bluuebunny/crossref_metadata_2025_split huggingface dataset:
EMD121974 (NSC 707544, cilengitide) in asymptomatic metastatic androgen independent prostate cancer (AIPCa) patients (pts): A randomized trial by the Prostate Cancer Clinical Trials Consortium (NCI 6372)
Authors: Bradley D. A. , Dunn R. , Ryan C. , DiPaola R. , Smith D. C. , Cooney K. A. , Mathew P. , Gross M. , Colevas A. D. , Hussain M. 
Published: March 2020

5137 Background: Integrins avβ3 and avβ5 are essential to PCa metastasis by regulating cell adhesion, migration, invasion and motility. Cilengitide is a potent and selective avβ3 and avβ5 integrin receptor antagonist that in phase I studies has shown clinical activity. Methods: Pts with asymptomatic, metastatic chemo-naive AIPCa with PSA or objective progression, no visceral disease, minimum PSA of 5ng/ml, and adequate organ function were randomized to cilengitide 500 mg or 2,000 mg IV 2X weekly in 6-week cycles, using modified randomized selection design. Disease status was assessed every 12 weeks. The primary end point is objective progression rate (not including PSA) at 6 months. The Simon 2-stage optimal design is used to accrue 53 pts/arm. After first stage (20 pts/arm), accrual continues if ≥ 6 pts have not progressed. If second stage accrual is initiated, at end of study, the better performing arm will be chosen for further study provided at least 18/53 pts in that arm have not progressed. Secondary end points include safety, response rates and correlative measures of cilengitide effect on circulating and bone marrow tumor and endothelial cells and on bone remodeling markers. Results: First stage accrual is complete with 42 pts registered. Median performance status is 0, median age is 71 years (range 52–85), and median PSA is 44ng/ml (range 5–870). Disease progression at registration was defined by PSA in 90%, soft tissue in 36% and bone in 31% of pts. Median number of cilengitide cycles is 3 (range 1–8). To date, 32/42 pts have received ≥ 2 cycles. The most common (>5%) treatment related adverse events (AE): fatigue (38%), constipation (13%), anorexia (10%), leucopenia (8%) and nausea (8%). There were only 3 grade (G) 3 AEs (neutropenia, lymph node pain, lymph NOS) and no G4 AEs. Only 3 pts required dose modification. 25/42 pts were removed from protocol on or before 6 months, 6 pts received therapy for more than 6 months, and 11 are too early to assess. Conclusions: Cilengitide is well tolerated. Final results (efficacy, safety, correlative studies) of the first stage of accrual will be reported. Supported by CTEP, Prostate SPORE Grant P50 CA069568- 09, PC051375, Merck KGaA, PC051382. [Table: see text]
Testosterone recovery after two years of androgen suppression in prostate cancer patients
Authors: Yoon F. , Choo R. , Gardner S. L. , Morton G. , Szumacher E. F. , Cheung P. , Loblaw D. A. , Danjoux C. 
Published: March 2020

5144 Background: The time course of testosterone (TST) recovery after prolonged androgen suppression (AS) is not well established. We examined TST recovery prospectively in prostate cancer (PCa) patients treated with 2 years of AS. Methods: 153 PCa men with pT3N0 or positive margins after radical prostatectomy (RP), or with PSA relapse (persistently detectable postoperative PSA [= 0.2 ng/mL], delayed detectable PSA = 6 months after surgery, or palpable/biopsy proven local recurrence after RP), were treated with radiation (RT) to the prostate bed (60 - 70 Gy in 30 - 35 fractions) plus 2 years of AS as part of a phase II study. AS consisted of nilutamide 100 mg PO tid for 4 weeks, starting within 1 week after completing RT, and busereline acetate 6.6 mg SC every 2 months for 2 years, starting within 2 weeks of nilutamide. The primary endpoint was PSA relapse-free survival. Serum TST levels were measured at baseline, every 4 months during AS, and every 6 months after completing AS. The planned sample size was 150 patients. Time to TST recovery was analyzed using the Kaplan-Meier method. Cox Proportional Hazards regression was used for a multivariate analysis of predictive factors for TST recovery. Results: 122 men completed the planned AS. Median follow up after finishing AS was 36.4 months (range 9.4 - 76.2). A castrate TST level was defined as =1.7 nmol/L (50 ng/dL), with normal levels being 10 - 40 nmol/L. All men achieved castrate TST levels on AS. Table 1 shows TST recovery at 36 months after completing AS and median times to recovery. Median recovery time to normal TST was 27 months, although 8% of men did not recover to above castrate levels by 3 years. On multivariate analysis, younger age (<60 vs. =60) predicted for a significantly shorter recovery time to normal TST (P = <0.0001), while baseline TST (<10 nmol/L vs. =10.0 nmol/L) was of borderline significance (P = 0.06). Conclusions: TST recovery after 2 years of AS is protracted. Older men have significantly longer recovery times. [Table: see text] [Table: see text]
Neoadjuvant docetaxel and capecitabine in patients (Pts) with high-risk prostate cancer (PCa): Final results of a phase II trial
Authors: Friedman J. D. , Vaishampayan U. , Wood D. , Wu A. , Bradley D. , Dunn R. L. , Montie J. , Sarkar F. H. , Shah R. , Hussain M. 
Published: March 2020

5147 Background: Docetaxel is the most active cytotoxic agent in PCa. Pre-clinically docetaxel increases the expression of thymidine phosphorylase (TP), an enzyme responsible for activation of capecitabine to 5-fluorouracil. We assessed the activity and safety of neoadjuvant docetaxel and capecitabine (DC) in pts with high risk PCa. Methods: Non-metastatic PCa pts with clinical stage >T2, or PSA = 15 ng/ml or biopsy Gleason sum (GS) = 8 received 3–6 cycles of docetaxel (36 mg/m2 IV on days 1, 8, and 15) and capecitabine (1,250 mg/m2/day PO on days 5–18) q 28 days, followed by local therapy. The primary endpoint of this 2-stage phase II trial was rate of = 50% decline in PSA. Secondary endpoints included safety and correlative measures of treatment effect (qualitative changes in histology, tissue TP and survivin expression, and CK18Asp396 [apoptosis marker] in serum). Results: Fifteen pts were enrolled with median age of 58 years, median GS =8 and PSA of 23.2 ng/mL. Five pts met 1, 7 met 2, and 3 met 3 entry criteria. 14 pts completed 3 or more cycles of DC, with a median follow up of 17.5 months (9–34). Six of the 15 patients (40%) experienced a = 50% decline in PSA, which was below the 7 required for expansion of the study. Median testosterone did not change post therapy. Eleven pts underwent radical prostatectomy (RP), with no increase in surgical complications. Six pts had positive margins, and 2 had lymph node involvement. Of the 8 patients who underwent RP alone, 5 developed a biochemical recurrence in a median time of 11 months. Grade 3 or 4 toxicities were diarrhea(3), mucositis(2), hand foot syndrome(1) and neutropenia(2). Post versus pre therapy tissue had only mild chemotherapy-effects (4/7 samples), including focal clear cell changes, apoptosis/pyknosis, and necrosis. While there was no discernable pattern of increased TP expression, 4/7 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy-induced apoptosis. There was no correlation of PSA response and survivin expression and no increase in serum CK18Asp396. Conclusions: Docetaxel and capecitabine in the neoadjuvant setting is well tolerated, but results in modest pathologic and PSA responses. Supported by Sanofi- Aventis. No significant financial relationships to disclose.
Phase I study of docetaxel and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC)
Authors: Morris M. J. , Pandit-Taskar N. , Amodio A. J. , Gignac G. A. , Flatts E. , Slovin S. , Solit D. , Rathkopf D. , Larson S. , Scher H. I. 
Published: March 2020

5152 Background: Docetaxel (Tax) prolongs survival in patients (pts) with CMPC. Early clinical data suggest that Tax combined with bone seeking radiopharmaceuticals may improve survival relative to chemotherapy alone. 153Sm-lexidronam (Sam) (Quadramet, Cytogen Inc.) is a radiopharmaceutical with a short T1/2 and a favorable toxicity profile. Methods: Pts with progressive CMPC are treated in cohorts of 3–6. Prior treatment with taxanes is permissible. Cohorts are defined by dose escalations of: Tax 65, 70, 75, 75, 75 mg/m2 and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle is 6 weeks. Tax is given day 1 and 22 and Sam day -1 to 1 of each cycle. DLT is defined as cycle 1 = grade 3 non-hematologic toxicity, grade 3 neutropenia that lasts for >29 days, or grade 3- 4 anemia or thrombocytopenia of = 5 days. Pts with an ANC of grade 0–1 or platelet count (PLT) of >100,000/mm3 at the end of cycle 1 may receive additional cycles. Pts are treated until progression or toxicity. Results: 18 pts have been treated in 5 cohorts of 3 pts to date. 6 pts were treated in cohort 2. Two pts have not yet received enough treatment to be evaluable. DLT has not yet been reached. The mean number of cycles/pt is 3 (range 1–6). As anticipated, toxicities have primarily been hematologic (see table ). Two pts came off study for hematologic toxicity; one in cohort 2 had grade 3 PLT after 5 cycles and has not recovered at >175 days and 1 pt (cohort 2) failed to recover PLT in the allotted time frame during cycle 4 prohibiting further treatment. No other pts required treatment delays for hematologic toxicity. Mean baseline PSA was 294.6ng/ml with 7/16 (44%) pts achieving = 50% decline in PSA. Conclusions: Coadministration of Tax and Sam has been well tolerated. Repetitive dosing is feasible. Standard approved doses of each drug are being tested in the present (and final) cohort. DLT has not yet been reached. Accrual continues, to refine the optimal dose and schedule in preparation for phase II. Support: Cytogen, Inc., NIH CA102544 [Table: see text] No significant financial relationships to disclose.
Effect on patient outcome of residual DCIS in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy
Authors: Mazouni C. , Peintinger F. , Wan-Kau S. , Andre F. , Gonzalez-Angulo A. M. , Symmans F. , Meric-Bernstam F. , Valero V. , Hortobagyi G. , Pusztai L. 
Published: March 2020

530 Background: To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with hiostologically defined complete eradication of invasive cancer. Methods: Retrospective analysis of a database including 2,302 breast cancer patients treated prospectively with neoadjuvant chemotherapy at the UT MD Anderson Cancer Center between 1980 and 2004 was performed. The overall, disease-free and local recurrence-free survivals were compared for patients with no residual invasive or in situ cancer (pCR) and those with no residual invasive cancer but persistent in situ disease (pCR+DCIS). Results: The mean follow-up was 250 months. Of the 2,302 treated patients 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2025 (88%) had residual invasive cancer. The 5-year (87.1% in both) and 10-year (81.3% vs 81.7%) disease-free survival rates were similar for cases with pCR and pCR+DCIS. The 5-year (91.9% vs. 92.5%) and 10-year (91.8% vs. 92.5%) overall survival rates were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%, p<0.001). The 5-year local-regional recurrence-free survival rates were also not different for patients with pCR (92.8%, 95% CI: 86.1%-96.4%) and those with pCR+DCIS (90.9%, 95% CI: 77.3%- 96.5%), p=0.63. Conclusions: Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of cases with residual DCIS in the definition of pathologic complete response is justified when this outcome is used as early surrogate for long term-survival. No significant financial relationships to disclose.
Competing causes of death in NCIC CTG MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients
Authors: Chapman J. , Meng D. , Shepherd L. , Parulekar W. , Ingle J. N. , Muss H. B. , Palmer M. , Yu C. , Goss P. E. 
Published: March 2020

540 Background: Risk of death from other malignancies (OM) and other causes (OC) than breast cancer (BC) increases with age. Effects of baseline factors on type of death were assessed with competing risks analyses. Methods: In NCIC CTG MA.17, 5,187 women free of recurrent breast cancer after 5 years of tamoxifen were randomized to letrozole (L, 2,593 women) or placebo (P, 2,594 women). The primary endpoint was disease free survival (DFS), and secondary, overall survival (OS). Follow-up was to October 9, 2005: median 3.9 years, range <0.1 to 7.0 years. Effects of competing risks were examined for endpoints of BC, OM, and OC for 11 baseline trial factors: treatment, age, menopausal status, duration of prior tamoxifen, adjuvant radiotherapy, bone fracture, osteoporosis, cardiovascular disease, hormone receptor status, nodal status, adjuvant chemotherapy. Lagakos’ hierarchical method (Lagakos, Appl. Statist. 1978; 27:235–241) was used to test for differential effects of baseline factors on type of death (BC, OM, OC). Results: Rate of censoring was 97.8%, with 256 deaths (BC, 102; OM, 50; OC, 100; unknown, 4). Non-breast cancer deaths accounted for 60% of known deaths; 72%, for those ≥70 years; and 48%, for those <70 years. Two baseline factors differentially affected type of death. Women with cardiovascular disease were more likely to die from OC (p=0.02), while those with osteoporosis were more likely to die of OM (p=0.03). Age and nodal status had directionally similar effects. Older women had shorter survival from all 3 causes of death (p=0.01). Lymph node positivity was associated with worse survival (p=0.003). Conclusions: Extended L provides similar proportional benefit in improving DFS for all ages of women (Muss ref abstract SABCS 2006). However, the magnitude of competing non-breast cancer, and non-treatment related, causes of death needs to be considered more frequently, since with early detection and improved therapies, breast cancer patients may increasingly be expected to survive their disease to die from another cause. The novel association between baseline osteoporosis and other malignancies is being explored quantitatively. No significant financial relationships to disclose.
Updated 12-year results of a randomized clinical trial comparing standard-dose to high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with more than three positive nodes (LN+)
Authors: Gianni A. M. , Bonadonna G. , Michelangelo G. 
Published: March 2020

549 Aims: We conducted a multicenter randomized trial comparing sequential adjuvant standard-dose with high-dose chemotherapy in breast cancer patients younger than 60 years, with 4 or more positive nodes. Patients: Following surgery, patients were stratified by number of positive nodes (4–9 or 9), and randomly assigned to either conventional Epi–CMF (3 courses of epirubicin 120 mg/m2, followed by 6 courses of CMF), or high-dose chemotherapy (HDS) with stem cells support (one course of cyclophosphamide 7 g/m2, followed by one course of methotrexate 8 g/m2 with leukovorin rescue, by two courses of epirubicin 120 mg/m2, and by one course of thiotepa 600 mg/m2 plus melphalan 160–180 mg/m2 with stem cell autografting). Tamoxifen (20 mg/d × 5 yr) was also planned regardless of menopausal and receptor status. The study was designed with a power of 80% to detect a 15% increase in progression-free survival at 5 years in the HDS arm. Results: Of the initially enrolled 398 patients, 16 were ineligible, and the remaining 382 patients (Epi–CMF: 197 patients, HDS: 185 patients) were analyzed according to intent-to- treat. One patient treated with HDS (0.5%) died of interstitial pneumonia. With a median follow-up of 136 months, the 12-year progression-free survival rates were 44% and 52% for the Epi–CMF and the HDS groups, respectively, and the overall survival rates were 51% and 60%, respectively. However, among the 68 patients younger than 36 years, and the 189 patients with 4–9 LN+, those in the HDS group showed a trend for a progression-free survival advantage (HR 0.76 and 0.74, respectively). Conclusions: In the intent-to-treat analysis the 9% overall survival advantage associated with the HDS regimen failed to reach statistical significance in a study powered to detect a 15% difference. To reliably define the role of high-dose therapy, meta-analysis of patient data from all relevant randomized trials (such as that planned by the Early Breast Cancer Trialists’ Collaborative Group) is needed. Supported in part by AIRC and Pharmacia & Upjohn, Milano, Italy. No significant financial relationships to disclose.
A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21)
Authors: Burnell M. J. , Levine M. N. , Chapman J. A. , Bramwell V. , Vandenberg T. , Chalchal H. I. , Albain K. , Perez E. , Rugo H. , Pritchard K. 
Published: March 2020

550 Background: CEF and AC followed by paclitaxel (AC/T) are commonly used adjuvant regimens in women with early breast cancer. In a trial conducted by the EORTC, NCIC CTG, and SAKK three months of dose-dense EC was equivalent to six months of CEF in women with locally advanced breast cancer. We hypothesized that three months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. The results of a planned interim analysis were presented in San Antonio 2006 (Abstract #53). We now present more detailed results on efficacy and toxicity. Methods: Women 60 years of age or younger, with axillary node positive or high risk node negative breast cancer were randomized to CEF, EC/T or AC/T for six months. Results: Between December 2000 and April 2005, 2104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are: AC/T vs. CEF, 1.49 (95% CI, 1.12–1.99), p=0.005; AC/T vs. EC/T, 1.68 (95% CI, 1.25–2.27), p=0.0006; and EC/T vs. CEF, 0.89 (95% CI, 0.64–1.22), p=0.46. Three year recurrence-free survival rates for CEF, EC/T, and AC/T are 90.1, 89.5 and 85.0%, respectively. There was no significant interaction between ER status and treatment. Multivariate analysis of predictive factors will be presented. The numbers of deaths are 50 (CEF), 47 (EC/T) and 65 (AC/T). There was more toxicity in CEF and EC/T compared to AC/T. Conclusion: AC/T given every three weeks, although less toxic is significantly inferior to CEF or EC/T in terms of relapse-free survival. It is too early to detect any difference between CEF and dose-dense EC/T. Our results indicate that there is still room to explore anthracycline and taxane adjuvant chemotherapy regimens. Supported by: NCI Canada and Canadian Cancer Society, Pfizer, Bristol-Myers Squibb, Amgen, Janssen Ortho, Ortho Biotech, and NCI US. [Table: see text] No significant financial relationships to disclose.
Use of predictive gene expression signature from advanced-stage serous papillary ovarian cancer to identify biologically relevant molecular targets for chemoresponse
Authors: Ozbun L. , Bonome T. , Radonovich M. , Pise-Masison C. , Brady J. , Caplen N. , Johnson M. , Mok S. C. , Birrer M. J. 
Published: March 2020

5500 Background: The aim of our study was to develop and validate a gene expression signature predictive for chemoresponse in advanced stage serous papillary ovarian cancer. Methods: Gene expression profiling was performed on 52 chemonaive, microdissected advanced stage, high-grade papillary serous ovarian cancers using Affymetrix whole-genome microarrays. Patient samples were grouped based on chemoresponse. 19 nonresponders were refractory to chemotherapy, 14 responders relapsing 6 months were considered chemosensitive. Each group was divided into training/validation sets. To generate a predictive gene signature, class prediction algorithms were applied to genes differentially expressed between chemosensitive/resistant or chemosensitive/refractory tumors (p<0.001) using leave-one-out cross-validation. Array validation was performed by qRT-PCR. Select genes underwent biological validation in a series of ovarian cancer cell lines. Results: 31 genes predictive for resistance and 105 genes predictive for refractory to chemotherapy were identified. Percentages of arrays accurately predicted in independent validation sets were 90% (9/10) for resistant and 92% (12/13) for refractory gene signatures. Correlations between microarray/qRT-PCR data were robust for both resistant (17/23 genes) and refractory gene signatures (25/34 genes). Data mining of the predictive signatures using PathwayStudio software identified several biological processes (collagen regulation, apoptosis, cell survival, and DNA repair) implicated in conferring resistance to chemotherapy. We transiently transfected RNAi molecules to silence several signature genes and determine their contribution to taxol/cisplatin sensitivity in a series ofl ovarian cancer cell lines. Preliminary data showed DUSP1 gene expression knockdown potentiated cisplatin sensitivity in SKOV3/OVCA429 cell lines, while POLH knockdown potentiated cisplatin sensitivity in OVCA429/OVCA420 cell lines. Conclusions: A gene expression signature predicts for chemoresponse in ovarian cancers, and has identified novel targets of biological/therapeutic interest. No significant financial relationships to disclose.
VEGF-Trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC): Preliminary results of a randomized, multicenter phase II study
Authors: Tew W. P. , Colombo N. , Ray-Coquard I. , Oza A. , del Campo J. , Scambia G. , Spriggs D. 
Published: March 2020

5508 Background: Vascular endothelial growth factor (VEGF) is over-expressed in EOC and associated with poor prognosis. VEGF Trap, a potent angiogenesis inhibitor fusion protein, is comprised of portions of human VEGF-receptor R1+R2 (Flt-1, KDR) extracellular domains and fused to the Fc portion of human IgG. VEGF Trap binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor. Methods: This is a randomized, double blind, multicenter, 2-stage, phase II trial of VEGF Trap (2 or 4 mg/kg) administered intravenously every 2 weeks, in pts with recurrent EOC. Eligible criteria included 2 or 3 prior chemo regimens for advanced disease; platinum- resistance, topotecan- and/or liposomal doxorubicin-resistance; no prior VEGF inhibitor treatment; ECOG performance status 0–2; normal organ function; no proteinuria (<500 mg/24hrs or UPCR =1); controlled blood pressure. This Simon 2 stage design, requires 3 responders out of 42 evaluable, in each arm to continue accrual into stage 2. Results: Across 62 centers in Europe, Canada and US, rapid accrual led to 162 pts randomized from 5/06 to 12/06. Median age: 58, PS (0,1,2): 56,40,4%. Of 45 pts currently in the database, across the two arms, adverse events included (any grade): headache (38%), fatigue (36%), dysphonia (33%), nausea (29%), asthenia (24%), diarrhea (18%), hypertension (16%), proteinuria (7%), renal dysfunction (4%). Grade 3–4, included: hypertension (9%), proteinuria (4%), encephalopathy (2%) and renal failure (2%). Of the 162 pts who had at minimum one cycle, study drug-related SAE include (N): thrombocytopenia (1), anemia (1), headache (1) asthenia (2),dyspnea (1), hypertension (4), bowel perforation (2), encephalopathy (1), renal failure (2), proteinuria (1), phlebitis (1) and pulmonary embolism (1). 5 partial responses (11%) have been reported. Conclusions: VEGF Trap has activity in this heavily-pretreated EOC population. The first stage of accrual is complete and updated results will be presented. No significant financial relationships to disclose.