bluuebunny/crossref_metadata_2025 huggingface dataset:
Choi response criteria for prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib
Authors: van der Veldt A. , Meijerink M. R. , van den Eertwegh A. J. , Haanen J. B. , Boven E.
Published: August 2020

5044

Background: Sunitinib (SU) has been approved for the treatment of metastatic renal cell cancer (mRCC). Since SU can induce extensive necrosis, RECIST may be inappropriate for tumor response evaluation. We evaluated whether the new Choi criteria (J Clin Oncol. 2007;25:1753–1759) are of additional value to predict outcome in mRCC patients (pts) treated with SU. Methods: 56 mRCC pts treated with SU were included. Imaging data consisted of thoracic and abdominal helical CT scans at baseline, after a median of 2 months and were repeated during treatment. For Choi criteria the longest diameter was ≥15 mm. Density of these lesions was determined in Hounsfield units. According to Choi criteria partial response (PR) was defined as ≥10% decrease in size or ≥15% decrease in density, while progressive disease (PD) was defined as ≥10% increase in size without meeting PR criteria by density. Progression-free survival (PFS) and overall survival (OS) were calculated according to Kaplan-Meier. Log rank test was used to test the statistical difference between survival curves. Results: For RECIST and Choi criteria, respectively, 230 and 156 tumor lesions were eligible. At first evaluation, according to RECIST 7 pts had PR, 39 stable disease (SD), and 10 PD, while according to Choi criteria 33 pts had PR, 8 SD and 15 PD. The median tumor density decreased significantly (Wilcoxon Signed Ranks test, p ≤ 0.001). At first evaluation in patients with PR, Choi criteria had a significantly better predictive value for PFS and OS (p < 0.001 and p < 0.001, respectively) than RECIST (p = 0.384 and p = 0.392, respectively). When best response during treatment was analyzed according to RECIST, the predictive value of RECIST increased for both PFS and OS (p = 0.004 and p = 0.002, respectively). For clinical benefit (PR+SD), the predictive value of RECIST and Choi criteria for PFS and OS were comparable (both p < 0.001). Conclusions: Choi criteria can be easily applied on contrast-enhanced CT scans. RECIST and Choi criteria have similar predictive value for outcome in pts with clinical benefit. Choi criteria, however, are more useful to early define a large pt population with favourable clinical outcome.

[Table: see text]
Phase II multicenter study of abiraterone acetate (AA) plus prednisone therapy in docetaxel-treated castration-resistant prostate cancer (CRPC) patients (pts): Impact of prior ketoconazole (keto)
Authors: Danila D. C. , de Bono J. , Ryan C. J. , Denmeade S. , Smith M. , Taplin M. , Bubley G. , Molina A. , Haqq C. , Scher H. I.
Published: August 2020

5048

Background: AA is a potent blocker of CYP17, required for synthesis of testosterone in the testes, adrenals, and prostate tissue. Study objectives included confirming AA antitumor activity and safety in multicenter setting, describing changes in ECOG PS, and comparing keto-naïve pts to keto-exposed pts. Methods: The 58 pts had progressive, metastatic CRPC and had failed hormonal therapy and up to two cytotoxic regimens, including docetaxel. AA (1,000 mg QD) and prednisone (5mg BID) were administered daily, the registration trial regimen. 56/58 pts had available data. Results: Baseline demographics: median age - 69.0 (44–86) yrs; median PSA - 151.00 (10.0–3846.0) ng/mL; ECOG 0 (n = 23), 1 (n = 30), 2 (n = 2), missing (n = 1); median prior hormonal therapies were 4 and chemo 1; 24 pts had prior keto, 32 pts were keto-naïve and 2 pts had no data on keto exposure. 45% pts had total maximal PSA decline ≥50%. Total maximal PSA decline (≥30%, ≥50% and ≥90%) in prior keto vs. keto-naïve pts was observed respectively, in: 10 (42%) vs. 20 (63%) pts; 8 (33%) vs. 17 (53%); 1 (4%) vs. 10 (31%). From 32 pts with ECOG 1 or 2, 16 pts (50%, 95% CI 32–68) improved (PS 1 to 0 in 14 pts, PS 2 to 1 in 1 pt; PS 2 to 0 in 1 pt); 39 pts (64% of total 58 pts) maintained PS. Median time to PSA progression was 169 days (95% CI 82–200): keto-naïve-198 days, prior keto-99 days. The majority of AA-related adverse events (AEs) were grade 1–2. No AA-related grade 4 AE was noted. Conclusions: Abiraterone acetate was well-tolerated and produced anti-tumor activity in heavily pretreated pts, as evidenced by PSA declines and improved PS. Incidence of mineralocorticoid-related AEs (HTN or hypokalemia) was reduced with the addition of low-dose prednisone. The keto-naïve post-docetaxel CRPC population was selected for the ongoing phase III pivotal study to confirm these results.

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Use of PSA threshold to identify an increased 4-year risk of a prostate cancer diagnosis in U.S. men
Authors: Crawford E. D. , Moul J.
Published: August 2020

5051

Background: Recent studies have shown that prostate specific antigen (PSA) values can be used to predict risk of developing prostate cancer (PCa) in the future. In the European Randomized Study of Screening for PCa (ERSPC) subjects with PSA of ≥1.5 ng/mL had a significantly greater risk of developing PCa after 4 years than subjects with PSA of <1.5 ng/mL (9.2% vs 1.5%, respectively; OR = 7.466; p < 0.001). This current analysis aimed to validate the ability of PSA of ≥1.5 ng/mL to predict the future risk of PCa in a US population of men within the Henry Ford Healthcare System (HFHS). Methods: This is a retrospective analysis of men enrolled in the Health Alliance Plan of the HFHS between 1997–2004 with at least 4 years of follow-up data. Men ≥40 years of age, with a baseline PSA value between 0–4.0 ng/mL, not receiving 5-alpha reductase inhibitors were included. Men were followed for 4 years after their first PSA value. The risk of 4-year PCa diagnosis was evaluated based on a 1.5 ng/mL PSA threshold, and was assessed by logistic regression, controlling for age and race. Results: A total of 21,502 patients were included in the analysis. At baseline, patients had a mean age of 55 years and a mean PSA of 1.0 ng/mL. Overall, 7.9% of patients with baseline PSA of 1.5–4 ng/mL were diagnosed with PCa after 4 years, compared to 0.5% of patients with a baseline PSA of <1.5 ng/mL. In a multivariate analysis (controlling for race and age), patients with a baseline PSA of 1.5–4 ng/mL were 12 times more likely to be diagnosed with PCa over 4 years than patients with baseline PSA of <1.5 ng/mL (OR = 12.4; 95% CI: 9.7–15.9; p < 0.0001). African Americans (n = 6,367) with baseline PSA 1.5–4 ng/mL vs baseline PSA<1.5 ng/mL had an even higher risk of being diagnosed with PCa over 4 years (OR = 17.0; 95% CI: 11.0–26.1; p < 0.0001). Conclusions: This analysis validates that men with PSA values 1.5 to 4 ng/mL are at a significantly increased risk for developing future prostate cancer compared to those with a PSA value below the 1.5 threshold. This threshold also confers increased 4-year risk in African American men.

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PCA3: A urine-based genetic assay for detection of prostate cancer in men with elevated PSA
Authors: Drewnowska K. , Crawford E. D. , Qian J. , Varvel S. , Wilk M. , Mason L. , Kaminetsky J. , Huisman T. K. , Bilowus M. , Freedman S. J. , Bostwick D. G.
Published: August 2020

5054

Background: Currently, early detection of prostate cancer relies primarily on an abnormal digital rectal examination (DRE) and an elevated prostate-specific antigen (PSA) level leading to a prostate biopsy. However, because of low positive predictive values, up to 75% of men with elevated PSA and/or suspicious DRE have a negative biopsy. We investigated the value of a new molecular marker–PCA3 in predicting the likelihood of prostate cancer. Methods: We undertook a prospective, multi-practice, community-urologist-based, and IRB approved clinical trial to evaluate PCA3. Urine samples were obtained from 974 men with elevated serum PSA (> 2.5ng/ml) and/or abnormal digital rectal examination prior to routine minimum 10-core prostate biopsy following standard study protocol in 30 medical practices. Urine samples were processed within 48 hours of collection. PCA3 and PSA mRNA were isolated, amplified and quantified by magnetic target capture, transcription-mediated amplification, and chemiluminescent hybridization protection assay technologies. The PCA3 value was determined using the ratio of PCA3 mRNA copy number to the PSA mRNA copy number multiplied by 1,000. Results: In total, 380 of 974 patients (39%) were diagnosed with prostate cancer, with a mean Gleason score of 7 (range, 6–9) and 26% (range 1–100%) of the biopsy specimens involved by cancer. An additional 106 cases (11%) had only high-grade PIN and/or atypical small acinar proliferation suspicious for cancer (ASAP), and 488 cases (50%) were benign. The mean PCA3 value in men with prostate cancer was significantly higher than in those without cancer (48 vs. 26, p < 0.0001). PCA3 score was associated with the presence of cancer (p < 0.0001) and Gleason score (p = 0.0001), but was not associated cancer volume (p = 0.56). Using a cutoff value of 35, PCA3 had an odds ratio of 2.6 for predicting prostate cancer. PCA3 had a specificity of 77% and a sensitivity of 44% for the diagnosis of prostate cancer, while the specificity and sensitivity for serum PSA were 22% and 87%, respectively. Conclusions: We found that the PCA3 urine test significantly improved the specificity for the detection of prostate cancer compared to serum PSA. Further evaluation of this urinary marker in screening for prostate cancer appears indicated.

No significant financial relationships to disclose.
Phase Ib dose finding trial of intravenous panobinostat with docetaxel in patients with castration-resistant prostate cancer (CRPC)
Authors: Rathkopf D. E. , Chi K. N. , Vaishampayan U. , Hotte S. , Vogelzang N. , Alumkal J. , Agrawal M. , Nydam T. M. , Fandi A. , Scher H. I.
Published: August 2020

5064

Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor that has demonstrated activity in both in vivo and in vitro prostate cancer models. Methods: An open-label, multicenter, dose-finding trial of i.v. panobinostat given on Days 1 and 8 (10, 15, and 20 mg/m2) with fixed-dose docetaxel on Day 1 (75 mg/m2) and prednisone (5 mg bid) in a 21-day cycle is being conducted in chemotherapy-naïve patients (pts) with CRPC. All pts have adequate organ function and ECOG performance status (PS) < 1. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG are excluded. This treatment is continued until disease progression or intolerability. The primary endpoint is determination of the maximum tolerated dose (MTD) of i.v. panobinostat in combination with docetaxel using the Bayesian logistic regression model. Dose-limiting toxicities (DLTs) are defined in first cycle. Results: Twenty-one pts (Cohort 1, n = 8; Cohort 2, n = 10; Cohort 3, n = 3) have been treated, with a median age of 66 yrs (range 50–88), median Gleason score of 9 (range 7–9), and median entry PSA of 67.1 (range 1.3–7920). DLTs include: Gr 4 bradycardia in Cohort 1 (n = 1) and Gr 4 neutropenia, resulting in Day 8 panobinostat dose omission (Cohort 2, n = 2; Cohort 3, n = 1). Gr 3/4 adverse events (AEs) include: neutropenia (n = 12), febrile neutropenia (n = 3), dizziness (n = 2), DVT (n = 1). Other Gr 1 or 2 AEs include: thrombocytopenia (n = 4), fatigue (n = 10), alopecia (n = 7), diarrhea, nausea, and rash (n = 5). Among the 599 ECGs, there was 1 QTcF increase of >60 ms from baseline and no QTcF >480 ms. Preliminary Cohort 1 pharmacokinetic (PK) data shows the mean panobinostat AUC0-inf does not differ between Day 1 (239 ng*hr/mL ) and Day 8 (254 ng*hr/mL), and the mean clearance value appeared to be similar between Days 1 and 8. In Cohort 1, the median number of cycles was 6. Four of 8 pts received >6 cycles. Five and four pts had >30% and >50% PSA reduction from baseline, respectively. In Cohort 2, 9 of 10 pts are still on treatment after 3 cycles. Conclusions: The combination of panobinostat at 10 or 15 mg/m2 with docetaxel is feasible and to date no PK interaction is apparent. Full safety, efficacy, and PK results will be presented. Under DOD PCCTC.

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Value of adjuvant radiation therapy in breast cancer patients with one to three positive lymph nodes undergoing a modified radical mastectomy and systemic therapy
Authors: Dawood S. , Gonzalez-Angulo A. M. , Woodward W. , Meric-Bernstam F. , Hunt K. , Buzdar A. , Hortobagyi G. , Buchholz T.
Published: August 2020

507

Background: Whether adjuvant radiation therapy should be utilized for patients (pts) with early stage breast cancer with up to 3 positive axillary lymph nodes treated with mastectomy and systemic therapy is controversial. This retrospective study was performed to determine if adjuvant radiation therapy had an impact on survival for this cohort of pts. Methods: 4240 pts with T1–2N0–1 breast cancers, diagnosed between 1980–2007, who underwent either mastectomy without adjuvant radiation therapy or segmental mastectomy with adjuvant radiation therapy were identified. All pts received systemic treatment. Women with >3 positive axillary lymph nodes were excluded. Overall (OS) and distant disease free survival (DDFS) were estimated using the Kaplan-Meir product method. Cox proportional hazards were used to determine associations between OS/DDFS and type of surgery after controlling for pt and disease characteristics. Results: 1336 (18.8%) had T1N0 disease, 1114 (26.27%) had T2N0 disease, 989 (23.33%) had T1N1 disease and 801 (18.89%) had T2N1 disease. Median follow-up was 54 months.5- year DDFS among women who underwent mastectomy and segmental mastectomy was 81% (95% 78%-83%) and 86% (95% CI 84%-87%), respectively (p < 0.0001). In the Cox analysis, pts who had mastectomy without radiation had a significantly increased risk of distant recurrence (HR= 1.39, 95% CI 1.14–1.70, p= 0.0013) than pts treated with segmental mastectomy and radiation. When looking at subgroups, no significant difference in DDFS was observed between the two groups in pts with lymph node negative disease. However, for pts with 1–3 positive lymph nodes, pts treated with mastectomy without radiation had significantly increased risk of distant recurrence compared to pts treated with segmental mastectomy with radiation (HR=1.614, 95% CI 1.198–2.177, p= 0.002). This difference was most pronounce in the subset of patients with T2N1 disease (HR= 1.794, 95% CI 1.220–2.637, p=0.003). Similar trends were observed for OS. Conclusions: This study provides provocative evidence for benefit of radiation therapy among pts with 1–3 positive axillary lymph nodes who are treated with surgery and systemic therapy.

No significant financial relationships to disclose.
Cross-validation of a new prognostic index integrating tumor marker decline in patients with relapsed disseminated germ cell tumors
Authors: Massard C. , Huguet H. , Kramar A. , Beyer J. , Hartmann J. T. , Lorch A. , Pico J. , Rosti G. , Droz J. , Fizazi K.
Published: August 2020

5086

Background: Early serum tumor marker decline during chemotherapy was previously shown to be prognostic for progression-free survival (PFS) and overall survival (OS) in patients with relapsed GCT in an analysis of the IT94 phase III trial, which compared conventional chemotherapy versus high dose chemotherapy (Massard C, ASCO 2008. Abstract No. 5085). The aim of this study was to validate this concept in an independent set of patients. Methods: Data on tumor site, response to first line chemotherapy, serum tumor markers at baseline and after two cycles of chemotherapy were obtained from 235 patients accrued in the IT94 trial (training set) and from 181 patients included in phase III prospective trials of high-dose chemotherapy conducted by the German GCT group (Lorch et al, J Clin Oncol. 2007) (validation set). The change from baseline of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) was assessed and classified into ‘favorable marker decline‘ and ‘unfavorable marker decline‘ group, as previously described (ASCO 2008. Abstract No. 5085). Results: In both series, favourable serum AFP decline was significantly associated with a better 2-year PFS (46% vs 24%; p < 0.0001) and OS (62% vs 34%; p = 0.0013) while serum hCG decline did not affect outcome. In multivariate analysis of the IT94 trial, an unfavorable AFP decline and a mediastinal primary site were adverse prognostic factors for both PFS and OS, and this was confirmed in the validation set. Among patients from the good prognostic group (favorable AFP decline and non-mediastinal primary site), those who were treated with high-dose chemotherapy had a better PFS (2-year PFS rate: 54% vs 37%; HR = 0.62; p = 0.017), and a trend for a better OS (2-year OS rate: 68% vs. 58%; HR = 0.77; p = 0.29) as compared to patients who were treated with conventional chemotherapy. In contrast, there was no difference in outcome in patients from the poor prognostic group (unfavourable AFP decline and/or mediastinal primary site), whether they received conventional chemotherapy or high-dose chemotherapy. Conclusions: AFP decline during the first 6 weeks of salvage chemotherapy and a mediastinal primary tumor site predict for PFS and OS in patients with relapsed disseminated GCT.

No significant financial relationships to disclose.
Laparoscopic renal cryoablation: Risk factor analysis to predict oncologic outcomes with minimum 5-year follow-up
Authors: Kamoi K. , Kawauchi A. , Miki T. , Aron M. , Remer E. , Haber G. , Berger A. , Crouzet S. , Ricardo B. , Gill I.
Published: August 2020

5094

Background: We analysed risk factors to predict oncologic outcomes at 5–11 year after laparoscopic renal cryoablation (LRC). Methods: Between 09/1997 and 010/2008, we performed renal cryoablation in 340 patients. Of these, 102 patients treated before 10/2003 (all laparoscopic) have minimum 5-year follow-up. Follow-up involved MRI imaging on postoperative day 1, 3 months, 6 months, 12 months, and then annually. Cryolesion biopsy was performed at 6-months. All data were prospectively accrued. Results: In the 102 patients with minimum 5-year follow-up, mean age was 66 years. Mean tumor size was 2.3 cm (0.9–5.0 cm). Median ASA score was 3 and mean BMI was 28. Six patients developed locoregional recurrence, 2 had locoregional recurrence with metastases, and 5 had distant metastases without locoregional recurrence. Overall, there were 7 cancer deaths. In the 69 patients with biopsy-proven renal cell cancer (median follow-up 81 mos; range 60–132 mos), 5-year overall, disease-specific, and disease- free survival was 75%, 92%, and 82%, respectively, while 10-year overall, disease-specific, and disease-free survival was 46%, 83%, and 79%, respectively. On multivariate analysis, previous radical nephrectomy for RCC was the only significant predictor for both recurrence- free survival and cancer-specific survival (p = 0.023 and 0.030, respectively). Relative risk of patients who has a history of radical nephrectomy for RCC treatment was 4.1 (95% CIs, 1.2 to 13.4), and 5.4 (95% CIs, 1.2 to 27.7) for disease-free survival and disease-specific survival, respectively. Conclusions: Laparoscopic renal cryoablation is effective oncologic treatment for renal mass in select patients. Disease-specific survival of 92% at 5-years and 83% at 10-years is possible. Preceding radical nephrectomy for RCC treatment was the only independent predicting factor for both disease-free and disease-specific survival.

[Table: see text]

No significant financial relationships to disclose.
Failure of initial VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC): What next?
Authors: Vickers M. M. , Choueiri T. K. , Zama I. , Cheng T. , North S. , Knox J. J. , Kollmannsberger C. , McDermott D. F. , Rini B. I. , Heng D. Y.
Published: August 2020

5098

Background: The characterization and efficacy of second-line targeted therapy in patients with metastatic RCC who failed first-line VEGF-targeted therapy in a population-based setting is of clinical relevance but remains to be assessed. Methods: Provincial registries and clinical databases from seven cancer centers (3 in US and 4 in Canada) identified patients with mRCC who received first-line anti-VEGF targeted therapy between 2005–2007. Patient characteristics, data on second-line therapy and outcomes were analyzed. Results: 645 patients with mRCC who received initial VEGF-targeted therapy were identified (sunitinib, sorafenib or bevacizumab) and had a median follow-up of 25 mos. Of these, 218 patients (34%) received second-line targeted therapy: the median age was 62 yrs (range, 41–87), median KPS was 90%, 90% had prior nephrectomy, 3.8% had non-clear cell histology, 5.8% had brain metastases and 79% had > 1 metastatic site. Second-line therapy included anti-VEGF agents (sunitinib n = 93, sorafenib n = 80, bevacizumab n = 11, axitinib n = 8) and mTOR-inhibiting agents (temsirolimus n = 21, everolimus n = 3). Patient characteristics were similar aside from more non-clear cell histology in patients receiving second-line mTOR-inhibiting agents (14% vs 3% p = 0.045). On multivariable analysis, only a higher baseline KPS score prior to first-line therapy predicted which patients were more likely to receive second-line therapy (p < 0.0001). The median time to treatment failure (TTF) of second-line therapy was 4.9 mos for anti-VEGF therapy and 2.5 mos for mTOR inhibitors (p = 0.014). After adjusting for MSKCC prognostic profile (favorable, intermediate, poor), the hazard ratio for TTF was 0.52 (95%CI:0.29–0.91) in pts receiving anti-VEGF therapy. Overall survival from start of second-line therapy was not different between anti-VEGF or anti-mTOR drugs (14.2 vs 10.6 respectively; p = 0.38). 70 patients (10%) received third-line therapy. Conclusions: Baseline KPS is an independent predictor of receiving second-line targeted therapy. Patients who receive a second-line anti-VEGF drug appear to have a longer TTF than those who receive a second-line anti-mTOR drug. However, patient selection may account for this finding and overall survival was not significantly different. Results of ongoing randomized trials are awaited.

[Table: see text]
Serum-sodium as an independent prognostic factor in metastatic renal cell carcinoma
Authors: Jeppesen A. N. , Jensen H. K. , Donskov F. , Marcussen N. , von der Maase H.
Published: August 2020

5102

Background: Recently, low serum sodium has been associated with poor disease-free and overall survival in localized renal cell carcinoma (RCC) (Vasudev, Clin Can Res. 2008). The present study investigated the prognostic impact of serum-sodium values below normal in patients with metastatic RCC (mRCC). Methods: A cohort of 120 consecutive patients with mRCC received subcutaneous, low-dose Interleukin-2 and Interferon-α at Dept. of Oncology, Aarhus University Hospital, from 2002 to 2004 (Cohort A). Baseline variables were collected retrospectively. Follow up was at least 4 years. Potential prognostic factors were analyzed by univariate and multivariate analyses. Endpoint was overall survival. An independent cohort of 120 consecutive patients with mRCC was used for validation. These patients were treated with interleukin-2 based regimens at the same institution from 1999 to 2002 (Cohort B). Data in this cohort were prospectively collected. Results: In cohort A, the estimated 5-year survival rate was 15% and the median survival was 15.1 months. Serum-sodium ranged between 126 and 144 mmol/l. Twenty-four patients (20%) had serum-sodium levels below normal range (<136 mmol/l). In the multivariate analysis, significant independent risk factors of short survival were serum-sodium below normal value (HR 1.90, CI 1.1–3.2, p = 0.014), high neutrophile count (>7) (HR 1.75, CI 1.1–2.8, p = 0.018), lactate dehydrogenase >1.5 upper normal level (HR 2.09, CI 1.3–3.3, p = 0.002), and number of sites (+3) (HR 1.92; CI 1.3–2.9, p = 0.003). In cohort B, the observed 5-year survival rate was 15% and the median survival was 15 months. Serum-sodium ranged between 128 mmol/l and 146 mmol/l. Seventeen patients (14%) had sodium levels below normal range. In the multivariate analysis, serum-sodium was validated as an independent prognostic factor (HR 2.98, CI 1.54–5.77, p = 0.001). Conclusions: Low serum-sodium is a new, validated, independent prognostic factor in patients with metastatic RCC.

No significant financial relationships to disclose.
Two-years biochemical failure-free survival following high intensity focused ultrasound (HIFU) for localized prostate cancer: Prospective single center study of 196 patients
Authors: Pinthus J. H. , Farrokhyar F. , Hassouna M. M. , Woods E. , Orovan W. L.
Published: August 2020

5117

Background: HIFU is an emerging ablative modality for the treatment of localized prostate cancer with limited reports on oncological outcome. We prospectively analyzed our 2-year results. Methods: 253 consecutive patients (age: 64+8) were treated with a planed single session of HIFU using the Ablatherm integrated imaging model system between January 2006 and June 2008. Patients were followed (median: 12; range 3–24 months) with PSA measurement every 3 months. Patients who received prior radiation or hormonal therapy (n=25) and patient for whom at least 2 consecutive PSA measurements were not available (n = 32) were excluded, leaving a total of 196 patients for analysis. Mean pre-treatment PSA was 6.9+3.3. Biopsy Gleason scores at diagnosis (median 9 cores) were 5, 6, 3+4, 4+3 in 1, 91, 66 and 38 patients, respectively. Biochemical failure (BCF) is reported using the Stephenson (PSA >0.4ng/ml and rising), Horwitz (2 consecutive increases of at least 0.5ng/ml) and Phoenix (nadir+2ng/ml) definitions. Results: 196 patients (age: 64+8) met the inclusion criteria for analysis. 75 had low and 121 had intermediate D'Amico's risk stratification disease. Mean and median absolute PSA nadir levels were 0.28+0.53 and 0.06 ng/ml respectively. It was achieved in median time of 3 months and remained unchanged in 70% of the patients throughout the follow-up. Overall 2 years BCF free rates were 70 % (62–78%), 86 % (81–91%) and 96% (91–99%) according to the Stephenson, Horwitz and Phoenix definitions, respectively; with no significant differences between risk groups. Predictors of BCF were absolute nadir [HR: 3.0 (2.3–3.8)] and pre-treatment PSA [HR: 1.1 (1.0–1.2)]. Conclusions: This is the only study to date that analyzed post HIFU BCF free rates according to post radical prostatectomy definition of BCF. BCF usually occur in the first year and plateau thereafter. Short term results by all BCF definitions are promising with similar results for patients with low and intermediate risk. Pre-HIFU PSA and post-HIFU PSA nadir levels are predictors for BCF.

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Effect of a soluble activin receptor type IIB on androgen-deprivation-induced effects on body composition
Authors: Lachey J. , Koncarevic A. , Ucran J. , Pearsall R. S. , Sherman M. L. , Seehra J.
Published: August 2020

5133

Background: Androgen deprivation therapy (ADT) is a well-established treatment for hormone sensitive prostate cancer, but is associated with adverse side effects including loss of bone and lean mass and increased adipose mass. Activin receptor type IIB (ActRIIB) signaling is necessary for the negative regulation of lean tissue mass and treatment with a non-signaling, decoy ActRIIB results in a robust increase in lean tissue mass. Methods: Similar to ADT patients, orchiectomized (ORX) mice lose bone and lean mass and gain fat mass. To determine the therapeutic potential of inhibiting ActRIIB signaling to reduce the negative effects associated with ADT, we treated sham-operated (SHAM) and orchiectomized (ORX) mice with RAP-031, a fusion protein comprised of a form of the extracellular domain of ActRIIB linked to a murine Fc. Mice received twice weekly injections for 10 weeks with either vehicle (VEH) or 10 mg/kg RAP-031 (RAP). NMR scanning was used to determine body composition and whole body DEXA scans were performed to determine bone mineral density (BMD). Results: ORX resulted in a 4.4% decrease in BMD, an 18% reduction in lean tissue and a 41.6% increase in adiposity compared to the VEH-SHAM cohort. Both RAP-031treated groups of mice had significantly increased BMD and lean tissue mass and decreased adipose mass compared to their respective VEH groups. However, BMD, lean tissue and adiposity were not significantly different between the VEH-SHAM and RAP-ORX groups. These data illustrate that RAP-031 treatment completely attenuates ORX-induced alterations in bone, lean and fat mass. Conclusions: These data support the hypothesis that treatment with a form of soluble ActRIIB can offset negative side effects of ADT and have significant therapeutic implications for the treatment of patients with prostate cancer.

[Table: see text]

[Table: see text]
Diabetes and the risk of death in men with favorable or high-risk prostate cancer following radiation therapy
Authors: D'Amico A. V. , Braccioforte M. H. , Moran B. J. , Chen M.
Published: August 2020

5157

Background: An increased risk of all cause mortality (ACM) has been observed in patients with cancer who have diabetes mellitus (DM) (JAMA 2008:300:2754–2764). Yet, how a diagnosis of DM affects survival across the risk-strata of men with prostate cancer (PC) remains unknown. Methods: The study cohort comprised 7041 men of median age 69.6 years treated with brachytherapy with or without external beam radiation therapy (RT) between 10/97 and 7/07. Short course neoadjuvant hormonal therapy (HT) was used in men with pubic arch interference in order to make them eligible for brachytherapy. Cox regression multivariable analyses were performed in men with Gleason score 8 to 10 disease and also in men with favorable-risk (low or intermediate) disease to assess whether men with DM were at increased risk for ACM compared to men without DM. The hazard ratios (HR) and 95% Confidence intervals (CI) reported were adjusted for age, extent of RT, history of myocardial infarction (MI), use of HT and known PC prognostic factors. Estimates of PC-specific mortality (PCSM) were estimated using a cumulative incidence method. Results: After a median follow-up of 4.1 years, 544 (8%) men had died. In the 466 men with Gleason score 8 to 10 cancers 31% (22/70) of deaths were from PC and a diagnosis of DM was not associated with an increased risk of ACM (Adjusted HR (AHR): 1.1 [95% CI: 0.6 to 2.2]; p = 0.78). However, as shown in the Table , for the 6575 men with favorable-risk disease where only 10% (49/474) of deaths were from PC, there was an increased risk of ACM (AHR: 1.5 [95% CI: 1.2 to 2.0]; p < 0.001) in men with diabetes as compared to those without diabetes. PCSM estimates were significantly higher (p < 0.001) in men with Gleason 8 to 10 as compared to low or intermediate-risk PC reaching 10% and 1% respectively by 7 years. Conclusions: These data highlight the importance of aggressive management of DM in men with favorable-risk PC where death from PC is unlikely.

[Table: see text]

No significant financial relationships to disclose.
Use of metformin and lifestyle intervention to prevent ADT-related metabolic syndrome in prostate cancer
Authors: Nobes J. P. , Langley S. E. , Laing R. W.
Published: August 2020

5159

Background: The association between androgen deprivation therapy (ADT) for prostate cancer and metabolic syndrome has been reported, with insulin resistance as the key to its development. This is the first study to investigate the effect of metformin and lifestyle changes on the development of ADT-related metabolic syndrome. Methods: Forty men with any stage of prostate cancer, due to receive ADT with a GnRH agonist, were recruited to a prospective randomised pilot study. The control arm comprised 20 patients receiving ADT alone. Men in the intervention arm (n=20) received ADT with 6 months of metformin, a low glycaemic index diet and a regular aerobic exercise programme. All patients were investigated pre-treatment and at 6 months for the metabolic syndrome, insulin resistance, and related biochemical and physical parameters. Results: After 6 months a significant reduction in metabolic syndrome cases (NCEP ATP III definition) was seen in the intervention arm (p=0.042), with an equal number seen in the control arm as at baseline. There was an increase in HDL cholesterol in both arms, which reached greater significance in the intervention arm (p=0.008) than the controls (p=0.015). The table shows an improvement in abdominal girth, weight, body mass index, and systolic blood pressure in the intervention arm, when measured as a % change over 6 months. Biochemical markers of insulin resistance did not significantly differ between each group. Conclusions: ADT is widely used in prostate cancer, but metabolic complications may be responsible for an increased cardiovascular mortality. The preventative role of metformin and lifestyle changes has been evaluated in this study, showing potential beneficial effects. However, the anticipated increased incidence of insulin resistance and metabolic syndrome has not been demonstrated in men receiving ADT alone, which may be due to small study size. Further studies will ascertain whether overall survival can ultimately be improved by this approach.

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No significant financial relationships to disclose.
Efficacy of docetaxel in metastatic, castration-resistant prostate cancer (mCRPC): Comparison with therapeutic standards in other solid tumors
Authors: Pappagallo G. L. , Spatafora S. , Bari M. , Sartori D. , Vinante O.
Published: August 2020

5167

Background: Difference of opinion exists between urologists and oncologists as to what constitutes a beneficial survival advantage from a drug. Therefore, the aim of this analysis was to consider the efficacy of docetaxel (DOC) in the treatment of mCRPC as compared with the efficacy results previously observed in breast cancer (BC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: A systematic review (Review Manager 5, Cochrane Collaboration, 2008) of the phase III studies which defined the new standard approaches in the 1st-line cytotoxic chemotherapy of metastatic disease for the above mentioned neoplasms was conducted. The relative efficacy of taxane combinations (TAX) in BC, cisplatin-based doublets (DDP) in NSCLC, 5FU/LV-oxaliplatin (FOLFOX) in CRC and DOC-based combinations in mCRPC were calculated. Efficacy parameters for the present analysis were: a) odds ratio for death (fixed method) and: b) NNT[odds ratio], e.g. the number of patients you need to treat to prevent one additional death, as compared with the control group; the NNT (odds ratio) is (1-(pc*(1-OR))/((1-pc)*pc*(1-OR)), where pc is the proportion of death events in the control arm and OR is the odds ratio for death. Results: BC (4 studies, 1313 patients), TAX vs non TAX: OR 0.84 (95% CL 0.66 1.07), NNT (odds ratio) at 5 years = 28. NSCLC (9 studies, 4671 patients), DDP vs non DDP: OR 0.83 (95% CL 0.74 0.94), NNT (odds ratio) at 1 year = 23. CRC (3 studies, 1256 patients), FOLFOX vs non FOLFOX: OR 0.72 (95% CL 0.54 0.98), NNT (odds ratio) at 5 years = 22. mCRPC (2 studies, 1439 patients), DOC vs non DOC: OR 0.78 (95%CL 0.63 0.96), NNT (odds ratio) at 3 years = 16. Conclusions: TAX in BC, DDP in NSCLC and FOLFOX in CRC are the 1st choice cytotoxic approach to metastatic disease, with relative reductions in the risk of death (RRR) of 16%, 17% and 28%, respectively; thus, you will need to treat 28, 23 and 22 patients to prevent one additional death, in the order. DOC had a similar RRR (22%) and the most favourable (16 patients) NNT (odds ratio) in this analysis. Both the quality of evidence and the small number of patients to treat with DOC to avoid one additional death did recommend this chemotherapy in 1st-line mCRPC.

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C-reactive protein as adverse prognostic marker for men with castration-resistant prostate cancer (CRPC): Confirmatory results
Authors: Prins R. , Rademacher B. L. , Mongoue-Tchokote S. , Eilers K. M. , Beer T. M.
Published: August 2020

5168

Background: We previously reported that higher serum concentrations of C-reactive protein (CRP) are associated with shorter survival in men with metastatic CRPC treated with docetaxel-containing chemotherapy. We sought to confirm these hypothesis-generating findings in an independent data set. Methods: Baseline samples were stored (-80ºC) from 119 CRPC patients enrolled in 6 phase I or II clinical trials of chemotherapy as well as non-cytotoxic agents conducted at OHSU. 91% of patients had metastases and 9% had PSA-only disease. 16% had prior chemotherapy exposure. Median follow-up is 19.7 months (0.9–98.5 months) and 89% have died. In addition to CRP, we examined alkaline phosphatase, hemoglobin, age, ECOG PS, and PSA collected at study entry. After examining the form of the risk function using the generalized additive model method, univariate and multivariate Cox proportional hazard models were used to assess associations between baseline individual categorical and continuous variables. Results: Quartiles of CRP were: 1: 0–1.0, 1.1–4.9, 5.0–17.0, and 17.1 to 311 mg/L, somewhat lower than in our previous study. In a Cox multivariate model, log2(CRP) (HR 1.09 p = 0.036) as well as hemoglobin and log2(Alk Phos) were independently associated with survival. Thus, the risk of death increased 8.7% for every doubling of CRP. Conclusions: In an independent data set from patients with CRPC, we confirmed that higher baseline CRP is associated with shorter survival. This readily measurable biomarker has the potential to improve prognostic models and should be validated in a prospective clinical trial. This finding also suggests that inflammation may play an important role in the natural history of advanced prostate cancer. Additional studies of the mechanisms that may explain the inverse relationship between CRP and survival are under way.

No significant financial relationships to disclose.
Early determination of metastatic potential in breast cancer: The 70-gene signature in small tumors
Authors: Knauer M. , Mook S. , Retèl V. , Kok M. , Wesseling J. , Glas A. M. , Rutgers E. J. , van 't Veer L. J. , Linn S. C.
Published: August 2020

518

Background: Small breast cancers are often considered as low risk tumors in clinico-pathologic risk assessment and treatment guidelines. However, since the ability to metastasize is an early and inherent genetic property of breast cancer and consequently even small tumors can metastasize, identification of prognostic subgroups for patients with small tumors would help to optimize treatment strategies. In the present study the 70-gene prognosis signature (MammaPrint), validated as independent prognostic indicator for node-negative and positive patients, was used to assess prognosis for pT1 breast cancer. Methods: 965 tumor samples of women with pT1 breast cancer from 7 previously reported studies were analyzed and classified by MammaPrint as good or poor prognosis. 10-year distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) was analyzed according to the 70-gene prognosis signature separately for pT1a/b (1–10mm) and pT1c (11–20mm) tumors. Results: Median follow-up was 7.1 years (range 0.2–25.2). 526 of 965 patients (55%) were classified as good prognosis and 439 (45%) as poor prognosis by the 70-gene signature. 562 patients (59%) received no adjuvant treatment, 19% received hormonal treatment only, 10% chemotherapy only and 12% both respectively. The 70-gene signature accurately predicted differences in 10-year DDFS (HR 2.7 [1.9–3.9], p<0.01) and BCSS (HR 4.0 [2.6–6.3], p<0.01) for all T1 tumors. Similar results were obtained by multivariate analysis for all patients, adjusted for known prognostic factors and adjuvant therapy, as well as for adjuvant untreated patients. At 10 years, for small pT1a/b tumors (n=140), DDFS was 93% vs. 78% for the good and poor prognosis groups (HR 3.9 [1.0–15.2], p=0.048), while in the T1c group (n=825) DDFS was 86% vs. 72% (HR 2.6 [1.8–4.0], p<0.01). BCSS was 87% vs. 73% for the good and poor prognosis groups in the T1a/b group (HR 2.4 [0.8–7.7], p=0.128) and 92% vs. 72% (HR 4.4 [2.7–7.1], p<0.01) in T1c tumors, respectively. Conclusions: The 70-gene signature is a strong and independent prognostic indicator also in small breast tumors. Patients with T1a/b or T1c tumors and a genomic high risk gene signature for developing distant metastases may be selected for additional adjuvant hormonal and chemotherapy.

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Association of the fibroblast growth factor receptor-4 (FGFR4) Gly388Arg polymorphism with clinical and pathological response to primary systemic therapy (PST) for early breast cancer (EBC)
Authors: Marme F. , Sohn C. , Burwinkel B. , Sinn P. , Hahn M. , Lichter P. , Benner A. , Schneeweiss A.
Published: August 2020

525

Background: The FGFR4 Arg388 genotype has recently been shown to be associated with decreased disease free survival after adjuvant systemic therapy for EBC and thus therapy resistance (Harbeck et al, J Clin Oncol. 2006). Primary systemic therapy (PST) for EBC allows in-vivo chemosensitivity testing. Pathological complete response (pCR) in the breast following PST is associated with improved survival. We evaluated the FGFR4 Gly388Arg polymorphism as a predictive factor for response to PST for EBC in the setting of a prospective, randomized phase 2 trial. Methods: Patients (pts, n = 257) with T2–4/N0–2/M0 EBC were randomized to 4 cycles (cy) A 60 mg/m2 + C 600 mg/m2 day (d) 1 every three weeks (q3w) followed by 4 cy D 100 mg/m2 d1 q3w, or 4 cy A 60 mg/m2 + P 500 mg/m2 on d1 q3w followed by 4 cy D 100 mg/m2 d1 q3w, stratified by hormone receptor (HR) status. Surgery was performed after last chemotherapy. Genotyping was performed using a Taqman Genotyping assay. The genotype was confirmed by RFLP-PCR for 50% of samples with 100% congruence. Results: Genotype was available for 252 of 257 pts enrolled into this study. Using Fisher´s Exact Test there was no correlation between genotype and clinical tumour size (cT), HR status, HER2neu status, grading, menopausal status or triple negative phenotype. The G/G genotype correlates significantly with clinically positive axillary lymph nodes before chemotherapy (p = 0.03). Considering all pts the G/G genotype (vs G/A + A/A) is associated with a significantly lower overall response rate (ORR)(OR 0,47; 65% vs 80%; p = 0.03). Separate analysis of treatment arms showed a significant correlation between the G/G genotype (vs other genotypes) and a lower pCR rate (OR 0.33; 12.5% vs 30.4%; p = 0.04), clinical complete response (p = 0.02) and ORR (OR 0.25; p = 0.01) in the AC-D arm, whereas there was no correlation for pts treated with AP-D. Conclusions: This study provides important evidence that the FGFR4 genotype might serve as a valuable predicitve marker for response to PST with AC-D for EBC.

No significant financial relationships to disclose.
What is the optimal strategy to confirm the diagnosis of epithelial ovarian carcinoma (EOC) prior to neoadjuvant chemotherapy (NAC)?
Authors: Dodge J. E. , Mackay H. , Klachook S. , Bernardini M. , Shaw P. , Murphy K. J. , Lo E. , Rosen B. P. , Freedman O.
Published: August 2020

5511

Background: NAC has been increasingly utilized in clinical practice yet no standard diagnostic strategy has been defined for EOC prior to the administration of NAC. We reviewed the diagnostic process for patients receiving NAC at our centre to determine if an optimal diagnostic strategy could be determined. Methods: A retrospective chart review of all patients known to receive NAC followed by cytoreductive surgery for presumed EOC between 1994 and 2007 was performed. Diagnostic strategies were defined as histology, cytology, and clinical. Performance of these strategies in predicting final pathology, based on expert pathology review of surgery specimens, was compared using Fisher's exact test. Results: 152 patients were included. Initial diagnosis was made on the basis of: cytology (paracentesis/thoracentesis)- 89 (59%); percutaneous biopsy- 40 (26%), radiology and CA-125–18 (12%), surgical biopsy -5 (3%). The final diagnosis was consistent with invasive EOC in 145 patients (95%). The remaining 7 were ovarian LMP (4), ovarian carcinosarcoma (1), endometrial serous cancer (1), and GI tumor (1). The diagnostic accuracies of the 3 strategies differed: histology (43/45), cytology (87/89), and clinical (15/18), p = 0.039. 17% of patients had an alternate final diagnosis when clinical parameters were the only basis for the diagnosis of EOC prior to NAC. A specific EOC subtype was identified pre-op in 82 patients (histology-31 cases, cytology-51 cases). Subtype differed between pre- and post-treatment samples in 13% of histology and 8% of cytology cases. Conclusions: Diagnosis of EOC based on cytology or histology-based strategies are superior to clinical factors alone. Even in a centre with trained gynecologic cytopathologists, cytology and biopsy strategies preclude accurate subtype diagnosis in a significant number of patients. These data are important for clinical practice and the design of future clinical trials.

No significant financial relationships to disclose.
Predictors for optimal cytoreduction following neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma
Authors: de Jong D. , Dodge J. E. , Freedman O. , Lo E. , Rosen B. P. , Mackay H.
Published: August 2020

5512

Background: Neoadjuvant chemotherapy (NAC) is increasingly used to treat patients (pts) with presumed advanced-stage epithelial ovarian cancer (EOC) who are deemed ineligible for upfront debulking surgery (DS). DS following NAC offers a survival benefit to those pts in whom optimal cytoreduction (< 1 cm residual tumor) is achieved. However, not all women who commence NAC have a subsequent attempt at DS. The aims of this study were to identify, in pts planned for NAC, predictive parameters for attempting DS and for achieving optimal cytoreduction in those undergoing surgery. Methods: Pts with presumed stage IIIC or IV EOC who started NAC between 1998 and 2004 were selected for chart review from our institutional ovarian cancer database. Pts with synchronous primary tumors or final pathology inconsistent with EOC were excluded. Age, presence of ascites, Pre NAC hemoglobin (Hb), platelet count (Pls), and CA-125 were explored as possible predictors of attempting DS and of optimal cytoreduction using Kruskal-Wallis analysis and multivariate regression analysis with backward elimination. Results: 212 pts met inclusion criteria. 164 pts (77.4%) had an attempt at DS after NAC; of these 109 pts (66.4%) were optimally cytoreduced. Age and pre-NAC Pls were independent predictors for attempting DS. Median age of pts undergoing DS was 65 years (range 42–82 yrs) compared to 77 yrs (range 54–89 yrs) in those in whom there was no DS attempt, p < 0.01. Median pre NAC Pls of pts undergoing DS was 398 (range 220–685) *109/L, compared to 298 (178–519) for those not proceeding to DS, p < 0.001. Pre NAC Hb, CA125, and ascites were not predictors of DS. Among pts undergoing DS, age was the only independent predictor of optimal cytoreduction identified: median age of pts (optimal vs. suboptimal cytoreduction) was 57yrs (range 42–73 yrs) vs. 67 yrs (49–82yrs), p < 0.001. Presence of ascites, pre-NAC Hb, pre-NAC Pls, and pre-NAC CA-125 were not predictors of optimal cytoreduction. Conclusions: At our centre, pt age and pre-NAC Pls are independent predictors for attempting DS following NAC for advanced stage EOC. In pts undergoing DS age was the only independent predictor of optimal cytoreduction identified. Further investigation of these findings is warranted.

No significant financial relationships to disclose.