bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II trial of GM-CSF and lenalidomide in patients with hormone refractory prostate cancer (HRPC)
Authors: Dreicer R. , Garcia J. , Smith S. , Elson P. , Triozzi P. , Hodnick S. , Rini B. , Klein E.
Published: March 2020

15515

Background: Administration of GM-CSF in combination with thalidomide induces PSA responses in 20–25% of pts with HRPC. When administered in the neoadjuvant setting, this combination induces T cell and dendritic cell (DC) infiltration in prostate tumor tissue. Lenalidomide is an immunomodulatory analogue of thalidomide. In an effort to evaluate the clinical and immune activity of GM-CSF plus lenalidomide, we conducted a phase I/II trial in pts with HRPC. Methods: Pts had progressive asymptomatic HRPC by Consensus Criteria. Prior immunotherapy or chemotherapy was not permitted. A phase I safety phase followed by a phase II trial was undertaken. All pts received GM-CSF at 250 μg administered SC three times weekly along with lenalidomide 25 mg/day orally on days 1–21 of a 28-day cycle. Primary endpoints were safety and objective and PSA responses. Exploratory endpoints included activation of circulating DC, regulatory T cells (Treg) and cytokine production. Results: To date 19 of 34 planned pts are enrolled (13 with evidence of metastases; 6 with PSA-only disease). Seventeen pts are eligible for response (2 pts too early) Median age is 71 (49–80), median PSA is 19.1 (2.1–153.1). Median cycles of therapy is 4 (range: 1–14+). Overall, 13 of 17 pts (76%) experienced a reduction in PSA (<20% 2/17; 20–40% 7/17,>50% 4/17). Objective and PSA partial responses were observed in 2 and 4 of 17 pts respectively. Nine pts discontinued therapy (5 due to PD, 3 due to toxicity, and 1 withdrew consent). No pts on the phase I portion of the trial experienced a DLT. Grade (G) 1–2 toxicities for all 17 pts included neutropenia (20%), thrombocytopenia (13%), diarrhea (43%), dizziness, (25%), and fatigue (90%). Three pts developed G4 toxicities (PE, neutropenia, and emesis). The number of Treg cells decreased after 2 cycles of therapy. Similarly, Th1 cytokine and TNF-a production was increased after therapy. Although mean serum VEGF levels were decreased after therapy, changes in the mean serum levels of IL-8 and bFGF were not observed. Conclusions: The combination of GM-CSF and lenalidomide is relatively well tolerated with evidence of antitumor activity. Exploratory studies support the ability of this therapy to modulate immune cells. Accrual to this study is ongoing.

[Table: see text]
Von Hippel-Lindau gene mutation status is associated with a dichotomous response in primary and metastatic tumors in patients receiving bevacizumab and erlotinib for metastatic renal cell carcinoma
Authors: Tsavachidou D. , Tannir N. M. , Wood C. G. , Corn P. , Do K. , Tamboli P. , Smith L. A. , Matin S. , Jonasch E.
Published: March 2020

15522

Background: A single arm phase II study is underway evaluating the safety and clinical benefit of presurgical bevacizumab and erlotinib in the management of patients with untreated conventional renal cell carcinoma (RCC). It is not known how the presence or absence of von Hippel Lindau (VHL) mutations affect the response to therapy in the primary or metastatic site, and whether VHL mutational status is predictive for either. Methods: Patients enrolled had conventional RCC, measurable metastatic disease, a primary tumor in place, no prior systemic therapy, a PS of 0 or 1 and no brain metastases. A total of 35 patients were enrolled as of January 8, 2007. Patients were treated with bevacizumab for 4 cycles and erlotinib for 8 weeks, and underwent cytoreductive nephrectomy at week 10 (4 weeks after the last dose of bevacizumab). A VHL gene mutation and methylation analysis was completed on nephrectomy specimens from the first 18 evaluable patients. Patients were grouped according to the presence or absence of functional VHL gene inactivation (mutation and/or methylation). Two-sample T-test and Fisher’s exact test were performed. Results: Ten patients (55%) demonstrated either VHL mutation or methylation ( table 1 ). Patients with no VHL gene inactivation demonstrated more robust primary tumor shrinkage, but did not demonstrate partial responses (PRs). Table 1 . Conclusions: These findings, although preliminary, suggest a dichotomous response in the primary and metastatic disease sites according to VHL functional status. Ongoing evaluation of new treatment strategies using antivascular/targeted agents in RCC may benefit from molecular stratification.

[Table: see text]

No significant financial relationships to disclose.
Potential targets in prostate tumor–associated stroma
Authors: Richardson A. , Player A. , Wang Y. , Rodriguez-Canales J. , Erickson H. , Kawasaki E. , Woodson K. , Chuaqui R. , Emmert-Buck M.
Published: March 2020

15529

Background: The past 20 years have seen a shift in the paradigm that the stromal compartment in tissues is merely a passive, supporting tissue for epithelial cells. Recent evidence shows that it plays a critical role not only in normal tissue development and homeostasis, but also in the progression of cancer. Further, as the stromal compartment is more readily accessible to vascular-delivered agents, this region might be particularly amenable to clinical intervention. As such, a broad-based study of the carcinoma-associated changes in stromal cells from patient samples could yield a wealth of information on the molecular mechansisms of tumorigenesis, and identify clinically important molecular targets. Methods: Five whole-mount frozen prostatectomy specimens were microdissected in four regions: normal epithelium, tumor epithelium, normal stroma, and tumor-associated stroma. Extracted and amplified mRNA was hybridized to the Human Genome U133 Plus 2.0 GeneChip (Affymetrix). Using the intersection of two statistical analysis packages (GCOS and RMA), we identified differentially expressed genes between the dissection groups. Quantitative RT-PCR was used to validate selected transcripts and immunohistochemistry to evaluate potential stromal molecular targets. Results: Tumor-associated stroma showed a distinctly different expression pattern compared to normal stroma with 675 differentially expressed transcripts, the majority of which were up-regulated. In contrast, tumor epithelium showed more down-regulation in the 829 transcripts that were differentially expressed relative to normal epithelium. Classes of up-regulated genes in the tumor-associated stroma showed a strong linkage to cell adhesion and migration as well as the calcium, MAPK, and TGF-beta signaling pathways. Quantitative RT-PCR was conducted to verify GeneChip findings and revealed over 80% concordance with the original data. Immunohistochemical staining further supported the expression differences. Conclusions: Global mRNA expression analysis of stromal cells within tumors provides insight into prostate cancer progression, and yields novel targets for future diagnostic and therapeutic intervention.

No significant financial relationships to disclose.
Analysis of lymphangiogenetic factors in invasive bladder cancer—A tissue microarray analysis
Authors: Wulfing C. , Herrmann E. , Kopke T. , Eltze E. , Neumann J. , Bierer S. , Hertle L.
Published: March 2020

15530

Introduction: Vascular endothelial growth factors (VEGF) -C, -D and their receptor Flt-4 play an emerging role in lymphangiogenesis of different tumor types. Our aim was to determine the role of VEGF-C, VEGF-D and Flt-4 in invasive transitional cell carcinoma of the bladder. Material and Methods: Archival tumor tissue of 286 patients, who had previously undergone radical cystectomy at our institution, was reviewed and representative tumor blocks were selected for constructing a tissue microarray (TMA). Paraffin sections were assessed immunohistochemically using mono- and polyclonal antibodies against VEGF-C, VEGF-D and Flt-4. Staining results were analysed semiquantitatively and correlated with various clinicopathological factors. Results: Overexpression of VEGF-C, VEGF-D and Flt-4 was found in 24.1%, 37.4% and 46.3% of cases, respectively. While there was no association of VEGF-C to histopathological parameters and clinical outcome, patients with VEGF-D overexpression had higher pathological tumor stages (p=0.021) and regional lymph node metastases (p=0.016). Furthermore, they had significantly worse disease-free survival (p=0.042). Overexpression of Flt-4 was found in the subgroup of G3- and G4-tumors (p=0.001) and correlated with a shorter period of disease- free survival (p=0.033). Conclusion: VEGF-C, VEGF-D and Flt-4 are overexpressed in bladder cancer. VEGF-D predicts higher tumor stages and regional lymph node metastases. It is associated with a worse disease-free survival as well as Flt-4 in the subgroup of high-grade tumors. Further studies should be initiated to evaluate VEGF-D and Flt-4 as potential targets in bladder cancer.

No significant financial relationships to disclose.
Pre-prostatectomy study of the effect of celecoxib versus placebo on androgen receptor (AR) expression in prostate cancer
Authors: Garzotto M. , Janeba N. , Eilers K. M. , Sekhon H. , Beer T. M.
Published: March 2020

15538

Background: Cyclooxygenase (COX) inhibitor drug use is associated with a reduction in prostate cancer incidence and mortality. Numerous potential mechanisms for the COX-2 inhibitor, celecoxib have been proposed, including a reduction in AR transactivation (Clin Cancer Res 10:7727, 2004). We hypothesized that pre-prostatectomy celecoxib therapy would result in reduced tissue AR levels. Methods: 28 patients with localized prostate cancer were randomized to celecoxib (400 mg bid) or placebo for 4 weeks prior to prostatectomy. Both benign and cancerous tissues were embedded in a tissue microarray. A single blinded pathologist quantified the percent of positive nuclei in benign versus malignant epithelial cells. Results: An increased number of AR-positive nuclei were observed in the malignant versus benign cells (65.9± 35.2% versus 49.9 ± 33.5 %, p <.001). There was no difference in AR expression between treatment and placebo groups in either benign or cancerous tissue (p = .9, .85, respectively). The median serum PSA at baseline was 6.0 and 6.2 ng/ml for the celecoxib and placebo groups. Over the treatment period, there was no detectable effect of celecoxib on serum PSA (p=0.91). Conclusions: Short-term COX-2 inhibitor therapy did not result in a significant change in either tissue AR or serum PSA. If celecoxib has inhibitory effects on prostate cancer, these may occur without an effect of AR activity.

No significant financial relationships to disclose.
Phase I trial of docetaxel (D) plus samarium153 (Sm 153) in patients (pts) with hormone refractory prostate cancer (HRPC)
Authors: Sinibaldi V. J. , Carducci M. A. , DeWeese T. , Weber J. , Drew R. , Moore-Cooper S. , Denmeade S. , Pili R. , Walczak J. , Sugar E. , Eisenberger M. A.
Published: March 2020

15547

Background: Bone targeted approaches hold great promise for improving outcomes in HRPC. Docetaxel (D) and samarium 153 (Sm153 ) have individually demonstrated a clinical benefit and preclinical data strongly support biological synergism in HRPC. Preclinical data suggests that 24 hour after a dose of D, there is maximum G2M arrest. This results in the accumulation of cells in the most radiosensitive phase of the cell cycle. This phase I trial was designed to evaluate toxicity and preliminary efficacy of combined D and Sm153 administered sequentially in advanced HRPC. Methods: HRPC pts progressing after anti-androgen withdrawal; = 2 prior chemotherapy regimens; acceptable bone marrow, renal and hepatic function were eligible. Planned D treatment in 4 cohorts (N=3/cohort) includes: Cohort 1: D 50mg/m2 IV on days 1, 22, 91, and 112; cohort 2: D 75mg/m2 IV on days 1 and 22 followed by 50mg/m2 IV on days 91 and 112; cohort 3: D 75mg/m2 IV on days 1 and 22 followed by 75mg/m2 IV on days 91 and 112; cohort 4: D 75 mg/m2 IV on days 1, 22, 42, 91, 112, and 133. Sm 153 (1.0 mi/Kg) is administered IV days 2 and 92 of each cycle. Cycles are repeated Q 12 wks (max 2 cycles). The endpoint for this trial is dose limiting toxicity and maximal tolerated dose. Results: From 5/11/05 - 1/7/07 ten pts were enrolled. Median: age 69.5 yrs (range 58–76), ECOG performance status 1 (range 0–1), baseline PSA 76.65 ng/ml (range 9.6–1064 ng/ml ), prior hormonal manipulations 3 (range1–6). Three pts had prior taxotere and 3 pts had prior palliative RT. All had bone metastases and 2 also had soft tissue disease. Five pts completed 2 cycles of treatment as planned. Five pts had 1 cycle (one pt is on treatment, 3 pts had PD and 1 had prolonged grade 1 thrombocytopenia =3 wks). Nine of 10 pts had reversible grade 3 / 4 neutropenia (1 pt had reversible episode of neutropenia with fever). Seven of 7 symptomatic pts had improvement in pain. Four of 10 of pts had a 50 % decline in PSA level lasting = 4 weeks; no soft tissue disease responses. Conclusions: Our preliminary data suggest that Q 3 wk D and Q 3 month Sm153 may be administered simultaneously at full doses in extensively pretreated HRPC pts, with acceptable toxicity and significant activity. This study is supported by a grant from sanofi- aventis and Sm153 is provided by Cytogen.

No significant financial relationships to disclose.
Docetaxel (D) and estramustine (E) as first-line chemotherapy for patients (pts) with hormone-refractory advanced prostate cancer (HRPC): Final results of a multicentric phase II randomized trial
Authors: Caffo O. , Sava T. , Comploj E. , Giampaolo M. , Zustovich F. , Segati R. , Sacco C. , Perin A. , Pappagallo G. , Valduga F.
Published: March 2020

15552

Background: Preclinical data showed a synergism between E and D and several studies supported an advantage in associating E and D. Nevertheless, D is considered a standard treatment for HRPC pts and the role of D+E combination remains controversial. Purpose of this study was to evaluate the activity, in terms of PSA decline (PSA↓), the safety and quality of life (QoL) of D±E in HRPC pts. Methods: Eligibility criteria included: HRPC diagnosis, hormone-refractory advanced disease (PSA progression after at least two hormonal therapy), ECOG PS < 2, adequate renal, hepatic and hematological functions, no prior chemotherapy. Pts were randomized to D 70 mg/m2 IV d1 q3w (arm A) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B). The treatments were planned until best PSA response achievement or PSA progression. Toxicity was recorded according to NCIC criteria. Qol was assessed by self-filled questionnaires during the treatment. Results: Between 04/2003 and 09/2005, 95 pts (median age 69 years, range 48–86, median PSA 80 ng/ml, range 5–2,166 and measurable disease in 45) were randomized to arm A (49) or arm B (46). In arm A, pts received 321 cycles (median 6, range 0–28) with only 13 (4 %) delays = 7 days. In arm B, pts received 338 cycles (median 7, range 0–20) with only 16 (4.7%) delays. Grade 3–4 hematological toxicities consisted of neutropenia, 4% in arm A and 6% in B. One pt in arm B had febrile neutropenia and grade 3 diarrhea. Grade 3–4 non-hematologic toxicities were vomiting (1 pt in both arms), stomatitis (1 pt in arm A and 2 pts in B) and diarrhoea (1 pt in arm B). Two cases of stroke were reported in arm A. No treatment related death was recorded. Responses, in terms of PSA↓ >50% were: 40% in arm A and 75%in arm B with PSA normalization in 5% and 32% respectively. After a median follow-up of 17 months, 65 patients are died (31 in Arm A and 34 in Arm B). Progression free survival (biochemical) was 20 weeks in arm A and 30 in B. Conclusions: D-based regimens are active in HRPC with a manageable toxicity profile. From this preliminary data, DE combination appears promising, in terms of activity and tolerability so, front-to-front formal comparison in a phase III trial can be recommended.

No significant financial relationships to disclose.
A set of nomograms predicting acute gastrointestinal syndrome after prostate cancer conformal radiation
Authors: Valdagni R. , Rancati T. , Fiorino C. , Fellin G. , Vera Righi L. , Magli A. , Mariani L. , Monti A. , Bianchi C. , Vavassori V.
Published: March 2020

15555

Background: To predict acute toxicities (tox) of the gastrointestinal syndrome (SOMA LENT) in prostate cancer (PCa) patients (pts) undergoing 3D-CRT using a tool (nomogram) with clinical as well as dosimetric variables which has proved to be significant in the AIROPROS 01–02 trial. Methods: Acute rectal tox was scored in 1,132 pts using a 10 item self assessed questionnaire (QST) describing radio-induced GI symptoms profiles for bowel frequency, tenesmus, fecal continence, rectal pain and bleeding. The correlation between hormonal therapy (HT), drug prescription, diabetes or hypertension, pelvic node or seminal vesicles irradiation, mean rectal dose, DVH constraints and rectal tox was investigated by uni- and multivariate (MVA) logistic analyses. MVA results were used the R-project software to create nomograms predicting the symptoms of the acute GI syndrome. Results: 4/10 items of the QST are reported: moderate/severe bleeding, increased bowel frequency, moderate/severe bowel urgency and severe fecal incontinence. Bleeding is related to haemorrhoids (OR=1.9), HT (protective factor, OR=0.78) and mean rectal dose (continuous variable (cv), OR=1.024). Bowel frequency is related to seminal vesicles irradiation (OR=2.8) and V60 (cv, OR=1.024), while bowel urgency is correlated to seminal vesicles irradiation (OR=3.3) and mean rectal dose (cv, OR=1.027). Fecal incontinence depends on seminal vesicles irradiation (OR=4.6) and V70 (cv, OR=1.029). MVA results were used to create a set of nomograms. Conclusions: The combined effect of several independent, prognostically valuable variables for a specific disease can be expressed using nomograms. They can evaluate clinical and technical parameters of the single pt and offer clinicians a tailored probability of a specific outcome. To our best knowledge, this work presents the first set of nomograms available in the literature specific symptoms of the GI syndrome. The prediction capability of these tools will be validated on a independent set of patients. This work was partly supported by Fondazione I. Monzino, Milan

No significant financial relationships to disclose.
Determinants of prostate volume changes following iodine-125 interstitial prostate implant
Authors: Bieniek E. , Ashamalla H. , Guirguis A.
Published: March 2020

15563

Purpose: Prostate brachytherapy (PB) has been linked with increase in prostate volume (PV). This study evaluates post- operative PV changes and the variables that might affect prostate swelling. Methods: Twenty four patients (pts) were analyzed. Twelve were treated with PB only, 8 with external beam radiation (EBRT) prior to implant, and 4 with EBRT after PB. Pre-treatment PSA and Gleason score ranges were 1.9–10.8 and 5–8 respectively. Pre- implant and post-implant day 1, 9, 30, and 60 (PV0, PV1, PV9, PV30, and PV60) measurements were done using computed tomography. Univariate analysis of PV change and the following was done: PV0, number of needles, seeds, and needle insertion attempts, seed activity (0.3 vs 0.5mCi), hormonal ablation therapy, and prior EBRT. Urinary symptoms were assessed using International Prostate Scoring System (IPSS). Results: Ninety six PV measurements were done by a single observer. PV0 ranged from 27.1 to 89.4 cc (mean 48.2). Largest PV was observed on day 1 (40.1–118.7, mean 67.1). Successive PV measurements afterwards continued to decrease. Mean PV values on day 9, 30, and 60 were 58.6, 51.5, and 42.3cc respectively. The differences between PV0 and all successive PV’s were statistically significant. Mean increase in PV1 from PV0 was 18.9±16.8cc (p<0.001), PV0 and PV9 9.7cc, PV0 and PV30 2.6cc. PV60 was smaller than PV0 by an average of 6.6cc. Statistically significant positive correlation was found between PV increase and seed activity (p=0.02) while treatment with EBRT prior to PB was associated with less prostate swelling (p=0.043). Other variables were not significantly correlated with PV changes. Although the mean IPSS score increased from pre-implant value of 9.2 to 13.7 on day 60, the differences between IPSS values were not statistically significant. Conclusions: Maximum prostate size is observed on the first day after implant. Prostate begins to decrease in size between day 1 and day 9 and reaches pre-procedure volume after day 30. Higher seed activity results in greater prostate swelling, while less brachytherapy- induced swelling is observed in patients treated with external radiation prior to implant. Resolution of prostate swelling does not appear to parallel with improvement in urinary symptoms in the first 2 months after implant.

No significant financial relationships to disclose.
Sorafenib for the treatment of metastatic renal cancer (MRC) in the real world: The Princess Margaret Hospital (PMH) experience
Authors: Chin S. , Riechelmann R. P. , Wang L. , Tannock I. F. , Berthold D. R. , Moore M. , Knox J. J.
Published: March 2020

15568

Background: Sorafenib, an oral multi-kinase inhibitor, prolonged progression free survival (PFS) of MRC patients (pts) in second line when compared to placebo in a phase III trial (Escudier at al ECCO 2005). Grade 3/4 adverse events (AE) were reported in 12% of pts. Here we present sorafenib’s efficacy and safety in a less selected cohort of pts enrolled in the Bayer Expanded Access Program at PMH. Methods: Pts with MRC received Sorafenib 400 mg bid continuously until disease progression (PD) and/or clinical deterioration..Tumor response was measured by RECIST criteria. AE were graded by NCI common toxicity criteria. Summary statistics and logistic regression were used to describe the results. Results: From Nov 2005 to Aug 2006, 58 pts were enrolled: median age was 59 years (range 14–86), 47 (81%) were male, 48 (83%) had clear cell histology and 46 (79%) received Sorafenib in first line. None received prior kinase-inhibitors. Using the Motzer Prognostic Index, 29 pts (50%) were low risk, 21 (36%) intermediate and 8 (14%) poor risk. Grade 3/4 AE occurred in 37 pts (64%, 95% CI 50–76%): 15 (26%) pts had skin rash, 10 (17%) hand-foot syndrome, 4 (7%) hypertension, 4 (7%) fatigue, and 4 (7%) diarrhea. Thirty-six (62%) pts required dose reductions and/or treatment interruptions, most due to skin reactions and hand-foot syndrome. Median follow-up was 9 months (IQR range 2–11), the median PFS was 7.5 months (IQR range 5.4–11.3), and the best responses among 56 evaluable pts were: 10 (17%) confirmed partial responses (median duration: 6 months, range 4–11), 14 (24%) stable diseases for = 6 months and 10 (18%) early progression. Pts with bony mets progressed earlier than pts without bony mets. Abnormal creatinine clearance, age, performance status, line of treatment and presence of significant comorbid conditions were not associated with grade 3/4 AE in univariate analysis. Conclusions: Sorafenib is effective in a ”real world”, less selected patient population with MRC but leads to more toxicity than described previously.

[Table: see text]
Monocentric evaluation of erlotinib in advanced prostate cancer
Authors: Gravis G. , Gonçalves A. , Bladou F. , Salem N. , Esterni B. , Bagattini S. , Viens P.
Published: March 2020

15569

Background: The human epidermal growth factor receptor (HER1/EGFR) is known to be over expressed in a variety of cancers, including prostate cancer. Erlotinib is an orally active small molecule tyrosine kinase inhibitor (TKI) targeted against HER1/EGFR (ErbB1). Methods: Pts with advanced or metastatic prostate cancer, adequate organ function and Karnofsky performance status (KPS) ≥ 50% were enrolled in a phase II single institution study. Pts were required to have documented PSA progression before study entry. The primary objective was to determine the efficacy of erlotinib defined as a decrease or stabilization of PSA. Pts received erlotinib 150 mg/day; if no acceptable toxicity was reported in the first 3 weeks, the dose was increased to 200 mg at week 4, and continued until disease progression or unacceptable toxicity. Results: Thirty patients were treated between April 2004 and February 2006, Median age was 69 years (range 51–77) median KPS was 80 (70–100). Median PAL was 85 UI/L (range 33–732), median LDH 224 UI/L (144–1,016) and PSA 102 ng/ml (3, 4–1213). Twenty-eight pts had metastatic disease, 2 had PSA relapse only and 29 were androgeno-independant. Twenty three had received prior chemotherapy (median 2 lines, range (1–7)). Dose escalation was possible in 16 (55%) pts and median duration of treatment was 60 days (14–99). The most common grade 3 toxicities were fatigue (3 ), anaemia (2), diarrhea (2) vomiting (2) cutaneous toxicity (1); one pt. had grade 4 anemia. Median PFS was 29 days (IC 95 [28–33]), median OS 17,38 months. PSA stabilization was observed in 4 pts; no pt had a decrease in PSA. Clinical benefit evaluation based on KPS and pain was achieved in 8 of 20 evaluable pts (40%). Conclusion: Erlotinib demonstrated some activity in advanced prostate cancer with 14% of pts achieving PSA stabilization and 40% a clinical benefit. Erlotinib was well tolerated. Future directions might include evaluating its use in less advanced disease and in pts with EGFR kinase domain mutations. Understanding which biomarkers predict response to erlotinib will likely be important in its application in the metastatic setting.

No significant financial relationships to disclose.
Target focal therapy in early prostate cancer: Initial single institution results
Authors: Barqawi A. , Lugg J. , Crawford E. D.
Published: March 2020

15574

Background: Currently the potential for over- and under-treatment using radical and watchful waiting options respectively constitutes a challenge in the management of patients with early organ-confined prostate cancer. Target focal therapy (TFT) is emerging as an intermediary alternative option for such men. The goal is to provide ablative treatment with minimal impact on morbidity. Methods: As part of an IRB approved study protocol a total of 24 patients initially underwent a 3 dimensional transperineal mapping biopsy under TRUS guidance to confirm the extent of tumor burden and localize the cancer foci within the prostate. Only 12 men qualified to undergo target focal cryotherapy. The remaining patients did not qualify due to upgrading or downgrading of their stage and opted for other treatment options. Follow- up consisted of serial PSA measurements at 3 months interval, disease specific QOL questionnaires, IPSS, and SHIM scores. Results: The mean age was 62.4 years. The mean (SD) prostate size at the time of mapping biopsy was 39 ±14.8g. After mapping biopsy all patients reported time limited hematuria and 2 patients developed urinary retention and were managed successfully with Foley’s catheter for 5 days. Mean PSA before treatment was 5.2 ± 4.1 ng/dl. 10/12 patients had Gleason score (GS) of 3+3, the remaining 2 patients had GS of 3+4. At 3 months follow-up. A median drop of PSA of 1.9 (0, 9.5) ng/dl. All patients reported full urinary continence post operatively. IPSS median drop of 0 (2, -16). Sexual health as assessed by SHIM score showed a median drop of 6 (1, -15) points. In general 4 patients reported a significant change in sexual performance. 2 of which opted for PDE inhibitor with successful regaining of erection at 6 months follow-up. Overall EPIC QOL scores showed no change in rectal, urinary and hormonal components. Sexual component registered a drop of 5 points. Conclusions: The current initial early results appear to be encouraging for future implementation of TFT on select patients with organ confined early stage cancer. Future larger randomized studies are needed to better understand the value of this alternative option in the management of prostate cancer.

No significant financial relationships to disclose.
Effect of obesity on overall survival following permanent prostate brachytherapy
Authors: Galbreath R. , Merrick G. S. , Butler W. , Wallner K. , Allen Z. , Adamovich E.
Published: March 2020

15576

Background: To evaluate the impact of obesity on cause-specific (CSS), biochemical progression-free (bPFS) and overall survival (OS) following prostate brachytherapy. Methods: From April 1995 through March 2003, 1,093 consecutive patients underwent brachytherapy for clinical T1b-T3a (2002 AJCC) prostate cancer. The median follow up was 5.6 years. All patients were implanted at least 3 years prior to analysis. Evaluated body mass index (BMI) subgroups were < 25 (n=258), 25.0 to 29.9 (n=547), 30.0 to 34.9 (n=214) and = 35 (n=74) kg/m2, respectively. Four-hundred and thirty (39.9%) and 589 (53.9%) of the patients received androgen deprivation therapy or supplemental external beam radiation therapy, respectively. Multiple clinical, treatment and dosimetric parameters were evaluated as predictors of CSS, bPFS and OS. Results: The 11 year CSS, bPFS and OS for the entire cohort were 97.5%, 95.6% and 77.6% respectively. BMI did not impact CSS or bPFS for any of the BMI cohorts. However, OS was statistically lower in patients with a BMI < 25 kg/m2 (p = 0.014). A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS while percent-positive biopsies, risk group,V100 and hypertension predicted for bPFS. Patient age and tobacco use were the strongest predictors of OS. One-hundred and twenty-eight patients have died with 108 (84.4%) of the deaths the result of cardiovascular/pulmonary disease (73) and second malignancies (35). To date, 12 patients have died of metastatic prostate cancer. Conclusions: Following brachytherapy, obesity did not impact CSS, bPFS or OS. Cardiovascular or pulmonary disease and second malignancies substantially outweighed prostate cancer as competing causes of death.

No significant financial relationships to disclose.
The effects of intermittent androgen deprivation therapy (ADT) and zoledronic acid administration on bone density in patients with prostate cancer
Authors: Katznelson L. , Kent K. , Srinivas S.
Published: March 2020

15593

Background: Intermittent ADT is commonly used in men with recurrent prostate cancer. Bone loss associated with ADT is well described. Bisphosphonate use in men undergoing ADT results in improvement in bone mineral density (BMD), although the utility and duration of bisphosphonate use in men undergoing intermittent ADT are unclear. Objective:To evaluate the effect of zoledronic acid administration every 3 months on BMD in men with prostate cancer undergoing intermittent ADT, and whether BMD is maintained upon discontinuation of both ADT and zoledronic acid. Methods: Patients with recurrent prostate cancer starting ADT were eligible to participate. Subjects received ADT for 9 months in addition to 3 doses of zoledronic acid every 3 months. At 9 months, patients who achieved an undetectable serum PSA were taken off ADT and then randomized either to continuing zoledronic acid every 3 months for an additional 3 doses vs. observation. BMD, assessed by DEXA scan, was determined at baseline, 9 months, and between 18 -24 months at hip, trochanter, femoral neck and lumbar spine sites. Results: Twenty two patients were treated with ADT and zoledronic acid between 2003–2006. Seven of these subjects had bone metastases and had previous treatment with ADT.There was one infusion related reaction, and one patient developed osteonecrosis of the jaw and was removed from the study. At baseline, 3 patients had osteoporosis at the lumbar spine. All patients who received zoledronic acid for 9 months had an improvement in BMD at all 3 sites. In the 7 subjects who had previously received ADT, BMD of the femoral neck increased significantly by approximately 1.9%. Among the 6 patients randomized to continuing zoledronic acid after discontinuing ADT at 9 months, all had a further, significant increase in BMD. Those randomized to observation were unable to maintain their BMD and had continued bone loss despite stopping ADT. Conclusions: This small study demonstrated an increase/maintenance of BMD in men receiving intermittent ADT and zoledronic acid. Only those men who continued zoledronic acid for up to a total of 9 mos after discontinuing ADT maintained BMD

No significant financial relationships to disclose.
Chromogranine A and neuron-specific enolase as the main predictors of survival for hormone-refractory prostate cancer (HRPC) patients
Authors: Banu A. , Banu E. , Dionysopoulos D. , Medioni J. , Scotte F. , Levy E. , Oudard S.
Published: March 2020

15594

Background: Clinical studies suggested that the extent of neuro-endocrine differentiation in prostate cancer increases with tumor progression and the development of androgen refractory status. Chromogranine (CgA) and neuron-specific enolase (NSE) are currently explored as surrogate markers. Methods: Eligible chemonaive HRPC patients (pts) were required to have an ECOG performance status (PS) ≤ 2. Before chemotherapy initiation, we quantified NSE, CgA and PSA in the venous blood using commercial kits. We evaluated the impact of baseline NSE, CgA and PSA on overall survival (OS) using multivariate Cox regression analysis, stratified by chemotherapy regimen. Secondary, we studied the correlation between NSE, CgA, PSA and other important variables as age, Gleason score, hemoglobin, number of metastatic sites and ECOG PS. Results: Data of 39 consecutive HRPC pts treated between December 01–06 in a single French center were analyzed. Chemotherapy was docetaxel-based in 92% of pts. Median age was 71 years (range 51–86) and 79% of pts had bone metastases. Elevated NSE, CgA and PSA were observed in 6, 9 and 30% of pts and median levels were 10.8, 67 and 23.3 ng/mL, respectively. Gleason 8–10 was present in 49% of pts. Significant correlations were observed between NSE and the number of metastatic sites and between CgA and age, hemoglobin and ECOG PS. The baseline PSA was only correlated with Gleason score. Median OS for the entire cohort was 24.4 months (95% CI, 18.8–29.9). Two-year OS was 15% and only 19% of patients are dead. Univariate Cox regression analysis showed only a significant relationship between OS and baseline NSE: hazard ratio= 1.09 (95% CI, 1.03–1.16), P=0.006. No other known prognostic factors are related to outcome. A multivariate model including baseline NSE, CgA, ECOG PS and Gleason score showed a 15% rise of the risk of death related to NSE (borderline P value). Conclusions: NSE was the most powerful predictor of survival for HRPC pts. Our results emphasize the theory that cells secreting NSE are chemoresistant, with a negative impact on OS.

No significant financial relationships to disclose.
First-line pemetrexed (P) for the treatment of hormone refractory prostate cancer (HRPC): A phase I/II study
Authors: Lehmann J. , Hack M. , Büttner H. , Stöckle M.
Published: March 2020

15597

Background: Evaluation of maximum tolerated dose (MTD), efficacy and toxicity of pemetrexed as first-line treatment in HRPC. Methods: Patients (pts) with metastatic and/or unresectable HRPC and progression received P monotherapy 500 mg/m2 i.v. d1 q21d-cycle for 6 cycles with VitB12 and folate supplementation until progression or dose-limiting toxicity. Corticosteroids were given 8 mg p.o. 3 d around P infusion. The primary outcome measure was PSA (serological) response (PSAr), defined as = 50% decline from baseline, confirmed at least 3 wks later. If no metastatic disease, baseline PSA > 5 ng/mL was required. Results: Patient characteristics: 12 pts were treated; median age was 67 yrs (61–76), median baseline PSA 138.6 ng/ml (9.4–2662), median Karnofsky status 95 (80–100). Cycles: A total of 55 treatment cycles was administered with a median of 5 cycles (1–6) per pt. Due to dose limiting toxicities (DLT) during the first cycle in 2/6 pts, P dose was reduced to 400 mg/m2 d1 q21d-cycle for the following 6 pts. One pt experienced a DLT during his first cycle with P 400 mg/m2. Dose needed to be reduced in 3/12 pts, treatment discontinuation occurred in 6/12 pts. Adverse Effects: 6 of 12 (50%) pts experienced a total of 18 grade 3 events according to CTC criteria, including neutropenia, anemia and pain. 4 of 12 (33%) pts experienced a total of 7 grade 4 events, mainly neutropenia and leucopenia. 1 death occurred after one dose of P 500 mg/m2; relationship to P could not be ruled out. Response: 11/12 pts were evaluable for response. On 500 mg/m2 1 pt showed serological response, 1 partial tumor-response in metastatic lymph-node disease was seen. Overall, 7 patients remained serologically stable (63.6%), 3 PSA progressions (27.3%) were seen. Stable serological status could be maintained for 3–43 wks. Conclusions: P 400 mg/m2 was determined the recommended dose for a potential phase II, with an acceptable toxicity profile in this patient population. Serological stability could be achieved in > 60% of patients for up to 43 wks. However, as no confirmed PSA response was achieved with P 400 mg/m2, in a potential phase II a schedule with P 400 mg/m2 but higher dose-density should be pursued as a first-line approach in pts with HRPC.

No significant financial relationships to disclose.
A phase II study of mammalian target of rapamycin (mTOR) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC)
Authors: Chan J. S. , Vuky J. , Besaw L. A. , Beer T. M. , Ryan C. W.
Published: March 2020

15600

Background: The serine-threonine kinase mTOR is a valid target for RCC therapy with temsirolimus treatment resulting in improved overall survival in poor-risk patients (Hudes G et al., ASCO 2006). RAD001 is an oral inhibitor of mTOR which has demonstrated activity in RCC at 10mg/day (Amato R et al., ASCO 2006). IM is a tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), a target that may promote angiogenesis and growth of RCC. Combined mTOR and PDGFR inhibition with RAD001 and IM may achieve vertical blockade through the PI3K/AKT pathway. Methods: Eligibility: metastatic clear cell RCC, performance status (PS) 0–2, adequate organ function, and prior treatment with = 1 systemic therapy. Doses were based on a phase I study of the combination in GIST (Van Oosterom AT et al., ASCO 2005): RAD001 2.5 mg p.o. daily and IM 600 mg p.o. daily. Patients were reimaged every 6 weeks. This is a 2-stage phase II study to determine the 3-month progression-free rate. Results: 14 pts have been enrolled. Median age 66 years (51–79). 6 pts PS 0 and 8 pts PS 1. Median number of prior therapies 1.5 (1–4). 12 of 14 patients had prior TKI therapy. Prior therapies included sorafenib (11 pts), interferon (7), sunitinib (3), bevacizumab (2), erlotinib (1), panitumumab (1), high-dose IL-2 (1). Of 10 pts evaluable for the primary endpoint, 3 are progression-free = 3 months. Best response for 9 pts evaluable by RECIST: PR/CR 0, SD 7, PD 2. Most common adverse events in 11 evaluable patients include nausea (8), edema (7), increased creatinine (7), fatigue (7), transaminase elevation (6), thrombocytopenia (5), leukopenia (5), cough (5), diarrhea (5). Grade 3 adverse events include fatigue (3), LE edema, rash, pleural effusion, increased creatinine, abdominal pain, and thrombocytopenia (1 each). There were no grade 4 toxicities. Unique suspected RAD001 toxicities include grade 3 pneumonitis (1) and angioedema (1). Conclusions: The combination of RAD001 and IM has moderate toxicity. This is one of the first studies in RCC patients predominantly pretreated with a TKI. 3 month progression-free rate appears to be a clinically relevant endpoint in this population.

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Erlotinib has activity in androgen-independent prostate cancer (AIPC) patients who are chemotherapy-naive: A phase II trial
Authors: Nabhan C. , Tolzien K. , Newman S. , Kelby S. , Lestingi T. , Galvez A. , Bitran J. D.
Published: March 2020

15606

Background: Mechanisms of hormone resistance for AIPC are variable. One proposed mechanism is the over expression of the epidermal growth factor receptor (EGFR) which in turn stimulates proliferation through its pathway. We aimed to determine the efficacy of an oral anti-EGFR inhibitor (erlotinib) in this patient population that was chemotherapy-naive. The primary end point was to evaluate the overall clinical benefit defined as the sum of complete response (CR), partial response (PR), and stable disease (SD). Methods: Between January and December 2006, sixteen patients were enrolled onto this phase II study. Median age was 78 years (66–85). Median PSA was 61.9 (9.2–800.2). Median time from initial diagnosis until starting Erlotinib was 7.8 years. Erlotinib was given daily at 150 mg until disease progression. Patients were evaluated every 2 weeks for toxicity. Response assessment took place every 2 cycles (each cycle was 4 weeks). Evaluations included computed tomography of measurable disease areas, bone scans, and serum PSAs. Patients who progressed radiographically but maintained a PSA response or those who progressed biochemically but maintained a radiographic response were considered stable and were allowed to continue on study. Results: Sixteen patients were enrolled with 14 being evaluable at this time (2 patients are early in their course). Median cycles received is 2 (range 1.5–12). One patient achieved a PR and continues on Erlotinib after one year of enrollment. Three patients demonstrated stable disease but two of them later progressed. One patient withdrew after 9 days of starting therapy due to fatigue and poor taste. All other patients developed disease progression after two cycles of therapy. The calculated overall clinical benefit was 28% (4 responses out of 14 patients). One patient died from pneumonia and seizures unrelated to Erlotinib as confirmed by an autopsy that showed progression in the central nervous system. Erlotinib was well-tolerated with skin rash and diarrhea being the most common toxicities. Conclusions: Erlotinib has clinical activity as a single agent in AIPC. Updated results of this ongoing study will be presented at the meeting. Further studies with this agent alone or in combination are warranted.

No significant financial relationships to disclose.
Sorafenib treatment of clear-cell renal cell carcinoma (CCRCC) and colorectal carcinoma (CRC) cells: Differential effects on gene expression and cell death pathways
Authors: Vaziri S. A. , Al-Hazzouri A. , Grabowski D. R. , Ganapathi M. K. , Bukowski R. M. , Ganapathi R.
Published: March 2020

15612

Background: The von Hippel Lindau gene (VHL) is often mutated in CCRCC and leads to loss of VHL protein (pVHL) expression. Sorafenib is a TKI with clinical activity in metastatic CCRCC. Studies to define mechanisms governing anti-tumor activity of this agent in CCRCC or CRC cell lines that express wild-type pVHL were conducted. Methods: We evaluated CAKI-1 (CCRCC) and HCT- 116/p53 +/+ (CRC) cell lines as model systems expressing wild-type pVHL. Cells were treated at 37°C in an atmosphere of normoxia (21% O2) or hypoxia (1% O2), 5% CO2 and the remainder N2 in the absence (control) or presence of sorafenib (2.5–20 μM) for 24–96 hours. Expression of target angiogenesis, apoptotic and anti-apoptotic genes was determined by real-time RT- PCR. Fluorescence microscopy following staining with Hoechst 33342 plus propidium iodide was used to analyze cell death by apoptosis and/or necrosis. Caspase-3 activity was measured using the target substrate DEVD-AFC. Results: In CAKI-1 and HCT-116 cells, exposure to 1% O2 relative to 21% O2, led to increased expression (2 to 6-fold) of angiogenesis (VEGF) and anti-apoptosis (TNFAIP3 & MCF2) genes. However, in an atmosphere of 1% O2 relative to 21% O2, a decreased (>2-fold) and increased (>3-fold) expression of the apoptotic (TNFRSF25) gene was observed in CAKI-1 cells and HCT-116 cells. Sorafenib treatment (7.5 μM) of CAKI-1 cells in 1% O2 led to a >3–4-fold decrease in expression of the VEGF and TNFAIP3 and a 3-fold increase TNFRSF25 genes. Following treatment with 10 μM sorafenib for 48h, cell death was >80% by necrosis in CAKI-1 cells and >95% by apoptosis in HCT-116 cells. Apoptotic cell death in the HCT-116 was also confirmed by increased caspase-3 activity in cell extracts following sorafenib treatment. Apoptotic cell death or necrotic cell death induced by sorafenib was unaffected by normoxia or hypoxia. Conclusions: In contrast to CCRCC cells, hypoxia led to upregulation of the apoptotic gene TNFRSF25 in the CRC cells. Anti- proliferative effects of sorafenib were primarily by necrosis in CCRCC cells and by apoptosis in CRC cells.

No significant financial relationships to disclose.
The effect of surgical volume on the rate of secondary therapy after radical prostatectomy
Authors: Jeldres C. , Gallina A. , Walz J. , Fred S. , Perrotte P. , Valiquette L. , McCormack M. , Huland H. , Montorsi F. , Karakiewicz P.
Published: March 2020

15620

Introduction and Objective: Some argue that prostate cancer (PCa) detection and treatment at a younger age may translate into higher rate of clinically insignificant PCa. We assessed the effect of patients age at diagnosis on the pathological stage at radical prostatectomy (RP). Methods: Clinical and pathological data were available for 11975 patients from 3 European and 3 North American tertiary care centers. All RPs were performed between 1987 and 2006. Univariable and multivariable logistic regression analyses addressed the effect of age at RP on the rate of extracapsular extension (ECE), seminal vesicle invasion (SVI) and lymph node invasion (LNI), after controlling for PSA, clinical stage, biopsy Gleason sum and year of surgery. Age at RP was coded as cubic spline to allow non-linear effects. Results: Mean age was 61.6 years (range 32–85) and mean PSA was 8.7 ng/mL (range 0.1–50.0). Biopsy Gleason sum was 2–6, 7 or 8–10 in 7510 (62.7%), 3656 (30.5%) and 809 (6.8%) patients, respectively. At RP, ECE, SVI and LNI were identified in 3383 (28.3%), 1309 (10.9%) and 469 (3.9%), respectively. In multivariable analyses, age was only an independent predictor of SVI (p<0.001). Older men had a higher rate of SVI. Conclusions: Pathological age only affects the rate of SVI. However, only one in ten men harbored SVI and this percentage may decrease even further with ongoing stage migration. Nonetheless, these data suggest that the removal of seminal vesicles should not be omitted in older men.

No significant financial relationships to disclose.