bluuebunny/crossref_metadata_2025 huggingface dataset:
Local variation in primary treatment of localized prostate cancer
Authors: Cooperberg M. R. , Broering J. M. , Carroll P. R.
Published: August 2020

5126

Background: We aimed to characterize and quantify variation in the primary management of localized prostate cancer at the level of clinical practice sites. Methods: Data were abstracted from patients accrued to the CaPSURE national prostate cancer registry. Patients were accrued from the 36 clinical practice sites which contributed at least 30 patients to the registry, and represented all those diagnosed since 1990 with localized disease who received radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy, active surveillance / watchful waiting (WW), or primary androgen deprivation therapy (PADT) were included. Descriptive analyses were performed, and a random effects logit hierarchical model was constructed, controlling for year of diagnosis, age, comorbidity, PSA, Gleason score, clinical T stage, and percent of biopsy cores positive, to estimate the proportion of variation in primary treatment selection explicable by practice site. Analyses were conducted for all patients and for low-risk patients (Gleason score ≤6, PSA ≤10 ng/ml, clinical stage ≤T2a). Results: 10,080 men were analyzed. The distribution among primary treatments at each clinical practice site varied widely: use of RP, for example, ranged from 12% to 95% of enrolled patients. Patterns of treatment are not reliably explained by patient risk distribution at each site. The proportion of variation attributable to clinical practice sites was 10% for PADT, 19% for WW, 21% for EBRT, 28% for RP, 37% for brachytherapy, and 75% for cryotherapy. For low-risk patients only, this proportion was higher for all treatment types except brachytherapy and cryotherapy. Only a small amount of the variation attributable to practice site can be explained by measured sociodemographic factors such as ethnicity, income, education, and geographic region. There are significant trends in treatments over time, including more use of PADT for intermediate- and high-risk patients, and more use of RP and WW for low-risk patients. Conclusions: These data do not represent a random sampling of the United States population. However, the significant variation in practice patterns across individual clinical sites suggests that factors other than patient clinical and sociodemographic factors may be driving selection of primary treatment.

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A randomized double blind phase I-II study to determine the tolerability/efficacy of two different doses of lenalidomide (L), CC- 5013, in biochemically relapsed (BR) prostate cancer (PC) patients (pts) (M0) after local treatment (LT)
Authors: Sinibaldi V. J. , Carducci M. A. , Moore-Cooper S. , George B. , Denmeade S. , Drake C. G. , Walczak J. , Pili R. , Zahurak M. L. , Eisenberger M. A.
Published: August 2020

5130

Background: BR following LT is common in PC with no defined standard treatment. Lenalidomide (L) is an immunomodulatory agent with anti-angiogenic and direct antitumor effects. Methods: This trial was designed to evaluate a dose-effect relationship of L in BR PC. Pts were randomized to either 5 or 25 mg/day(d), PO, d 1–21 (28-d cycles); then stratified by PSADT (< 3, 3–8.9, ≥ 9 mos), LT and prior ADT. Eligible pts had: rising PSA (≥1 ng/mL), M0 disease, testosterone > 150 ng/mL, adequate bone marrow, renal, and hepatic function. Baseline and Q 2 mos PSA's were processed after Q 6 mos of L, along with CT and bone scan. Toxicity exams were Q mo. Primary endpoints are safety and progression after 6 mo of L (defined by a confirmed ↑ in PSA > 25% over the baseline value or mets). Secondary endpoints are changes of slopes in PSA related to pharmacokinetics (pk). A sample size of 30 pts/arm provides an 85% power to detect a PSA progression rate of 40% (compared to 80% predicted ) with a Type I error = 0.05 (Fishers exact test). Results: 59 pts were entered July 20, 2006-December 31, 2008. Pooled data from the 2 arms: median: age 64 (50–81), ECOG PS 0, baseline PSA 9.3 ng/ml (1.3–92.8 ng/ml). 16 pts had PSADT <3 mos, 26 from 3–8.9 mos, and 17 ≥ 9 mos. Median: F/U on all 59 pts is 351 + d (9 +-887+d); # cycles = 6 (1–30). Thus far, 44/59 pts completed 6 cycles of L (1 had PD, 6 stopped L due to toxicity, 8 too early). 22 /44 who completed 6 mos of L remained on L > 6 mos ( 7+-30+ mos); including 7 pts ≥ 24 mos. Of 44 pts, blinded evaluation of PSA's at 6 mos: 4 pts had ≥ 50% ↓, 22 had stable PSA,17 had PD, 1 too early . Rash was DLT. Other Gr toxicities: appendicitis, abd pain, neck pain, venous thrombolic disease, fatigue, pruritus. Conclusions: Preliminary data prior to unblinding the study treatment arms, from pooled data, suggest that L may be administered > 6 mos with acceptable toxicity, and is associated with PSA declines and long term stabilization in pts with BR. Supported by a grant from Celgene Corporation. Data coordination infrastructure is supported by the Prostate Cancer Foundation and The James Stine research fund.

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HLA-associated multipeptide vaccination in biochemically relapsed prostate cancer patients
Authors: Feyerabend S. , Stefanovic S. , Gouttefangeas C. , Widenmeyer M. , Wernet D. , Hennenlotter J. , Bedke J. , Dietz K. , Pascolo S. , Rammensee H. , Stenzl A.
Published: August 2020

5134

Background: We conduct a phase I/II monocenter clinical trial using multi peptide vaccination in patients with hormone naive, biochemically relapsed prostate cancer. The synthetic peptides applied are MHC-class I (HLA-A2) and -class II binders for activating CD4+ and CD8+ T- effector cells in vivo. Study endpoints are side effects as well as PSA- and T-cell response. Methods: Patients (pts) with rising PSA after primary curative surgical treatment without metastatic imageable lesions receive 14 peptides emulsified in Montanide ISA51 subcutaneously, combined with one of four T-cell stimulatory adjuvants versus no adjuvant for 18 months (mo) or until progression. PSA doubling time (DT) and clinical performance are monitored. T-cell activity and specifity are assessed with Elispot assay, tetramer staining and intracellular cytokine stainings. Results: 25 out of 35 pts have terminated the study treatment so far. During the vaccination period, geometric mean PSA DT increased from 7.8 mo (range 1.5 - 44.8 mo, 25 pts) to 11.8 months (range 2.2 - 571.3 mo, 24pts) whereas 1 pt showed a decreasing PSA value. Overall 8/25 pts (32%) had a mean rise of PSA DT of 81.6 mo and four of them did not receive any further treatment and were evaluable for follow-up (FU) after peptide vaccination (FU median 16 mo, range 5–33). These four pts raised their mean geometric PSA DT from 8.2 mo prior study treatment to 51.9 mo at treatment end and 52.5 mo at end of FU. PSA progressed unchanged in 10 patients (40%) or increased intermittently only in 4 pts. Two pts had PSA decline or DT increase during FU but not during the treatment period. Four patients (16%) exhibited an allergic reaction CTCAE II°. All pts reacted to at least one of the tumor antigen-derived HLA-class I epitopes after the fourth vaccine injection and up to six peptides were recognized simultaneously by CD8+ T cells in some individuals. Conclusions: Multi peptide vaccination stabilized or slowed down PSA progress in 11 of 25 cases. Stimulation of specific T-cell response is observed. Rise of PSA DT delaying standard treatment up to 33 mo and thus, delaying disease specific mortality is feasible.

No significant financial relationships to disclose.
A randomized, phase II study of ATN-224 in patients with biochemically relapsed, hormone-naive prostate cancer: A DOD/PCF Prostate Cancer Clinical Trials Consortium trial
Authors: Lin J. , Beer T. M. , Ryan C. J. , Mathew P. , Wilding G. , Morris M. , Callahan J. A. , Gordon G. , Reich S. , Carducci M. A.
Published: August 2020

5135

Background: ATN-224 (choline tetrathiomolybdate) is an orally active, small molecule that has antiangiogenic and antitumor effects in prostate cancer (PCa) models. ATN-224 targets Cu2+/Zn2+superoxide dismutase 1 (SOD1) and suppress the generation of H2O2 leading to activation of a number of phosphatases, a group of negative growth regulatory enzymes. We hypothesized that ATN-224 may induce antitumor effect as an antiangiogenic (at 30 mg dose level) and possesses direct antitumor activity at higher dose (300 mg/day). Methods: PCa pts with PSA doubling time (PSADT) of < 12 months, no radiographic evidence of metastasis, no hormonal therapy within 6 months were enrolled. All pts had testosterone > 150 ng/dL at baseline. ATN-224 was administered at 2 dose levels. PSA progression was defined as at least a 50% increase in PSA and >5 ng/mL increase from baseline or post-treatment nadir and confirmed. Endpoints included the proportion of pts who did not have PSA progression for 24 weeks, change in PSA slope/PSADT, and assessment of safety and tolerability. The study was not powered to detect difference between the two groups. Results: 52 pts were enrolled at 6 centers. Fourteen of 27 (52%) in the low dose and 6/25 (24%) in the high dose cohort were PSA progression free for 24 weeks. One patient in high dose cohort showed PSA >50% decrease of 40 days duration. Pre- and on-treatment PSA kinetics are shown below. Median duration on study was 134 days in both groups. ATN-224 was well tolerated with a few reversible Grade 3/4 neutropenia and Grade 3 skin rash (both 4%). Conclusions: ATN-224 may have biologic activity in men with androgen-dependent PCa at low doses, as demonstrated by > 50% of pts being PSA progression free at 6 month and a significant decrease in mean PSA slope. The implication of this study is not clear without a comparative design and ceruloplasmin correlation which is still pending.

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Correlation of hypoxic prostate/muscle pO2 (P/M PO2) ratio and biochemical failure in patients with localized prostate cancer: Long-term results
Authors: Turaka A. , Buyyounouski M. K. , Hanlon A. L. , Horwitz E. M. , Greenberg R. E. , Movsas B.
Published: August 2020

5136

Background: Tumor hypoxia may confer radioresistance in prostate cancer. The purpose of this study was to correlate tumor oxygenation status with long term biochemical outcome following prostate bracytherapy. Methods: Custom made Eppendorf PO2 microelectrodes were used to obtain PO2 measurements from the prostate (P), focused on + biopsy locations, and normal muscle tissue (M), as a control, in the operating room using a sterile technique. A total of 11,516 measurements were obtained in 57 patients with localized prostate cancer immediately prior to prostate brachytherapy. The Eppendorf histograms provided the median PO2, mean PO2, and % < 5 mm Hg or < 10 mm Hg. All patients received brachytherapy implants (48 low dose rate and 9 high dose rate) and five patients had received prior hormonal therapy. Biochemical failure (BF) was defined using both the newer Phoenix (PSA nadir + 2 ng/mL) the prior ASTRO (three consecutive rises) definitions (dfn). A Cox proportional hazards regression model evaluated the influence of hypoxia on BF with P/M ratio as a continuous variable and dichotomized at 0.05, 0.10, and 0.20. Results: The median follow-up was 8 years (range: 0.8- 9.4 years). Twelve patients developed BF via ASTRO dfn and 8 via Phoenix dfn. On stepwise multivariate analysis, P/M ratio < 0.10 was a significant predictor of BF (ASTRO, p = 0.03; Phoenix p = 0.02) in a model including initial PSA, Gleason score, T-stage, perineural invasion, age, hemoglobin and use of hormonal therapy. Kaplan-Meier freedom from BF for P/M ratio < 0.10 vs. ≥ 0.10 at 8 years was 46% vs 78% (p = 0.03) for the ASTRO dfn and 66% vs 83% (p = 0.02) for the Phoenix dfn. Only one patient (in the P/M ratio < 0.10) manifested distant failure. Conclusions: Hypoxia in prostate cancer (low P/M PO2 ratio) significantly predicts for poor long term biochemical outcome on multivariate analysis, suggesting that novel hypoxic strategies should be investigated.

No significant financial relationships to disclose.
Analyses of circulating tumor cell (CTC) dynamics and treatment response in prostate cancer using the CTC-chip microfluidic device
Authors: Lee R. J. , Stott S. L. , Nagrath S. , Ulkus L. E. , Dahl D. M. , Smith M. R. , Toner M. , Maheswaran S. , Haber D. A.
Published: August 2020

5149

Background: The CTC-Chip reliably detects CTCs in patients with localized and metastatic prostate cancer. In localized disease, CTCs may be indicative of tumor invasiveness. In the metastatic setting, CTCs may be useful in monitoring response to therapy. Molecular analyses of CTCs through this minimally invasive technique may provide insights into disease behavior, whereas sampling of metastatic deposits in bone (the predominant site of prostate metastasis) is not feasible. Methods: Peripheral blood was collected from patients undergoing treatment. CTCs were captured on the CTC-Chip. Quantities were determined using cytokeratin- and PSA-based staining and enumeration. In some cases, molecular analyses for the TMPRSS2:ERG chromosomal translocation were performed using FISH in intact cells or nuclei, or RT-PCR in extracted RNA. Subgroups of patients (n) included: localized disease undergoing prostatectomy (25), and metastatic disease undergoing either androgen deprivation therapy (ADT) (12) or docetaxel chemotherapy (5). Results: PSA-stained CTCs were captured in all patients. In localized disease, CTC quantities fell to undetectable levels 7–14 days after surgery; some patients exhibited an immediate decline while others had a delayed decline (>24 hours). In patients with metastatic disease undergoing either ADT or chemotherapy, CTC quantities generally corresponded with changes in serum PSA and radiographic assessments. Approximately 50% of patients exhibited the TMPRSS2:ERG translocation. Conclusions: These studies are the first to use the highly sensitive CTC-Chip technology to assess dynamic changes in CTCs in patients undergoing prostatectomy, ADT, or chemotherapy. Ongoing larger studies will assess whether patterns of CTC changes predict recurrence or treatment response. Molecular characterization of CTCs may provide new insights into prostate cancer biology, clinical behavior, and therapeutic targets.

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Correlation of progression-free survival (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) who failed first-line chemotherapy: Results from the SPARC Trial
Authors: Halabi S. , Sartor O. , Petrylak D. , Sternberg C. N. , Witjes J. A. , Noursalehi M. , McKearn T. J. , George M. J.
Published: August 2020

5150

Background: It has been shown in chemotherapy naïve patients that PFS is a statistically significant predictor of OS. The main objectives of this analysis were to explore whether PFS at 3-months is a predictor of OS and to investigate the dependence between PFS and OS in CRPC men who failed first line chemotherapy. Methods: Data from SPARC, a multi-national, randomized, double-blind trial, comparing satraplatin + prednisone vs placebo + prednisone in 950 CRPC patients were used. For the purpose of this analysis, the two treatment groups were combined. PFS was defined as the time from date of randomization to date of first progression (bone scan progression, radiographic, soft-tissue progression, symptomatic, or skeletal related events) or death, whichever occurred first. PFS at 3-months was defined as a binary variable in the following manner: if a patient experienced any type of progression at or before 3-months then this was considered as an event. If a patient did not progress at 3 months then he was censored. Landmark analysis of PFS at 3-months predicting OS was performed. In addition, the proportional hazards model was used to assess the significance effect of PFS at 3-months in predicting OS adjusting for the stratification factors. Finally, the association between OS and PFS was investigated using a statistic that estimates Kendall's tau measure of association for bivariate time to event outcomes subject to censoring. Results: 477 (56%) men progressed at 3-months of 853 men who were alive at 3-months. The median survival times were 34.5 weeks (95% CI = 30.8–40.4) and 78.7 weeks (95% CI=70.1–83.2, p-value<0.001) respectively in men who did and did not experience progression at 3-months. Men who had progressed at 3-months were more likely to die than men who did not progress (hazard ratio = 2.16, 95% CI =1.84 -2.55, p-value < 0.001). The dependence between PFS and OS was 0.29 (95% confidence limits = 0.24–0.33, p-value < 0.00001). Conclusions: PFS at 3-months predicts OS. The results of this large retrospective analysis show moderate, but strong statistical dependence between PFS and OS. Future studies are needed to assess the clinical relevance of the distinct components of progression.

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Phase I trial with a combination of docetaxel and 153Sm- EDTMP in patients (pts) with castration-resistant metastatic prostate cancer (mCRPC)
Authors: Eisenberger M. A. , Lin J. , Sinibaldi V. J. , Carducci M. A. , Denmeade S. , DeWeese T. , Song D.
Published: August 2020

5155

Background: Bone targeted therapy holds great promise for improving outcomes in mCRPC. Preclinical data strongly supported biological synergism of docetaxel (Tax) and 153Sm-EDTMP (Sm) in mCRPC. Concurrent Tax and Sm regimens were reported feasible and tolerable in phase I studies. This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles (12 wks/cycle, C) of concomitant standard dose/schedule of Sm plus Q3 wks schedule of Tax in mCRPC. Methods: mCRPC pts with progressive bone metastases were treated in 4 cohorts ( CH). Previous Tax and palliative RT to bone was admissible. Dose escalation of Tax was implemented if no DLT was observed in the preceding CH. Tax doses (on days 1, 22, per 12 wk cycle) were given as follows: CH 1- 50mg/m2 (C1 and 2); CH 2–75mg/m2 (C1) and 50mg/m2 (C2); CH3 - 75mg/m2 (C1 and 2) and CH4 ( Tax day 1, 22, 43 per 12 wk C) 75mg/m2 (C1 and 2). Sm was administered on days 2 (Q12 wks X 2) at dose of 1 mCi/kg/cycle (max. of 2 cycles). Disease status was assessed (with bone /CT scans and PSA) after every cycle. Results: Thirteen pts with progressive bone metastases were enrolled. Three had prior Tax and 3 had prior palliative radiation. Thirteen pts received total 20 cycles in 4 cohorts. Toxicity was primarily hematological. There were total 34 episodes Grade 3/4 neutropenia with a median 7 (range 7 -14) days to recovery to ≤ grade1. Tax dose was reduced to 50% in 2 CH4 pts at C2. Only 1 DLT G3 thrombocytopenia occurred on cohort 4 with duration of 9 wks. Median baseline PSA was 100.4 ng/ml (range 8.6 - 1064), 9/13 (69%) pts had PSA>50% decrease. Median time to disease progression was 147 days (range 72 days - 10 months+); 6/13 (46%) pts had stable/improved bone scans at 6 months and 8/8 (100%) symptomatic pts had improvement in pain. Conclusions: Concurrent 6-month administration of 2 and possibly 3 full dose /standard schedule of Tax with 2 full doses of Sm is feasible with reversible bone marrow suppression. The combination may provide additional clinical benefits for mCRPC pts with extensive bone metastasis.

No significant financial relationships to disclose.
Metabolic syndrome, diabetes mellitus, and the subsequent development of prostate cancer
Authors: Lawrence Y. R. , Morag O. , Boyko V. , Benderly M. , Goldbourt U. , Barchana M. , Behar S. , Wolf I. , Dicker A. P. , Catane R.
Published: August 2020

5158

Background: The lifetime risk of an American man developing prostate cancer (PC) is one in six. Metabolic syndrome (MS) is a cluster of medical disorders (hypertension, dyslipidaemia, hyperglycaemia, obesity) associated with the subsequent development of diabetes mellitus (DM). DM and MS afflict 11% and 22% of US adults respectively. MS and DM are associated with disturbed lipid homeostasis, and hypogonadism. DM and MS predispose to the development of gastrointestinal and endometrial cancer. DM and MS's influence on PC is less clear; some studies have suggested that whereas DM inhibits PC, MS promotes PC development. Methods: The Bezafibrate Infarction Prevention study was a randomized trial of fibrate therapy for the secondary prevention of ischemic heart disease. Between 1990–2 15524 men and women with ischemic heart disease were screened, of whom 3090 entered the trial. 81% were male. Participants were divided into three groups according to baseline parameters: (A) those with neither MS nor DM, (B) those with MS but no DM, (C) those with DM (with or without MS). MS was defined according to ATPIII guidelines. DM was defined by medical history or fasting glucose > 125 mg/dL. Follow-up for PC incidence and all-cause mortality was obtained through the Israeli cancer registry and the Ministry of the Interior respectively. Analysis accounts for differences in age and non-cancer-related-mortality between groups. Ethics approval was obtained. Results: 1350 participants were excluded due to missing data or previous cancer diagnosis, leaving 11,541 men. Mean age at enrollment 61 years (45–74). Median follow-up was 12 years. There were 6119 (53%), 3,376 (29%), and 2,046 (18%) participants in groups A, B and C respectively. Overall there were 459 cases of PC; 298, 123 and 48 in groups A, B and C. The age adjusted PC rates were 4.30, 3.61 and 2.55 per 1,000 patient years in groups A, B and C respectively (A vs C p = 0.003). Data were also analyzed examining PC incidence as a function of ‘number of components of MS present’ after pooling groups A, B and C. Relative risk of developing PC was 1.00, 0.92, 0.90, 0.69, 0.71, and 0.33 for 0, 1, 2, 3, 4, and 5 components respectively. Conclusions: A baseline diagnosis of DM (highly significant) or MS (trend) was associated with a decreased prostate cancer rate over the subsequent 12 years.

No significant financial relationships to disclose.
Phase III trial comparing 4-cycle doxorubicin plus cyclophosphamide followed by 4-cycle taxan with 8-cycle taxan as adjuvant therapy for node-positive breast cancer: Results of N-SAS-BC02 trial
Authors: Watanabe T. , Kuranami M. , Inoue K. , Masuda N. , Aogi K. , Iwata H. , Mukai H. , Tanaka S. , Yamaguchi T. , Ohashi Y.
Published: August 2020

516

Background: Anthracyclines are the key agents in postoperative regimens for breast cancer (BC). However, relatively rare but life threatening toxicity such as cardiac failure and secondary leukemia are the major concern with anthracycline containing regimens. Retrospective analyses suggested that anthracyclines can be excluded in some pts. Methods: Eligibility included node positive BC age less than 70 yo. Pts were randomized to receive either AC (doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2) every(q) 3 weeks(wks) x 4 -> P (paclitaxel) 175 mg/m2 q3 wks x 4 (ACP), the same AC -> D(docetaxel) 75 mg/m2 q3 wks x 4 (ACD), P 175 mg/m2 q3 wks x 8 (PTX) or D 75 mg/m2 q3 wks x 8(DTX). Comparison included P vs.D (ACP+PTX vs. ACD+DTX) and with AC or without AC (ACP+ACD vs. PTX+DTX). The primary endpoint was disease free survival (DFS) and the secondary endpoints included overall survival, adverse events (AE) and quality of life (QOL). The trial was powered to prove the non-inferiority of regimens without AC to those with AC (threshold hazard ratio [HR] 1.321) in terms of DFS. Results: 1,060 pts were accrued between Dec. 2000 and Mar.2006. 270 DFS events and 106 deaths after a median follow-up of 46.5 months were observed. In all randomised patients, 8 cycles taxane is not inferior to 4 cycles AC -> 4 cycles taxane in terms of DFS (HR:1.26, 95% CI; 0.99–1.60, p = 0.67). In the subset of HER-2 positive patients, 4 cycles AC -> 4 cycles taxane produced superior DFS to 8 cycles taxane (HR:1.63, 95% CI:1.05 - 2.54) but this is not observed in patients with HER-2 negative patients (HR:1.13, 95% CI: 0.85 - 1.50). D 75 mg/m2 tends to show superior DFS to P 175 mg/m2 (HR: 0.81, 95% CI; 0.64–1.03, p = 0.08). Nausea and vomiting was more frequent with AC -> a taxane than 8 cycles taxane. Edema and febrile neutropenia was more frequently observed with D 75 mg/m2 than P 175 mg/m2. The incidence of sensory neuropathy was higher with P 175 mg/m2 than D 75 mg/m2. Conclusions: AC improved DFS in the subset of pts with HER-2 overexpressing BC but not in non-selected population. DFS was better in the arms containing D than in the arms with P. Higher incidence of severe AEs was observed in the arms containing D than in arms with P.

No significant financial relationships to disclose.
MER-101–03, a multicenter, phase II study to compare MER-101 20mg tablets to intravenous zoledronic acid 4mg in prostate cancer patients
Authors: McHugh C. , Madigan K. , Walsh A. , Fox J. , Leonard T. W. , Quint J. B.
Published: August 2020

5161

Background: The primary objective of this study is to examine the pharmacodynamic effects of two different regimens of zoledronic acid, Orazol 20 mg tablets versus Zometa 4mg IV infusion once-monthly therapy on biomarkers in male bisphosphonate-naïve hormone-refractory prostate cancer patients. Methods: The study is an open-label, multi-center phase II clinical trial to compare oral Orazol 20 mg tablets weekly, to infusions of intravenous Zometa 4mg monthly, in males with hormone-refractory prostate cancer, bone metastases, and no prior bisphosphonate treatment. Patients were assigned into one of three cohorts. The three treatments administered were IV Zometa, 4 mg, 15 minute infusion, Day 0 and Day 28; Orazol po, 20 mg, Days 0, 7, 14, 21, 28, 35, 42, and 49; and Orazol po, 20 mg, Days 0, 1, 2, 3, 28, 35, 42, and 49. The study population consisted of men with hormone refractory prostate cancer as evidenced by history of rising PSA levels (last 2 of 3 PSA levels must be above nadir), who are bisphosphonate-naive, and have radiographically-confirmed bone metastases. Efficacy assessments: The primary endpoints are the assessment of response of four biomarkers, urinary NTX, serum CTX, serum bone specific alkaline phosphatase, and serum calcium on days -7, 0, 7, 14, 21, 28, 35, 42, 49, and 56. Secondary endpoints are assessments of performance and pain scores based on ECOG performance status, BPI, and analgesic use. Safety assessments include physical examinations, vital signs and body weight, hematology panel, urinalysis, and blood chemistry panel. Results: The results demonstrated a rapid decrease for all four biomarkers. This decrease was seen at seven days, and was sustained throughout the study. There were no statistically significant differences between any of the treatments in the primary and secondary endpoints. Conclusions: From the results of MER-101–03, Orazol weekly therapy appears to be as effective as Zometa, based on the biomarkers analyzed. Orazol offers a substantial improvement in therapy over IV infusion for patients, with efficacy that is at least comparable based on the results obtained here.

No significant financial relationships to disclose.
Expression of LHRH receptors in prostate cancer cells prior to therapy, following castration, or following treatment with LHRH agonists
Authors: Liu S. , Schally A. V. , Xiong S. , Cote R. , Hawes D. , Fazli L. , Gleave M. , Cai J. , Brands F. , Engel J. , Pinski J.
Published: August 2020

5163

Background: In the treatment of advanced prostate cancer, the effects of luteinizing hormone releasing hormone (LHRH) agonists are mediated through the down-regulation of pituitary LHRH receptors, inhibiting the pituitary-gonadal axis. Several groups have demonstrated LHRH receptor expression on prostate cancer cells. These tumoral receptors have been shown to mediate direct inhibitory effects in vitro. That expression of LHRH receptors persists in the castrate resistant state. To date, there is no information on LHRH receptor expression on the prostate after LHRH agonist therapy. This study investigates the expression of LHRH receptors following prolonged exposure to LHRH agonists. Methods: Expression of LHRH receptors was determined using immunohistochemistry and the intensity was graded on a scale from zero to 3. The expression was analyzed in three cohorts of patients: (1) 47 men with localized prostate cancer treated with radical prostatectomy with no hormone therapy, (2) 61 men with localized prostate cancer treated with neoadjuvant LHRH agonists for varying duration prior to prostatectomy, and (3) 22 men with metastatic prostate cancer who received a palliative transurethral resection of the prostate after clinical progression. In the final cohort, 15 men were treated with castration and 7 were treated with LHRH agonists. Results: 45 of 47 hormone naïve samples (95.7%) demonstrated LHRH receptor expression. Statistical analysis revealed a correlation between strong receptor expression and higher pathologic tumor stage as well as shorter overall survival. 60 of 61 samples treated with neoadjuvant LHRH agonist therapy (98.4%) demonstrated LHRH receptor expression. All 22 samples from patients with metastatic disease demonstrated LHRH receptor expression. The majority of these samples demonstrated moderate to strong intensity. Conclusions: LHRH receptors are expressed on prostate cancers cells of hormone naïve and castrated patients. The expression of these receptors appears to persist despite prolonged treatment with LHRH agonists. The continued expression of these receptors supports the concept of targeting prostatic LHRH receptors to deliver cytotoxic therapy based on LHRH analogs, such as AN-152.

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Sunitinib in combination with docetaxel and prednisone in patients (pts) with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: Zurita A. J. , Liu G. , Hutson T. , Kozloff M. , Shore N. , Wilding G. , Logothetis C. J. , Chen I. , Chow Maneval E. , George D.
Published: August 2020

5166

Background: Overexpression of VEGF and PDGF has been implicated in prostate cancer progression and bone metastases. Sunitinib is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, and other tyrosine kinases which may improve the efficacy of chemotherapy in pts with mHRPC. We performed a multicenter phase I/II study of sunitinib in combination with docetaxel and prednisone as first-line therapy in pts with mHRPC. The combination dose was established in phase I (Zurita et al, ECCO. 2007). Final results from phase II will be reported. Methods: Pts received treatment in a 21-day cycle: sunitinib 37.5 mg/d on days 1–14, docetaxel 75 mg/m2 on day 1, and prednisone 5 mg BID on days 1–21. Dose reductions were permitted for treatment-related toxicity. The primary endpoint was PSA response rate (PSA Working Group Criteria). Secondary endpoints included tumor response rate (RECIST), safety and patient-reported outcomes. Results: Fifty-five pts were enrolled and 13 remained on study at the time of the data cutoff (1 Oct 08). Thirty-six discontinued from the study due to disease progression (16), adverse events (AEs; 13), consent withdrawal (6) and other (1). Six pts completed the study (16 cycles) and continued treatment on another protocol. Pts received a median of 23 weeks of therapy (range, 2–84). The most common treatment-related grade 3–4 AEs were neutropenia (75%), febrile neutropenia (15%), fatigue (15%), stomatitis (7%), and anorexia (7%). Sunitinib dose reduction to 25 mg/d was required in 14 pts (26%), and 3 pts (6%) had a further dose reduction to 12.5 mg/d. Docetaxel dose reduction to 60 mg/m2 was required in 18 pts (33%). PSA responses occurred in 31 pts (56%), with a preliminary median time to PSA progression of 42.1 weeks. Out of 33 pts with measurable disease, thirteen (39%) had a confirmed partial response (PR) and another 7 (21%) had an initial PR. The median progression-free and overall survivals have not been reached, but the probability of survival at 48 weeks is 92.4% (95% CI: 77.5, 97.6). Patient-reported assessments of pain and quality of life will be reported. Conclusions: Sunitinib in combination with docetaxel and prednisone is tolerated and has antitumor activity in pts with mHRPC, as indicated by both PSA and RECIST-defined tumor responses.

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Ineligibility of prostate cancer patients in the VA Connecticut Healthcare System (VACHS) to participate in clinical trials due to comorbidities
Authors: Mayer T. M. , Kelly W. K. , Concato J. , Chao H.
Published: August 2020

5169

Background: A large proportion of prostate cancer patients receive their care within the VA Healthcare System. As this is a population affected by complex comorbidities, they may be underrepresented in oncology clinical trials. Our objective was to quantify the frequency with which castrate resistant prostate cancer (CRPC) patients in VACHS would be excluded from major phase III randomized controlled trials. Methods: We reviewed records of all prostate cancer patients at the VACHS between 2004–2007 and identified patients with CRPC. We reviewed eligibility criteria of 24 major phase III clinical trials, from 2006 onwards, studying investigational drugs for CRPC and created a “master list” (ML) of the most pertinent criteria. We analyzed our patient population according to both the ML criteria and to the TAX327 study criteria. Results: We identified 106 patients with CRPC, excluded 7 patients with insufficient medical records, and analyzed 99 patients. Performance status and life expectancy could not be accurately assessed from most charts and were excluded as specific criteria (though reflected in other serious medical condition). Major reasons for exclusion according to ML/TAX327 criteria include: 10/10 other malignancy within 5 years; 11/14 abnormal laboratory parameters; 27/30 other serious medical conditions; 3/4 abnormal cardiac function. ML list only exclusions: 5 active angina; 1 unstable DM; 1 major GI surgery; 1 contraindication to steroids. Serious medical conditions included: active cardiac disease, dementia, serious neurologic, psychiatric, vascular, pulmonary or hematologic disease, and poor performance status or compliance. Overall, 45% (45/99) of patients were excluded when using both the ML and TAX327 criteria. Conclusions: Approximately half of CRPC patients in the VACHS between 2004–2007 did not meet eligibility criteria for major therapeutic trials for CRPC. This retrospective review demonstrates that VA patients are underrepresented in randomized clinical trials for CRPC and are a special population due to their complex comorbidities. These findings underscore the importance of designing better clinical trials for CRPC with less barriers for this underrepresented but common patient population.

No significant financial relationships to disclose.
Visit and treatment patterns over time among elderly patients (pts) with M1 prostate cancer (PC): An analysis using SEER-Medicare
Authors: Hussain A. , Onukwugha E. , Seal B. , Mullins C. D.
Published: August 2020

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Background: Treatment options for the management of pts diagnosed with M1 PC have evolved over time. It is unknown whether visits to medical oncologists/hematologist oncologists (MOH) and treatment patterns are also changing over time. The objective of this study is to examine changes in visit and treatment patterns over time. Methods: A retrospective analysis of SEER Medicare data included pts diagnosed with M1 PC from 1994–2002 (age > 65 years) and residing in SEER registries that were present for the entire period. The study included pts with a post-diagnosis visit to a urologist; pts who saw a MOH prior to the urologist visit were excluded. Pts were grouped as 1) no MOH visit, 2) MOH visit w/in 3 mos of a urologist visit, 3) MOH visit => 3 mos after a urologist visit. Treatment with hormone therapy or chemotherapy was defined as 1) none received; 2) timely (i.e. within 6 mos of diagnosis); and 3) delayed, i.e. => 6 mos following the diagnosis. Time periods were defined as early (1994–1996), middle (1997–1999) and late (2000–2002). Results: 3,269 pts (mean age 77, 81% white) were available for analysis. Ninety-three percent of pts received treatment. Thirty-eight percent of pts saw a MOH during the study period; over the study period (early; middle; late) 13% (10%; 13%; 17%) of pts had a timely visit to the MOH and 25% (24%; 28%; 25%) had a delayed visit to the MOH. The proportion of patients seeing a MOH increased (34%; 41%; 42%, p < 0.001) and the proportion of treated pts increased (93%; 93%; 95%, p = 0.03) over the early, middle, and late periods. Conclusions: Approximately one-third of patients with M1 disease and a post-diagnosis urologist visit also see a medical oncologist. The vast majority of these patients receive treatment. Over time, a larger proportion of patients are seeing medical oncologists.

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Benefit of adjuvant trastuzumab in breast cancer patients with focal HER2 amplified clones: Data from N9831 Intergroup Adjuvant Trial
Authors: Sukov W. R. , Miller D. V. , Dueck A. C. , Tenner K. S. , Jenkins R. B. , Kaufman P. A. , Davidson N. E. , Dakhil S. R. , Martino S. , Roy V. , Perez E. A.
Published: August 2020

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Background: Targeted therapy using trastuzumab (an anti-HER-2 receptor monoclonal antibody) has significantly improved survival in breast carcinoma patients (pts), but determining which pts will respond to this therapy remains a challenge. We previously reported (Miller DV, ASCO 2004 abstract #568) a subset of pts with breast cancers demonstrating focal HER-2 amplified clones (FHAC) amidst otherwise nonamplified tumor cells by fluorescence in-situ hybridization. These accounted for 21% of the HER-2 amplified but immunohistochemistry (IHC) negative cases and 30% of the HER-2 amplified but IHC equivocal cases. The clinical significance of this phenomenon was unclear at that time. We now report the disease-free survival (DFS) data on 91 FHAC pts with a comparison to the diffusely amplified (DA) cases in this trial group. Methods: Breast tumors were evaluated for HER-2 gene amplification using PathVysion™. FHAC cases demonstrated 2–40% of cells with >10 HER-2 signals and HER-2:CEP17 ratio >5.0, regardless of the overall HER-2:CEP17 ratio. Patient and disease characteristics were compared using chi-square tests. Cox regression models compared DFS between pts randomized to arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) within 91 FHAC and 1571 DA cases. Median follow up was 4.0 years. Results: Age, race, menopausal status, surgical procedure, nodal status, histologic type and grade, and tumor size, were not significantly different between pateints with FHAC and DA. Pateints with FHAC had more frequent hormone receptor positivity compared to DA cases (66% vs 50%; p = 0.004). Hazard ratios between pts with FHAC and DA showed that both groups of pts had similar DFS (A: HR = 0.86, p = 0.65; C: HR = 0.72, p = 0.57). Hazard ratios between arms within FHAC and DA groups demonstrated similar benefit from trastuzumab in each group (FHAC: HR = 0.50, p = 0.30; DA: HR = 0.59, p < 0.0001). Results remained consistent when including hormone receptor status in the model. Conclusions: Based on a small number (n = 91) of pts with FHAC, benefit from trastuzumab appears to be similar whether the population of HER-2 amplified cells with breast carcinomas is focal or diffuse.

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Impact of study participation on survival of early-stage breast cancer patients: Results from the BRENDA study, a multicenter clinical cohort on quality of breast cancer care
Authors: Kurzeder C. , König J. , Woeckel A. , Sauer G. , Wischnewsky M. , Blettner M. , Kreienberg R.
Published: August 2020

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Background: Over the past two decades significant progress in treatment of early breast cancer has been accomplished through well designed, clinical trials (CTs). It has been hypothesized that trial participation could also be beneficial for the individual breast cancer patient. The BRENDA study group has been analysing quality of care provided by one university based and 16 regional breast cancer centers in south germany. In this study we investigated the impact of study participation on survival in an unselected clinical cohort of early stage breast cancer patients. Methods: The study population includes 5,966 patients who received primary therapy for early breast cancer between 1992 and 2005. Influence on survival by study participation was calculated by Cox proportional hazard analyses. Model adjustments include prognostic factors, type of treatment, age, risk group and time period. Guideline compliant treatment was assessed based on the St Gallen expert consensus recommendations and the German national S3 Guidelines. Results: A total of 738 patients (12%) received adjuvant (n = 552) or neoadjuvant (n = 186) systemic therapy within one out of 42 registered prospective multicenter phase II or III clinical trials. For patients not receiving neoadjuvant systemic therapy trial participation was associated with improved overall and disease free survival (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.57–0.99, HR = 0.78, CI 0.63 - 0.97, respectively). The calculated effect was of similar magnitude after additional adjustment for co-existing morbidity of patients. Descriptional analysis revealed that guideline violations for locoregional or systemic treatment were more frequently found in patients receiving adjuvant treatment outside CTs. No significant effect on survival was calculated for 183 patients receiving neoadjuvant systemic therapy within CT protocols. Conclusions: In our study population participation in prospective clinical trials for adjuvant systemic therapy was associated with improved survival irrespective of treatment actually given. Intrinsic mechanisms within the framework of clinical trials can improve quality of breast cancer patient care.

No significant financial relationships to disclose.
ZORO: A prospective randomized multicenter study to prevent chemotherapy-induced ovarian failure with the GnRH-agonist goserelin in young hormone-insensitive breast cancer patients receiving anthracycline containing (neo-) adjuvant chemotherapy (GBG 37)
Authors: Gerber B. , Stehle H. , Ricardo F. , Maass N. , Fischer D. , Sommer H. L. , Conrad B. , Mehta K. , Loibl S.
Published: August 2020

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Background: Premature ovarian failure due to chemotherapy leads to premature menopause and infertility. To prevent related health problems and to maintain fertility after chemotherapy in patients with hormone insensitive breast cancer, ovarian function might be protected by using a GnRH-agonist. Methods: Patients (pts) < 46 years, with a hormone insensitive breast cancer were randomized to receive an anthracycline/taxane containing chemotherapy with or without goserelin 3.6mg in parallel as subcutaneous injection in the abdominal wall starting at least 2 weeks before chemotherapy, and thereafter every 4 weeks (28 ± 3 days) until the end of the last chemotherapy cycle (EOC). Primary objective is the ovarian function 6 months after EOC. The endpoint normal ovarian function 6 months after EOC is defined by two consecutive menstrual periods within 21–35 days within a time frame of 5–8 months after last application of goserelin. Secondary objectives are treatment compliance, toxicity, quality of life; menopausal symptoms score; ovarian function at 0, 6, 12, 18, and 24 months by menstruation and endocrine function (estradiol, progesterone, FSH, LH, SHBG), duration until recovery of regular menstrual period, pregnancy rate. Results: Between March 2005 and August 2007, 63 pts in16 sites were enrolled. 60 are considered to be evaluable, 3 pts withdrew their informed consent. Nine serious adverse events occurred, which were mainly chemotherapy related and had no relationship to goserelin (3 febrile neutropenias, 2 neutropenias, 2 nauseas, 1 infection of port-catheter, and 1 psychogenic hyperventilation). No treatment related deaths occurred. Two women became pregnant, one in each group. Conclusions: There have been no risks identified related to the safety of the ZORO trial. The treatment with goserelin is feasible in all pts with acceptable hematological and non-hematological tolerability. Final efficacy analysis will be presented at the Meeting.

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MRI tumor volume for predicting response to neoadjuvant chemotherapy in locally advanced breast cancer: Findings from ACRIN 6657/CALGB 150007
Authors: Hylton N. , Blume J. , Gatsonis C. , Gomez R. , Bernreuter W. , Pisano E. , Rosen M. , Marques H. , Esserman L. , Schnall M.
Published: August 2020

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Background: American College of Radiology Imaging Network (ACRIN) trial 6657, the imaging component of the I-SPY trial (CALGB 150007/150012), is testing MRI for predicting response to treatment and stratifying risk-of-recurrence in patients with locally-advanced breast cancer. We report preliminary results evaluating MRI for prediction of pathologic response. Methods: Women with ≥3 cm invasive breast cancer receiving neoadjuvant chemotherapy (NACT) with anthracycline-cyclophosphamide (AC) followed by a taxane (T) were enrolled from May 2002 to March 2006. MRI was performed prior to NACT (t1), after 1 cycle AC (t2), between AC and T (t3), and following T prior to surgery (t4). MRI tumor size assessments included longest diameter (MRLD) and tumor volume (MRVol). Clinical size (clinsize) and mammographic longest diameter (MGLD) were also recorded. Linear dimension was measured by the radiologist for MGLD and MRLD; MRVol was calculated by computer using signal enhancement ratio (SER) thresholds. Change in clinical and MRI variables at t2 were compared for ability to predict pathologic complete response (pCR). Results: 237 patients were enrolled at 9 institutions. 216 patients with complete imaging were analyzed. Of tumor size measurements at t4, MRVol showed the strongest correlation with pathsize among clinsize (r = 0.44), MGLD (ns), MRLD (r = 0.28) and MRVol (r = 0.61). Early change in MRVol measured at t2 was the only variable predictive of pCR among clinsize (p = 0.14, 0.15), MRLD (p = 0.40, 0.07), MRVol (p = 0.02, 0.01) and peak SER (p = 0.53, 0.72) in univariate and multivariate logistic regression, respectively. Conclusions: Tumor response measured volumetrically by MRI is a stronger and earlier predictor of pathologic response after NACT than clinical exam or tumor diameter. This work is funded by NIH/ACRIN U01 CA79778; CALGB CA31946, CA33601; NCI SPORE CA58207.

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