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178 Abstracts

  • Introduction & Objectives

    Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs survival of metastatic castration-resistant prostate cancer (mCRPC) patients. A low dose of prednisone (P) is given when AA is administered to mCRPC patients. Long-term use of moderate-/high-dose corticosteroids (CS) has an established adverse event (AE) profile. We investigated whether long-term use of low-dose P with or without AA led to CS-associated AEs.

    Material & Methods

    2267 mCRPC patients in COU-AA-301 and COU-AA-302 received 5 mg bid P, representing 2006 patient-years of P exposure. 1333 patients received AA + P. We used an inclusive Standardized MedDRA Queries–oriented approach to identify 112 preferred terms for known CS-associated AEs from both databases. CS-associated AEs during each 3-month exposure interval and across all exposure to P were assessed.

    Results

    The overall incidence of CS-associated AEs for any P exposure was 25%, 26%, and 23% for all patients, AA + P, and P alone, respectively. The incidence of grade ≥ 3 CS-associated AEs with any P exposure was 5%, 5%, and 4% for all patients, AA + P, and P alone, respectively. The most common grade ≥ 3 CS-associated AEs occurring in ≥ 0.1% of all patients were hyperglycemia (2%), cataract (0.4%), diabetes mellitus (0.4%), gastrointestinal hemorrhage (0.3%), adrenal insufficiency (0.1%), hip fracture (0.1%), melena (0.1%), and osteoporotic spinal compression fracture (0.1%). The overall incidence of weight increase (grade 1 and 2 only) was 4%, 4%, and 5% for all patients, AA + P, and P alone, respectively. Most were grade 1 (3.4%). When assessed by duration of exposure (3-month intervals up to ≥ 30 months), grade ≥ 3 CS-associated AEs fluctuated between 1% and 2%, but no discernable trend was observed. The observed change in weight from baseline showed no apparent increase over time.

    Conclusions

    With more than 2000 patient-years of exposure, low-dose P given with or without AA is associated with an overall low incidence of CS-associated AEs. The occurrence of CS-associated AEs remained low with increased duration of exposure to P.

  • Introduction & Objectives

    Decrease in the peripheral blood leukocyte count is a well-known side effect of radiation therapy for prostate cancer and it is considered a negative prognostic factor. Beside the direct toxicity to the bone marrow, a redistribution of circulating leukocytes after pelvic irradiation is also a relevant factor, which is still poorly investigated.

    Material & Methods

    We have set up an animal model to allow tracking of peripheral leukocyte relocation after radiation treatment focused to the urinary bladder. This method will serve to investigate a possible selective accumulation of circulating leucocytes to specific anatomical districts affected by the radiations. Fisher female rats (n=6) were adoptively transferred IV with 4x107 VivoTag-750-labelled syngeneic primary splenocytes, two hours before bladder irradiation. Animals were transurethrally catheterized to allow contrast agent instillation and undergone to a kV cone beam computed tomography (CBCT) imaging to precisely deliver monofraction radiation treatment (15-25 Gy range). Bladder tissue reaction to the radiation was followed over time by ultrasonography, while possible accumulation sites of labelled leukocytes were evaluated by in vivo fluorescent imaging.

    Results

    Preliminary results show that a significant increase in the bladder wall thickness peaked 4 days after radiotreatment in animals treated at a dose of 25 Gy. A fluorescent signal, secondary to labelled splenocytes accumulation, was detectable in the liver and lymph nodes of all adoptively transferred rats, 2 and 6 days after transfer, as expected. A modest specific signal (30% increase) at the bladder level was detected only in animals (n=2) subjected to 25 Gy irradiation (figure 1.a), when compared to the non-irradiated controls (n=3) (figure 1.b). No specific fluorescent signal was detected at the bladder levels in animals treated with 20 and 15 Gy (n=2/group).

    Conclusions

    These data suggest that relocalization to the damaged tissue of peripheral leukocytes can be followed in a non-invasive way and may occur dependently on the radiation dosage. Further analyses are currently ongoing.

  • Introduction & Objectives

    For patients with advanced TCC who have progressed on a platinum-based regimen, no widely accepted standard second line therapy currently exists. A 2-stage phase II study was conducted to assess the activity and toxicity profile of the microtubule inhibitor cabazitaxel (Jevtana; FDA-approved in hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen) in patients with metastatic TCC after failure of prior platinum-based chemotherapy. ClinicalTrials.gov NCT01600339

    Material & Methods

    Patients with one prior platinum based systemic therapy for metastatic TCC received cabazitaxel at a dose of 25 mg\m2 every 21 days with prophylactic GCSF support, until disease progression or unacceptable toxicity. The primary endpoint was objective tumour response rate (ORR). Secondary endpoints included safety, time to progression (TTP), and overall survival (OS).

    Results

    Twenty-three patients were enrolled to the study, 19 of whom received treatment. Male\female ratio was 15\4 and the median age was 67 (range, 56-81) years. Partial response (PR) was observed in 1 patient (5.3%), 10 patients (52.6%) achieved stable disease (SD), including 8 (42.1%) that had prolonged SD (≥16 weeks). Furthermore, the disease control rate (PR or prolonged SD) was 47.4%. At a median follow up of 10.1 months, all patients progressed and 16/19 (84%) died. The median TTP and OS were 4.2 (95% CI, 2.0-6.0) months and 9.9 (95% CI 5.6-13.2) months, respectively. Neutrophil to lymphocyte ratio-NLR ≥3 vs ≤ 3 was associated resistance to treatment: 7/7 progressive disease (P≤0.0023). The median number of treatment cycles was 5 (range 1-10). One patient experienced Grade 5 toxicity. Neutropenic fever occurred in 10.6% of patients. Most common toxicities were anemia and diarrhea.

    Conclusions

    Cabazitaxel had modest efficacy in the treatment of advanced TCC, and there was no evidence of a significant response. Toxicity profile was considerable. The role of Cabazitaxel in urothelial carcinoma may need further evaluation in rational combination strategies, but not as a single agent.

  • Introduction & Objectives

    The phase III trial (Motzer RJ, 2007)that led to the approval of Sunitinib for first line treatment in stage IV renal cell carcinoma, clear-cell type, showed benefit by increasing progression-free survival and response rate. The criteria for patient selection used in clinical trials are defined in order to ensure greater safety and homogeneity of the study population. However, this population may not represent the actual population in clinical practice.
    We applied the inclusion and exclusion criteria of this trial in outpatient population and verified if they resembled the trial population as well as the patient outcomes regarding Progression Free Survival (PFS) and Overall Survival (OS).

    Material & Methods

    We analysed patients that received treatment with Sunitinib at our hospital between January 2011 and June 2015.
    54 patients were older than 18 years, renal cancer clear-cell type, Stage IV, first line treatment. The patients considered ineligible for the clinical trial were those who did not fulfil at least one of the inclusion criteria from the study (measurable disease, performance status 0 or 1, normal hemoglobin, coagulation, hepatic, renal and cardiac function) or who had at least one of the exclusion criteria (brain metastasis, uncontrolled hypertension, cardiovascular events in the previous 12 months). After we analysed treatment duration, reason for stopping treatment and PFS.

    Results

    Of the 54 patients, 47 (87%) would have been considered ineligible for clinical trial. The reasons were in descending order of frequency: Impaired renal function (29 patients) and anemia (29), impaired liver function (11), PS 2 or 3 (8), cerebral metastasis (6), heart failure (4), no measurable disease (4), cardiovascular events in the last 12 months (3) and impaired coagulation (2).
    Regarding the number of criteria not met, 18 patients did not meet 1 criterion, 16 patients did not meet 2 criteria, 11 patients did not meet 3, 2 patients did not meet more than 4 criteria.
    The median time between diagnosis and start of treatment was 7 months. The median duration of treatment was 5 months.
    The reason for discontinuation was progression in 47% (22) cases, toxicity in 15% (7), disease stability in 11% (5) and death in 6%(3).
    PFS was 7.7 months and OS was 21.4 months.

    Conclusions

    The number of patients in clinical practice that would be ineligible for clinical trial is substantial. Most patients failed to meet criteria for participation in the clinical trial population, the most common being renal insufficiency and anemia. Disease progression was the most common cause of Sunitinib discontinuation. Our daily practice patients are different from those selected in clinical trials and may have different outcomes.

  • Introduction & Objectives

    Data on the predictive value (i.e. identifying disease progression) of MRI after previous confirmatory biopsy in men on Active Surveillance (AS) are limited.

    To compare outcomes of MRI + target biopsy (TBx) vs. TRUS-guided systematic biopsy (SBx) at 2nd surveillance biopsy in men on AS and assess whether MRI can selectively identify patients with disease progression (i.e. Gleason score upgrading) to avoid biopsy procedures in those with stable disease.

    Material & Methods

    A total of 30 men on AS received multiparametric MRI in our academic institute at 2nd surveillance biopsy after previous confirmatory biopsy.TBx of suspicious lesions (PI-RADS >= 3) was performed using the MRI-US fusion technique. 62 men (all participants in the PRIAS study; www.prias-project.org)
    who received 2nd surveillance SBx served as a control group. Outcomes of TBx and SBx were compared to assess the upgrading rates and potentially
    saved biopsy procedures when biopsying only those men with a positive MRI. Cox proportional hazard regression analysis was performed to assess whether receiving MRI was an independent predictor for upgrading, after correction for age and PSA.

    Results

      MRI + TBx SBx
    Age (years), median (IQR) 67.5 (62.1 – 72.0) 68.6 (63.5 – 74.3)
    Time between diagnosis and biopsy (years),
    median (IQR)
    3.8 (2.8 – 5.6) 3.9 (2.5 – 4.2)
    PSA at diagnosis (ng/ml), median (IQR) 7.2 (4.8 – 9.3) 4.5 (3.0 – 6.1)
    PSA at biopsy (ng/ml), median (IQR) 10.3 (5.9 – 15.0) 5.2 (3.0 – 8.5)
    Outcome 2nd surveillance biopsy    
    MRI   not suspicious for PCa 8 (27%) /
    No   PCa in biopsy 6 (20%) 24 (39%)
    Gleason   score = 3+3 PCa in biopsy 8 (27%) 33 (53%)
    Gleason   score >= 3+4 PCa in biopsy 8 (27%) 5 (8%)
    Total nr. of patients 30 (100%) 62 (100%)

    MRI+ TBx resulted in more Gleason score upgrading than SBx (27% vs. 8%). However, men who received MRI instead of SBx had higher PSA-levels both at diagnosis and at 2nd surveillance biopsy. After correction for the PSA-levels, receiving MRI was no independent predictor for upgrading: HR = 1.39 (95% CI 0.16 – 3.3), p = 0.672.  Although the PSA-levels and high-grade (Gleason score >= 3+4) PCa rate were higher in the MRI group, 27% of these men had a negative MRI and thus did not receive TBx.

    Conclusions

    A larger sample size and follow-up data are needed to confirm these preliminary results: Performing a MRI at 2nd surveillance biopsy could save app. 30% of prostate biopsy procedures without compromising the identification of disease progression.

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