bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination therapy of meloxicam, a selective COX-2 inhibitor, and interferon alfa in metastatic renal cell carcinoma: A phase II study on efficacy and toxicity
Authors: Shinohara N. , Harabayashi T. , Sazawa A. , Nonomura K. , Watarai Y. , Kumagai A. , Murakumo M. , Kanagawa K. , Sakashita S. 
Published: March 2020

5105 Background: Cyclooxygenase (COX)-2 plays a major role in the development of cancer through numerous mechanisms. We have previously confirmed that COX-2 is expressed in a renal cell carcinoma (RCC) and it has an important role in tumorigenesis and angiogenesis (Int J Cancer 2004). Some preclinical studies suggest that a selective COX-2 inhibitor may augment the antitumor effects of immunotherapeutic agents. We conducted a phase II trial of the combination of meloxicam, a selective COX-2 inhibitor, and interferon (IFN)-alfa 2a in metastatic RCC in order to test the hypothesis that meloxicam enhances the response to the immunotherapy. Methods: Eligible patients had metastatic RCC, no prior systemic therapy, performance status 0–2, measurable disease. Patients received IFN 3–5 MIU 3x/week and meloxicam 10 mg/daily orally. This was a single-stage trial. Primary end points were RECIST response rates and toxicity. Results: Twenty-one patients were enrolled. Patients characteristics included: median age 63 years (49–75), male/female: 16/5, PS 0/1/2: 11/6/4, prior nephrectomy: 16 (76%). MSKCC prognostic categories were good: intermediate: poor (24%: 48%: 29%). A median follow-up was 8 months (range 3–29+) and 18 of 21 (86%) patients are still alive. Toxicities were mostly grade 1 or 2 (fever, fatigue, anorexia, depression), except 1 patient with grade 3 liver dysfunction. Among 20 patients evaluable for response, complete response (CR) was observed in 3 patients (15%) and partial response (PR) in 5 (25%), yielding an overall response rate of 40% (95% CI: 17–63). An additional 5 patients (25%) had stable disease. Five of 6 patients classified as poor risk by MSKCC prognostic classification obtained a CR or PR, as did 3 of 14 patients as good or intermediate risk (p=0.038). Median time to progression for 20 patients was 6 months (1–29+). Conclusions: The overall response rate of 40% for the combination of meloxicam and IFN-alfa in metastatic RCC is greater than that of IFN-alfa alone reported previously, suggesting that meloxicam can enhance the response to immunotherapy. Further investigation with this combination is warranted. No significant financial relationships to disclose.
Randomized phase II trial of docetaxel, with or without doxercalciferol, in advanced, androgen-independent prostate cancer
Authors: Attia S. , Eickhoff J. , Wilding G. , Blank J. , Rezazadeh H. , Shevrin D. , Glode M. , Jumonville A. , Eastman M. , Liu G. 
Published: March 2020

5119 Background: Docetaxel is the standard of care for advanced androgen-independent prostate cancer (AIPC). Doxercalciferol, a vitamin D analog (1a-hydroxyvitamin D2), has single-agent activity in AIPC (Clin Cancer Res 9(11), 2003). Preclinical evidence supports combining vitamin D with chemotherapy to treat AIPC. Here we report results of a multi-institutional trial combining docetaxel and doxercalciferol. Methods: Patients with chemo-naive AIPC were randomized 1:1 to receive, on a four week cycle, docetaxel (35 mg/m2 IV; days 1, 8 and 15) with either doxercalciferol (10 mcg PO daily, days 1–28) or placebo in a double-blind fashion. The primary endpoint was to compare progression-free survival (PFS). Secondary endpoints were to assess overall survival (OS), objective response (RECIST), PSA response (consensus criteria), and toxicity. PFS and OS were analyzed on an intent-to-treat basis. Eligibility criteria included no prior cytotoxic therapy; radiographic evidence of metastasis; performance status ≤ 2 and no recent history of nephrolithiasis. Results: Seventy patients were randomized. Median follow-up time was 16.2 months (range, 0–40.5 months). Median PFS in the doxercalciferol arm was 14.9 months (95% CI: 8.7–16.6 months) versus 11.9 months (95% CI: 8.9–16.4 months) in the placebo arm (p=0.73). Median OS in the doxercalciferol arm was 18.1 months (95% CI: 14.9–26.2 months) and 17.9 months (95% CI: 12.1–24.6 months) in the placebo arm (p=0.63). Twenty-nine patients in the doxercalciferol arm and 33 in the placebo arm were evaluable for objective response. No complete responses were seen. Partial response rate was 14% (doxercalciferol) vs. 15% (placebo) (p=0.88). PSA response rate was 44% (95% CI: 29%-60%) in the doxercalciferol arm and 42% (95% CI: 27%-59%) in the placebo arm (p=0.87). Grade 3/4 toxicity rates were 38% in the doxercalciferol arm and 39% in the placebo arm (p=0.99). Conclusions: Despite encouraging data with other vitamin D analogs combined with docetaxel in AIPC, the addition of daily doxercalciferol to weekly docetaxel did not enhance median PFS, OS or tumor response. Toxicity was similar between treatment groups. Further evaluation of vitamin D analogs in combination with chemotherapy in AIPC remains of interest. No significant financial relationships to disclose.
Cancer gene therapy with a retrovirally transduced IL2-IFNγ-secreting allogeneic tumorvaccine in patients with progressive hormone refractory prostate cancer—A phase I/II trial
Authors: Gansbacher B. , Brill T. , Eisele B. , Kuebler H. , van Randenborgh H. , Paul R. , Hartung R. , Fend F. , Pohla H. , Schendel D. 
Published: March 2020

5127 Background: The purpose of this study was to determine whether immunization with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-γ (IFN-γ), would be tolerated and able to induce a prolongation of PSA doubling time in patients with progressive hormone refractory prostate cancer. Methods: 30 HLA-A0201-matched patients with progressive, hormone refractory prostate cancer, demonstrating three successive elevations in prostate specific antigen (PSA) values, received four intradermal injections on days 1, 15, 29 and 92, and then every 90 days as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, 27 patients received 15 million cells. The primary efficacy criterion was the difference in PSA doubling time (PSA-DT) determined in the pre-treatment phase (before start of vaccination) and in the trial treatment phase (during vaccination). Results: The study was completed according to protocol. Immunostimulation could be demonstrated in most of the 30 patients (histological evaluation of injection site biopsies, serial ELISPOT analysis of PBMCs). During vaccination there was a significant prolongation of the PSA-DT compared to the pre-vaccination period that came to 81% (prolongation from 63 days to 114 days (p < 0.0035; ITT)). Twenty two of 30 patients (73%) responded to the vaccine administration as judged by prolongation of PSA-DT. In the majority of patients the administration was followed by a period of PSA stabilisation that was up to 641 days (“PSA plateau”). No dose limiting or autoimmune toxicities were seen. The median overall survival time since first vaccination was 981 days (mean value: 770 days). Conclusions: This vaccine strategy showed a prolongation of PSA-DT and was found to be safe and well tolerated. The results of this trial warrant the vaccine’s further clinical development. No significant financial relationships to disclose.
A model assessing how variable timing of outcome assessments impacts progression-free survival (PFS)
Authors: Gignac G. A. , Morris M. J. , Heller G. , Scher H. I. 
Published: March 2020

5130 Background: PFS has been proposed as an endpoint in prostate cancer because tumor regression cannot be assessed easily and the significance of post-therapy changes in PSA is uncertain. There is significant variability in the frequency by which outcomes are assessed across clinical trials. We sought to create a model that would define the degree of error in estimating PFS from this variability. Methods: A simulation experiment was performed. An exponential distribution was used to generate 100 progression times for 3 hypothetical risk cohorts: rapid (median PFS of 18 wks), intermediate (36 wks) and slow progressors (72 wks). We examined how reported PFS would change depending on 3 assessment schedules: every (q) 6, 8 and 12 wks for 48 wks each, then q6 months for 2 years. The logrank statistic was used to compare PFS between schedules. If different schedules have no impact the expected type 1 error rate should be 5% (where a difference in PFS time is detected when none existed). Each simulation was repeated 1000 times. Results: Nine pairwise comparisons were performed and Kaplan-Meier PFS estimates created for the 3 assessment schedules and 3 risk cohorts (see table 1 ). In the highest risk cohort, PFS of 18 wks, 38% of the time the logrank test showed a falsely prolonged PFS for pts assessed on the q12 vs 6 wks schedule. This type 1 error rate (by simulation) was reduced to 20% and 11%, when the schedules were q8 vs 12 wks and q6 vs 8 wks, respectively, but remained above the 5% expected rate for type 1 error. For lower risk pts, PFS of 72 wks, the disparity in PFS times was diminished. Conclusions: Progression free survival is significantly skewed by the schedule of assessing treatment effects in clinical trials. This argues for uniformity in the timing of outcome assessments across trials and between arms in randomized trials. Grant support: 5T32CA09207 [Table: see text] No significant financial relationships to disclose.
A novel androgen receptor (AR) suppressor complex (ARS)—An essential factor in androgen-independent progression of prostate cancer (PC)
Authors: Ferrari A. C. , Wang L. , Johnson E. M. , Melamed J. , Liu X. , Kinoshita Y. , Buckley M. T. , Liebes L. F. , Kurek R. , Ossowski L. , Babb J. S. 
Published: March 2020

5145 Background: Increased AR level, characteristic of advanced PC, has been linked to AI growth while its down-regulation to restored androgen-dependence (AD). However, the mechanisms of AR overexpression remain in dispute. The objectives were to study the proteins comprising a novel ARS that binds to 5’-UTR of AR gene, which is partially lost in AI LNCaP cells; the status of ARS proteins in AD and AI human specimens and therapeutic modulation of ARS proteins. Methods: Parental AD LNCaP cells and its AI- derivative expressing 4 fold more AR-mRNA and protein than parental AD LNCaP were used to isolate, in vitro/in vivo characterize and therapeutically modulate ARS proteins and cell growth. NYU Tissue Bank provided human samples. Assays: column chromatography, SDS-PAGE, mass spectrometry, EMSA, Southwersten-Western, ChIP, cDNA array, real time PCR, si-RNA, immunohistochemistry. Results: Pur alpha (Pura) and hnRNP-K are part of ARS complex that binds in vitro and in vivo to a defined DNA sequence in 5’UTR of AR gene. AI cells with high AR had 3 times less Pura: its forced expression lowered AR levels. Pura knockdown in AD cells yielded higher AR levels and AI growth. Hormone-naive human PC specimens had significantly increased AR (0.0317) and lower Pura-RNA (0.0317) than hormone resistant PCs. In-vivo binding of Pura (ChIP) to 5’UTR was also reduced (p=0.0028). Histone deactetylase inibitors (HDACI) increased binding of Pura to 5’UTR, decreased AR levels and inhibited AI-growth of LNCaP cells. Conclusions: We show that AR over-expression and AI-growth of a hormone resistant PC cell line are affected by a loss of a repressor complex that binds to 5’-UTR of AR gene. Pura is a crucial part of this complex. We have convincing evidence obtained in hormone naive and resistant human samples to indicate that similar mechanism might be responsible for human PC progression. We determined HDACI can restore Pura levels and androgen-dependence. No significant financial relationships to disclose.
Duration of the first off treatment period is associated with time to androgen independence (AI) and survival in men with localized or biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation (IAD)
Authors: Telesca D. , Higano C. S. , Yu E. Y. , Montgomery R. B. , Tam S. L. , Russell K. J. , Nelson P. S. , Etzioni R. B. 
Published: March 2020

5146 Background: Patients (pts) with localized prostate cancer or biochemical relapse who are treated with AD eventually develop AI and die. In an effort to better understand the natural history of this population, various characteristics of the patients and the first cycle of IAD were analyzed. Methods: Eligible pts had histological diagnosis of prostate cancer, no evidence of bone metastases by bone scan or visceral disease by CT scan, and at least 2 consecutive rising PSA = 2 weeks apart after diagnosis, radical prostatectomy (RP), or radiation therapy (XRT). Pts were treated with IAD consisting of 9 months of leuprolide acetate and an anti-androgen. Subsequently AD was stopped and monthly PSA and testosterone levels were followed during the off treatment period (Toff) until the PSA reached a threshold value (1 ng/mL if prostate removed or 4 ng/mL if prostate intact). At that time AD was resumed as before in a new cycle. Pts were treated until AI, defined as two rising PSAs while on AD with a castrate level of testosterone. Results: To date, 57 of 88 accrued pts are evaluable for this analysis. The median age at diagnosis is 62.2 yrs (range 43.9–77.4 yrs), median Gleason sum is 7. For the 49 pts with biochemical relapse after prior RP or XRT, median time from diagnosis to PSA relapse is 3.2 yrs (0–14.7 yrs) and from diagnosis to IAD was 4.9 yrs (range 0.1–14.9 yrs). For the 8 pts with no prior therapy, median time from diagnosis to IAD is 0.2 yrs (range 0–3.9 yrs). The median PSA value for all pts at study entry is 16 ng/mL (range 4–175 ng/mL); the value at study entry or after 3, 5, or 7 months of AD is not associated with time to AI or survival. Entry PSA is predictive of length of first Toff, and the length of the first Toff is associated with both time to AI (P<0.010) and survival (P<0.01). Conclusions: The duration of the first Toff in other studies of IAD should be evaluated for similar associations with time to AI and survival. No significant financial relationships to disclose.
Long-term effects of pre-surgical stress management for men with early stage prostate cancer undergoing radical prostatectomy (RP)
Authors: Cohen L. , Pettaway C. , Babaian R. , Pisters L. , Miles B. , Harrison-Fortier A. , Devine D. , Wei Q. , Parker P. 
Published: March 2020

5148 Background: We conducted a randomized trial to examine pre-surgical stress management for men undergoing RP. We previously reported on the short-term benefits in reducing mood disturbances before and after surgery. Methods: One hundred and fifty- eight men were randomly assigned to one of three conditions. Men in the stress management (SM) group discussed their fears and concerns about the upcoming surgery and were taught diaphragmatic breathing, guided imagery, an imaginal exposure to the day of surgery, and exposure to adaptive coping skills. Men in the supportive attention (SA) group discussed their fears and concerns about the upcoming surgery and then a semi-structured interview was conducted. Men in the SM and SA groups met with a clinical psychologist two times prior to surgery, a brief session just prior to surgery, and then again prior to discharge. Men in the usual care (UC) group had no meetings with a psychologist. Men completed psychosocial and quality of life (QOL) measures including distress (BSI-GSI), intrusive thoughts (IES), and QOL (SF-36), at baseline and 6 and 12 months later. Results: Men were primarily Caucasian (78%), married (85%) and highly educated (80% some college or higher). Mixed model analyses, controlling for ethnicity, age, martial status, stage, baseline PSA, Gleason score, and the respective baseline measure, indicated a significant group main effect for SF-36 Role Physical (SF-RP)(p=0.01). Post-hoc analyses revealed significantly higher SF-RP scores for the SM (86) vs. UC (63) group and marginally higher scores for the SM (86) vs. SA (73) group. There was a marginally significant group main effect for pain scores (SF-BP) (p=0.12) with the SM group reporting significantly better pain scores than the UC group (80 vs. 71), and neither group differed from the SA group (77). There was also a group by time effect for general health scores (SF-GH) revealing by 12 months after surgery that the SM (74) and SA (76) groups both reported higher SF-GH scores than the UC group (68). There were no group differences on any of the other outcomes. Conclusions: Results suggest that even a brief pre-surgical stress management intervention is beneficial in terms of improving aspects of QOL 6 and 12 months after RP. Funding: NIMH/NCI RO1MH59432 No significant financial relationships to disclose.
A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer
Authors: Loesch D. M. , Greco F. , O’Shaughnessy J. , Hainsworth J. D. , Vukelja S. J. , Sandbach J. , Boehm K. A. , Ilegbodu D. , Asmar L. , Robert N. J. 
Published: March 2020

517 Background: This study compared the disease-free survival (DFS) obtained with 2 regimens of adjuvant therapy for patients (pts) with high-risk breast cancer Methods: Women PS 0–1 with local, operable, confirmed stage I-III adenocarcinoma were eligible. Pts may have had primary surgery, with no residual tumor. Therapy was as follows:Arm 1 (AC→T) - doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 repeated every 3 weeks for 4 cycles → paclitaxel 175 mg/m2 repeated every 3 weeks for 4 cycles; Arm 2 (AT→T) - doxorubicin 50 mg/m2 plus paclitaxel 200 mg/m2 repeated every 3 weeks for 4 cycles → paclitaxel 80 mg/m2 weekly ×12. Results: 1,830 pts were enrolled and treated; n=915 Arm 1 (AC→T) and n=915 Arm 2 (AT→T). Pts were: PS=0 (70%/Arm), ER+/PR+ (54% and 50%, Arms 1 and 2 respectively), ER-/PR- (35% and 34%) with 0 positive nodes (N+) (28% and 27%), 1–3 (N+) (44% and 46%), 4–9 (N+) (21% and 18%) and 10+ (N+) (7% and 8.5%). Most were postmenopausal (57%/Arm); median age was 52 years/Arm. To date 1,655 pts (90%) are alive. 5-year DFS was 80% vs 81% for Arms 1 and 2 Overall 5-year survival was 86% vs 89%, in Arms 1 and 2. Cause of death was recurrence for 76 pts in Arm 1 and 56 pts in Arm 2. The main reasons for pts being taken off study treatment were toxicity (85 pts Arm 1 vs 128 pts Arm 2), recurrence (79 pts Arm 1 vs 52 pts Arm 2), and consent withdrawal (18 pts Arm 1 vs 30 pts Arm 2). The most frequent toxicities were neutropenia, leukopenia, neuropathy, febrile neutropenia, nausea, vomiting, arthralgia, and myalgia. GI toxicities were more frequent in Arm 1. Alopecia occurred in both Arms (77%). Conclusions: At 5-years, the AT→T produced significantly better OS (p=0.054) and improved DFS (p=0.19). Clinically important toxicities were more frequent with AC→T. Given this, AT→T in the adjuvant treatment of breast cancer is well tolerated and warranted in place of AC→T in these pts. Research support provided by Bristol-Myers Squibb (Princeton, NJ). No significant financial relationships to disclose.
Comparison of survival rates in carcinoma in situ of the breast treated with total mastectomy to breast-conserving surgery and radiotherapy
Authors: Ibrahim M. N. , Abdullah Z. , Healy L. , Murphy C. , Yousif I. Y. , Martin M. J. 
Published: March 2020

519 Background: Carcinoma in situ (CIS) of the breast is a precancerous lesion with the potential to progress to invasive cancer. In 2003, CIS accounted for 19% of all newly diagnosed invasive and non-invasive breast lesions combined in the United States. Current treatment options are mastectomy ± tamoxifen, and breast-conserving surgery with radiotherapy ± tamoxifen. As there are no randomized comparisons of these 2 treatments, data from the Surveillance Epidemiology and End Results (SEER) database was used to compare their survival rates. Methods: 88,285 patients were identified with CIS from 1988 - 2003. Of these, 27,728 patients were treated with a total mastectomy, and 25,240 patients received breast-conserving surgery with radiotherapy. Kaplan-Meier survival analyses and Cox proportional hazards regression were used to compare overall survival and disease specific survival at 5 and 10 years. Results: Kaplan-Meier analyses demonstrated 5 year overall survival rates for total mastectomy vs. breast conserving surgery with radiotherapy of 95.46% vs. 97.59% respectively (Log-rank P < 0.0001). The 5 year rates for disease specific survival were 99.16% vs. 99.72% respectively (Log-rank P < 0.0001). At 10 years the overall survival rates had fallen to 91.96% vs. 96.09% respectively (Log-rank P < 0.0001). The 10 year disease specific survival rates were 98.61% vs. 99.50% respectively (Log-rank P < 0.0001). Cox proportional hazards regression demonstrated a relative risk of 0.847 (95% confidence interval (CI) 0.790 - 0.907) and 1.110 (95% CI 0.931 - 1.324) for 5 year overall survival and disease specific survival respectively, when total mastectomy was compared with breast conserving surgery and radiotherapy. At 10 years, the relative risks were 0.865 (95% CI 0.820 - 0.913) and 1.035 (95% CI 0.900 - 1.190) for overall survival and disease specific survival respectively. Conclusions: Overall, when looking at disease-specific survival rates by multi-variate analysis, there does not appear to be a significant difference between total mastectomy and breast-conserving surgery with radiotherapy in the treatment of CIS. No significant financial relationships to disclose.
Long-term outcomes after invasive breast tumor recurrence (IBTR) in women with DCIS in NSABP B-17 and B-24
Authors: Wapnir I. , Dignam J. , Julian T. B. , Land S. , Mamounas E. P. , Anderson S. , Fourchotte V. , Costantino J. , Wolmark N. 
Published: March 2020

520 Background: DCIS patients treated with lumpectomy have a very favorable outcome but are at risk for IBTR. Local control is improved by radiotherapy (RT) and adjuvant tamoxifen (TAM). Local failures, specifically invasive IBTRs (I-IBTR), may impact on long-term outcome. We present long-term outcome results from a cohort of DCIS patients from two NSABP randomized trials. Patients and Methods: A total of 2,615 women with primary DCIS from NSABP B-17 and B-24 (randomized from 1985 to 1994) were included. Median follow-up was > 12 yrs. In B-17 treatment was lumpectomy (LO, 403) or lumpectomy with whole breast irradiation (LRT, 410). In B-24 patients received LRT (901) or LRT plus TAM [901]. Hazard ratio and cumulative incidence of IBTR were examined by treatment. Mortality hazard was evaluated in relation to prior IBTR. Results: IBTR was a first failure in 465 patients (243 invasive, 222 noninvasive). The 12 year cumulative incidence of all IBTRs was 32.9% for LO, 15.8% LRT, and 12.5% LRT+TAM. RT significantly reduced I-IBTR (LRT/LO hazard ratio (HR) = 0.39; 95% confidence interval (CI) =0.26 to 0.59). TAM conferred additional benefit on I-IBTR (LRT+TAM/LRT HR=0.68; 95% CI= 0.48 to 0.97). Overall mortality was low. Women with I-IBTR had a two-fold greater mortality risk relative to those without I-IBTR (HR=2.08; 95% CI = 1.46 to 2.98). The effect was greater for LRT patients (HR=3.04; 95% CI= 1.92 to 4.84) than for LO patients (HR=1.17; 95% CI = 0.57 to 2.39). For LRT+TAM patients, the effect was similar to that for LRT patients HR=1.91; 95% CI= 0.76 to 4.78). Conclusions: As in cases of I- IBTR after an invasive index tumor, the occurrence of an I-IBTR with a DCIS index tumor, particularly after RT, confers increased risk for subsequent mortality. No significant financial relationships to disclose.