bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer
Authors: Fabbri F. , Montanari M. , Cruciani G. , Amadori D. , Zoli W. 
Published: August 2020

e16026 Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m2) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (> 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of >10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. No significant financial relationships to disclose.
Phase II dose escalation study of sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have had prior treatment with VEGFR-TKI antiangiogenic treatment
Authors: Mancuso A. P. , Donato De Paola E. , Catalano A. , Calabrò F. , Messina C. , Zivi A. , Cerbone L. , Vigna L. , Caristo R. , Sternberg C. N. 
Published: August 2020

e16027 Background: Sorafenib is an orally active multikinase inhibitor (Raf kinase, VEGFR 1, 2, 3 and PDGFR inhibitor) for the treatment of advanced RCC. The purpose of this study was to assess the efficacy and toxicity of Sorafenib in mRCC patients (pts) previously treated with an anti-angiogenic VEGFR-TKI using escalating dose levels. Methods: Pts with mRCC, PS 0–2 and adequate organ function were eligible. Pts received Sorafenib 400 mg/BID/continuously in 4-wk cycles. Pts with no progressive disease (evaluated at 12 weeks) continued to receive Sorafenib at the standard dose, while progressive pts received an increasing dose (600 mg BID) with early disease restaging after 4 weeks. Pts who progressed at 600 mg BID were taken off study. Efficacy was assessed by RECIST criteria. Results: 18 pts were entered; baseline characteristics: PS 0–1: 94%; median age 62 years (41–82); nephrectomy: 100%; surgery for metastatic disease: 28%, clear-cell 78%, papillary-cell 16%, sarcomatoid 6%.≥ 2 metastatic sites: 84%. 10 pts were refractory to cytokine treatment and all progressed or experienced unacceptable toxicity after anti-angiogenic VEGFR-TKI treatment, Sunitinib (13 pts) or Pazopanib (5 pts). Median number of cycles was 7.5 (1–16). Overall, 72% of pts had disease control without significant correlations between response to prior therapy and hypertension. 14 pts had progression free survival (PFS) of 4.3 months (mos). 4 pts are still in treatment with a median PFS > 8 mos. Of 6 pts in which the dose was escalated, 3 benefitted with a PFS of > 3 mos. The most common toxicity (NCIC 3.0, all pts) was grade (g) ≥ 1 diarrhea in 10 pts, g2–3 hand-foot syndrome in 7 pts and g-3 mucositis in 1 pt. Other hematological and non-hematological toxicities were g1 with a frequency < 15%. Conclusions: Sorafenib at doses of 400–600 mg/BID/continuosly results in acceptable and well tolerated salvage treatment after VEGFR-TKI failure. In progressive patients, treatment with a higher dose could be a valid option. Final and mature data will be presented in combination with translational research evaluating biological characteristics on tissue and blood. No significant financial relationships to disclose.
Worldwide comparison of prostate needle biopsy quality in the reduction by dutasteride of prostate cancer events (REDUCE) study: Improvement with investigator training
Authors: Bostwick D. G. , Teloken C. , Brawley O. W. , Marberger M. , Qian J. , Drewnowska K. , Niyuhire F. , Rittmaster R. R. , Fowler I. L. , Somerville M. C. 
Published: August 2020

e16029 Background: The accuracy of prostate cancer detection by biopsy is influenced by the number and length of needle biopsy cores. We compared these two biopsy quality factors among study sites worldwide for the pre-study entry biopsies (6–12 cores) and study-mandated biopsies (10 cores) at year 2 of the REDUCE study. Methods: Prostate biopsy quality indicators were evaluated retrospectively. Data were compared from entry and year 2 biopsies for subjects enrolled in the study in 6 geographic regions (see table ). Investigator training was provided for REDUCE study protocol-required standardization prior to year 2 biopsies. Training included emphasis on quality of the biopsies. Results: Data were collected from 4638 entry and 6275 year 2 subjects, respectively. At entry, the aggregate length of biopsies, number of cores per subject, and core length differed significantly among regions (p < 0.0001). Aggregate length was longest in biopsies obtained in Australia and the highest core number was observed in South America. At year 2, each region collected a mean of 10 cores per subject (per protocol), and the aggregate length and mean core length were greater than the entry biopsies (for each analyzed parameter, p < 0.0001); variance among sites was reduced for all quality measures. Conclusions: There were significant differences in biopsy quality (number of cores and length of tissue obtained) around the world at entry. Following the REDUCE study protocol-required standardization and investigator training, biopsies obtained at year 2 showed an increase in the mean aggregate length, mean core number, and mean core length compared with the entry biopsies. Our data suggests that variance in biopsy quality may be reduced by investigator training, thereby optimizing quality and cancer detection. [Table: see text] [Table: see text]
Phase II study of docetaxel-prednisone (DP) in combination with metronomic cyclophosphamide (CTX) and celecoxib (C) as first-line treatment in castration resistant prostate cancer (CRPC) patients (Pts)
Authors: Fontana A. , Bocci G. , Galli L. , Derosa L. , Minuti G. , D'Arcangelo M. , Santini D. , Landi L. , Bursi S. , Falcone A. 
Published: August 2020

e16032 Background: Metronomic oral CTX and C has demonstrated activity and a favourable toxicity profile in CRCP. Combination of such strategy with the standard DP could be of interest. Methods: Pts with CRPC received D 60 mg/sqm iv day 1 every 3 weeks up to 12 cycles and from day 2 continuously: P 5 mg po BID, CTX 50 mg po daily, and C 200 mg po BID. Primary objective is the percentage of pts free of progression at 6 months; secondary are: PSA levels decrease ≥ 50%, objective responses (RECIST), toxicities (NCI-CTC criteria) survival and pharmacodynamic evaluations. Results: To date 29 pts have been enrolled. Main pts characteristics are: median age 72 years (52–78 years), median PS 0 (0–2), median baseline PSA level 38,8 ng/mL (2.5–1309 ng/mL); main sites of disease: bone 23 pts (79%), lymphnodes 6 pts (21%), liver 1 pt (3,5%). Twenty-nine pts are evaluable for toxicity whereas 28 for PSA response (1 pt abandoned the study due to allergic reaction after first D administration). Median number of D cycles delivered is 10 (1–12) and median duration of metronomic CTX plus P and C is 224 days (35–874 days). Main grade 3 side-effects are: neutropenia (2 pt; 7%), thrombocytopenia, diarrhoea, stomatitis and onycholysis (1 pt; 3.5%). No grade 4 toxicities have been observed.The rate of pts free of progression at 6 months is 80%. Overall 18 pts (64%) showed a PSA decrease ≥ 50% and 23 pts (82%) showed any PSA decrease from baseline (range: 4%-99%of decrease). Four pts are evaluable according to RECIST criteria: we observed 1 CR, 2 SD and 1 PD. At a median follow up of 12,4 months median time to PSA progression is 11.6 months (95% CI 8,3–15). Conclusions: Metronomic CTX plus C in combination with DP is a feasible and tolerable regimen with a promising preliminary activity. The evaluation of plasma levels of thrombospondin-1 (TSP-1), VEGF, sVEGFR-2, VE-cadherin mRNA, and the expression of TSP-1 and VEGF in peripheral blood mononuclear cells, as potential surrogated markers of antiangiogenic activity of the combination, is ongoing. No significant financial relationships to disclose.
Prognostic factors in advanced seminoma in the era of etoposide- and cisplatin-based chemotherapy: Importance of pretreatment LDH-level
Authors: Tryakin A. , Fedyanin M. , Bulanov A. , Titov D. , Allakhverdiyeva G. , Mitin A. , Sergeev J. , Zaharova T. , Garin A. , Tjulandin S. 
Published: August 2020

e16038 Background: The commonly used IGCCCG classification probably underestimates other prognostic factors (tumor markers, stage) for advanced seminoma, which was shown later (Fossa S., 1997). Furthermore, in contrast to nonseminoma different cisplatin-based regimens have not been directly compared in this population. We performed an analysis to review the outcome and prognostic factors of patients (pts) with advanced seminoma treated in our center during the last two decades. Methods: From 1983 to 2005, 250 chemotherapy (CT)-naïve pts with advanced seminoma received induction platinum-based CT, which was divided as an “older” (76 pts) and “modern” (174 pts) one. “Older CT” included cyclophosphamide + cisplatin (46 pts), ifosfamide + carboplatin (12 pts), PVB (8 pts) and other regimens (10 pts). “Modern CT” contained BEP (26 pts) and EP (148 pts) regimens. 227 (91%) pts had primary testicular tumor, 241 (96%) pts belonged to IGCCCG good prognostic group. Median follow-up was 57 (range, 3–276) months for the pts who survived. Prognostic factors were analyzed in “modern CT” group. Progression-free survival (PFS) was an end-point for Cox‘ stepwise regression analysis. Results: “Modern CT” significantly improved PFS (5-years, 91% and 74%, p = 0.002) but not OS (5-years, 92% and 89%, p = 0.28), which could be explained by effective salvage CT. Univariate analysis revealed following factors as significant: number of metastatic sites, presence of pulmonary metastases, RPLN size, hCG level, and LDH level. Cox‘ regression analysis showed pre-CT LDH as the only prognostic factor for PFS (HR 7,6, 95% CI 1,6–36.3). Using cut-off 2 x upper limit of normal for LDH level, “modern CT” group can be divided into favorable (105 [60%] pts) and unfavorable (69 (40%) pts) groups with 5-years DFS 98% vs. 78% (HR 11.1, 95% CI 3.2–33.3) and 5-years OS 99% vs. 80% (HR 11.07, 95% CI 3.09–27.92), respectively. Conclusions: Comparing with older cisplatin-based regimens, the new ones (BEP or EP) improved PFS without significant influence on OS in pts with advanced seminoma. Pre-treatment LDH level is an important independent prognostic factor, which could help stratify pts better into risk groups. Further studies with risk-adapted policy in advanced seminoma are warranted. No significant financial relationships to disclose.
Survival advantage in patients treated with high-dose interleukin-2 (HDIL2) for metastatic renal cell carcinoma (mRCC)
Authors: Lee S. , Baig M. , Rusciano V. , Gao Y. , Malik S. , Wiernik P. H. , Dutcher J. P. 
Published: August 2020

e16039 Background: A prognostic index developed at MSKCC(Memorial-Sloan-Kettering Cancer Center) relates to survival in mRCC patients (pts) treated with interferon. We evaluated 79 pts treated first line with HDIL2 to see if this prognostic index is applicable. Eligibility for HDIL2 was based on cardiopulmonary screening and performance status (PS). Method: Medical records were analyzed retrospectively from 2000–2008. Pts were categorized into favorable, intermediate & poor risk category according to MSKCC prognostic index, which includes time from diagnosis to treatment, serum calcium & LDH, hemoglobin and PS. Median survival (OS) & median progression free survival (PFS) were compared between risk categories. Results were evaluated taking into consideration potential confounders such as subsequent treatment with tyrosine kinase inhibitors (TKI) & time from nephrectomy to metastasis interval of more than 1 year. Statistical analysis utilized SPSS. Results: 29 pts (36.7%) were treated with TKIs subsequently and this had no impact on median OS compared to those not receiving TKIs. 19 pts (24%) had nephrectomy to metastasis interval of more than 1 year and this also did not impact on OS analysis compared to those with shorter time to metastasis. Poor risk group was not analyzed due to small sample size. Conclusions: Median OS for mRCC pts eligible for and treated with HDIL2 as first line therapy exceeds reports of other first line treatment, either cytokines or TKIs. The survival advantage occurs regardless of being in either favorable or intermediate risk category and this benefit is not confounded by subsequent treatment with TKIs or nephrectomy to treatment interval more than 1 year. HDIL2 pts requires good PS and organ function, but 72% were intermediate risk pts. Thus, MSKCC risk categories do not predict for HDIL2 treatment outcome. HDIL2 should still be considered as a first line agent for mRCC, in the era of TKIs, as long as patients meet the eligibility criteria, as it infers survival advantage. [Table: see text] [Table: see text]
A combined phase I/II trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of refractory non–muscle- invasive transitional cell bladder cancer
Authors: Barlow L. , Laudano M. , Mann M. , Desai M. , Petrylak D. , Benson M. , McKiernan J. 
Published: August 2020

e16047 Background: Up to 50% of patients treated with intravesical agents for non-muscle-invasive bladder cancer will recur. Response rates to current second line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Our previously completed phase I trial showed docetaxel to be a safe and efficacious agent for intravesical therapy. Nanoparticle albumin-bound (nab-) paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy and is therefore an appropriate candidate for further investigation as an intravesical agent. Methods: The ongoing phase I component of this combined phase I/II trial began enrollment on 1/1/08 and has reached 72% accrual as of 1/1/09. Inclusion criteria include recurrent high grade (HG) Ta, T1 and Tis transitional cell carcinoma failing at least one prior regimen with any intravesical agent. In phase I, 6 weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg with a dose escalation model used until a maximal tolerated dose (MTD) was achieved. The primary endpoints were dose- limiting toxicity (DLT) and MTD; the secondary endpoint was response rate. Efficacy was evaluated by cystoscopy with biopsy, cytology, and CT imaging. Results: 13/18 patients have enrolled in this phase I trial to date, and the distribution of stages included 5 patients with Tis, 4 patients with HGTa, and 4 patients with HGT1. No patient has had any systemic absorption of nab-paclitaxel as measured by HPLC assays, and no grade 3 or 4 DLT has been encountered. Fifty-four percent (7/13) patients were noted to experience grade 1 toxicities, with dysuria being the most common. Forty-two percent (5/12) of completed patients had no evidence of disease at their post-treatment cystoscopy. None of the patients who developed recurrent disease have had disease progression. Conclusions: Intravesical nab-paclitaxel has exhibited minimal toxicity and no systemic absorption in the first ever human intravesical dose escalation trial. Upon completion of this ongoing phase I trial, we plan to evaluate this agent in a larger phase II efficacy study. No significant financial relationships to disclose.
Cardiovascular toxicity follwing sunitinib therapy in metastatic renal cell cancer: A multicenter analysis
Authors: Di Lorenzo G. , De Placido S. , Cartenì G. , Autorino R. , Gonnella A. , Rizzo M. , Perdona S. , Ricevuto E. , Aieta M. , Ewer M. 
Published: August 2020

e16051 Background: Recent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent. Methods: The medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian Institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with pre-existing cardiac risk factors were specifically scrutinized for increased expression of cardiac changes. Results: Grade 3 hypertension was seen in 17 patients (9.7%); in twelve of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left-ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were of classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). A significant univariate association for predictors of CHF were history of hypertension (p=0.008), history of coronary heart disease (p=0.0005) and prior treatment with an angiotensin converting enzyme inhibitor (ACE) (p= 0.04). Multivariate analysis suggested that a history of coronary artery disease (OR 18, 95% CI, 4–160 p 0.005) and hypertension (OR 3, 95% CI, 1.5–80 p 0.04) were the only significant independent predictors of CHF. Conclusions: Patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment. [Table: see text]
Tolerability of ongoing phase II study of concomitant radiation and docetaxel followed by docetaxel in prostate cancer patients with a persistent or rising PSA after radical prostatectomy
Authors: Harris A. M. , Eng T. Y. , Karnad A. B. , Swanson G. P. , Jenkins C. , Greene R. 
Published: August 2020

e16054 Background: Patients with a detectable PSA after radical prostatectomy (RRP) have persistent disease and inevitably succumb to disease as progression ensues. Radiation has been used in the salvage setting, but has only been found to cure less than half of these patients. SWOG 8794 has recently reported a significant increase in metastasis free survival in 15 years with adjuvant radiation for patients with high risk findings after RRP. It is of particular interest if adjuvant chemoradiation (CRT) can improve the rate of reaching a PSA nadir of zero after RRP in men with persistent or rising PSA. This ongoing IRB approved trial has thus far evaluated the tolerability of CRT utilizing the radiosensitizing agent Docetaxel (DX) for 7 weeks after RRP followed by adjuvant full dose DX (75mg/m2). Methods: Patients: Chemotherapy/hormone naïve, status post RRP, post-op PSA > 0.2 ng/mL on two separate occasions, ECOG ≤ 2; treated with taxane-based chemotherapy (DX 20mg/m2 weekly) concurrent with standard dose radiation for 7 weeks, and post-radiation chemotherapy DX (75mg/ m2) given every 21 days for 4 cycles with premedication intravenous dexamethasone. Primary endpoint: Rate of PSA decline; Number of subjects reaching PSA nadir of zero. Secondary endpoints: Progression Free Survival (PFS) based on PSA progression, toxicity graded via Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE), and overall survival (OS). Results: From 5/07 to 12/08, 16 pts with detectable PSA after RRP were treated; Median age 65 [48–74]; 16/16 completed CRT; 11/16 completed CRT and adjuvant DX; 3/16 dropped out due to adverse events after CRT; Toxicity: 19% (3/16) patients experienced Grade 3 toxicity during CRT and adjuvant DX; 29% (4/14) patients had Grade 3 toxicity during adjuvant DX; no Grade 4 toxicities. See Table . Conclusions: DX in combination with standard radiation appears to be well tolerated in patients with persistent PSA after RRP. [Table: see text] No significant financial relationships to disclose.
Long-term safety of sorafenib (SOR) for the treatment (tx) of advanced clear-cell renal-cell carcinoma (RCC): Data analysis from patients (pts) treated for over 1 year in the phase III TARGET study
Authors: Hutson T. E. , Bellmunt J. , Porta C. , Staehler M. , Szczylik C. , Nadel A. , Anderson S. , Bukowski R. M. , Eisen T. , Escudier B. 
Published: August 2020

e16057 Background: Results of the phase III multicenter TARGET study, a randomized, double-blind, placebo (PBO)- controlled study of tx with SOR in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective (PFS 5.5 vs 2.8 mo, HR=0.44, P<0.000001, and 39% increase in survival for SOR vs PBO, HR=0.71, P=0.015) and safe in pts with advanced RCC (Escudier et al. N Engl J Med. 2007). With a database cut-off of Sept 8, 2006, we analyzed the safety of long-term use of SOR in pts in TARGET (study start Nov 2003). Methods: Pts (N=903) with advanced metastatic clear-cell RCC that had progressed after 1 systemic tx, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or PBO. End points included OS, PFS, and safety. A single planned analysis of PFS showed a significant benefit of SOR over PBO; consequently, pts assigned to PBO were offered SOR. Descriptive analysis of safety and efficacy of pts treated >1 year (y) was conducted. Results: 169/903 pts were randomized to SOR and treated >1 y and 27 pts treated >2 y. Due to crossover of PBO to SOR, only 6 pts randomized to PBO were treated with SOR >1 y. Pts treated with SOR >1 y had median PFS of 10.9 months and a response rate of 22.5%. Median tx duration was 20 months. Drug-related adverse events (AEs) were mainly grades 1 and 2 and occurred early during tx (see Table ); 31% and 22% of pts required dose interruption and reduction, respectively, because of AEs. Conclusions: Long-term tx with SOR did not result in new toxicities or an increase in overall incidence of tx-related AEs. Toxicity was not cumulative and no increase in grades 3/4 AEs was observed. Pts with preexisting cardiac disease or hypertension tolerated long-term tx with SOR; no dose reduction was required. No increase in cardiovascular toxicity was observed in this pt population. Long-term tx of pts with advanced RCC with SOR is medically manageable, with a predictable AE profile. [Table: see text] [Table: see text]