Performance of a Region of Interest-based Algorithm in Diagnosing International Society of Urological Pathology Grade Group ≥2 Prostate Cancer on the MRI-FIRST Database-CAD-FIRST Study.

BACKGROUND AND OBJECTIVE: Prostate multiparametric magnetic resonance imaging (MRI) shows high sensitivity for International Society of Urological Pathology grade group (GG) ≥2 cancers. Many artificial intelligence algorithms have shown promising results in diagnosing clinically significant prostate cancer on MRI. To assess a region-of-interest-based machine-learning algorithm aimed at characterising GG ≥2 prostate cancer on multiparametric MRI. METHODS: The lesions targeted at biopsy in the MRI-FIRST dataset were retrospectively delineated and assessed using a previously developed algorithm. The Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2) score assigned prospectively before biopsy and the algorithm score calculated retrospectively in the regions of interest were compared for diagnosing GG ≥2 cancer, using the areas under the curve (AUCs), and sensitivities and specificities calculated with predefined thresholds (PIRADSv2 scores ≥3 and ≥4; algorithm scores yielding 90% sensitivity in the training database). Ten predefined biopsy strategies were assessed retrospectively. KEY FINDINGS AND LIMITATIONS: After excluding 19 patients, we analysed 232 patients imaged on 16 different scanners; 85 had GG ≥2 cancer at biopsy. At patient level, AUCs of the algorithm and PI-RADSv2 were 77% (95% confidence interval [CI]: 70-82) and 80% (CI: 74-85; p = 0.36), respectively. The algorithm's sensitivity and specificity were 86% (CI: 76-93) and 65% (CI: 54-73), respectively. PI-RADSv2 sensitivities and specificities were 95% (CI: 89-100) and 38% (CI: 26-47), and 89% (CI: 79-96) and 47% (CI: 35-57) for thresholds of ≥3 and ≥4, respectively. Using the PI-RADSv2 score to trigger a biopsy would have avoided 26-34% of biopsies while missing 5-11% of GG ≥2 cancers. Combining prostate-specific antigen density, the PI-RADSv2 and algorithm's scores would have avoided 44-47% of biopsies while missing 6-9% of GG ≥2 cancers. Limitations include the retrospective nature of the study and a lack of PI-RADS version 2.1 assessment. CONCLUSIONS AND CLINICAL IMPLICATIONS: The algorithm provided robust results in the multicentre multiscanner MRI-FIRST database and could help select patients for biopsy. PATIENT SUMMARY: An artificial intelligence-based algorithm aimed at diagnosing aggressive cancers on prostate magnetic resonance imaging showed results similar to expert human assessment in a prospectively acquired multicentre test database.

Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted Biopsies for Prostate Cancer Diagnosis: Final Results of the Randomized PERFECT trial (CCAFU-PR1).

BACKGROUND: Recent guidelines favor transperineal (TP) prostate biopsies over the transrectal (TR) approach due to a reduced sepsis risk. Yet, evidence from controlled trial comparing both approaches within the MRI-targeted pathway for significant prostate cancer (PCa) detection is lacking. OBJECTIVE: To compare the significant PCa detection rate between magnetic resonance imaging (MRI)-targeted TR and TP approaches in biopsy-naïve patients. DESIGN, SETTING, AND PARTICIPANTS: In this noninferiority controlled trial, we randomized (ratio 1:1) 270 MRI-positive biopsy-naïve patients. INTERVENTION: MRI-targeted TP versus TR biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary outcome was the detection rate of significant PCa (International Society of Urological Pathology [ISUP] ≥2) in MRI-targeted biopsies. Secondary outcomes were any-grade PCa detection, detection on concomitant systematic biopsy, complications, and functional outcomes. RESULTS AND LIMITATIONS: Targeted biopsies identified significant PCa in 47.2% of TP and 54.2% of TR participants (-7%, p = 0.6235). On a per-lesion analysis, posterior lesions yielded higher detection rates via TR (59.0% vs 44.3%, p = 0.0443), while anterior lesions were more frequently detected via TP (40.6% vs 26.5%, p = 0.2228). The overall (any grade) cancer detection rate in targeted biopsies was comparable between groups: 71.3% (TP) versus 64.1% (TR; p = 0.2209) with significantly more ISUP 1 cases detected in the TP arm. Adverse events of grade ≥2 were not different between TP (35.7%) and TR (40.5%, p = 0.4256). One TR patient (0.8%) experienced grade 3 sepsis. Quality of life, and urinary and sexual function, as well as pain scores, were comparable between groups. CONCLUSIONS: Despite a comparable overall detection rate for any-grade PCa, noninferiority of TP over TR for MRI-targeted biopsies for significant PCa detection was not demonstrated. However, MRI lesion location influenced biopsy route performance, suggesting that a pragmatic approach based on lesion location might enhance significant PCa assessment. PATIENT SUMMARY: This trial compared the efficacy and safety of two biopsy approaches for prostate cancer diagnosis. Both approaches seem complementary according to the lesion location.

Psoas muscle index is not representative of skeletal muscle index for evaluating cancer sarcopenia.

BACKGROUND: A common method for diagnosing sarcopenia involves estimating the muscle mass by computed tomography (CT) via measurements of the cross-sectional muscle area (CSMA) of all muscles at the third lumbar vertebra (L3) level. Recently, single-muscle measurements of the psoas major muscle at L3 have emerged as a surrogate for sarcopenia detection, but its reliability and accuracy remain to be demonstrated. METHODS: This prospective cross-sectional study involved 29 healthcare establishments and recruited patients with metastatic cancers. The correlation between skeletal muscle index (SMI = CSMA of all muscles at L3/height2 , cm2 /m2 ) and psoas muscle index (PMI = CSMA of psoas at L3/height2 , cm2 /m2 ) was determined (Pearson's r). ROC curves were prepared based on SMI data from a development population (n = 488) to estimate suitable PMI thresholds. International low SMI cut-offs according to gender were studied for males (<55cm2 /m2 ) and for females (<39 cm2 /m2 ). Youden's index (J) and Cohen's kappa (κ) were calculated to estimate the test's accuracy and reliability. PMI cut-offs were validated in a validation population (n = 243) by estimating the percentage concordance of sarcopenia diagnoses with the SMI thresholds. RESULTS: Seven hundred and sixty-six patients were analysed (mean age 65.0 ± 11.8 years, 50.1% female). Low SMI prevalence was 69.1%. Correlation between the SMI and PMI for the entire population was 0.69 (n = 731, P < 0.01). PMI cut-offs for sarcopenia were estimated in the development population at <6.6cm2 /m2 in males and at <4.8 cm2 /m2 for females. The J and κ coefficients for PMI diagnostic tests were weak. The PMI cut-offs were tested in the validation population where 33.3% of the PMI measurements were dichotomously discordant. CONCLUSIONS: A diagnostic test employing single-muscle measurements of the psoas major muscle as a surrogate for sarcopenia detection was evaluated but found to be unreliable. The CSMA of all muscles must be considered for evaluating cancer sarcopenia at L3.

Systemic treatment with or without ablative therapies in oligometastatic breast cancer: A single institution analysis of patient outcomes.

PURPOSE: Local ablative treatment (LAT) is increasingly combined with systemic therapy in oligometastatic breast cancer (OMBC), without a high-level evidence to support this strategy. We evaluated the addition of LAT to systemic treatment in terms of progression-free survival (PFS) and overall survival (OS). Secondary endpoints were local control (LC) and toxicity. We sought to identify prognostic factors associated with longer OS and PFS. METHODS AND MATERIALS: We identified consecutive patients treated between 2014 and 2018 for synchronous or metachronous OMBC (defined as ≤ 5 metastases). LAT included stereotactic body radiation therapy (SBRT) and volumetric modulated arc therapy (VMAT), surgery, cryotherapy and percutaneous radiofrequency ablation (PRA). PFS and OS were calculated, and Cox regression models analyzed for potential predictors of survival. RESULTS: One hundred two patients were included (no-LAT, n = 62; LAT, n = 40). Sixty-four metastases received LAT. Median follow-up was 50.4 months (95% CI [44.4; 53.4]). One patient experienced grade 3 toxicity in the LAT group. Five-year PFS and OS were 34.75% (95% CI [24.42-45.26]) and 63.21% (95% CI [50.69-73.37]) respectively. Patients receiving both LAT and systemic therapy had longer PFS and OS than those with no-LAT ([HR 0.39, p = 0.002]) and ([HR 0.31, p = 0.01]). The use of LAT, HER2-positive status and hormone-receptor positivity were associated with longer PFS and OS whereas liver metastases led to worse PFS. CONCLUSIONS: LAT was associated with improved outcomes in OMBC when added to systemic treatment, without significantly increasing toxicity. The prognostic factors identified to extend PFS and OS may help guide clinicians in selecting patients for LAT.

Managing Discordant Findings Between Multiparametric Magnetic Resonance Imaging and Transrectal Magnetic Resonance Imaging-directed Prostate Biopsy-The Key Role of Magnetic Resonance Imaging-directed Transperineal Biopsy.

BACKGROUND: Discordant findings between multiparametric magnetic resonance imaging (mpMRI) and transrectal image-guided biopsies of the prostate (TRUS-P) may result in inadequate risk stratification of localized prostate cancer. OBJECTIVE: To assess transperineal image-guided biopsies of the index target (TPER-IT) in terms of disease reclassification and treatment recommendations. DESIGN, SETTING, AND PARTICIPANTS: Cases referred for suspicion or treatment of localized prostate cancer were reviewed in a multidisciplinary setting, and discordance was characterized into three scenarios: type I-negative biopsies or International Society of Urological Pathology (ISUP) grade 1 cancer in Prostate Imaging Reporting and Data System (PI-RADS) ≥4 index target (IT); type II-negative biopsies or ISUP grade 1 cancer in anterior IT; and type III-<3 mm stretch of cancer in PI-RADS ≥3 IT. Discordant findings were characterized in 132/558 (23.7%) patients after TRUS-P. Of these patients, 102 received reassessment TPER-IT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to report changes in treatment recommendations after TPER-IT. Therefore, cores obtained by primary TRUS-P and TPER-IT were analyzed in terms of cancer detection, ISUP grade, and Cambridge Prognostic Group classification using descriptive statistics. RESULTS AND LIMITATIONS: TPER-IT biopsies that consisted of fewer cores than the initial TRUS-P (seven vs 14, p < 0.0001) resulted in more cancer tissue materials for analysis (56 vs 42.5 mm, p = 0.0003). As a result, 40% of patients initially considered for follow-up (12/30) and 49% for active surveillance (30/61) were reassigned after TPER-IT to surgery or intensity-modulated radiotherapy. CONCLUSIONS: Nonconcordance between pathology and imaging was observed in a significant proportion of patients receiving TRUS-P. TPER-IT better informed the presence and grade of cancer, resulting in a significant impact on treatment recommendations. A multidisciplinary review of mpMRI and TRUS-P findings and reassessment TPER-IT in type I-II discordances is recommended. PATIENT SUMMARY: In this report, patients with suspicious imaging of the prostate, but no or well-differentiated cancer on transrectal image-guided -biopsies, were offered transperineal image-guided biopsies for reassessment. We found that a large share of these had a more aggressive cancer than initially suspected. We conclude that discordant results warrant reassessment transperineal image-guided biopsies as these may impact disease risk classification and treatment recommendations.

Diagnosis, biology and epidemiology of oligometastatic breast cancer.

Does oligometastatic breast cancer (OMBC) deserve a dedicated treatment? Although some authors recommend multidisciplinary management of OMBC with a curative intent, there is no evidence proving this strategy beneficial in the absence of a randomized trial. The existing literature sheds little light on OMBC. Incidence is unknown; data available are either obsolete or biased; there is no consensus on the definition of OMBC and metastatic sites, nor on necessary imaging techniques. However, certain proposals merit consideration. Knowledge of eventual specific OMBC biological characteristics is limited to circulating tumor cell (CTC) counts. Given the data available for other cancers, studies on microRNAs (miRNAs), circulating tumor DNA (ctDNA) and genomic alterations should be developed Finally, safe and effective therapies do exist, but results of randomized trials will not be available for many years. Prospective observational cohort studies need to be implemented.

MRI Characteristics Accurately Predict Biochemical Recurrence after Radical Prostatectomy.

BACKGROUND: After radical prostatectomy (RP), biochemical recurrence (BCR) is associated with an increased risk of developing distant metastasis and prostate cancer specific and overall mortality. METHODS: The two-centre study included 521 consecutive patients undergoing RP for positive pre-biopsy magnetic resonance imaging (MRI) and pathologically proven prostate cancer (PCa), after which a combination scheme of fusion-targeted biopsy (TB) and systematic biopsy was performed. We assessed correlations between MRI characteristics, International Society of Urological Pathology (ISUP) grade group in TB, and outcomes after RP. We developed an imaging-based risk classification for improving BCR prediction. RESULTS: Higher Prostate Imaging and Reporting and Data System (PI-RADS) score (p = 0.013), higher ISUP grade group in TB, and extracapsular extension (ECE) on the MRI were significantly associated with more advanced disease (pTstage), higher ISUP grade group (p = 0.001), regional lymph nodes metastasis in RP specimens (p < 0.001), and an increased risk of recurrence after surgery. A positive margin status was significantly associated with ECE-MRI (p < 0.001). Our imaging-based classification included ECE on MRI, ISUP grade group on TB, and PI-RADS accurately predicted BCR (AUC = 0.714, p < 0.001). This classification had more improved area under the curve (AUC) than the standard d'Amico classification in our population. Validation was performed in a two-centre cohort. CONCLUSIONS: In this cohort, PI-RADS score, MRI stage, and ISUP grade group in MRI-TB were significantly predictive for disease features and recurrence after RP. Imaging-based risk classification integrating these three factors competed with d'Amico classification for predicting BCR.

Intercenter reproducibility of software-based fusion biopsies for grade group prediction when targeting suspicious MRI lesions.

PURPOSE: To assess the intercenter reproducibility of software-based fusion targeted biopsy (TB) for grade-group assessment and pretherapeutic evaluation of highly suspicious MRI lesions. PATIENTS AND METHODS: In this study, were included 380 consecutive patients who underwent radical prostatectomy (RP) after prostate cancer diagnosis and a prebiopsy MRI showing Prostate Imaging-Reporting and Data System (PIRADS) score 4 or 5 lesions. All patients underwent systematic biopsies (SB) combined with software-based fusion TB in the 2 centers. Biopsies were only performed by expert urologists or radiologists in a contemporary time frame. The primary endpoint was the center difference of concordance/upgrading rates between biopsy and RP specimens. RESULTS: Pathological features on biopsy and RP specimens were significantly different among centers with more unfavourable disease in center 1. The rate of TB upgrading was 33.6% in center 1 vs. 35.4% (P = 0.860) in center 2. Grading concordance was also comparable among centers (50.0% vs. 47.1%) as well as the SB upgrading rate. Regression analysis did not find any baseline characteristics (Age, prostate-specific antigen, MRI lesions, center) predictive for TB upgrading. These findings were achieved by using fewer TB per lesion in center 1 (2.3 vs. 5.0, P < 0.001), at the expense of more SB cores (14.4 vs. 8.5, P < 0.001). The influence of MRI characteristics (lesion size and number, PIRADS score) on upgrading rates was consistent among centers. CONCLUSIONS: Software-based fusion TB technique leads to comparable outcomes in terms of grade group prediction accuracy in PIRADS 4 to 5 lesions, insignificant between centers, in spite of different non imaging-based aggressiveness features.

Improvement of the intermediate risk prostate cancer sub-classification by integrating MRI and fusion biopsy features.

INTRODUCTION: Treatment decision-making for intermediate-risk prostate cancer (CaP) is mainly based on grade and tumor involvement on systematic biopsy. We aimed to assess the added value of multi-parametric magnetic resonance imaging (mpMRI) and targeted biopsy (TB) features for predicting final pathology and for improving the well-established favourable/unfavourable systematic biopsy-based sub-classification. MATERIALS AND METHODS: From a prospective database of 377 intermediate risk CaP cases, we evaluated the performance of the standard intermediate risk classification (IRC), and the predictive factors for unfavourable disease on final pathology aiming to build a new model. Overall unfavourable disease (OUD) was defined by any pT3-4 and/or pN1 and/or grade group (GG) ≥ 3. RESULTS: The standard IRC was found to be predictive for unfavourable disease in this population. However, in multivariable analysis regression, ECE on mpMRI and GG ≥3 on TB remained the 2 independent predictive factors for OUD disease (HR = 2.7, P = 0.032, and HR = 2.41, P = 0.01, respectively). By using the new IRC in which unfavorable risk was defined by ECE on mpMRI and/or GG ≥3 on TB, the proportion of unfavorable cases decreased from 62.3% to 34.1% while better predicting unfavorable disease in RP speciments. The new model displayed a better accuracy than the standard IRC for predicting OUD (AUC: 0.66 vs. 0.55). CONCLUSIONS: The integration of imaging and TB features drastically improves the intermediate risk sub-classification performance and better discriminates the unfavourable risk group that could benefit from more aggressive therapy such as neo-adjuvant and/or adjuvant treatment, and the favourable group that could avoid over-treatment. External validation in other datasets is needed.

Impact of MRI and Targeted Biopsies on Eligibility and Disease Reclassification in MRI-positive Candidates for Active Surveillance on Systematic Biopsies.

OBJECTIVE: To assess the impact of concomitant targeted biopsies (TB) for predicting final disease reclassification in MRI-positive low-risk prostate cancer patients eligible for active surveillance (AS) on systematic biopsies (SB). MATERIALS AND METHODS: From a prospective database, we included all prebiopsy MRI-positive men fulfilling AS criteria at diagnosis (Toronto [n = 114], UCSF [n = 82], or PRIAS [n = 60] criteria) on SB. All patients underwent a combination of SB and software-based fusion TB, and an immediate radical prostatectomy. The primary endpoints were the pathologic upgrading and upstaging rates. RESULTS: Biopsy grade group was upgraded to grade group (GG) 2 and to GG≥3 on TB in 65.9%-76.7% and in 12.2-16.7%, respectively. The rate of GG ≥3 in radical prostatectomy specimens varied from 31.6% to 43.3% with no relation between strictest criteria and lower upgrading rates. The proportion of not organ-confined disease (35%-39%) was comparable among the AS cohorts. Negative TB was strongly associated with the absence of final GG ≥3. Tumor grade on TB was significantly correlated with the risk of final GG ≥3 in both Toronto and UCSF cohorts, not in the PRIAS cohort. In the PRIAS cohort, the only independent predictive factor for GG ≥3 disease was the maximal tumor length in any core (P = .034). CONCLUSION: In MRI-positive patients, the risk of disease reclassification was comparable whatever the SB-based AS criteria used. TB were predictive of final upgrading, with a varied impact according to the AS criteria. SB features remained relevant for reclassification prediction even in case of positive TB. The risk of upstaged disease remains important, approximately one third, and neither TB/SB parameters nor MRI findings could accurately predict it.

Performance of systematic, MRI-targeted biopsies alone or in combination for the prediction of unfavourable disease in MRI-positive low-risk prostate cancer patients eligible for active surveillance.

PURPOSE: To assess the upstaging/upgrading rates of low-risk prostate cancer (PCa) according to the biopsy scheme used (systematic (SB), targeted biopsies (TB), or both) in the setting of positive pre-biopsy MRI. PATIENTS AND METHODS: We included 143 consecutive men fulfilling the Toronto University active surveillance (AS) criteria who underwent a pre-biopsy positive MRI, a combination of SB and software-based fusion TB, and a radical prostatectomy, in two expert centres. The primary endpoints were the pathological upgrading and upstaging rates. Overall unfavourable disease (OUD) was defined by any pT3-4 and/or pN1 and/or ≥ GG 3. RESULTS: Using TB alone would have missed 21.7% of cancers including 16.7% of ≥ GG 3. The use of TB was significantly associated with a lower risk of ≥ Grade Group (GG) 3 disease (p < 0.006) in RP specimens. Combination of SB and TB lowered this risk by 39%, compared with TB alone. The biopsy scheme did not affect the upstaging rates which were substantial even in case of combination scheme (from 37 to 46%). OUD was detected in approximately 50% of cases. The presence of high grade on TB was the only independent predictive factor for both ≥ GG 2 (p = 0.015) and ≥ GG 3 (p = 0.023) in RP specimens. CONCLUSIONS: High grade on TB biopsies represented the major predictor of upgrading. Combination of SB and TB better defined the sub-group of patients having the lowest risk of reclassification, compared with TB or SB alone. The risk of non-organ-confined disease remained high, and could not be accurately predicted by MRI or systematic/targeted biopsy features.

Active surveillance eligibility of MRI-positive patients with grade group 2 prostate cancer: a pathological study.

PURPOSE: To assess the final pathology risk in MRI-positive grade group (GG) 2 prostate cancer (PCa) patients undergoing targeted (TB) and systematic (SB) biopsies, and thereby, the possibility of active surveillance (AS) in this population. PATIENTS AND METHODS: We included 242 consecutive men diagnosed with GG2 PCa by a combination of SB and software-based fusion TB undergoing a radical prostatectomy (RP). The primary endpoints were the pathological findings in RP specimens, including favourable disease which was defined by a pT2 and GG1-2 disease. RESULTS: The rate of upgrading was 33% including 3% of GG 4-5 disease. MRI lesion size (p = 0.038) and tumor length per core (p < 0.001) were significantly lower in case of favourable pathology. Only 34.2% of not organ-confined disease was reported when only SB were positive, compared with 45.7% and 57.1% when GG2 was detected on TB only and on TB plus SB, respectively (p = 0.035). The number of positive cores on SB was significantly higher in not organ-confined disease (4.3 versus 2.9; p = 0.005). The risk of not organ-confined disease was only 20.8% in men who had a PSAD ≤ 0.20 ng/ml/gr, 1-2 positive biopsies and a maximal tumor length ≤ 6 mm per core, compared with 52.3% in men who did not fulfil all these criteria (p = 0.003). CONCLUSIONS: This study identified clinical, imaging, and pathological factors that were significantly associated with the final pathology risk. In case of positive MRI followed by TB showing GG2, AS could be offered in patients having a PSAD ≤ 0.20, a tumor length ≤ 6 mm and 1-2 positive cores.

Added Value of Concomitant Systematic and Fusion Targeted Biopsies for Grade Group Prediction Based on Radical Prostatectomy Final Pathology on Positive Magnetic Resonance Imaging.

PURPOSE: We assessed the added value of concomitant systematic biopsy for final grade group prediction in patients with positive magnetic resonance imaging who were undergoing targeted biopsy. MATERIALS AND METHODS: Included in study were 478 consecutive patients with prebiopsy positive multiparametric magnetic resonance imaging and a greater than 10-core systematic biopsy combined with fusion targeted biopsy who underwent radical prostatectomy. The primary end point was the grade group concordance between biopsy and radical prostatectomy pathology according to the biopsy technique. Clinical and biological factors associated with the performance of systematic biopsy were analyzed. RESULTS: Adding systematic biopsy to targeted biopsy modified the d'Amico risk classification toward more intermediate and high risk in 7.8% of cases, mainly from low to intermediate risk with low risk prostate cancer on targeted biopsy in 44.3%. This reclassification was significantly higher in patients with lower prostate specific antigen and with prostate specific antigen density less than 0.20 ng/ml/gm (11.7% vs 2.4%, p <0.001). The concordance rate between biopsy pathology and radical prostatectomy pathology significantly differed between targeted biopsy and targeted biopsy plus systematic biopsy (45.2% and 51.7%, respectively). The upgrading rate in radical prostatectomy specimens decreased by 22% when systematic biopsy was added to targeted biopsy. Patients in whom systematic biopsy did not modify grading were more likely to have pT3-4 and/or pN1 disease on final pathology (56.9% vs 38.3%, p=0.007). CONCLUSIONS: Grading concordance between biopsy pathology and radical prostatectomy pathology was improved by adding systematic biopsy in all patient subgroups. Patients with prostate specific antigen density less than 0.20 ng/ml/gm benefited the most from this combined biopsy strategy. Systematic biopsy reclassified a nonnegligible number of cases toward a higher risk category, mainly the low risk cases. Thus, systematic biopsy could modify treatment decision making.

Refining the risk-stratification of transrectal biopsy-detected prostate cancer by elastic fusion registration transperineal biopsies.

PURPOSE: To evaluate image-guided Transperineal Elastic-Registration biopsy (TPER-B) in the risk-stratification of low-intermediate risk prostate cancer detected by Transrectal-ultrasound biopsy (TRUS-B) when estimates of cancer grade and volume discorded with multiparametric Magnetic Resonance Imaging (MRI). METHODS: All patients referred for active surveillance or organ-conservative management were collegially reviewed for consistency between TRUS-B results and MRI. Image-guided TPER-B of the index target (IT) defined as the largest Prostate Imaging-Reporting Data System-v2 ≥ 3 abnormality was organized for discordant cases. Pathology reported Gleason grade, maximum cancer core length (MCCL) and total CCL (TCCL). RESULTS: Of 237 prostate cancer patients (1-4/2018), 30 were required TPER-B for risk-stratification. Eight cores were obtained [Median and IQR: 8 (6-9)] including six (IQR: 4-6) in the IT. TPER-B of the IT yielded longer MCCL [Mean and (95%CI): 6.9 (5.0-8.8) vs. 2.6 mm (1.9-3.3), p < 0.0001] and TCCL [19.7 (11.6-27.8) vs. 3.6 mm (2.6-4.5), p = 0.0002] than TRUS-B of the gland. On TPER-B cores, longer MCCL [Mean and (95%CI): 8.7 mm (6.7-10.7) vs. 4.1 mm (0.6-7.6), p = 0.002] were measured in Gleason score-7 cancers. TPER-B cores upgraded 13/30 (43.3%) patients. 14/30 (46.7%) met University College London-definition 1 and 18/30 (60.0%) definition 2, which correlate with clinically significant cancers > 0.5 mL and > 0.2 mL, respectively. 7/16 (43.8%) patients under active surveillance were re-allocated toward prostatectomy (n = 5) or radiation therapy (n = 2). In 14 patients not yet assigned, TPER-B risk-stratification spurred the selection (13/14, 92.9%) of treatments with curative intent. CONCLUSION: Image-guided TPER-B of the index target provided more cancer material for pathology. Subsequent re-evaluation of cancer volume and grade switched a majority of patients towards higher-risk groups and treatments with curative intent.

New approach of ultra-focal brachytherapy for low- and intermediate-risk prostate cancer with custom-linked I-125 seeds: A feasibility study of optimal dose coverage.

PURPOSE: To present the feasibility study of optimal dose coverage in ultra-focal brachytherapy (UFB) with multiparametric MRI for low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: UFB provisional dose plans for small target volumes (<7 cc) were calculated on a prostate training phantom to optimize the seeds number and strength. Clinical UFB consisted in a contour-based nonrigid registration (MRI/Ultrasound) to implant a fiducial marker at the location of the tumor focus. Dosimetry was performed with iodine-125 seeds and a prescribed dose of 160 Gy. On CT scans acquired at 1 month, dose coverage of 152 Gy to the ultra-focal gross tumor volume was evaluated. Registrations between magnetic resonance and CT scans were assessed on the first 8 patients with three software solutions: VariSeed, 3D Slicer, and Mirada, and quantitative evaluations of the registrations were performed. Impact of these registrations on the initial dose matrix was performed. RESULTS: Mean differences between simulated dose plans and extrapolated Bard nomogram for UFB volumes were 36.3% (26-56) for the total activity, 18.3% (10-30) for seed strength, and 22.5% (16-38) for number of seeds. Registration method implemented in Mirada performed significantly better than VariSeed and 3D Slicer (p = 0.0117 and p = 0.0357, respectively). For dose plan evaluation between Mirada and VariSeed, D100% (Gy) for ultra-focal gross tumor volume had a mean difference of 28.06 Gy, mean values being still above the objective of 152 Gy. D90% for the prostate had a mean difference of 1.17 Gy. For urethra and rectum, dose limits were far below the recommendations. CONCLUSIONS: This UFB study confirmed the possibility to treat with optimal dose coverage target volumes smaller than 7 cc.

IDEAL 2a Phase II Study of Ultrafocal Brachytherapy for Low- and Intermediate-risk Prostate Cancer.

PURPOSE: Focal therapy of prostate cancer requires precise positioning of therapeutic agents within well-characterized index tumors (ITs). We assessed the feasibility of low-dose-rate ultrafocal brachytherapy. METHODS AND MATERIALS: The present study was an institutional review board-approved European Clinical Trials Database-registered phase II protocol. Patients referred (October 2013 to August 2016) for active surveillance (prostate-specific antigen <10 ng/mL, cT1c-cT2a, Gleason score on referring biopsy specimens ≤6 (3+3), ≤3 positive biopsy cores, ≤50% of cancer) were preselected. Inclusion was confirmed when complementary image-guided biopsy findings informed a single Prostate Imaging Reporting and Data System (PI-RADS) ≥3, Gleason score ≤7a (3+4) lesion. A ultrasound-visible ancillary marker was positioned within the IT using a magnetic resonance imaging (MRI)/3-dimensional transrectal ultrasound (TRUS) elastic fusion-guided system (Koelis). Ultrafocal transperineal delivery of 125I seeds used classic 2-dimensional TRUS (Bard-FlexFocus) and dose optimization (Variseed Treatment Planning System). Following Simon's optimal design, 17 patients were required to assess the feasibility of delivering ≥95% of the prescribed dose (160 Gy) to the IT (primary objective). Adverse events (Common Terminology Criteria for Adverse Events) and quality of life (5-item International Index of Erectile Function, International Prostate Symptom Score) were recorded. One-year control biopsy specimens were obtained from the IT and untreated segments. RESULTS: Of the 44 preselected patients, 27 did not meet the inclusion criteria. Of the 17 ultrafocal brachytherapy-treated patients, 16 met the primary objective (per protocol success). The prescription dose was delivered to 14.5% ± 6.4% of the prostate volume, resulting in negligible urethral and rectal irradiation and toxicity. No recurrence was evidenced on the 1-year follow-up MRI studies or IT biopsy specimens. Seven nonclinically significant cancers and one Gleason score 7a (3+4) cancer (salvage prostatectomy) were observed in the untreated parenchyma. CONCLUSIONS: Recent technology has allowed for selective and effective brachytherapy of small MRI targets.

Continuous Infusion of Cilengitide Plus Chemoradiotherapy for Patients With Stage III Non-Small-cell Lung Cancer: A Phase I Study.

INTRODUCTION: Because of our previous preclinical results, we conducted a phase I study associating the specific αvß3/αvß5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.

Phase I study of axitinib and everolimus in metastatic solid tumours and extension to metastatic renal cell carcinoma: Results of EVAX study.

PURPOSE: Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. EXPERIMENTAL DESIGN: Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. RESULTS: 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. CONCLUSION: The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.