 Pts followed for 4+ weeks have had PSA declines. Conclusions: MDV3100, a rationally designed AR antagonist with a novel mechanism of action, has resulted in PSA reductions in a high proportion of evaluable pts. The drug has been well-tolerated to date and appears to be a promising candidate for the treatment of progressive CRPC. Pt accrual is ongoing. Cohort Number Chemotherapy- Naive Number Post- Chemotherapy Follow-up (Weeks) Status Dose Escalation 30 mg 3 0 19+ All on therapy 60 mg 3 0 14+ All on therapy 150 mg 2 1 8+ 2 of 3 on therapy 240 mg 3 0 2+ All on therapy Dose Expansion 60 mg 11 7 3+-6+ All on therapy 150 mg 3 6 2+-3+ All on therapy Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medivation Medivation Medivation Medivation
Investigation of whether expression of bcl-2 influences the apoptotic response of doxorubicin-resistant breast cancer cells to a novel anthracycline
Authors: M. A. Fanale, Y. Liu, T. S. McKenzie, I. Fokt, W. Priebe, K. K. Hunt
Journal: Journal of Clinical Oncology (2005)

2082 Background: Doxorubicin is a mainstay of therapy for breast cancer patients. Recent studies have investigated the role of the anti-apoptotic protein bcl-2 in doxorubicin-resistance. Several reports describe that breast tumors with high levels of bcl-2 expression have decreased pathological and clinical responses to doxorubicin. WP744 is a doxorubicin analog which is benzylated at the C-4’ hydroxyl. We have previously shown that WP744 is superior to doxorubicin at inducing both growth inhibition and apoptosis of both doxorubicin-sensitive (MCF-Her-18) and doxorubicin-resistant (231-GFP, MCF-7) breast cancer cells. We now wished to determine the role of bcl-2 in the therapeutic response to WP744. Methods: MCF-Her-18, 231-GFP, and MCF-7 cells were incubated with PBS, doxorubicin (0.1 μg/ml), and WP744 (0.1 μg/ml). 231-GFP cells were transfected with vectors that overexpress bcl-2 (bcl-2 # 4, bcl-2 # 5) and a control vector (neu). At 72 h protein was isolated, subjected to gel electrophoresis, and transferred to nitrocellulose membranes that were incubated with antibodies against bcl-2 and β-actin. The transfected cell lines (231-GFP-bcl-2 # 4, -bcl-2 #5, -neu) and MCF-7 cells were then incubated with WP744 (0.05 and 0.1 μg/ml) and PBS. At 72 h apoptosis was analyzed by FACS. Results: Western blot demonstrated that MCF-Her-18 cells and 231-GFP cells had a low level of bcl-2 expression. However, MCF-7 cells (IC50 0.14 μg/ml with WP744 vs. > 0.5 μg/ml with doxorubicin) had a high level of bcl-2 expression. 231-GFP cells transfected with vectors bcl-2 # 4 and # 5 had significantly higher levels of bcl-2 expression on Western blot than the 231-GFP or 231-GFP-neu cells. However, 231-GFP-neu had a similar level of apoptosis for both dose levels of WP744 as compared 231-GFP-bcl-2 #4, respectively 10% vs. 11% at 0.1 μg/ml. Conclusions: WP744 is able to cause significant growth inhibition even in the presence of high levels of bcl-2 expression, and the apoptotic effects of WP744 appear to be independent of bcl-2. Therefore, we believe that WP744 has considerable promise for clinical development as an antitumor agent for the anthracycline-based treatment of breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Reata Discovery
Phase II study of lenalidomide (CC-5013) for patients with myelofibrosis
Authors: S. Verstovsek, J. Cortes, D. Thomas, M. Beran, C. Koller, F. Giles, H. Kantarjian
Journal: Journal of Clinical Oncology (2006)

6510 Background: Lenalidomide (CC-5013, Revlimid), analogue of thalidomide, a new drug in a group known as ImiDs, with broad cytokine modulatory activity. Lenalidomide is less toxic than thalidomide without teratogenicity, sedation, or neurotoxicity, and is 50,000-fold more potent in inhibiting, tumor necrosis factor-α, that is involved in the pathophysiology of myelofibrosis (MF). Patients (pts) with MF currently have no approved standard effective therapy. Methods: Phase II study of lenalidomide for MF pts with plts &gt;30×10 9 , performance status ≥3, total bilirubin and creatinine of &lt;3mg/dL, accrued 41 pts. Pts with prior hypersensitivity to thalidomide excluded. Pts received lenalidomide 10mg orally daily (5mg if platelets &lt;100x10 9 ). Median age 65 (range, 42–83). 36 pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 13 (32%), interferon 11 (27%), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was &lt;10g/dl in 19 (46%) (13 or 32% were transfusion dependent), platelets &lt;100x10 9 in 12 (29%), absolute neutrophils &lt;1.5x10 9 in 2 (5%), 20/34 (59%) had splenomegaly (median 10cm BCM, range 1–30; 7 with prior splenectomy), and 17 (42%) had cytogenetic abnormality. Results: Median follow is 5 months (range 1–14). Therapy has been well tolerated. Most common toxicities of any grade were rash 6(39%) and pruritus 9 (22%). Grade ≥3 toxicities were neutropenia 13 (32%), thrombocytopenia 11 (27%), fatigue 3 (7%) and rash 2 (5%). 8 (20%) pts required dose reduction; 4 discontinued therapy due to toxicity. Responses have been observed in 19 (46%) pts. These include CR 3(7%; normalization of hemoglobin and WBC), PR 5 (12%; improvement in platelets and hemoglobin ± spleen), and hematologic improvement 11 (27%) pts (improvement in platelets - 4, spleen - 2, WBC - 4, BM blasts - 1). 5 of 13 transfusion-dependent pts have become transfusion-independent. 6 of 12 (50%) pts with platelets &lt;100x10 9 improved the count by &gt;50%. Median time to response was 6 wks (range 1–22). Responses have been sustained for a median of 31+ wks (range 1+-40+). Conclusions: Lenalidomide has clinical activity in a subset of pts with MF with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are planned. No significant financial relationships to disclose.
P63 in cytologic material is helpful for detection of squamous differentiation in non-small cell carcinomas of lung and treatment selection
Authors: M. Jorda, F. Mousavi, C. Gomez-Fernandez, Z. Maleki, G. Walker, P. Ganjei-Azar
Journal: Journal of Clinical Oncology (2007)

18052 Background: Bevacizumab in combination with carboplatin and paclitaxel improves overall response and survival in patients with advanced or recurrent non-small cell lung carcinoma. However, this drug is not recommended in patients with carcinomas with squamous differentiation. Therefore, identification of squamous cell component is desirable. In many instances, cytology is the diagnostic tool of choice; however, routine cytomorphology is limited in classification of non small-cell carcinomas into squamous and non-squamous subtypes. The aim of this study is to identify the value of immunocytochemistry for p63 in this distinction. Methods: Review of cytology records identified 51 consecutive pulmonary specimens with the diagnosis of non-small cell carcinoma (9 squamous cell carcinomas and 42 carcinomas without squamous differentiation). Histologically, they proved to be 26 squamous cell carcinomas and 25 non-small cell carcinomas without squamous differentiation. P63 immunocytochemical stain was performed on archival alcohol-fixed Papanicolaou stained cytology slides, using standard immunocytochemical methods. Results: Twenty-three (88 %) of the 26 histologically proven squamous cell carcinomas were positive for p63 on cytologic smears. Using p63, we detected 14 carcinomas with squamous differentiation not identified by cytomorphology. Smears from all carcinomas with squamous differentiation were positive for p63. Sensitivity of cytology for the detection of squamous differentiation increased from 35% to 88% using p63 immunocytochemistry (p=0.001, McNemar’s test). Four carcinomas with squamous differentiation were detected only in cytologic and not in corresponding histologic samples. Conclusions: 1- p63 is a useful marker for the detection of squamous differentiation in cytologic pulmonary samples; 2- p63 immunocytochemistry significantly increases the sensitivity for the identification of squamous cell carcinomas of lung from 35% to 88% (p=0.001); 3- p63 immunocytochemistry should be used in all pulmonary cytologic samples with a diagnosis of non-small cell carcinoma to improve therapeutic selection of patients; 4- Cytologic sampling may provide better representation of tumor subtypes. No significant financial relationships to disclose.
In Vitro Generation of Highly-Purified Functional Invariant NKT Cells: A Strategy for Immunotherapy in Multiple Myeloma.
Authors: Weihua Song, Hans J.J. van der Vliet, Ruojie Wang, Rao Prabhala, Klaus Podar, Yu-Tzu Tai, Laurence Catley, Masood Shammas, Kenneth C. Anderson, Steven P. Balk, Mark A. Exley, Nikhil C. Munshi
Journal: Blood (2005)
An analysis and epidemiologic study on new cancer patients admitted to our department between 1999–2003
Authors: B. O. Dernek, M. H. Akboru, A. Yoney, S. Altin, M. Unsal
Journal: Journal of Clinical Oncology (2006)

20108 Background: Cancer is one of the most important health problems existing 10.1 millions of new patients and 6.2 millions dead in 2000. 15 millions of new patients will be supposed to be seen in 2020. Method: In this study; between 1999–2003, 41,564 new patients diagnosed as cancer admitted to our center were analyzed. International Classification Disease of Oncology (ICD-O) was used to classify the patients. Basal cell carcinoma and epidermoid carcinoma of the skin were not included. Rest of 41116 patients were reviewed according to their age, sex, diagnosis and coming region. Results: 55.6% of the patients were male. Top five location of the disease can be listed as follows: respiratory system (25.6%), gastrointestinal system (19.2%), breast (15.1%), genitourinary system (11.3%) and lymphoma (4.7%). Analysis according to gender is illustrated in Table . Most cases have come from Marmara Region. While peak incidence was detected between 60–69 years of age in males, it was 50–59 years of age in females. Least comings were seen below 20 years of ages in both sexes. Conclusions: Admission to our department increases gradually while it was 7,020 patients in 1999, it reached to 10,035 person in 2003. General population and population insured by Social Insurance Institution are mostly living in Marmara Region (48.16% of the population are insured by this institution and 41.72% of them reside in Marmara Region). Our department was unique active center in Social Insurance Institution’s order at that time. According to SEER (U.S. Surveillance Epidemiology and EndResults) data in United States (US); although prostate cancer is mostly seen cancer (15%) and lung cancer is recorded in just 13% of cases it is the leading data in our study (22.4%) and prostate cancer is only seen 3.8% of cases. This difference can be explained by effective screening programs in US and prostatic cancer patients mostly prefer to apply the Urology Department in our country. Smoking and environmental conditions may be the reason of high incidence in lung cancer. [Table: see text] No significant financial relationships to disclose.
The role of paclitaxel in the first-line treatment of patients with ‘poor prognosis’ germ cell tumor (GCT) undergoing sequential high dose chemotherapy
Authors: J. T. Hartmann, O. Rick, M. Thomas, J. Schleicher, B. Metzner, M. Flasshove, C. Kollmannsberger, H.-J. Schmoll, L. Kanz, C. Bokemeyer
Journal: Journal of Clinical Oncology (2004)

4633 Background: Paclitaxel (T) has shown significant activity both in cisplatin-refractory and untreated GCT patients (pts). In order to determine the impact of T on survival (OS) and toxicity the analysis compares the results of two prospective trials in pts with ‘poor prognosis’ GCT. Methods: In the first trial pts have received high dose VIP chemotherapy (HD-VIP) at dose level [etoposide 250 mg/sqm, ifosfamide 2 g/sqm, cisplatin 20 mg/sqm, d1–5, q d22] for 3 consecutive cycles as part of a phase I/II dose trial. Pts received G-CSF 5 μg/kg s.c. from d+1 after treatment to leukocyte recovery >2000/μl and reinfusion of PBSC at day +2. The comparative trial consisted of pts treated in an identical fashion but additionally receiving T at a dose of 225 mg/sqm added on day 1 as a 3-h infusion prior to cisplatin (HD-VIP+T. Results: 155 pts have been analyzed, 59 pts in HD-VIP and 96 pts in HD-VIP+T. 112 pts and 414 cycles are fully assessable for toxicity, 152 pts for OS. Pts characteristics (HD-VIP compared to HDVIP+T): Median age 29 (16–42) vs. 31 yrs (18–54), mediastinal primary 11 vs. 24%, liver mets 40 vs. 40%, bone 7 vs. 4%, CNS 20 vs. 19%, elevated AFP, HCG, LDH: 39 vs. 30%, 61 vs. 58% and 77 vs. 77%. Dose intensity of the 3- vs. 4-drug regimen achieved have been 98% and 95%. Median time to recovery of granulocytes and thrombocytes (>500/μl resp. >25.000μl) have been day 15 and 16 independent from the addition of T. Differences in grade III/IV toxicity in favor of HD-VIP were seen in terms of stomatitis (14 vs. 49%), neutropenic fever (3 vs. 20%) and manifest infection (3 vs. 19%) (P.05). 88% of pts attained a favorable response (NED/CR/PRm-) to HD-VIP compared to 67% in the HD-VIP+T (P<.05). After a median follow up period of 34 mos (range, 9–78) and 16 (0–47) the calculated 3-yr OS rates were 69.9 (CI95%, 54.3–83.3) for HD-VIP and 67.3% (56.3–78.3) for HD-VIP+T (P=.3). Early death rate due to progression/toxicity was 3% in both trials. Conclusions: The addition of paclitaxel to HD-VIP dose level 6 as first-line therapy was associated with a moderately elevated toxicity. No substantial impact on survival can be anticipated for HD-VIP+T. No significant financial relationships to disclose.
Cyclophosphamide and fludarabine (CF) in advanced indolent lymphoma: Results from the ECOG/CALGB intergroup E1496 trial
Authors: H. S. Hochster, E. Weller, R. D. Gascoyne, T. Ryan, T. M. Habermann, L. I. Gordon, S. R. Frankel, S. J. Horning
Journal: Journal of Clinical Oncology (2007)

8004 Background: To determine optimal induction and the role of maintenance, the E1496 study randomized patients (pts) to induction CVP (cyclophosphamide, vincristine, prednisone) versus CF (cyclophosphamide 1 G/m 2 d1, fludarabine 20 mg/m 2 d1–5 every 28 d) for 2 cycles beyond best response (maximum 8). Responding and stable pts were secondarily randomized to MR (375 mg/m 2 weekly × 4 every 6 months for 2 years [yr]) or observation (OBS). Methods: Due to early deaths the CF arm was closed to accrual with 115 pts randomized to CF and 119 pts to CVP (thereafter all pts were assigned to CVP prior to maintenance randomization). The results presented here compare the outcome of CF patients with the subset of E1496 pts randomized to CVP (CVP R ). Results: Median follow-up on pts randomized to induction is 6.5 yr. Toxic deaths occurred in 8 (7%) CF pts during induction and 4 additional deaths (1 OBS, 3 MR) occurred among the 69 (6%) CF pts randomized to MR or OBS. Causes of death were infection (9), liver failure (2), CNS gliosis (1). CF pts received a median of 5 cycles compared to 7 cycles for CVP R. The CR rate was 51% vs 22% (p=0.00001) and the PR rate was 35% vs 55% for CF vs. CVP R, respectively. Four-yr PFS for CF vs. CVP R was 49% vs 45% (p=0.19) and OS was 66% vs. 81% (p=0.12), respectively. Of 45 CF deaths, 23 (51%) occurred without lymphoma progression compared to 5 (13%) of 38 CVP R deaths (p=0.0004). More than 90% of CF patients randomized to maintenance achieved protocol-defined minimal residual disease compared with 64% CVP R pts. Maintenance therapy had no impact on 2 yr PFS for the 67 evaluable randomized CF pts, which was 74% for MR vs. 73% for OBS (p=0.19). In contrast, 2 yr PFS was 73% for MR and 42% for OBS in randomized CVP R pts (p=0.004). Survival at 2 yr for MR vs OBS was: CF 79% vs 91% (p=0.19) compared with CVP 98% vs 93% (p=0.21). Conclusions: Induction with CF results in higher CR and miminal residual disease rates than CVP. However, gains in remission quality with CF (in the dose and schedule used here) were offset by early and late deaths in the absence of progressive lymphoma. In E1496, the benefit of MR was influenced by the induction chemotherapy. [Table: see text]