bluuebunny/crossref_metadata_2025_split huggingface dataset:
A budget impact analysis of extended adjuvant letrozole following five years of tamoxifen in postmenopausal women with early breast cancer
Authors: Calabró A. A. , Portella M. S. , Garcia M. 
Published: March 2020

646 Background: MA17 study wasa randomized double-blind placebo-controlled trial of 5 years of extended adjuvant therapy with letrozole (Femara) in 5187 postmenopausal women with early breast cancer after adjuvant tamoxifen. MA17 study demonstrated significant improvement in disease-free survival (93% vs. 87% at 4 yrs, HR 0.57) and a similar trend in overall survival (96% vs. 94% at 4 yrs, HR 0.76). Objective: To estimate the budget impact of adding extended adjuvant letrozole in the management of postmenopausal women with early breast cancer after 5 years adjuvant tamoxifen. Methods: A budget impact analysis over 4 years of letrozole vs. no extended adjuvant therapy was developed from the perspective of a health care payer in terms of total treatment costs following the introduction of letrozole. Model inputs included the overall survival, disease-free survival and probabilities of recurrence from the MA17 trial, additional cost of letrozole and the average annual cost to treat a given type of recurrence (contralateral, loncoregional, metastatic). Only direct medical costs were included using the consumer price index. Costs and cost-savings were reported as 2005 US dollars and discounted at 3%. The average annual cost to treat a recurrence was calculated through a retrospective analysis of a healthcare plan database with 147 postmenopausal women and data from published literature. The recurrence cost included chemotherapy in the first year (drug costs, dispensing fee, materials), health professional contacts, laboratory tests, diagnostic procedures, radiotherapy, bisphosphonate (metastatic recurrence), health professional contacts and hospitalization. Surgery costs were not considered in the study. Results: The average annual cost to treat a recurrence was estimated in US$83,064. For the base-case analysis of 100 patients, savings due to reduced recurrence were $1,006,446, in the letrozole patients. Subtracting the cost of letrozole treatment for 100 patients from savings yielded projected net savings of $36,314. Conclusions: In post-menopausal women who have completed 5 years adjuvant tamoxifen therapy, extended adjuvant letrozole is a cost-saving use of healthcare resources in additional to its clinical benefits. [Table: see text]
Trastuzumab and vinorelbine or taxane chemotherapy for HER2+ metastatic breast cancer: The TRAVIOTA study
Authors: Burstein H. J. , Keshaviah A. , Baron A. , Hart R. , Lambert-Falls R. , Marcom P. K. , Gelman R. , Winer E. P. 
Published: March 2020

650 Background: The optimal trastuzumab/chemotherapy regimen for advanced breast cancer is not known. We performed a multicenter, randomized clinical trial to compare TRastuzumab And VInorebline Or TAxane (TRAVIOTA) chemo- and bio-therapy combination treatment given on a weekly schedule for HER2+ metastatic breast cancer. Patients and Methods: Eligible patients had stage IV breast cancer, measurable disease (by RECIST criteria), HER2+ tumors (IHC 3+ or FISH+), no prior chemotherapy or trastuzumab for advanced breast cancer, and LVEF > 50%. Patients were randomized 1:1 to trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter) with either weekly vinorelbine (25 mg/m2) or weekly taxane (paclitaxel 80 mg/m2 or docetaxel 35 mg/m2, selected by the treating investigator). The primary endpoint was response rate. The study opened in August 2001 and planned to accrue 250 patients. It was closed in December 2003 having accrued only 85 patients. Results are presented for the 81 patients who received any protocol-based therapy. Results: Patients receiving trastuzumab and vinorelbine tended to have higher response rates and TTP than those assigned trastuzumab and taxane therapy but the results were not statistically significant (see Table ). Vinorelbine therapy was associated with more frequent grade 3 or 4 hematological toxicity and dose delay because of myelosuppression. Other toxicities generally reflected the known side effects of the chemotherapy agents. Conclusions: The TRAVIOTA study suggests at least comparable clinical activity of trastuzumab with vinorelbine as with weekly taxane chemotherapy in HER2+ metastatic breast cancer, with side effect profiles consistent with previous experience with these regimens. [Table: see text] [Table: see text]
Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)
Authors: Issa J. , Kantarjian H. M. , Saba H. I. 
Published: March 2020

6501 Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p<0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects. [Table: see text]
Dasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial
Authors: Shah N. P. , Rousselot P. , Pasquini R. , Hamerschlak N. , Holowiecki J. , Gerard B. , Dejardin D. , Kantarjian H. 
Published: March 2020

6507 Background: High dose imatinib (800 mg/day) has been shown to have efficacy in a subset of CML patients with resistance to IM, although the durability of responses is not well-established. Dasatinib (BMS-354825) is a novel, highly potent, oral multi-targeted kinase inhibitor of BCR-ABL and SRC with activity against 18/19 imatinib resistant BCR-ABL mutants tested in vitro. Methods: START-R is a multicenter randomized (2:1 ratio) trial of D 70 mg twice daily (bid) and IM 800 mg/day in pts with CP-CML resistant to prior IM 400 to 600 mg/day. Cross-over was allowed for lack of response or intolerance (grade 3–4 non hematologic toxicity). D dose escalation to 90 mg bid was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40 mg bid for drug toxicity. IM dose reduction to 600 mg/day was allowed. Evaluations consisted of weekly blood counts for the first 12 wks, bone marrow cytology and cytogenetics every 12 wks. The primary endpoint was major cytogenetic response (MCyR) rate at wk 12. Results: From February 2005 to November 2005, 150 pts were randomized of whom the first 36 pts (D 22, IM 14) are reported. Median age was 57 yrs, with 12 males and 24 females. Treatment groups were balanced with respect to CML characteristics; median time from initial diagnosis was 61 months for D and IM; prior interferon 64% and 79%; no prior CyR on IM 36% and 57%. BCR-ABL mutations were documented in 10 D pts and 1 IM pt. Dose reductions were required in 8 D pts and 1 IM pt. Complete hematologic response was documented in 21 D and 13 IM pts. MCyR rate at 12 wks was 45% for D and 21% for IM (7 complete for D and 1 for IM). With a 95% CI on the difference between D and IM was - 9.9 to +51.2. Two (9%) D and 11 (79%) IM pts crossed over for intolerance (1 D and 6 IM) or no MCyR (1 D and 5 IM). Grade 3–4 neutropenia or thrombopenia occurred in 8 and 9 dasatinib pts and in 8 and 2 IM pts. Most common grade 1–2 non-hematologic toxicities in D and IM groups were diarrhea (7 and 1 pts), nausea (7 and 7 pts), and facial/peripheral edema (8 and 7 pts). Conclusions: Dasatinib was effective in pts with CP-CML resistant to IM 400 to 600 mg/day. Preliminary data suggest that D is more effective and better tolerated than high dose IM. An updated analysis of all randomized pts will be presented. [Table: see text]
Clofarabine in previously untreated elderly (>65 yrs) AML patients with an unfavourable cytogenetic profile who are considered unfit for standard intensive chemotherapy
Authors: Burnett A. K. , Baccarani M. , Johnson P. , Yin J. , Russell N. 
Published: March 2020

6513 Background: Elderly AML patients (>65 yrs) are a very poor prognostic population. Standard treatment achieves an 18% overall response (OR) rate (low dose Ara-C, U.K. AML 14 trial) with no little or no responses observed in high-risk cytogenetic patients. BIOV-121 is a Phase II non-randomized study of clofarabine, a novel, next generation purine nucleoside analogue, in older patients (>65 yrs) with previously untreated acute myeloid leukemia (AML) for whom standard intensive chemotherapy is not considered suitable. Methods: 66 patients aged > 65 yrs with untreated AML were enrolled in study BIOV-121. All patients were considered unfit for standard intensive chemotherapy based primarily on age (> 65 years) and/or performance status. All patients received clofarabine 30mg/m2 for 5 consecutive days repeated every 28 days (1 course) for a maximum of 6 courses. The primary study endpoint was overall response rate (ORR) defined as the number of patients achieving a CR, CRi, or PR according to the international working group guidelines. A preliminary analysis was conducted on both patients with an unfavourable cytogenetic profile (11/44 patients), for whom data was available, and on patients > 70 years of age (36/66 patients). Unfavourable cytogenetic prognostic risk was defined as the presence of a complex karyotype, monosomies of chromosome 5 (del [5q]/5q-), or 3q abnormalities as reported by Grimwade et al (U.K. MRC AML 10 trial). Results: Of 44 patients for whom cytogenetic data was available, 25% (11/44) had an unfavourable cytogenetic prognostic risk profile. The median number of clofarabine courses administered in this patient group was one. With a median age of 68 years the overall response rate (ORR) in this unfavourable cytogenetic patient group was 36% (4/11) with a 27% complete response (CR) rate. 55% (36/66) of patients were aged >70 years. The ORR and CR rate was 56% and 44% respectively in patients aged >70 years. The toxicity of clofarabine was acceptable and manageable in elderly AML patients. Conclusions: Clofarabine appears superior to current standard treatment (low-dose Ara-C) in both unfavourable cytogenetic AML (>65 years) and AML patients > 70 years (all cytogenetic risk groups). [Table: see text]
Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) or refractory (ref) chronic lymphocytic leukemia (CLL)
Authors: Miller K. , Czuczman M. S. , Dimiceli L. , Padmanabhan S. , Lawrence D. , Bernstein Z. , Takeshita K. , Spaner D. , Byrne C. , Crystal C. , Chanan-Khan A. A. 
Published: March 2020

6517 Background: Tumor microenvironment (ME) is critical in CLL pathogenesis. Targeting the ME is a novel approach in CLL therapeutics. Lenalidomide (Revlimid, L) is an immunomodulating agent (IMiD), approved for pts with transfusion-dependent low or intermediate-1 risk myelodysplastic syndrome with deletion 5q cytogenetic abnormality. Its antitumor activity is possibly mediated through (a) downregulation of cytokine(s) - TNF-α, VEGF, PDGF and IL-6 and/or (b) activation of immune effector cells (T & NK cells). We investigated its antitumor activity in rel/ref CLL pts. Here we present the final results of the first cohort of pts treated with 25mg daily dose of L. Methods: Oral L was given at 25mg/day for 21 out of a 28 day cycle. Anti-leukemic effects were recorded after each cycle using NCI-WG 1996 criteria. Treatment was continued until molecular complete response (mCR) or progressive disease (PD). Those with PD were then treated with L in combination with rituximab (reported separately). Polymerase chain reaction (PCR) for immunoglobulin heavy chain gene was used to determine molecular remission (mCR). Results: Twenty-nine pts (median age 64 years; range: 47–75) have been enrolled. Toxicity is reported on all, while response on 19 evaluable pts. Nine pts are inevaluable (2 withdrew consent and 5 received < 2 months of therapy due to toxicity). Major response was noted in 13 of 19 evaluable pts (68%) with 3 CR (2 mCR) and 10 PR. Toxicity: Most common grade 3/4 adverse effects (AE) were neutropenia (60%) and thrombocytopenia (55%). Another common AE was tumor flare (79%); characterized by tender swelling of lymph nodes and/or rash, noted in almost all pts. Conclusions: L at 25mg/day dose given on days 1–21 in a 28 day cycle yields high ORR including mCR in rel/ref CLL. Hematologic toxicity was the most common AE requiring dose reduction. Overall safety profile was predictable and manageable. A slow dose escalation schema, starting at 15mg is being investigated. [Table: see text]
E7389, a novel anti-tubulin, in patients with refractory breast cancer
Authors: Forero J. BlumL. , Heiskala M. K. , Meneses N. , Chandrawansa K. , Fang F. , Shapiro G. , Fields S. Z. , Silberman S. , Vahdat L. 
Published: March 2020

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]
Imatinib mesylate is effective in the treatment of polycythemia vera: A multi-institutional clinical trial
Authors: Feldman E. J. , Spivak J. L. , Lee S. , Rivera M. , Fruchtman S. M. , Salvado A. , Silver R. T. 
Published: March 2020

6532 Background: We previously reported that the erythrocytosis of polycythemia vera (PV) was controlled with imatinib mesylate in a cohort of patients. This effect may involve inhibition of tyrosine phosphorylation of c-Kit, the stem cell factor receptor essential for erythroid progenitor cell proliferation. Methods: We report treating an expanded cohort of 37 PV patients with imatinib in a multi-institutional phase II trial. All patients had an increased 51Cr RBC mass determination at diagnosis and fulfilled the stipulated criteria for the diagnosis of PV. Men were initially phlebotomized to a hematocrit (HCT) ≤ 45%; women to HCT ≤ 42%. Imatinib was started at 400 mg qd escalating 100 mg every 2 weeks to a maximum of 800 mg for persistent phlebotomy (PHL) requirements or for platelet counts > 600 × 109/L. All patients received 81 mg of aspirin qd. Results: There were 21 men, 16 women, median age 51 years, range 29–83. Prior to imatinib, mean disease duration was 60.2 mos; average number of PHLs per year ranged from 0–23 (mean=9). After 1 year of imatinib, PHLs ranged from 0 to 9 (mean=2). There were 9 complete remissions (PHL-free, platelets ≤ 600 × 109/L, no splenomegaly) and 10 partial remissions (PHL and/or splenomegaly decreased by 50% of initial values with platelets ≤ 600 × 109/L, or platelets > 600 × 109/L but no PHL requirements or splenomegaly); 1 patient, protocol violation. Thus, of 36 evaluable patients, 19 (53%) responded. Of the remaining 17, 10 failed due to disease progression: myelofibrosis (n=2); platelets > 1,000 × 109/L with PHL and/or splenomegaly (n=2); repeated PHLs (n=1); cytogenetic abnormalities (n=1); increasing thrombocytosis (n=1); and a TIA (n=1). Seven of 17 with no remission developed toxicity: grade 3 dermatologic (n=2); grade 3 diarrhea (n=2); grade 3 bone pain (n=1), liver (n=1); heart failure (n=1). Median treatment duration: 17.2 months. Conclusions: We conclude that imatinib is useful for treating erythrocytosis and controlling splenomegaly in a significant proportion of PV patients, but is less effective for controlling thrombocytosis or splenomegaly in others. These data suggest heterogeneity of hematopoietic stem cell proliferation in PV or patient variability with respect to imatinib metabolism. [Table: see text]
Changes in thymidine phosphorylase expression in response to neoadjuvant chemotherapy for primary breast cancer
Authors: Puglisi F. , Mansutti M. , Minisini A. , Russo S. , Cardellino G. , Andreetta C. , Rijavec E. , Pizzolitto S. , Pandolfi M. , Di Loreto C. 
Published: March 2020

655 Background: Thymidine phosphorilase (TP) is a key enzyme involved in nucleoside metabolism. Recently, it has been hypothesized that TP modulation could enhance the therapeutic activity of TP-targeting chemotherapy such as capecitabine. In addition, some evidence exists that anticancer agents could upregulate TP. The present study analyzed TP immunohistochemical expression in response to neoadjuvant chemotherapy for primary breast cancer. Methods: Fifty-five women with operable breast cancer (T ≥ 2 cm, N0–1, M0) were treated with anthracycline-based (all cases) and anthracycline/taxane-based (n= 40 cases) neoadjuvant chemotherapy. Tumor samples from diagnostic large core biopsy (n=55) and from surgery (n=53) were available for histological evaluation and immunohistochemical analysis of TP. Immunohistochemistry was performed at a single central laboratory using a primary mouse anti-TP monoclonal antibody (Roche molecular biochemicals).TP expression was evaluated on tumor cells (nuclear and cytoplasmic staining) and on stromal cells. The intensity of cytoplasmic immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, moderate and strong staining, respectively. Results: An increase in TP cytoplasmic expression was observed in 35.89% (95% CI: 0.21–0.52%) of tumor samples after neoadjuvant chemotherapy. In particular, increases in cytoplasmic TP score were more common after taxane-containing regimens (40.74%, 95% CI: 0.22–0.61%) than after regimens without taxanes (25%, 95% CI: 0.05–0.57%). No significant changes of TP expression were found in nuclei of tumor cells after neoadjuvant chemotherapy. Similarly, no significant changes of TP expression were observed in stromal cells. There was no significant association between clinical or pathological response rate and TP changes in both tumor and stromal cells. Conclusions: This study provides further evidence that, at least in breast cancer, TP is upregulated after anthracycline and/or taxane-containing chemotherapy. According to these results, a strong rationale exists in combining TP-inducing and TP-targeting anticancer agents. No significant financial relationships to disclose.
Elevated serum ras level predicts decreased survival in patients with hematologic malignancies
Authors: Nelli E. M. , Leitzel K. , Ali S. M. , Al-Mondhiry H. A. , Demers L. , Harvey H. A. , Carney W. P. , Hamer P. J. , Lipton A. 
Published: March 2020

6562 Background: Ras is a GDP/GTP binding G protein that acts as a molecular switch converting signals from the cell membrane to the nucleus to regulate cell proliferation, differentiation, and protein synthesis. Activation of ras oncogenes has been identified in a variety of cancers, including 30% of acute myelogenous leukemia patients. The purpose of our study was to evaluate serum ras levels and correlate with survival in hematologic cancer patients. Methods: A novel ras p21 ELISA (Oncogene Science/Bayer Diagnostics, Cambridge, MA) employing two monoclonal antibodies reactive with H, K, and N ras was utilized to quantify total ras levels in serum obtained from patients with various hematologic malignancies including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Results: The total leukemia patient group consisted of 52 patients. At the 75th percentile serum ras cutpoint (524 pg/ml) 11/52 patients were defined as elevated for serum ras. From this patient group, 38 patients had clinical followup available and were included in the Kaplan-Meier analysis of overall survival. Patients with elevated serum ras (>524 pg/ml) had significantly shorter overall survival compared to those without (median OS 205 vs. 677 days) (p= 0.04). In a multivariate analysis including serum ras level and type of leukemia, serum ras level remained a significant independent variable for shorter overall survival (p=0.004). Within leukemia subtypes 2/18 AML, 4/9 CML, 3/7 ALL, and 0/4 CLL patients had elevated serum ras levels. Conclusions: Leukemia patients with elevated serum ras levels had a significantly shorter overall survival. Serum ras should be evaluated as a potential biomarker in larger leukemia trials, especially for response to treatment with inhibitors of the ras signaling pathway. [Table: see text]