bluuebunny/crossref_metadata_2025 huggingface dataset:
Damage of bone metabolism and osteoporosis in testicular cancer patients
Authors: Mardiak J. , Ondrus D. , Spanikova B. , Ostatnikova B.
Published: March 2020

5052

Background: Improved survival of testicular cancer (TC) patients leads to rising of interest on late toxicity. Treatment-related bone loss is well recognized in breast and prostate cancer, but there has been little information in long-term survivors from other tumors. The aim of the study was to assign the damage of bone metabolism in TC patients. Materials: Bone mineral density (BMD) was measured by dual energy photon x-ray absorptiometry in the lumbar spine and hips. BMD was classified as osteopenia (T score ranging from -1 to -2,5) and osteoporosis (T score less -2,5). C-terminal cross-linked telopeptides of type I collagen (CTX) were measured using ELISA. Additionally serum total testosterone was measured. Comparison was made with matched control data. Relationships between baseline characteristics (age, treatment type and time from orchiectomy) and BMD were assessed using univariate and multivariate analysis tools. Results: We included 257 patients in the study (17 - 72 yrs old, median: 36 yrs) who were treated for GCT since 1982. 29 (11%) of them had bilateral orchiectomy (OE) due to bilateral TC. 23% of pts were treated by OE alone, 17% by subsequent radiotherapy of para-aortic field and 59% by subsequent chemotherapy. Median time since the OE was 4 years (1–36 yrs). Pts after bilateral OE had significantly lower BMD comparing with pts with unilateral OE. We didn’t find any differences between TC pts and matched control data regarding incidence of osteopenia and CTX, but the incidence of osteoporosis was considerably higher in TC pts. The incidence of osteoporosis appeared to increase with age and slightly correlated with time since OE, particularly after 10 years after OE. Type of therapy did not prove to have significant impact on the appearance of osteoporosis. Serum testosterone level did not correlate with BMD. Conclusion: The long term survivors from GCP have significantly higher risk of osteoporosis than healthy matched population.

No significant financial relationships to disclose.
Bone abnormalities in male germ-cell cancer survivors
Authors: Willemse P. M. , van Wulften L. , van Steijn A. Q. , Hamdy N. A. , Osanto S.
Published: March 2020

5053

Background: Survival of men with testicular cancer is long due to successful therapeutic intervention, which usually includes orchidectomy. Therefore, we studied the prevalence of osteoporosis in a single center cohort of long term survivors of germ cell cancer. Methods: In a cross-sectional study design, we studied 186 male patients with a mean age of 39.6 years (range 18.1–66.8), who were treated between 1977 and 2006 for germ cell cancer. 181 (97.3%) patients underwent an unilateral, 3 (1.6%) a bilateral orchidectomy and in 2 (1.1%) patients no orchidectomy but retroperitoneal or mediastinal tumor biopsy was performed to confirm the diagnosis. 141 (75.8%) patients received cisplatin-based combination chemotherapy for metastases or primary extra-gonadal tumor at a mean age of 29.4 years (range 14.2- 62.6). Between 2003 and 2006, bone mineral density (BMD) was measured at the lumbar spine and femoral neck by DXA and Z-scores calculated. Vertebral deformities were evaluated by a semi-quantitative measurement on lateral x-rays of the spine. Non-vertebral fractures were evaluated by questionnaire and confirmed by x-ray. All patients had normal total testosterone, estradiol, parathyroid hormone, 25(OH)- vitamin D and 1,25(OH)2-vitamin D concentrations, evaluated by fasting blood samples. Results: BMD was low in 59 (31.7%) patients; 46 (24.7%) patients had Z-scores between -1 and -2 SD, while thirteen (7.0%) had Z-scores below -2 SD. Vertebral deformities were present in 57 of 151 (37.7 %) evaluated patients, sixteen of whom also had low BMD. There was no relationship between vertebral deformities and either age, chemotherapy or testosterone/estradiol levels. No correlation was found between vertebral deformities and low BMD. Eight of 114 (7.0%) patients who responded to the questionnaire had non-vertebral fractures at a mean age of 44.9 years (range 33.1–54.2); 1–17 years after the initial diagnosis of testicular cancer. Conclusions: More than one third of the eugonadal male survivors of germ cell cancer survivors have vertebral abnormalities which are not related to age, chemotherapy or genital hormone concentrations. The underlying mechanism remains unknown. This high prevalence of bone abnormalities indicates that screening should be advocated in all germ cell cancer survivors.

No significant financial relationships to disclose.
Coordinated modulation of sonic hedgehog (Shh) signaling and androgen receptor (AR) in the prostate tumor microenvironment by chemo-hormonal therapy
Authors: Efstathiou E. , Troncoso P. , Wen S. , Do K. , Pettaway C. A. , Logothetis C. J.
Published: March 2020

5066

Background: Shh and androgen signaling are implicated experimentally in prostate development, regeneration and neoplastic progression. We assessed expression of components of these pathways in pretreated and control high risk prostate cancers (PCa) in a hypothesis generating search for an association with resistance to therapy. Methods: Sixty-four men with high risk PCa were randomized to receive either complete androgen ablation (AA) or AA and ketoconazole, adriamycin, vinblastine and estramustine (KAVE) for 16 weeks followed by radical prostatectomy (RP). We constructed 3 tissue microarrays from RP specimens of: a) (AA) 26 men pretreated with AA, b) (CH) 27 men pretreated with AA + KAVE and c) (Control) 26 untreated men matched for clinical stage, biopsy Gleason Score and PSA. A total of 3,178 cores were obtained [median cores: 36 (range 18–90), median blocks: 5 (range 3–9) per specimen]. Immunohistochemical expression of Shh pathway components (Shh, patched, smoothened, gli2) and AR were assessed in the tumor epithelium and stroma and recorded as percentage of cells exhibiting staining. A mixed model was used for fitting the correlated data (multiple observations from a subject). Pearson’s correlations between biomarkers were calculated based on mean expression. Results: Shh signaling, as indicated by mean expression (standard deviation) of nuclear gli2, was observed in the residual tumor epithelium [AA: 79.9 (17.4), CH: 85.7 (12.2)] and adjacent stroma [ AA: 43 (18.2),CH: 53 (16.4)] following treatment, in parallel (0.78 by Pearson’s correlation), and higher than in untreated control tumor epithelium [39.9 (20.6)] and stroma [22.9 (15.2)] (P<.0001). Smoothened and Shh were expressed accordingly. AR expression was lower in the treated tumor epithelium [AA: 47.3 (20.8), CH: 46.8 (21.1)] (P<.0001), with a trend toward increased stromal AR [AA: 8.6 (10.4), CH: 10.5 (8.2)] compared to control tumor epithelium [60.1 (24.1)] and stroma [6.4 (11.7)]. Conclusions: Shh and androgen pathways are modulated in a manner that suggests they behave in a compensatory fashion, and are determinants of response to therapy. These data support the hypothesis that the tumor microenvironment is implicated in PCa therapy resistance.

No significant financial relationships to disclose.
MRI of the breast before and after primary systemic therapy correlates with histopathological tumor size in patients with locally advanced breast cancer (LABC)
Authors: Russu V. , Lex B. , Popovich M. , Pfaffenberger K. , Volkholz H. , Tulusan A.
Published: March 2020

507

Background: Primary systemic therapy (PST) is a widely accepted preoperative treatment for patients with locally advanced breast cancer (LABC). Different authors beside our study-group showed that MRI is a sensitive method in describing the remaining size of an invasive breast lesion after PST. The established methods for measuring the size of lesions and monitoring the tumour-response to chemotherapy are clinical palpation, mammography and ultrasound, but specificity of these methods is unsatisfactory. Our prospective data is to clarify the accuracy of MRI in monitoring the tumour-response to PST is presented. Methods: 207 female patients (range of age: 26a- 78a) with LABC (cT2 â€“ cT4) were examined with dynamic contrast enhanced MRI after PST. 173 (84%) patients have had MRI examination before and after PST. 145 (70%) patients had a ductal-invasive, 48 (23%) patients a lobular-invasive carcinoma. 70 (34%) patients were treated with sequential anthracyclin- and taxan-based chemotherapy and 137(66%) with only anthracyclin based chemotherapy. 51% patients were premenopausal. 70% had an ER-positive tumour. The measure of tumour-response to PST was graded in partial response (PR: >50% of tumour reduction mm2), no change (NC: <50%) and complete response (CR: no evidence of residual tumour-cells). Results: Comparing tumour-size measured by MRI before and after PST 119 (69 %) of the patients had PR and 25 (14.5%) CR. The histological tumour- size after PST strongly correlated with the size measured by MRI r = 0,758 (pâ€1 0.001). Analyzing the tumour-types ductal-invasive carcinomas were significant (p<0.001) better to monitor than lobular-invasive types (r=0.824/r=0.210). Conclusions: preoperative MRI seems to be a helpful tool in estimating the efficacy of the tumour-response to chemotherapy and for the operative planning in the patients with LABC after PST, especially for ductal-invasive tumours.

No significant financial relationships to disclose.
Efficacy of neo-adjuvant gemcitabine plus cisplatin (GC) in muscle-invasive urothelial cancer (UC)
Authors: Dash A. , Pettus J. A. , Bochner B. H. , Dalbagni G. , Donat S. M. , Herr H. W. , Bajorin D. F.
Published: March 2020

5077

Background: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) plus radical cystectomy (RC) improves survival over cystectomy alone in urothelial cancer (UC); survival is greatest for patients achieving either pT0 or = pT1 after chemotherapy. GC is less toxic and achieves a similar response and survival to MVAC in metastatic UC, but is untested as neoadjuvant therapy. This study compared GC-induced pathological response in the bladder to that seen with neoadjuvant MVAC in an historic control series (1983–88) at our center (JCO 12:1394, 1994). Methods: We retrospectively reviewed records from muscle-invasive UC patients who received neoadjuvant chemotherapy from 11/2000 to 5/2006; 43 received GC (planned 4 cycles) followed by RC. Post-chemotherapy pathologic response was compared to neoadjuvant MVAC pts (planned 4 cycles) but whose post-chemotherapy surgery varied by surgeon’s discretion. 34 of 111 MVAC patients underwent post-chemotherapy RC and an additional 21 patients underwent partial cystectomy (PC). Pathologic outcomes of the GC cohort were compared to MVAC patients that underwent either RC (n=34) or to either RC or PC (n=55). IRB approval was obtained. Results: Baseline characteristics and treatment results were similar for both groups. The median time from start of GC chemotherapy to RC was 141 days (IQ range 123–155). Start of MVAC to RC (n=34) was 95 days (IQ range 76–163) and to either RC or PC (n=55) was 119 days (IQ range 89–175). Achieving = pT1 was similar for GC (15/43; 35%, 95% CI 21–51%) and MVAC followed by RC (6/34; 18%, 95% CI 7–35) or MVAC followed by either RC or PC (20/55; 36%, 95% CI 24–50). Achieving pT0 for GC patients (11/43; 26%, 95% CI 14–41) was also similar to MVAC plus RC (5/34; 15%, 95% CI 5–31) and MVAC plus either RC or PC (15/55; 27%, 95% CI 16–41). Conclusions: Neoadjuvant GC is similar to MVAC in both pathologic response in the bladder and time to cystectomy. The efficacy and tolerance of neoadjuvant GC warrants further study to assess overall survival.

No significant financial relationships to disclose.
Combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel in patients with cisplatin-refractory or relapsed germ cell tumors (gct)
Authors: Oechsle K. , Bokemeyer C. , Honecker F. , Mayer F. , Waller C. F. , Boehlke I. , Hartmann J. T. , Kollmannsberger C.
Published: March 2020

5084

Background: Treatment of pts with cisplatin-refractory GCT remains a therapeutic challenge. The present phase II study investigates the toxicity and activity of triple combination of gemcitabine/oxaliplatin/paclitaxel (GOP) in pts with multiple relapse or cisplatin- refractory GCT. Patients and Methods: Between 04/03 - 10/06, 41 patients (pts) refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy plus autologous peripheral blood stem cell transplantation (PBSCT) received 800 mg/m2gemcitabine, 80 mg/m2 paclitaxel, both on days 1+8, and oxaliplatin 130 mg/m2 on day 1 of a three week cycle for at least 2 cycles. Treatment was continued until tumor progression or a maximum of 8 cycles. Results: Pts were pretreated with a median number of 2 previous lines of platin-based chemotherapy (range, 1 - 3) and 78 % had relapsed after either first- (39%) or second-line high-dose chemotherapy (39%) with PBSCT. Responses: 5% of the pts achieved a complete response (CR), 47% a partial response and 20% a disease stabilisation. 20% of the pts underwent a secondary complete tumor resection resulting in a total NED-rate of 22%. After a median follow up time of 5 months (mos) (0 - 20+) 17% of the pts are continuously disease-free with a median response duration of 8 mos (1–17+). Median progression free and overall survival was 3 mos (1–17+) and 6 mos (1–19+), respectively. Toxicity was acceptable. 51% of 150 cycles could be applied without dose modifications or delay. Leucocytopenia grade 3/4 was observed in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients. Grade 3/4 nonhematologic toxicities (diarrhoea, nausea and neurotoxicity) occurred in one patient each (2%). Conclusion: The triple combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel is feasible and effective in patients with cisplatin-refractory or multiply relapsed germ cell tumors exhibiting an overall response rate of >50% and prolonged survival in about 20% of the pts. Despite a significant rate of grade 3/4 thrombocytopenia the overall toxicity profile is acceptable.

No significant financial relationships to disclose.
Sunitinib malate (SU) plus interferon (IFN) in first line metastatic renal cell cancer (mRCC): Results of a dose-finding study
Authors: Kondagunta G. V. , Hudes G. R. , Figlin R. , Wilding G. , Hariharan S. , Kempin S. N. , Fayyad R. , Hoosen S. , Motzer R. J.
Published: March 2020

5101

Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs with anti-tumor activity in mRCC patients previously treated with cytokines (JAMA, 2006;295:2516). A phase 3 randomized trial showed superiority for SU over IFN in first-line mRCC (PROC ASCO 24,18S, 2006). Dose and safety for SU combined with IFN was investigated in this phase I trial. Methods: Patients (pts) with previously untreated clear-cell mRCC received SU in repeated 6-week cycles of 50 or 37.5 mg/day orally for 4 weeks, followed by 2 weeks off treatment. IFN was given continuously, starting at 3 MU SC 3x/week with intrapatient dose escalation weekly as tolerated, to a maximum of 9 MU. Pts not tolerating a dose combination received lower doses of SU or IFN, or had dose interruptions. Doses of SU plus IFN were considered tolerable if = 4/6 pts completed 2 cycles without dose reduction or interruption. Results: 25 pts were enrolled; 19 are evaluable for safety/response. 6 pts who started treatment at 37.5 SU and 3 MU IFN are too early. The median age of the 19 pts (16 M: 3 F) was 63 years (range 45–77). MSKCC risk group (JCO 20:289–96, 2002) was 37% good and 63% intermediate. 12 pts started treatment with SU 50 mg and dose escalated IFN to 6 or 9 MU TIW. 13 pts started treatment with SU 37.5 mg and dose escalated IFN at 3 MU or to 6 MU TIW. 4 of 19 pts tolerated two cycles. 68% of pts had dose interruptions of SU; 90% of pts had dose interruptions of IFN. 15/19 pts had grade 3 toxicity, 1 pt had grade 4 hypertension and 1 pt grade 5 toxicity (myocardial infarction). Most common grade 3 toxicities were neutropenia (26%), fatigue (26%), and hand-foot syndrome (16%). Although response was not a primary endpoint, at a median of 3 cycles, there were 2 PR, 14 SD, 2 PD and 1 pt was not evaluable. Conclusions: The adverse events seen with combination SU and IFN in mRCC, neutropenia and fatigue, were similar to those seen with single agent SU and IFN, and resulted in frequent dose modifications and interruptions. The safety and efficacy of 37.5 mg sunitinib and 3 MU IFN is being evaluated.

No significant financial relationships to disclose.
Randomized phase II study of sorafenib with or without low-dose IFN in patients with metastatic renal cell carcinoma
Authors: Jonasch E. , Corn P. , Ashe R. G. , Do K. , Tannir N. M.
Published: March 2020

5104

Background: An 80 patient randomized open label phase II study is underway evaluating the safety and clinical benefit of sorafenib with or without low-dose interferon (LD IFN) in patients with untreated metastatic conventional (clear cell) renal cell carcinoma (mRCC). Prior studies combining sorafenib and conventional dose IFN demonstrated a response rate (RR) in the 20–30 percent range, higher than the 2–10 percent RR seen with sorafenib monotherapy, but with increased toxicity. Prior data suggest equivalent efficacy between LD and conventional dose IFN with fewer side effects. We postulated that low-dose IFN will add to the clinical benefit of sorafenib in patients with mRCC with minimal additional toxicity. Methods: Eligibility included conventional mRCC, measurable disease, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. Patients were treated with sorafenib 400mg PO BID or sorafenib at the same dose plus interferon alfa 0.5 million units SC BID. Primary endpoints included response rate and progression free survival (PFS). The probabilities of PFS and overall survival (OS) were estimated for each arm using Kaplan-Meier methods. Median PFS and OS were summarized, along with the 95% confidence intervals for each arm separately. Results: A total of 60 patients were enrolled as of January 8, 2007. Five patients were inevaluable, and 5 patients had not undergone first restaging. Treatment was well tolerated in both groups. Best response and PFS are summarized below. In the sorafenib arm, 13 out of 25 patients progressed or died. The median time to progression was 9.3 months (95% CI 5.8- not reached). In the sorafenib + IFN arm, 13 out of 25 patients progressed or died. Median time to progression was 9.3 months (95% CI 5.2- not reached). Median OS was not reached in either arm. Conclusions: These findings, although preliminary, suggest that adding low dose interferon therapy to sorafenib therapy does not provide superior cytoreduction of metastatic RCC, but provides equivalent PFS.

[Table: see text]

No significant financial relationships to disclose.
Cardiac involvement in patients with sorafenib or sunitinib treatment for metastatic renal cell carcinoma
Authors: Schmidinger M. , Vogl U. M. , Schukro C. , Bojic A. , Bojic M. , Schmidinger H. , Zielinski C. C.
Published: March 2020

5110

Background: Tyrosine-kinase inhibitors (TKI) of the VEGF and PDGF-receptor have significant clinical activity in patients with renal cell carcinoma (RCC). These agents target the VHL-hypoxia-inducible gene pathway and lead to inhibition of hypoxia- inducible factor (HIF)-induced gene products. Physiologically, HIF-1 related gene products are important mediators of myocardial response to ischemia, myocardial remodeling, peri-infarct vascularisation and vascular permeability. The aim of this prospective observational study was to investigate clinical and biochemical signs of myocardial damage in patients undergoing TKI-treatment for RCC. Methods: 73 consecutive patients (median age 65, range 44–68) intended for TKI treatment were analyzed for medical history of coronary artery disease (CAD) and risk-factors. Measurements of biochemical markers of cardiac damage (creatine kinase MB -CK-MB- and cardiac troponin T -cTNT-) and electrocardiogram (ECG) were performed before treatment. In patients developing cardiac symptoms during TKI treatment and/or at occurrence of CK-MB or TNT elevations, changes in ECG were analyzed and patients underwent echocardiography. Results: All patients had normal CK-MB and TNT levels at baseline. 17 patients (23%) developed (week 2–32 of treatment) significant CK-MB elevation, (TNT n=5), with clinical symptoms in 7 patients. No patient had uncontrolled hypertension. Detailed ECG’s comparison before and during treatment revealed significant changes in 10 out of 17 patients, such as ST-segment depression or elevation, T-wave changes and symptomatic AV-conduction disturbance, requiring pacemaker-implantation. 3 patients underwent coronary angiography with one patient showing acute coronary artery occlusion and myocardial infarction. 6 out of 17 patients had abnormal findings on echocardiography, such as reduced left ventricular function Conclusions: TKI-induced HIF-inhibition may be associated with severe myocardial damage. The underlying mechanism may not necessarily be caused by overt coronary artery occlusion. ECG-changes and biochemical markers are the most important indicators in the preclinical stage. Therefore, careful cardiac monitoring during TKI-treatment is strongly recommended.

No significant financial relationships to disclose.
Cost effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma in Canada
Authors: Jaszewski B. , Gao X. , Reddy P. , Bhardwaj T. , Bjarnason G. , Finelli A. , Kapoor A. , Abugaber A.
Published: March 2020

5111

Background: Sorafenib is an oral multi-kinase inhibitor that targets tumour cell proliferation and tumour angiogenesis. In the TARGETs study (phase III trial), sorafenib plus best supportive care (BSC) significantly prolonged progression-free survival (PFS) compared with BSC alone (P<0.000001) in patients with advanced renal cell carcinoma (RCC). The objective of this study was to evaluate the costeffectiveness of sorafenib plus BSC versus BSC alone in advanced RCC from a Canadian provincial Ministry of Health perspective. Methods: A Markov model was developed to project the lifetime survival and costs associated with the two treatment groups. The model tracked patients with advanced RCC through three disease states - PFS, progression, and death. Resource utilization included drug, drug administration, physician visits, monitoring, and adverse events. Costs and survival benefits were discounted annually at 5%. Results: The lifetime per patient costs were $62,426 CDN and $18,898 CDN for sorafenib + BSC and BSC alone, respectively. The life-years gained (LYG) were higher for sorafenib relative to BSC. The incremental cost-effectiveness ratio (ICER) of sorafenib plus BSC versus BSC alone over a lifetime horizon was $36,046/LYG CDN (with a half cycle correction). Univariate sensitivity analyses yielded ICERs below $70,000/LYG CDN. Probabilistic sensitivity analyses showed that the results were moderately sensitive to the clinical variables and less sensitive to the cost variables, yielding ICERs below $100,000/LYG CDN in most cases. Conclusion: Sorafenib is cost effective with an ICER of $36,046/LYG CDN which is below the suggested cost effectiveness threshold of $100,000/QALY ($CDN 1992) or $130,860/QALY ($CDN 2006).

[Table: see text]
Prospective evaluation of carbonic anhydrase IX (CAIX) as a molecular marker in metastatic renal cell carcinoma
Authors: Klatte T. , Zomorodian N. , Kabbinavar F. F. , Belldegrun A. S. , Pantuck A. J.
Published: March 2020

5112

Background: CAIX is an important molecular marker of survival and response to immunotherapy in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to prospectively evaluate the performance of CAIX in patients with metastatic RCC. Methods: This study accrued 32 consecutive patients who were treated for metastatic clear cell RCC between January 2004 and May 2006. Immunohistochemical staining of the primary tumor was performed using the mouse monoclonal antibody MN-75. Patients were stratified into two groups: high CAIX expression (>85%) and low CAIX expression (=85%) according to the percentage of cells staining positive for CAIX. Study endpoints included disease-specific survival time (DSS) and response to treatment according to RECIST criteria. Results: Four (12.5%), 21 (65.6%), and 7 patients (21.9%) were classified into low risk, intermediate risk, and high risk groups according to the University of California Integrated Staging System (UISS). Twenty (62.5%) of the 32 patients had high CAIX expression. The median follow-up was 11.4 months. Patients with low CAIX expression had significantly worse prognosis than patients with high CAIX expression (median survival: 15.2 months vs. not reached, p=0.01, 1-year DSS rate: 63% vs. 83%) and a 3.9 fold increased risk of death from RCC (95% CI, 1.2–12.7). All 4 patients in the low risk UISS group had high CAIX expression, and all were alive at 1 year. Nine patients received high dose IL-2 based immunotherapy, including 8 who had high CAIX expression, and a 1-year DSS rate of 87.5%. Of the patients expressing high CAIX, 3 (37.5%) were responders to IL-2 including 1 partial and 2 complete responses, 3 (37.5%) exhibited stable disease and 2 (25.0%) progressed during treatment. Conclusions: The results of this first prospective study of CAIX in metastatic RCC confirm that high CAIX expression is associated with better survival and enhanced response to IL-2 based immunotherapy. Patients with high CAIX expression, specifically those with low risk RCC, should be considered candidates to receive immunotherapy, whereas patients with low CAIX expression or in higher risk groups may be better candidates for targeted or other experimental therapy.

No significant financial relationships to disclose.
Osteopenia (OP) induced by 6 and 18 months androgen deprivation (AD)
Authors: Ball J.
Published: March 2020

5123

Background: In a trial evaluating the optimal duration of AD in locally advanced prostate cancer (PC) we sought to determine whether 18 months of zoledronate (Zd) would reverse AD induced OP and reduce bony failure. Methods: In the four arm 2x2 TROG 03.04 (RADAR) trial, men with T2b,c-4 and T2a (Gleason score >6, PSA >10) N0 M0 PC (but without osteoporosis) were randomised to leuprotide (Lp) 22.5 mgs i.m. 3 monthly for 6 months starting 5 months prior to radiotherapy (RT) in Arm A, or the same treatment with Zd mgs i.v.i. 3 months for 18 months commencing on Day 1 (in Arms B and D), or with Lp 22.5 mg i.m. 3 monthly for 12 months after RT (in Arms C and D). Hip and spinal bone mineral densities (BMD) were measured before treatment (bt) and then at 2 and 4 years using DEXA and differences between trial arms were assessed by paired t tests. OP was defined by T- scores <-1. Results: Between October 2003 and January 2006, 930 men were randomized. 124 men with BMD measures bt and at 2 years are evaluable. Mean change (±SD) in BMD between 0 and 2 years was -0.005 ±0.05 (p=0.57) in Arm A, 0.085 ±0.06 (p=<0.001) in Arm B, 0.054 ±0.07 (p=<0.001) in Arm C, and 0.065 ±0.05 (p=<0.001) in Arm D. 98 men had normal BMD bt. Of these 6 of 51 in Arms A, C (no Zd) have developed OP at 2 years while none of 47 in Arms B, D (+Zd) have as yet. Conclusions: At 2 years OP caused by 6 months AD is minimal, but remains significant after 18 months AD. This is reversed by 18 months Zd, but further follow up will determine whether this degree of OP resolves with time or causes fractures.

No significant financial relationships to disclose.
Effect of toremifene in lowering total cholesterol, LDL, and triglycerides and raising HDL in prostate cancer patients on androgen deprivation therapy
Authors: Smith M. , Chu F. , Forrest J. , Malkowicz S. B. , Price D. , Sieber P. , Barnette K. G. , Rodriguez D. , Steiner M. S.
Published: March 2020

5124

Introduction: Androgen deprivation therapy (ADT) is the standard treatment for men with advanced prostate cancer. ADT has been shown to detrimentally affect lipids (average 9% increase in total cholesterol and 26% increase in triglycerides) and is associated with increased risk of coronary heart disease and myocardial infarction. Toremifene, a selective estrogen receptor modulator (SERM), improves bone mineral density and lipid profiles in women. An ongoing phase III trial will assess the safety and efficacy of toremifene in treating multiple side effects of ADT including osteoporosis, hot flashes, gynecomastia and lipid profiles. Given the emerging recognition of increased cardiovascular risk during ADT, an interim analysis was conducted to assess the effects of toremifene on lipid profiles in the ongoing phase III study. Methods: 1,392 men = 50 years old with histologically documented prostate cancer and receiving ADT were randomized to toremifene (80 mg/day) or placebo. An interim analysis evaluated changes in lipids from baseline to month 12 in the first 197 subjects to complete one-year follow up. The outcomes measured in this interim analysis were total cholesterol, LDL cholesterol, triglycerides, total cholesterol/HDL ratio, and HDL cholesterol. Results: Compared to treatment with placebo, toremifene decreased total cholesterol (7.1%; p=0.001 for between group comparison), LDL cholesterol (9.0%; p=0.003), and triglycerides (20.1%; p=0.009) levels, and the total cholesterol/HDL ratio (11.7%; p<0.001). Toremifene also significantly increased HDL levels (5.4%; p=0.018) compared to placebo. The effects of toremifene were observed in both statin users and nonusers. Conclusions: Toremifene decreases total cholesterol, LDL cholesterol, and triglycerides and increases HDL cholesterol in men receiving ADT for advanced prostate cancer compared to placebo. Conclusions regarding the clinical significance of these observations will be based on the full cohort of patients at the conclusion of the trial.

No significant financial relationships to disclose.
Cardiac safety in patients (pts) with metastatic breast cancer (MBC) treated with lapatinib (L) and trastuzumab (TRA)
Authors: Storniolo A. M. , Koehler M. , Preston A. , Rappold E. , Byrne J. , Ewer M. S.
Published: March 2020

514

Background: Clearly defined standards for assessing cardiac toxicity do not exist for newer agents used as treatment for BC, e.g., tyrosine kinase inhibitors. To evaluate the usefulness of increased cardiac monitoring and cardiac function (LVEF) in pts treated with L+TRA, data from 4 trials were analyzed. Methods: From July 2003 to Dec 2006, 238 pts received L+TRA (n=203) or L+TRA with paclitaxel or docetaxel (n=35) for HER2-positive MBC. LVEF was evaluated at screening, every 8 weeks after starting L+TRA, and at withdrawal via multiple-gated acquisition scans or echocardiograms. Rate of symptomatic cardiac events (CE; NCI CTCAE Grade 3 or 4 LV systolic dysfunction) or asymptomatic LVEF decreases (=20% relative to baseline and below the institution’s lower limit of normal) were assessed. Results: None of the 238 pts had a symptomatic CE. Four pts had a single asymptomatic LVEF decrease and 1 pt had 2 asymptomatic LVEF decreases, totaling 6 decreases in 5 (2.1%) pts. These pts were women aged 36–64 years and had previously received anthracyclines (A; n=2), A+TRA (n=2), or unknown therapy (n=1). Median time to onset of LVEF decrease was 83 days; all but 1 decrease occurred within 75 days after initiating L+TRA (range: 18–221 days). Baseline LVEFs of 62%, 60%, 62%, 74% and 58% decreased to 47%, 46%, 45%, 45%, and 45%, respectively. L+TRA was temporarily interrupted in 3 pts and continued in 2 pts despite LVEF decrease. Per investigators, LVEF decrease resolved with no further sequelae in 4 pts (59%, 56%, 60%, and 50%) and was ongoing in 1 pt. Conclusion: Initial data indicate L+TRA or L+TRA with taxanes does not constitute a serious incremental cardiac risk and may not require more stringent cardiac monitoring than is used for A or TRA alone. The combined effect of HER2 inhibition with L+TRA appears not to increase the risk of CE in this population.

No significant financial relationships to disclose.
Preoperative platelet-derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation in high-risk localized prostate cancer
Authors: Mathew P. , Pettaway C. , Pisters L. , Williams D. , Troncoso P. , Logothetis C.
Published: March 2020

5141

Background: Reduction in tumor interstitial fluid pressure with platelet-derived growth factor receptor (PDGFR) inhibitor therapy in experimental systems improves drug delivery and the therapeutic index of taxane chemotherapy (Pietras, Cancer Research, 2002). We hypothesized that PDGFR inhibitor therapy with imatinib mesylate combined with androgen ablation (AA) and docetaxel (D) induces pathological complete responses (pCR) in high-risk localized prostate adenocarcinoma (PC) prior to radical prostatectomy and pelvic lymph node dissection (RP). Methods: Thirty six men with PC ≥T2 disease or Gleason grade 8–10 or serum prostate-specific antigen (PSA) > 20 ng/ml or cT2b and PSA >10 ng/ml and Gleason 7 disease (AJCC, 1992), without radiological evidence of metastases, were planned to receive intramuscular leuprolide, imatinib 600mg orally daily, and weekly D 30 mg/m2 on D1, 8, 15, 22 q42 for three cycles (18 weeks) before RP [β (0.02, 1.98) prior on the possibility of pCR]. Unresectable pelvic nodal disease, post-operative PSA > 0.2 ng/ml or administration of post-operative radiation or AA were defined as treatment failure. Results: Between 6–03 and 9–04, 39 men were registered; median age 57 years (range, 44–71); 35 Caucasian, 2 Hispanic, 4 African-American. Risk factors included T3 disease (22/39), Gleason 8–10 disease (31/39), PSA > 20 ng/ml (12/39). Three men were ineligible or declined therapy; 29/36 (80%) received three cycles of therapy; 7/36 (20%) discontinued therapy related to toxicity. Grade 3–4 toxicity included rash (n=3), diarrhea (n=5), fatigue (n=3), neutropenia (n=2), hepatic (n=1). Severe or unexpected surgical complications were not encountered. No pCRs were defined; 15/36 (42%) have PSA < 0.2 ng/ml [12/36 (33%), <0.1 ng/ml] at 24 months and 13/36 (36%) met definition for treatment failure. Conclusions: The addition of the PDGFR inhibitor imatinib to pre-operative AA and D, although feasible, did not induce pCR in PC.

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Is age an independent predictor of clincially significant prostate cancer in a referral population? A case for needle biopsy in the elderly
Authors: Hanson G. , Wright J. , Kim J. , Borden L. S. , Porter C. R.
Published: March 2020

5142

Background: Approximately 232,090 new cases of prostate cancer were diagnosed in the U.S. in 2005. As the population ages and life expectancy increases, physicians will increasingly be faced with patients in their 70’s who can be expected to live for greater than 10 years. Many of these patients are screened for prostate cancer and may ultimately be evaluated by a urologist. Clinically significant prostate cancer is still diagnosed in men in this age group. To address this issue, we evaluated a large prostate biopsy database to assess the nature of prostate cancer diagnosed in elderly men in a referral population. Methods: A prospective database of 790 men who had undergone biopsy by a single urologist (CRP) was reviewed. Demographic data was recorded. Patients with Gleason score 7–10 were defined as having clinically significant disease. Multivariate regression analysis was performed to determine the relationship of increasing age with higher Gleason scores (7–10) on biopsy. We divided our patients into clinically applicable age groups of greater than or equal to 70 and less than 70 years. Results: The mean age of patients was 63.1 years. Men over 70 years old were more likely to have increased mean prostatic volume (P < 0.001), abnormal DRE (P < 0.001) and presence of prostate cancer (P < 0.001). Patients aged 70 or older had more than a three-fold increased risk of Gleason 7 or greater cancer (OR 3.32, p <0.001). An abnormal DRE (OR 3.65, p<0.001) and PSA >10 (OR 4.05, p <0.001) were also independently associated with a statistically significant chance of detecting Gleason 7 or greater cancer. Conclusions: Age is an independent predictor of clinically significant prostate cancer in a referral population. Patients who are 70 years or older with a 10-year life expectancy should be counseled that they are at higher risk of harboring clinically significant prostate cancer and should therefore be considered for prostate needle biopsy.

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No significant financial relationships to disclose.
What is the real impact of bone pain on survival of hormone-refractory prostate cancer (HRPC) patients treated with docetaxel?
Authors: Oudard S. , Banu E. , Medioni J. , Dionysopoulos D. , Cojocarasu O. , Banu A.
Published: March 2020

5149

Background: Docetaxel is currently the standard of care for HRPC patients (pts). The moment of docetaxel initiation according to the presence or absence of the bone pain was less explored. Methods: Eligible HRPC pts were required to have a baseline bone pain evaluation using the rank-scores as follows: no pain or minimal pain (0), mild (1), moderate and severe pain (2), respectively. The main endpoint was to explore the overall survival (OS) impact of the bone pain (presence and intensity) using the Cox regression analysis, stratified by chemotherapy regimen. OS was calculated between start of chemotherapy and death or last follow-up for censored pts. Secondary endpoint was to evaluate the relationship between PSA doubling time (DT) and survival of pts with minimal or no pain. Results: Data of 145 consecutive HRPC pts treated in a single French center were analyzed. Chemotherapy was docetaxel (67%) or mitoxantrone-based. The median age was 68 years and 93% of pts had bone metastases, 55% with minimal or no pain at baseline. Median OS was 17.3 months (95% CI, 14.6–20) and 93% of pts died. There were OS differences between pain categories ( Table ). Pain intensity was significantly related with OS: hazard ratio=1.50 (95% CI, 1.20–1.88), P=0.0001 at the univariate analysis. Multivariate analysis adjusted by ECOG PS, hemoglobin and number of metastatic sites showed a 16% rise of the risk of death for pts with severe and mild pain. Pts with minimal or no pain at baseline have a different outcome depending of PSA DT (≥ 45 and < 45 days): median OS 32.4 months (95% CI, 16.2–48.7) and 16.5 months (95% CI, 10–22.9), respectively. Conclusions: Our results suggest that HRPC pts with minimal or without bone pain can experience a better OS with docetaxel-based therapy. This motivates the use of docetaxel early, before bone pain apparition. The OS benefit was even higher for asymptomatic pts with a longer PSA DT.

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No significant financial relationships to disclose.
A prospective study of carboplatin-etoposide in docetaxel-pretreated patients with hormone-refractory prostate cancer (HRPC): Clinical activity and correlation with neuroendocrine features
Authors: Loriot Y. , Massard C. , Plantade A. , Escudier B. , Chauchereau A. , De Crevoisier R. , Fizazi K.
Published: March 2020

5151

Background: There is currently no standard of care for patients (pts) with HRPC and disease progression after docetaxel-based chemotherapy. Platin compounds have demonstrated activity in this setting and in vitro evidence of synergy between carboplatin and etoposide has previously been reported. A significant proportion of advanced HRPC exhibit neuroendocrine features but there are limited data on whether these patients should be treated differently or not. Methods: Pts with HRPC who experienced failure after first-line docetaxel-based chemotherapy were prospectively treated with carboplatin (AUC 5 day 1) and etoposide (80 mg/m2 day 1 to 3), repeated every 3 weeks as second-line chemotherapy. The response rate (defined as a serum PSA decline of = 50%), progression-free survival (PFS) and overall survival (OS) were evaluated using consensus criteria (Bubley JCO 1999). Pain relief was evaluated using a visual analogic scale. Serum chromogranin A and neurone specific enolase (NSE) levels were measured at baseline. Toxicity was evaluated according to NCI criteria. Results: Forty-one HRPC pts, previously treated with docetaxel with (n=24) or without (n=17) estramustine, prospectively received carboplatin-etoposide as second-line chemotherapy. A PSA response was obtained in 9 pts (22%). Pain relief was achieved in 18 pts (45%). Median progression-free survival was 9 weeks and median overall survival was 19 months. Toxicity included grade 3–4 anemia in 25% and febrile neutropenia in 2%. Biological neuroendocrine features (e.g. elevated baseline serum chromogranin A and NSE) were not associated with response or PFS. The response rate was 18% and 31% in pts with normal and elevated baseline chromogranin A, respectively. Conclusions: The carboplatin-etoposide regimen is active and well-tolerated as second-line chemotherapy after docetaxel-based chemotherapy in HRPC patients. Activity was detected in both tumors with and without neuroendocrine features.

No significant financial relationships to disclose.
Reasons for initial PSA (iPSA) and biochemical failure (BF) being poor predictors of prostate cancer (PC) mortality
Authors: Denham J. W.
Published: March 2020

5153

Background: iPSA and BF are often poor predictors of mortality in men treated for locally advanced PC. We sought to find out why from prospective randomised trial data. Methods: In the TROG 96.01 trial men with T2b,c, 3, 4 N0 PC were randomised to 0, 3 or 6 months maximal androgen deprivation (AD) (goserelin 3.6 mg sc monthly and flutamide 250 mg po tid) prior to 66 Gy to the prostate and seminal vesicles. Failure site was diagnosed prior to salvage hormone therapy (ST) where possible, and type, timing and duration of response to ST recorded. Proportional hazards modeling was used to identify predictors of cause specific and overall survival (CSS, OS) at follow-up landmark points (where p>0.05=NS, <0.01=S, <0.001=H). Results: Between 1996 and 2000, 802 eligible men were randomised. Higher iPSA was found to be a potent predictor of BF (Houston [HF])H but a poor one for of CSSNS and OSNS. Patients having HF and/or clinical failure had unfavourable initial prognostic factors (high iPSAH, stageH, Gleason scoreH or risk groupH) compared to patients who did not fail. However in this cohort poor initial prognostic features did not predict PC death when the relapse characteristics (failure siteH and PSA doubling timeH [PSA DT]) were accounted for. Instead lower iPSA levels were predictive of worse outcome in these modelsS, a finding supported by univariate analyses. PSA DT was found to correlate positively with interval between HF and STH and the likelihoodS and duration of response to STH, and survivalH. Thus lower PSA DTs were associated with earlier intervention but poorer responses and outcomes. Conclusions: Prognosis after BF is related more to tumour biology at relapse than to initial prognostic factors. ST alone is an unsatisfactory treatment for rapid PSA DT relapses.

No significant financial relationships to disclose.
Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in operable breast cancer: Results of Intergroup Trial E1199
Authors: Sparano J. A. , Wang M. , Martino S. , Jones V. , Perez E. , Saphner T. , Wolff A. C. , Sledge G. W. , Wood W. C. , Davidson N. E.
Published: March 2020

516

Background: Evidence suggests that docetaxel is more effective than paclitaxel, and paclitaxel is more effective when given weekly than every 3 weeks in metastatic breast cancer (BC). Methods: Eligibility included axillary lymph node positive or high-risk (tumor at least 2 cm) node-negative BC. All patients received 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks × 4 (P3), (2) paclitaxel 80 mg/m2 weekly × 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks × 4 (D3), or (4) docetaxel 35 mg/m2 weekly × 12 (D1). The primary comparisons included taxane (P vs. D) and schedule (every 3 weeks vs. weekly), and secondary comparisons included P3 vs. other arms. The trial had 86% power to detect a 17.5% decrease in disease-free survival (DFS) for either primary comparison, and 80% power to detect a 22% decrease for the secondary comparisons (2-sided nomimal 5% level tests corrected for multiple comparisons). Results: A total of 4,950 eligible patients were accrued. There was no difference in the primary comparisons afer 856 DFS events and 483 deaths after a median follow-up of 46.5 months at the 4th interim analysis ( www.sabcs.org , abstract 48). This is the final pre-specified analysis for the primary comparisons after 1,042 DFS events and 650 deaths (with 1,020 DFS events at this time, to be updated at the meeting). After a median followup of 60.2 months, there remains no significant difference in the hazard ratio (HR) for the taxane (1.02; p=0.73) or schedule (1.07; p=0.30) (as in the first analysis). In secondary comparisons of the standard arm (P3) with the other arms (HR > 1 favoring the experimental arms), the HRs were 1.30 (p = 0.003) for arm P1, 1.24 (p=0.02) for arm D3, and 1.09 (p=0.33) for arm D1. Analysis of interaction by hormone-receptor status will be presented. The incidence of worst grade toxicity (grade 3/4) was 24%/6% for arm P3, 24%/3% for arm P1, 21%/50% for arm D3, and 38%/6% for arm D1. Conclusions: There were no differences in DFS when comparing taxane or schedule overall. DFS was significantly improved in the weekly paclitaxel and every 3-week docetaxel arms compared with the every 3-week paclitaxel arm.

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Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Updated safety analysis of trial BIG 1–98
Authors: Coates A. S. , Mouridsen H. , Sun Z. , Rabaglio M. , Castiglione-Gertsch M. , Thürlimann B. , Mauriac L. , Price K. N. , Colleoni M. , Smith I.
Published: March 2020

521

Background: Studies of aromatase inhibitors (AI) vs. tamoxifen (T) including the BIG 1–98 study have suggested a small numerical excess of cardiac adverse events (AEs) and increased incidence of hypercholesterolemia on AIs, and significantly higher incidence of thromboembolic AEs on T. Methods: 8,028 postmenopausal women with receptor-positive early breast cancer were randomized (double-blind) between March 1998 and May 2003 to receive 5 years letrozole (L), T, or a sequence of these agents. 7,963 patients who actually received therapy are included. AEs were recorded through 30 days after therapy completion or after switch on the sequential arms. Cardiovascular AEs were prospectively collected and graded. Cholesterol measurements were analyzed for percent change in total cholesterol from baseline by follow-up visit. Cox proportional hazards models were used to compare T and L according to time to first cardiovascular AE, adjusting for hypercholesterolemia at baseline or prior to the event, age, BMI, and history of smoking, hypertension, diabetes, and cardiac morbidity. The median follow-up was 30.1 months. Results: Baseline co-morbidities were balanced. Cox model results for time to first grade 3–5 cardiovascular AE are below. Cholesterol values decreased over time on both treatments, but to a greater extent and earlier on T. Conclusion: Taken together, cardiovascular AEs were relatively rare, and any excess of cardiac events on L seems to be outweighed by the superior control of recurrence afforded by L compared to T. An understanding of the nature, frequency and mechanism of such AEs is important to the optimization of the therapeutic ratio in adjuvant endocrine therapy with AIs.

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No significant financial relationships to disclose.