Gennaro Musi

Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) Significantly Improve Prostate Cancer Detection at Initial Biopsy in a Total PSA Range of 2–10 ng/ml

Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2–10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), % fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p<0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2–10 ng/ml at initial biopsy, outperforming currently used %fPSA.

Robot-assisted simple prostatectomy (RASP): does it make sense?

Study Type – Therapy (case series)

Dose Escalation for Prostate Cancer Using the Three-Dimensional Conformal Dynamic Arc Technique: Analysis of 542 Consecutive Patients

PURPOSE To present the results of dose escalation using three-dimensional conformal dynamic arc radiotherapy (3D-ART) for prostate cancer. METHODS AND MATERIALS Five hundred and forty two T1-T3N0M0 prostate cancer patients were treated with 3D-ART. Dose escalation (from 76 Gy/38 fractions to 80 Gy/40 fractions) was introduced in September 2003; 32% of patients received 80 Gy. In 366 patients, androgen deprivation was added to 3D-ART. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median follow-up was 25 months. RESULTS Acute toxicity included rectal (G1-2 28.9%; G3 0.5%) and urinary events (G1-2 57.9%; G3-4 2.4%). Late toxicity included rectal (G1-2 15.8%; G3-4 3.1%) and urinary events (G1-2 26.9%; G3-4 1.6%). Two-year failure-free survival and overall survival rates were 94.1% and 97.9%, respectively. Poor prognostic group (GS, iPSA, T), transurethral prostate resection, and dose >76 Gy showed significant association to high risk of progression in multivariate analysis (p = 0.014, p = 0.045, and p = 0.04, respectively). The negative effect of dose >76 Gy was not observed (p = 0.10), when the analysis was limited to 353 patients treated after September 2003 (when dose escalation was introduced). Higher dose was not associated with higher late toxicity. CONCLUSIONS Three-dimensional-ART is a feasible modality allowing for dose escalation (no increase in toxicity has been observed with higher doses). However, the dose increase from 76 to 80 Gy was not associated with better tumor outcome. Further investigation is warranted for better understanding of the dose effect for prostate cancer.

Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer: A Systematic Diagnostic Attempt

BACKGROUND Assessing the neuroendocrine (NE) pattern in castration-resistant prostate cancer (CRPC) may prove useful in selecting potential responders to target therapies such as somatostatin analogues. The aim of this study was to define a panel of markers or examinations appropriate to characterize NE differentiation (NED). METHODS Forty-seven patients with CRPC underwent a systematic diagnostic attempt to characterize the NE phenotype using a plasma blood test for chromogranin A (CgA) and immunohistochemical staining of needle biopsy-obtained specimens (CgA, somatostatin receptor 2 [SSTR2], Ki-67, and androgen receptors). In a subgroup of 26 patients, somatostatin receptor scintigraphy using (111)In-DTPA-d-Phe octreotide (octreotide scintigraphy; Octreoscan, Covidien, Hazelwood, MO) was also performed. RESULTS NED was found in 85.1% of patients (if serum CgA, tissular CgA, and tissular SSTR2 were considered separately: 54%, 67%, and 58%, respectively). Only 15% of the 26-patient subgroup had an abnormal octreotide scintigraphy result. Although p-CgA and t-CgA were associated with more aggressive disease with a worse prognosis, patients with positive tissular SSTR2 staining had longer overall survival (OS). CONCLUSION This systematic approach to explore the NED in a quite homogeneous group of patients with CRPC seems reproducible and appropriate. Further investigations are required to validate this panel and better characterize potential responders to targeted therapy.

Acute toxicity of image-guided hypofractionated radiotherapy for prostate cancer: nonrandomized comparison with conventional fractionation

OBJECTIVES To compare acute toxicity of prostate cancer image-guided hypofractionated radiotherapy (hypo-IGRT) with conventional fractionation without image-guidance (non-IGRT). To test the hypothesis that the potentially injurious effect of hypofractionation can be counterbalanced by the reduced irradiated normal tissue volume using IGRT approach. MATERIALS AND METHODS One hundred seventy-nine cT1-T2N0M0 prostate cancer patients were treated within the prospective study with 70.2 Gy/26 fractions (equivalent to 84 Gy/42 fractions, α/β 1.5 Gy) using IGRT (transabdominal ultrasound, ExacTrac X-Ray system, or cone-beam computer tomography). Their prospectively collected data were compared with data of 174 patients treated to 80 Gy/40 fractions with non-IGRT. The difference between hypo-IGRT and non-IGRT cohorts included fractionation (hypofractionation vs. conventional fractionation), margins (hypo-IGRT margins: 7 mm and 3 mm, for all but posterior margins; respectively; non-IGRT margins: 10 and 5 mm, for all but posterior margins, respectively), and use of image-guidance or not. Multivariate analysis was performed to define the tumor-, patient-, and treatment-related predictors for acute toxicity. RESULTS All patients completed the prescribed radiotherapy course. Acute toxicity in the hypo-IGRT cohort included rectal (G1: 29.1%; G2: 11.2%; G3: 1.1%) and urinary events (G1: 33.5%; G2: 39.1%; G3: 5%). Acute toxicity in the non-IGRT patients included rectal (G1: 16.1%; G2: 6.3%) and urinary events (G1: 36.2%; G2: 20.7%; G3: 0.6%). In 1 hypo-IGRT and 2 non-IGRT patients, radiotherapy was temporarily interrupted due to acute toxicity. The incidence of mild (G1-2) rectal and bladder complications was significantly higher for hypo-IGRT (P = 0.0014 and P < 0.0001, respectively). Multivariate analysis showed that hypo-IGRT (P = 0.001) and higher PSA (P = 0.046) are correlated with higher acute urinary toxicity. No independent factor was identified for acute rectal toxicity. No significant impact of IGRT system on acute toxicity was observed. CONCLUSIONS The acute toxicity rates were low and similar in both study groups with some increase in mild acute urinary injury in the hypo-IGRT patients (most probably due to the under-reporting in the retrospectively analyzed non-IGRT cohort). The higher incidence of acute bowel reactions observed in hypo-IGRT group was not significant in the multivariate analysis. Further investigation is warranted in order to exclude the bias due to the nonrandomized character of the study.

Image Guided Hypofractionated Radiotherapy and Quality of Life for Localized Prostate Cancer: Prospective Longitudinal Study in 337 Patients

PURPOSE We prospectively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy. MATERIALS AND METHODS Between August 2006 and January 2011, 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospective, longitudinal study of hypofractionated image guided radiotherapy (70.2 Gy/26 fractions) using 1 of 3 image guided radiotherapy modalities (transabdominal ultrasound, x-ray or cone beam computerized tomography) available in our radiation oncology department. Patients completed 4 questionnaires before treatment, and 6, 12 and 24 months later, including the International Index of Erectile Function-5, International Prostate Symptom Score, and EORTC (European Organization for Research and Treatment of Cancer) prostate cancer specific QLQ-PR25 and QLQ-C30. RESULTS Patient followup was updated to at least the last questionnaire time point. Median followup was 19 months. Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without androgen deprivation (p = 0.0002). No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score. Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed (p = 0.02). Overall QLQ-C30 Global Health Status improved with time (p = 0.03). On univariate analysis it significantly correlated with the maximum RTOG (Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy. CONCLUSIONS The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time.

Body mass index was associated with upstaging and upgrading in patients with low-risk prostate cancer who met the inclusion criteria for active surveillance

BACKGROUND Obesity is associated with an increased risk of high-grade prostate cancer (PCa). The effect of body mass index (BMI) as a predictor of progression in men with low-risk PCa has been only poorly assessed. In this study, we evaluated the association of BMI with progression in patients with low-risk PCa who met the inclusion criteria for the active surveillance (AS) protocol. METHODS We assessed 311 patients who underwent radical prostatectomy and were eligible for AS according to the following criteria: clinical stage T2a or less, prostate-specific antigen level < 10 ng/ml, 2 or fewer cores involved with cancer, Gleason score ≤ 6 grade, and prostate-specific antigen density < 0.2 ng/ml/cc. Reclassification was defined as upstaged (pathological stage > pT2) and upgraded (Gleason score ≥ 7; primary Gleason pattern 4) disease. Seminal vesicle invasion, positive lymph nodes, and tumor volume ≥ 0.5 ml were also recorded. RESULTS We found that high BMI was significantly associated with upgrading, upstaging, and seminal vesicle invasion, whereas it was not associated with positive lymph nodes or large tumor volume. At multivariate analysis, 1 unit increase of BMI significantly increased the risk of upgrading, upstaging, seminal vesicle invasion, and any outcome by 21%, 23%, 27%, and 20%, respectively. The differences between areas under the receiver operating characteristics curves comparing models with and without BMI were statistically significant for upgrading (P = 0.0002), upstaging (P = 0.0007), and any outcome (P = 0.0001). CONCLUSIONS BMI should be a selection criterion for inclusion of patients with low-risk PCa in AS programs. Our results support the idea that obesity is associated with worse prognosis and suggest that a close AS program is an appropriate treatment option for obese subjects.

Diagnostic Accuracy of 64Copper Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography for Primary Lymph Node Staging of Intermediate- to High-risk Prostate Cancer: Our Preliminary Experience

OBJECTIVE To assess the diagnostic accuracy of 64Copper prostate-specific membrane antigen (64Cu-PSMA) positron emission tomography/computed tomography (PET/CT) in the primary lymph node (LN) staging of a selected cohort of intermediate- to high-risk prostate cancer (PCa) patients. MATERIALS AND METHODS An observational prospective study was performed in 23 patients with intermediate- to high-risk PCa, who underwent 64Cu-PSMA PET/CT for local and lymph nodal staging before laparoscopic radical prostatectomy with an extended pelvic LN dissection. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for LN status of 64Cu-PSMA PET/CT were calculated using the final pathological findings as reference. Furthermore, we evaluated the correlation of intraprostatic tumor extent and grading with 64Cu-PSMA intraprostatic distribution. RESULTS Pathological analysis of LN involvement in 413 LNs harvested from our study cohort identified a total of 22 LN metastases in 8 (5%) of the 23 (35%) PCa patients. Imaging-based LN staging in a per-patient analysis showed that 64Cu-PSMA PET/CT was positive in 7 of 8 LN-positive patients (22%) with a sensitivity of 87.5%, specificity of 100%, PPV of 100%, and NPV of 93.7%, considering the maximum standardized uptake value (SUVmax) at 4 hours as our reference. Receiver operating characteristic curve was characterized by an area under the curve of 0.938. A significant positive association was observed between SUVmax at 4 hours with Gleason score, index, and cumulative tumor volume. CONCLUSION In our intermediate- to high-risk PCa patients study cohort, we showed the high diagnostic accuracy of 64Cu-PSMA PET/CT for primary LN staging before radical prostatectomy.

Salvage Stereotactic Body Radiotherapy for Isolated Lymph Node Recurrent Prostate Cancer: Single Institution Series of 94 Consecutive Patients and 124 Lymph Nodes

Background The purpose of the study was to evaluate the prostate serum antigen (PSA) response, local control, progression‐free survival (PFS), and toxicity of stereotactic body radiotherapy (SBRT) for lymph node (LN) oligorecurrent prostate cancer. Patients and Methods Between May 2012 and October 2015, 124 lesions were treated in 94 patients with a median dose of 24 Gy in 3 fractions. Seventy patients were treated for a single lesion and 25 for > 1 lesion. In 34 patients androgen deprivation (AD) was combined with SBRT. We evaluated biochemical response according to PSA level every 3 months after SBRT: a 3‐month PSA decrease from pre‐SBRT PSA of more than 10% identified responder patients. In case of PSA level increase, imaging was performed to evaluate clinical progression. Toxicity was assessed every 6 to 9 months after SBRT. Results Median follow‐up was 18.5 months. In 13 patients (14%) Grade 1 to 2 toxicity was reported without any Grade 3 to 4 toxicity. Biochemical response, stabilization, and progression were observed in 64 (68%), 10 (11%), and 20 (21%) of 94 evaluable patients. Clinical progression was observed in 31 patients (33%) after a median time of 8.1 months. In‐field progression occurred in 12 lesions (9.7%). Two‐year local control and PFS rates were 84% and 30%, respectively. Age older than 75 years correlated with better biochemical response rate. Age older than 75 years, concomitant AD administered up to 12 months, and pelvic LN involvement correlated with longer PFS. Conclusion SBRT is safe and offers good in‐field control. At 2 years after SBRT, 1 of 3 patients is progression‐free. Further investigation is warranted to identify patients who benefit most from SBRT and to define the optimal combination with AD. Micro‐Abstract Stereotactic body radiotherapy is being investigated in nodal oligometastatic prostate cancer recurrences as an alternative to systemic treatment. This approach yields excellent in‐field control and a low toxicity profile. In selected cases, this approach might also defer palliative androgen deprivation therapy.

Modified Glasgow Prognostic Score is Associated With Risk of Recurrence in Bladder Cancer Patients After Radical Cystectomy: A Multicenter Experience

Abstract Recently, many studies explored the role of inflammation parameters in the prognosis of urinary cancers, but the results were not consistent. The modified Glasgow Prognostic Score (mGPS), a systemic inflammation marker, is a prognostic marker in various types of cancers. The aim of the present study was to investigate the usefulness of the preoperative mGPS as predictor of recurrence-free (RFS), overall (OS), and cancer-specific (CSS) survivals in a large cohort of urothelial bladder cancer (UBC) patients. A total of 1037 patients with UBC were included in this study with a median follow-up of 22 months (range 3–60 months). An mGPS = 0 was observed in 646 patients (62.3%), mGPS = 1 in 297 patients (28.6 %), and mGPS = 2 in 94 patients (9.1%). In our study cohort, subjects with an mGPS equal to 2 had a significantly shorter median RFS compared with subjects with mGPS equal to 1 (16 vs 19 months, hazard ratio [HR] 1.54, 95% CI 1.31–1.81, P < 0.001) or with subjects with mGPS equal to 0 (16 vs 29 months, HR 2.38, 95% CI 1.86–3.05, P < 0.001). The association between mGPS and RFS was confirmed by weighted multivariate Cox model. Although in univariate analysis higher mGPS was associated with lower OS and CSS, this association disappeared in multivariate analysis where only the presence of lymph node-positive bladder cancer and T4 stage were predictors of worse prognosis for OS and CSS. In conclusion, the mGPS is an easily measured and inexpensive prognostic marker that was significantly associated with RFS in UBC patients.