bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-Related Quality of Life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate adenocarcinoma (mPCa) and urothelial carcinoma (mUC).
Authors: Jiang Di Maria , Brundage Michael Donald , Sweeney Christopher , Fizazi Karim , Bellmunt Joaquim , Vaughn David J. , Powles Thomas , Perlis Nathan , Kulkarni Girish S. , Sridhar Srikala S.
Published: March 2019

478

Background: HRQOL outcomes are increasingly used to guide patient-centered care and health policy decisions, especially when treatment has a limited impact on survival. Our aim was to systematically evaluate the quality of HRQOL reporting in phase III RCTs of mPCa and mUC. Methods: A systematic literature review identified phase III RCTs evaluating palliative systemic therapies for castrate sensitive or castrate resistant mPCa (excluding androgen-deprivation therapy) and mUC, published in English between 1985 and 2018. Supplementary material and companion publications on HRQOL were also reviewed. RCTs reporting HRQOL outcomes were scored by the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (range 0-11). Results: Of 44 RCTs in mPCa, 25 (56.8%) reported HRQOL outcomes. BPI-SF or BPI (14 RCTs) and McGill-Melzack pain questionnaire (6 RCTs) were the most commonly used generic instruments, whereas FACT-P (16 trials), validated in advanced PCa, was the most commonly used disease-specific instrument. Average score of HRQOL reporting in mPCa was 6.7. Of 21 RCTs in mUC, 7 (33.3%) reported HRQOL. EORTC QLQ-C30 (6 RCTs) was the most commonly used generic instrument. Only 1 trial used a disease-specific instrument, FACT-BL, which lacks validation in mUC. Average score in mUC was 6.6. Conclusions: Robust HRQOL data from phase III RCTs in mPCa and mUC remain limited, and most HRQOL reports had methodologic shortcomings. Although the disease-specific FACT-P questionnaire being used is validated in advanced PCa, mUC RCTs have yet to use a culturally validated instrument to assess HRQOL. Quality of HRQOL reporting has improved over time but needs to be better harmonized across trials. [Table: see text]
The predictive value of DRE in the modern era of prostate cancer diagnostics.
Authors: Andersson Joel Marcus , Nordström Tobias , Eklund Martin , Gronberg Henrik
Published: March 2019

48

Background: DRE (digital rectal examination) suspicious for prostate cancer is still used as a clinical tool to diagnose prostate cancer. We aim to analyse the predictive value of DRE to diagnose prostate cancer ISUP grade group ≥2 (GG≥2) prostate cancer including the setting of STHLM3 test as a variable. Methods: The previously described STHLM3 screening-cohort included men between 50 to 70 years with ≥10% risk of prostate cancer as assessed by PSA or the Stockholm3 test and invited for transrectal biopsy (TRUSbx). All 7415 biopsied men was included for analysis. DRE status was categorized as T1-T4. We analysed sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for DRE status of T2-4 to predict GG≥2 and GG≥3 in biopsies. In a multivariate logistic regression analysis; we adjusted for PSA, age, PVol, earlier biopsy (EB) and adjusted STHLM3 model risk set to exclude DRE and prostate volume (PVol). We calculated adjusted odds ratio (OR) for different strata of adjusted STHLM3 risk. Results: Prevalence of ISUP≥2 was 16.8% (1,243/7415). 9.7% (716/7415) men had DRE suspicious for cancer (T2-4) with a Sn to detect GG≥2 of 25.2%. Sp, PPV and NPV was 93.5%, 43.7% and 86.1%, respectively. In univariate model the OR for DRE T2-4 vs. T1 to predict GG≥2 was 4.28 (95% CI 4.09–5.67). Logistic regression analysis including also age, PVol, PSA, earlier biopsies and adjusted STHLM3 risk (%) gave an OR for DRE T2-4 of 2.87 (95% CI 2.36–3.49). In the same analysis stratified PSA group 5-10 ng/ml with PSA < 3 ng/ml as baseline gave OR = 3.21. Using the same univariate model, OR for DRE T2-4 vs. T1 to predict GG≥3 was 6.68 (95% CI 5.44–8.21) and in the multivariate model OR was 3.25 (95% CI 2.54–4.17). Conclusions: As a diagnostic test DRE holds little merit on its own but in combination with other clinical factors and biomarkers in this study we could show that it contributes with value. Just under half of men with DRE suspicious for cancer has GG≥2 cancer. This study does not establish evidence to rule out DRE as a clinically valuable adjunct to PSA, other clinical parameters and new biomarkers like STHLM3.
Sarcopenia in bladder cancer patients is an unmodifiable outcomes predictor.
Authors: Barton Gregory John , Wang Jeanette , Chang Andrew , Tan Wei Phin , Fantony Joseph J , Wischmeyer Paul E , Gupta Rajan T. , Inman Brant Allen
Published: March 2019

480

Background: Sarcopenia, a severe loss of skeletal muscle mass, predicts poor outcomes in bladder cancer (BC). But, why sarcopenia occurs in BC is unknown. Our objective was to assess if diet and physical activity were the primary factors causing sarcopenia, and thus assess if sarcopenia could be addressed by lifestyle interventions. Methods: 286 patients filled out the International Physical Activity Questionnaire Long Form (IPAQ-L) and the Diet History Questionnaire II (DHQ2), had a CT abdomen/pelvis within 6 months of questionnaire administration and met inclusion criteria. The DHQ2 was converted into Healthy Eating Index 2010 scores (HEI2010). Skeletal muscle area (SM, cm2) area was measured at the L3 level using Slice-O-Matic software and divided by height (m2) to arrive at skeletal muscle index (SMI). Sarcopenia was defined as SMI < 52.4 in men and < 38.5 in women. Three raters read the images and inter-rater reliability was measured by the intra-class correlation coefficient (ICC). Associations among patient demographics, tumor characteristics, physical activity, diet quality, and body composition were examined by stratified analyses and regression models with R 3.2.3. Results: Reliability was very high, ICC=0.97. Sarcopenia was present in 71% of males and 55% of females. Key predictors of decreasing SMI included increasing age (p < 0.001), female gender (p < 0.001), and white race (p < 0.001). When adjusted for these unmodifiable patient factors, there was no association between SMI and variables such as Elixhauser comorbidity score, AJCC stage, tumor grade, and procedure type. With respect to modifiable lifestyle factors, there was no association between SMI and average weekly MET-min of physical activity level (p = 0.99) nor the daily consumption of calories (p = 0.69), protein (p = 0.28), fat (p = 0.19), or carbohydrate (p = 0.77). The HEI2010 diet score was not associated with SMI (p = 0.66). Conclusions: The three strongest predictors of decreasing muscle mass (i.e. sarcopenia) in BC patients are age, gender, and race. Modifiable risk factors, such as diet and physical activity levels, did not affect sarcopenia. Therefore, we would not expect that targeted lifestyle interventions would affect sarcopenia and improve BC outcomes.
Comprehensive radiogenomics analysis of qualitative and quantitative features of cross-sectional imaging in the TCGA project in MIBC.
Authors: Lerner Seth P. , Duddalwar Vinay , Huang Erich , Altun Ersan , Bathala Tharakeswara , Kennish Steven , Ibarra Juan , Lucchesi Fabiano , Muglia Valdair Francisco , Thomas Stephen , Vikram Raghu , Vargas Hebert Alberto , Cen Steven Yong , Hwang Darryl , King Kevin George , Varghese Bino , Fevrier-Sullivan Brenda , Kirby Justin , Jaffe Carl , Freymann John
Published: March 2019

482

Background: Quantitative imaging descriptors derived from CT and MRI can be integrated with genomic data that may be used as non-invasive prognostic or predictive biomarkers. We report an integrated radiogenomics project designed to develop subjective and objective parameters extracted from cross-sectional imaging of MIBC from studies archived in the TCIA and linked to the TCGA project. Methods: We reported comprehensive integrated genomic analysis of 412 tumors (Cell 2017). 7 of 33 tissue source sites submitted CT scans to the TCIA (n=106). We developed 17 features describing tumor size/location, metastases sites, and tumor morphology; 9 GU radiologists reviewed the scans in a blinded manner. EH analyzed the data independent of the radiologists. We computed kappa statistics for categorical features and coverage probabilities for quantitative features (Lin et al 2002). The tumor was segmented on an axial image and the segmented image analyzed using a radiomics panel (radiomicslab.usc.edu). Associations between individual features and subtypes were assessed (Fisher’s Exact Test) for categorical features and Kruskal-Wallis Test for quantitative features. Results: Substantial agreement (k≥ 0.6) was observed in 4 features: tumor laterality, tumor within bladder diverticulum, right and left UVJ involvement and hydroureter. We observed weak agreement (95% CI <0.4) for bladder neck, posterior bladder, dome, and trigone involvement, tumor margin, internal architecture, radiographic stage, left upper tract involvement, and metastases. The coverage probability for lesion size was 0.59 (0.544-0.638) (Figure). Tumor morphology was associated with microRNA cluster, with diffuse wall thickening having a higher tendency toward Clusters 3 and 4 (p < .001). Radiomic analysis identified statistically significant associations of mutations in FGFR3, CREBBP, CASP8 and EP300 with multiple radiomic features. Conclusions: This blinded comprehensive assessment of features extracted from CT images highlights many of the ongoing challenges in staging patients with MIBC. Preliminary analysis shows promise in analyzing associations between radiomic features and mutations.
Utilization and outcomes of adjuvant radiation therapy after cystectomy for urothelial carcinoma.
Authors: Verlage Kenneth , Isharwal Sudhir
Published: March 2019

487

Background: Positive surgical margins with radical cystectomy for invasive urothelial cancer are associated with adverse prognosis. In non-metastatic patients, adjuvant radiation therapy (ART) is sometimes employed for patients with positive margins or locally advanced stage. However, evidence for benefit of ART in these patients to improve survival is limited. In this study, using a national database we investigate the factors associated with use of ART and its impact of the overall survival. Methods: National Cancer Database was queried for patients who underwent radical cystectomy from 2004-2013 for invasive urothelial cancer. Inclusion criteria were urothelial histology, pT2 stage with positive surgical margins or ³pT3 , and no evidence metastasis. Patients with regional or distant metastasis or patient who underwent adjuvant chemotherapy were excluded. Univariate and multivariate analysis performed to assess the factors associated with the use of ART. Overall survival was compared using log rank test. Results: In total, 18,828 patients met the inclusion criteria, of which 359 (1.91%) underwent ART. Mean duration between radical cystectomy and ART was 4.4 months. On univariable analysis, Black or Hispanic race, Medicare/Medicaid insurance status, treatment at community health center, ileal conduit diversion, advanced pathological stage (pT3/T4) were associated with higher use of ART (all p<0.005). On multivariate analysis community health facility and adequate lymph node dissection (>10 lymph nodes excision) were associated with use of ART (all p<0.05) (see table). The use of ART was not associated with improved overall survival. Conclusions: The utilization of ART after radical cystectomy for urothelial carcinoma is low. The benefit of ART on the overall survival is not clear and would need further investigation. [Table: see text]
Urologic malignancies: A comparison of outcomes after index surgery between academic and community hospitals.
Authors: Syed Jamil , Abello Alejandro , Javier-Desloges Juan , Leapman Michael , Kenney Patrick Aloysius
Published: March 2019

489

Background: To compare the rate of hospital based outcomes in patients with urologic malignancies who underwent surgery as part of treatment in academic and community hospitals. Methods: We reviewed the Vizient Clinical Database from September 2014 to December 2017. Vizient is a member-driven health services organization that includes ~99% of academic hospitals (AH) and more than 40 community hospitals (CH). This is a comparative database comprised of administrative billing. Data include patient demographics, readmission rates, costs, LOS, case mix index (CMI) and mortality. Patients aged ≥ 18 were included and ICD-9 and ICD-10 codes were used to identify patients with urologic malignancies who underwent surgical treatment. Chi square and student t-tests were used to compare categorical and continuous variables, respectively. Results: We identified a total of 37,628 cases. There were 33,290 (88%) procedures performed in AH and 4,330 (12%) in CH. These included radical prostatectomy (RP) 18,540, radical nephrectomy (rNx) 8,059, partial nephrectomy (pNx) (5,287), radical cystectomy (4,421), radical nephroureterectomy (rNu) (1,006), and partial cystectomy (321). There were no significant differences in 30-day readmission rates or mortality for any procedure between AH and CH. LOS was significantly lower (P<0.01) for radical cystectomy (8.83 vs 11.43 days) and RP (1.63 days vs 1.77 days) in AH, and lower in CH for rNx (4.93 vs 4.51, P: 0.03). AH had a significantly lower amount of partial cystectomies performed when compared to community centers (6.2% vs 16.2% P<0.001), and a similar number of partial nephrectomies performed (39.8% vs 38.0%, P=0.2). The mean direct cost for index admission was significantly higher in AH for rNx, pNx, rNu, and RP. Case complexity using the CMI was similar between CH and AH. Conclusions: The Vizient clinical database provides a novel resource for observational data at US hospitals. Despite academic and community hospitals having similar case complexity, direct costs were lower in community hospitals without an associated increase in readmission rates or deaths. The only clinically significant difference in length of stay was shorter stays for cystectomy in academic centers.
Rectal toxicity results for patients treated with HDR brachytherapy as monotherapy versus dose-escalated external beam radiotherapy for localized prostate cancer.
Authors: Parzen Jacob Samuel , Ye Hong , Gustafson Gary S. , Martinez Alvaro , Sebastian Evelyn , Limbacher Amy , Krauss Daniel J.
Published: March 2019

5

Background: We present a large retrospective analysis comparing rectal toxicity following high dose rate (HDR) brachytherapy as monotherapy relative to dose-escalated external beam radiotherapy (EBRT) for patients with localized prostate cancer. Methods: 2683 patients treated with HDR or EBRT between 1994 and 2017 were included. 545 (20.3%) received HDR and 2138 (79.7%) EBRT. HDR fractionation was 38 Gy/4 fractions (n=321), 24 Gy/2 (n=96), or 27 Gy/2 (n=128). EBRT patients received a median dose of 75.6 Gy in 1.8 Gy fractions [range 70.2-82.8 Gy], using either 3D conformal or intensity modulated radiotherapy (IMRT). All EBRT patients underwent 3D image guidance via an off-line adaptive process. Treatment was directed to prostate only (n=780) or prostate and seminal vesicles (n=1351). No nodal therapy was given. Target volume for HDR patients included the prostate with no expansion. Acute and chronic gastrointestinal (GI) toxicity was defined as occurring ≤ 6 and > 6 months, respectively, after radiotherapy and was graded per CTCAE version 3.0. Toxicity variables were analyzed with χ2 test. Results: Median follow-up was 7.5 years (7.4 years for EBRT and 7.9 years for HDR). 69.1% of EBRT patients received IMRT with the remainder treated using 3D conformal technique. Compared to EBRT, HDR was associated with decreased rates of acute grade ≥ 2 diarrhea (0.7% vs. 4.5%, p < 0.001), rectal pain/tenesmus (0.6% vs. 7.9%, p < 0.001), and rectal bleeding (0% vs. 1.6%, p=0.001). Rates of chronic grade ≥ 2 rectal bleeding (1.3% vs. 8.7%, p < 0.001) and radiation proctitis (0.9% vs. 3.3%, p=0.001) favored HDR over EBRT. Rates of any chronic rectal toxicity grade ≥ 2 were 2.4% vs. 10.5% (p < 0.001) for HDR vs. EBRT, respectively. For the 1478 EBRT patients treated with IMRT, acute and chronic rates of any grade ≥ 2GI toxicity were 4.2% and 5.6%, respectively, compared to 1.5% (p=0.002) and 2.4% (p=0.002), respectively, for HDR patients. Conclusions: In appropriately selected patients with localized prostate cancer undergoing definitive radiation therapy, HDR brachytherapy as monotherapy is an effective strategy for reducing acute and chronic rectal toxicity.
Multi-institutional analysis of high-risk prostate cancer patients treated with stereotactic body radiotherapy.
Authors: Jiang Naomi Y , King Christopher R. , Katz Alan J. , Collins Sean P. , Aghdam Nima , Suy Simeng , Stephans Kevin L. , Reddy Chandana A. , Kaplan Irving D. , Appelbaum Limor , Dang Audrey , Yuan Ye , Nickols Nicholas George , Steinberg Michael L. , Kupelian Patrick , Kishan Amar Upadhyaya
Published: March 2019

51

Background: Stereotactic Body Radiotherapy (SBRT) delivers ablative doses of radiation (RT) over a course of five treatments and has been increasingly used as a definitive RT option for low- and intermediate-risk prostate cancer (PCa). Ongoing prospective trials are evaluating the efficacy of SBRT for high-risk PCa, but clinical outcomes reports are limited. Methods: Patients treated for high-risk PCa between 2006-2017 at any of five institutions were included. SBRT doses ranged from 35-40 Gy in 5 fractions per institutional standards, with one institution using an integrated boost approach. The Phoenix definition was used to define biochemical failure (BCR). Physician-reported genitourinary (GU) and gastrointestinal (GI) toxicity outcomes were scored using the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events systems. Results: In total, 182 patients were included in this study with a median follow-up time of 38.4 months (mos). The median age was 72. Most patients (72%) had Gleason 8-10 disease. Sixty-eight percent of patients received androgen deprivation therapy (ADT) for a median of 9 mos (interquartile range 6-9 mos). The rate of distant metastases was 3.8%. There were no acute Grade 3 (G3) or higher GU or GI toxicities. Three patients (1.6%) experienced a late G3 GU toxicity and one patient (0.5%) experienced a late G3 GI toxicity. The incidence of BCR was significantly higher in patients who did not receive ADT (30% vs. 15%, p = 0.02 by Chi-square). Conclusions: In this multi-institutional study, SBRT demonstrated an acceptable safety profile for the treatment of high-risk PCa. Longer term follow-up is necessary to evaluate the oncologic efficacy of this approach, but given the potentially higher incidence of BCR without ADT, ADT likely has an important oncologic role even with SBRT regimens.
Outcome of men with relapses after adjuvant BEP for clinical stage I nonseminoma.
Authors: Fischer Stefanie Christine , Tandstad Torgrim , Cohn-Cedermark Gabriella Elisabeth , Thibault Constance , Vincenzi Bruno , Klingbiel Dirk , Albany Costantine , Necchi Andrea , Terbuch Angelika , Lorch Anja , Aparicio Jorge , Heidenreich Axel , Hentrich Marcus , Wheater Matthew James , Langberg Carl Wilhelm , Stahl Olof , Beyer Joerg , Gillessen Silke
Published: March 2019

510

Background: Clin. stage I (CSI) non-seminoma (NS) is disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant (adjuv) chemotherapy with BEP after which relapses are rare. Little is known about the outcome of patients (pts) relapsing after such treatment. Methods: Data from 51 pts with CSI NS and relapse after adjuv BEP from 18 centers/11 countries was collected and retrospectively analyzed. Primary endpoints were OS and PFS calculated from start of treatment of relapse. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results: 23 pts received one cycle adjuv BEP and 28 pts two. Median time to relapse was 13 months, with the earliest relapse two months after start of adjuv BEP and the latest relapse recorded after 26 years. According to IGCCCG, 84% of pts classified as good prognosis at relapse. With a median follow up of 50 months 5y PFS was 64% (95% CI 52-80%) and 5y OS 79% (95% CI 68-92%). Treatment upon relapse was diverse, the majority of pts received combination- chemotherapy and surgery. 10 pts (20%) had pure mature teratoma at relapse treated with surgery alone. None of these pts experienced a second relapse. If teratoma relapses were excluded, 5y PFS dropped to 58% (44-77%) and 5y OS to 76% (63-92%). Relapses later than three years after adjuv therapy occured in 15/51 pts. (29%) and were associated with a statistically significant higher risk of death from germ-cell cancer (p=0.02). 15/51 pts (29%) experienced a subsequent relapse. Excluding pts with teratoma only, subsequent relapses occured in 15 of the remaining 41 pts (37%). At last follow-up, 41/51 (80%) pts were alive and disease-free, 8/51 (16%) had died from progressive disease and one pt each had died from therapy-related or other causes. Conclusions: Outcome of pts with relapse after adjuv BEP seems to be better compared to pts with relapse after metastatic disease, but worse compared to de novo metastatic pts. There is a substantial rate of late and subsequent relapses. Pts and care-takers need to be informed about this and therapy intensification at first relapse might be considered. However, considering the low rate of relapses, OS in general for CSI NS pts receiving adjuv BEP is excellent.
Cross-trial comparison of taxane versus non-taxane combination chemotherapy regimens for advanced penile cancer (APC): A systematic review.
Authors: Al-Ezzi Esmail Mutahar , Riromar Jamila Jama Almi , Amir Eitan , Fazelzad Rouhi , Hansen Aaron Richard
Published: March 2019

511

Background: Penile cancer is rare and there are scant data on the optimal chemotherapy regimen. The majority of trials are single arm, non-randomized studies. Here we report on a systematic review aiming to compare taxane combination chemotherapy regimens with non-taxane regimens for APC. Methods: A systematic review was conducted in accordance with the PRISMA guidelines. Medline, Embase and Cochrane Central Register of Controlled Trials databases were searched using the following terms: penile cancer, penis, antineoplastic combined chemotherapy, taxane, docetaxel, paclitaxel, platinum, cisplatin, carboplatin. Studies were identified using preplanned eligibility criteria by 2 investigators (EA-E and JR). Data were extracted independently by EA-E and JR. Studies were weighted by study sample size and those comparing taxane-based chemotherapy were compared to non-taxane therapy using the Mann Whitney test. Results: The search identified 1929 publications and 40 were selected for further assessment. Of these, 8 met eligibility criteria (7 prospective and 1 retrospective). Three studies tested taxane combinations (docetaxel, cisplatin and 5FU [DCF] and paclitaxel, ifosfamide and cisplatin [TIP]). A total of 148 men with APC were treated with non-taxane regimens and 98 men received a taxane combination. Patient characteristics (age, ECOG status, stage, number of cycles) were comparable between the two groups. Partial response and overall response rates were significantly higher in the taxane versus the non-taxane group (35.7% vs. 24.2% p = 0.01 and 41.9% vs. 32.5% p = 0.007) respectively. Grade3/4 neutropenia was significantly higher in taxane group than non-taxane group (27.8% vs 19.4% p = 0.02). Median PFS and OS was numerically but not significantly higher in the taxane versus the non-taxane group (5.7 vs. 4.4 months, p = 0.45 and 12.1 vs 10 months, p = 0.48, respectively). Conclusions: Compared to non-taxane-based regimens, taxane combinations have higher response rates and may improve survival in APC. Hematologic toxicities are worse with taxane containing regimens. Taxane combinations should be the preferred regimen for suitable men with APC.
Penile and uterine cervical squamous cell carcinomas: A comparative genomic profiling study.
Authors: Jacob Joseph , Pinkhasov Rubin , Shapiro Oleg , Liu Nick , Gay Laurie M. , Alexander Brian Michael , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Venkataprasanth P. , Miller Vincent A. , Corona Robert John , Ross Jeffrey S. , de La Roza Gustavo , Bratslavsky Gennady
Published: March 2019

514

Background: Metastatic penile (mPSCC) and uterine cervical squamous cell carcinoma (mCSCC) are aggressive forms of malignancy with limited treatment options. We used comprehensive genomic profiling (CGP) to compare the genomic alterations (GA) and their potential impact on targeted and immunotherapy options of mPSCC and mCSCC. Methods: 78 metastatic mPSCC and 604 mCSCC underwent CGP using a hybrid-capture-based next-generation sequencing assay with a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The median age of mPSCC men was higher than mCSCC women. The HPV+/CDKN2A- status was more frequent in the mCSCC than mPSCC. The GA/tumor were similar for both tumor types (table). TP53 mutations were more common in mPSCC likely linked to loss of original HPV+ status. TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC. MSI-High status was extremely rare in all cases, but the relatively high frequencies of TMB ≥ 10/20 mut/Mb in both mPSCC and mCSCC were noteworthy. Examples of patients with mCSCC and mPSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC and mPSCC share a variety of genomic features, the 2 tumor types can nonetheless be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with viral identification much higher in the mCSCC group. There are opportunities for targeted therapies in both groups predominantly identified in the MTOR pathway. Numerous cases with significantly elevated TMB in both mPSCC and mCSCC suggest that immunotherapies might be of benefit in a subset of patients. [Table: see text]
PD-L1 and p16 expression in penile squamous cell carcinoma from an endemic region.
Authors: De Bacco Mateus Webber , Fay Andre P. , Carvalhal Gustavo , Copetti Josenel , McGregor Bradley Alexander , Sonpavde Guru , Wagner Mario
Published: March 2019

515

Background: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited treatment option in advanced stages. Brazil has one of the highest incidences of PSCC in the world, and different biology has been postulated across distinct populations. We evaluate PD-L1 and p16 expressionand its association with clinical outcomes in PSCC patients from an endemic region. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 35 patients with PSSC. PD-L1 and p16 expression were evaluated by immunohistochemistry. PD-L1 tumor positivity (PD-L1+) was defined as ≥1% tumor cell membrane staining using ZR3 antibody. Any tumor cell membrane staining of p16 was considered positive (p16+). Baseline characteristics including tumor size, stage, grade, subtype, and survival data were collected. Comparisons between PD-L1 and/or p16 expression and clinicopathological features were evaluated using fisher exact testor wilcoxon rank sum tests. Cox model tested the association of PD-L1 and/or p16 expression and 5-year-survival. Results: Clinical features were summarized in table1 according to PD-L1 expression. PD-L1 positivity was significantly associated with larger tumor size ( p=0.027), and p16 expression, a surrogate for HPV infection ( p=0.002). There was a non-statistically significant trend to a shorter 5-year-survival for PD-L1+/p16+ vs. PD-L1-/p16- patients (30.8% vs. 60.6% HR: 2.27 95% CI - 0.61-8.42 p=0.22). Conclusions: PD-L1 expression appears to be associated with p16 expression, larger tumors, higher proliferative rate and worse clinical outcomes in patients with PSCC. provide additional rationale for PD1/PD-L1 inhibitors alone or in combination with chemotherapy foradvanced PSCC in endemic regions. Clinical features. [Table: see text]
Comprehensive and epidemiological characterization of urachal adenocarcinoma: A pan-Canadian collaboration.
Authors: Wiam Belkaid , Hamilou Zineb , Soulieres Denis , Canil Christina M. , Zalewski Pawel , Heng Daniel Yick Chin , Da Silva Vitor , Castonguay Mathias , Routy Bertrand , Blais Normand
Published: March 2019

516

Background: Urachal cancer is a rare form of urothelial cancer representing 0,1-0,2% of bladder cancers. The exact underlying cause of urachal cancer is still widely unknown and there is much speculation on multiple factors such as genetic and environmental ones that may play a role. Moreover, given the lack of treatment consensus, we proposed the first study that assesses the clinical, genetic and molecular features of this disease in Canada. Methods: This ongoing study is recruiting in Canadian centers from the year 2005 onwards. The clinical database is constructed using the hospital electronic medical file. In addition, pathological tissues are centralized for molecular and genetic analysis. Results: To this date, 15 patients were included, 12 males and 3 females. Median age was of 49 years old with a disease distribution of Stage II (4), Stage III (3) and Stage IV (4). 8/15 patients developed metastasis after initial cystectomy in the lungs (n = 7), peritoneum (n = 2), lymph nodes (n = 4), and bone (1). Median survival of all patients was 23 months. Metastatic patients after cystectomy had a shorter overall survival (OS) of 21 months compared to non-metastatic patients (OS – not reached). The majority of metastatic patients (6/8) died of their underlying malignancy. Conclusions: This study is an ongoing country-wide effort to expand knowledge of this poorly studied disease. With ongoing accrual, the clinical features will be better defined and further molecular characterization will be performed to better predict response to therapy.
Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in patients with testis cancer in the salvage setting.
Authors: Albers Peter , Nini Alessandro , Hiester Andreas , Winter Christian , Lusch Achim , Lorch Anja
Published: March 2019

524

Background: Although the use of PC-RPLND in testis cancer patients in the salvage setting has been reported, existing data characterizing histologic findings are poor. Methods: 179 PC-RPLNDs after salvage chemotherapy were selected from a prospective database of 504 RTRs (434 patients, 2003-2018). Uni- and multivariate analyses were used to assess the impact of preoperative positive markers, residual diameter, and type of salvage chemotherapy (either conventional salvage [CTX] or high dose chemotherapy [HDC]) on vital cancer histology (including teratoma with malignant transformation) at PC-RPLND. Results: Median age was 37 years (IQR 30-45). 11.5% of patients underwent thoraco-abdominal PC-RPLND and adjunctive surgeries were needed in 41.7%. Clavien-Dindo > II complications were registered in 5% of cases. After stratification for CTX and HDC, AFP only, β-HCG only, and both markers elevated were seen in 27.8%, 7.8%, and 2.2%, and 33%, 18.2% and 5.7% of patients, respectively. Overall, necrosis, postpubertal teratoma, and vital cancer were found in 30%, 29%, and 42%, respectively. Vital cancer was found in residual tumor sizes of < 2 cm and ≥ 2 cm in 41.2% and 32.9%, respectively. After stratification for CTX and HDC, patients after CTX had lower rates of necrosis (26% vs. 34%, p = 0.2) but not of vital cancer (42% vs. 42%, p = 0.9). The predictors of vital cancer were represented by the presence of AFP elevation only (OR 4.7, p = 0.001) and both markers elevated (OR 8.6, p = 0.02). Conclusions: In the salvage setting, the rate of vital cancer in residual tumor is three times higher as compared to the first-line setting. Presence of AFP elevation only or both markers elevated represent predictors of vital cancer. PC-RPLND has to be performed after salvage chemotherapy independent of the residual tumor diameter. [Table: see text]
Analysis of overall survival (OS) based on early tumor shrinkage in the phase III METEOR study of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC).
Authors: Duran Ignacio , Maroto Pablo , Suárez Cristina , Castellano Daniel E. , Garcia del Muro Xavier , Costa Luis , Martin-Couce Lidia , Benzaghou Fawzi , Thomas Stephane , Markby David W. , Choueiri Toni K.
Published: March 2019

550

Background: In the phase 3 METEOR study (NCT01865747), cabo improved OS (median 21.4 vs 16.5 mo; HR, 0.66; 95% CI, 0.53–0.83), progression-free survival and objective response rate compared with eve in patients (pts) with previously treated advanced RCC (Choueiri 2016). Retrospective studies have shown that early tumour shrinkage (eTS), based on target lesion reduction from baseline to first post-baseline scan, has predictive value for targeted therapies in RCC (Grunwald 2015; Grunwald 2016); here we evaluate its impact on OS in METEOR. Methods: In total, 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd), stratified by MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed by independent radiology review using CT/MRI scans at baseline, every 8 wk for the first 12 mo and every 12 wk thereafter. Median OS was estimated for pts with ≥30% eTS, any eTS or no eTS at first post-baseline scan (week 8); data cutoff, 2 October 2016 (Motzer 2018). Results: Median follow-up was 28 mo (IQR 25, 30). Median (range) time to objective response was 1.91 (1.6, 11.0) mo with cabo and 2.14 (1.9, 9.2) mo with eve, and corresponded to the time to the first post-baseline scan. A greater proportion of pts had ≥30% eTS with cabo (20%) than with eve (5%) and the rate of any eTS was higher in the cabo arm (73%) than with eve (47%; Table). Median OS with cabo vs eve for pts with ≥30% eTS was not reached (NR; 95% CI, 23.7–NR) vs 10.2 mo (95% CI, 3.9–NE), respectively (stratified HR, 0.45; 95% CI, 0.21–0.95; p<0.05). Median OS with cabo vs eve for pts with any eTS was 23.7 (95% CI, 21.7–27.7) vs 17.3 mo (95% CI, 15.4–20.8), respectively; (stratified HR, 0.62; 95% CI, 0.48–0.80; p<0.05). OS was similar for cabo and eve for pts with no eTS. Conclusions: Cabo demonstrated a higher rate and greater magnitude of eTS at first post-baseline scan compared with eve, and eTS was associated with prolonged OS in pts treated with cabo. Clinical trial information: NCT01865747. [Table: see text]
Molecular characterization of longitudinally tracked prostate cancer foci in men on active surveillance for low-risk disease.
Authors: Tosoian Jeffrey J. , Salami Simpa Samuel , Nallandhighal Srinivas , Jones Tonye A. , Plouffe Komal R. , Elkhoury Fuad F. , Morgan Todd Matthew , Liu Chia-Jen , Kunju Lakshmi Priya , Montgomery Jeffrey S. , Natarajan Shyam , Sisk Anthony , Tomlins Scott A. , Palapattu Ganesh S. , Marks Leonard S.
Published: March 2019

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Background: The biological trajectory of Gleason score 6 (GS6) prostate cancer (PCa) in men on active surveillance (AS) is unknown. We herein evaluate the potential for high grade PCa to arise clonally from GS 6 disease and determine the capacity of tissue-based biomarkers to predict grade progression. Methods: Men on AS with GS6 PCa who underwent magnetic resonance imaging/ultrasound (MRI/US) fusion biopsy on two occasions from 2012 through 2017 were enrolled. Tumor foci were tracked and re-sampled using the MRI/US fusion biopsy platform. ERG immunohistochemistry (IHC) and DNA/RNA next generation sequencing (NGS) were performed on formalin-fixed paraffin-embedded (FFPE) initial and repeat biopsy specimens to assess tumor clonality and evaluate candidate molecular markers of PCa grade progression. Results: Sixty-seven men of median age 64 years (IQR 59-69) and PSA 4.9 ng/ml (IQR 3.3-6.4) underwent repeat sampling of a single tracked tumor focus using MRI/US fusion biopsy. The median interval to repeat biopsy was 11 months (IQR 6-13). On repeat biopsy, 31 (46%) men progressed to high-grade (GS≥7) disease (n = 24, GS 3+4 = 7; n = 7, GS ≥4+3 = 7). Among the 67 subjects, ERG IHC status was concordant between initial and repeat biopsy in 64 (96%). Of 134 total specimens obtained (67 initial + 67 repeat biopsies), ERG status determined by NGS was concordant with ERG status by IHC in 132 (99%). Comparing the initial biopsy specimens in men who did versus did not undergo grade progression on follow up biopsy, derived cell cycle progression (CCP) scores (median 57.3 vs. 44.0, p = 0.11) and genomic prostate scores (GPS; median 73.8 vs. 64.4, p = 0.15) were not significantly different. Similarly, expression of FOLH1, PCAT4, SCHLAP1, and SPINK1 on initial biopsy did not significantly differ among men who did and did not undergo grade progression. Conclusions: Use of MRI/US fusion biopsy facilitated resampling of the same clonal focus of cancer over time, with high concordance of ERG status determined by both IHC and NGS. Derived genomic classifiers and candidate individual gene expression markers measured on initial biopsy tissue were not significantly different between patients who progressed and those who did not.
Evolving patterns of metastatic renal cell carcinoma: A meta-analysis.
Authors: Lin Justin , Oh William K. , Liaw Bobby Chi-Hung , Galsky Matt D. , Tsao Che-Kai
Published: March 2019

563

Background: Advances in diagnostic and treatment modalities have resulted in better outcomes in metastatic renal cell carcinoma (mRCC) patients. With new therapies extending survival, we hypothesize that pattern of metastatic disease has evolved over time. We assessed the pattern of metastases as reported in baseline characteristics of prospective clinical trial patients between 1990 and 2018. Methods: This study identified all phase I-III mRCC therapeutic clinical trials published between January 1990 and July 2018 in PubMed and ClinicalTrials.gov. Studies that included patients with other cancers or did not report metastases were excluded. Data was stratified to examine differences in three listed treatment eras for first-line therapy. Linear regression models were used to evaluate temporal trends and subcategorized as either First Line Only treatments (FLO) or Second-Line and Beyond (SLB). Results: 127 clinical trials encompassing 16534 subjects were identified. Between 1990 and 2018, rates of lymph node metastases in the FLO population increased significantly at 1.03% per year ( P < 0.05). The rate of lung and liver metastases in FLO showed a trend of increase at 0.48% and 0.04% per year, respectively, but decreased -0.73% and -0.15% per year in the SLB population. Moreover, rate of bone metastasis showed a trend of increase in both populations, particularly between the VEGF/TKI and Immunotherapy/TKI eras in the SLB population (18.89% to 29.19%). Conclusions: Notable changes were found in the pattern of metastasis in patients with mRCC. Increasing rate of bone metastasis may warrant dedicated bone imaging for routine staging in patients with mRCC. These evolving patterns may have important implications in treatment selection and prognosis in this patient population. [Table: see text]
Impact of body mass index (BMI) on treatment outcomes to immune checkpoint blockade (ICB) in metastatic renal cell carcinoma (mRCC).
Authors: Lalani Aly-Khan A. , Xie Wanling , Flippot Ronan , Steinharter John A. , Harshman Lauren Christine , McGregor Bradley Alexander , Heng Daniel Yick Chin , Choueiri Toni K.
Published: March 2019

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Background: An elevated BMI is associated with improved survival in mRCC patients treated with oral targeted therapies (TT); however, this relationship in the contemporary treatment landscape is unknown. We investigated the effect of BMI on outcomes in mRCC patients treated with PD-1/PD-L1 ICB. Methods: We analyzed 147 patients with mRCC who received ICB alone or in combination with VEGF or other therapies. The association of BMI with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic and Cox regression models, adjusted for known prognostic factors including International Metastatic RCC Database Consortium (IMDC) risk groups, line of therapy, ECOG (0 vs ≥1), and histology. Results: Median follow up was 25.5 (4.3-78.6) months (mos). Median time on ICB was 5.1 ( < 0.1-69.7) mos. Overall, most patients were male (71%), had clear cell histology (85%), and were intermediate risk (60%). 43% received first-line ICB and 45% received ICB in combination therapy (37% with VEGF inhibition, 8% with other therapies). At ICB initiation, 46 (31%) patients were considered underweight/normal weight (BMI < 25 kg/m2), 56 (38%) overweight (BMI 25-30 kg/m2), and 45 (31%) obese (BMI > 30 kg/m2). Patients with high BMI (≥ 25) had improved OS (median 34.3 vs 16.7 mos, 2-yr OS 61 vs 42%, p = 0.016) compared to those with low BMI ( < 25), with an adjusted hazard ratio (HR) = 0.74 (0.44-1.26). ORR (33 vs 28%, p = 0.7) and PFS (median 8.2 vs 5.9 mos, p = 0.4) did not statistically differ. Patients who experienced a BMI change from ≥ 25 at start of first-line TT to < 25 at start of subsequent-line ICB displayed shorter OS (adjusted HR = 2.25 (0.94-5.35)) compared to those with no change. Conclusions: High BMI appears to be associated with improved OS in mRCC patients treated with ICB. This contemporary data is consistent with the “obesity paradox” demonstrated in the TT era. Validation with the IMDC database and examination of underlying mechanisms are ongoing.
Efficacy of targeted therapy (TT) after checkpoint inhibitors (CPI) in metastatic renal cell carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis).
Authors: Kalirai Austin , Wood Lori , Lalani Aly-Khan A. , Heng Daniel Yick Chin , Ghosh Sunita , Iafolla Marco Adelmo James , Kollmannsberger Christian K. , Soulieres Denis , Castonguay Vincent , Bossé Dominick , Winquist Eric , Kapoor Anil , Basappa Naveen S.
Published: March 2019

568

Background: While the use of CPI has demonstrated clinical benefit in patients with mRCC, data showing the efficacy of subsequent TT is limited. This real-world analysis evaluated the efficacy of TT post CPI in mRCC patients. Methods: Data was collected and analyzed from CKCis. Patients with mRCC who received TT after CPI were identified and analyzed based on line of therapy. Time to treatment failure (TTF – time from starting first subsequent TT to stopping TT) and overall survival (OS) were calculated. Hazard Ratio (HR) calculations were adjusted for IMDC group and age. Results: 102 patients were treated with TT post CPI (table). Those who received first-line ipilimumab + nivolumab (I/N) versus a vascular endothelial growth factor inhibitor (VEGFi) + CPI combination prior to second-line TT had a median TTF of 8.0 vs 5.2 months (m) (HR=0.43, 95% CI: 0.13-1.44) and median OS of 16.5 m vs not reached (HR=0.76, 95% CI: 0.11-5.24). Patients who received a VEGFi versus a mammalian target of rapamycin inhibitor (mTORi) as third-line TT had a median TTF of 7.6 vs 4.4 m (HR=0.52, 95% CI: 0.24-1.10) and median OS of 21.7 vs 16.2 m (HR=0.41, 95% CI: 0.16-1.08). All third-line TT patients received first-line VEGFi and second-line nivolumab. Of the third-line VEGFi TT patients, 24 received axitinib (TTF 7.1 m, OS 21.7 m) and 22 received cabozantinib (data immature). Conclusions: Activity of TT in mRCC patients after CPI is demonstrated in multiple lines. In second-line, VEGFi TT had numerically better outcomes after I/N than after VEGFi+CPI combination. Efficacy of third-line TT was seen with a trend favoring VEGFi over mTORi. Axitinib in the third-line has notable activity after CPI, while data on cabozantinib and fourth-line TT are maturing. These results support the use of VEGFi after CPI in mRCC patients. [Table: see text]
Systematic review and REMARK scoring of renal cell carcinoma (RCC) prognostic circulating biomarker manuscripts.
Authors: Iafolla Marco Adelmo James , Picardo Sarah Louise , Aung Kyaw Lwin , Hansen Aaron Richard
Published: March 2019

569

Background: No validated biomarkers exist to help guide prognosis of RCC patients. This study seeks to determine the current state of published prognostic RCC biomarker manuscripts and evaluate their quality using the REMARK criteria. Methods: The phrase “(renal cell carcinoma OR renal cancer OR kidney cancer OR kidney carcinoma) AND circulating AND (biomarkers OR cell free DNA OR tumor DNA OR methylated cell free DNA OR methylated tumor DNA)” was searched in Embase, Medline and PubMed during March 2018. One author (MI) selected all relevant manuscripts from the search results, and two authors (MI and SP) independently scored all relevant manuscripts using the REMARK guidelines (maximum 20 points comprised of 20 items subdivided into 48 criteria). Results: The search identified 525 publications: 73 were valid, 436 were rejected, and 26 were uncertain of their relevance. Amongst the valid publications, 33 were manuscripts of primary research (remainder: 26 review papers, 14 abstracts): manuscripts evaluating ≥ 2 biomarkers (n = 8) and novel biomarkers not published elsewhere (n = 7) comprised the majority. The median REMARK score was 10.6 (range 6.4-14.2). All manuscripts stated their marker, study objectives and method of case selection. The lowest scoring criteria were lack of: description of time between storage of blood/serum and marker assay (n = 2); flow or study profile diagram (n = 2); blinding of the person making the marker assessment to clinical outcomes (n = 3); and pre-specified hypotheses (n = 3). In total, only 8 studies reported a hazard or odds ratio. Using Pearson’s correlation, there was no association with either year of publication (median 2014; range 2004-2018; r2 = 0.14; p = 0.44) or impact factor (median 5.168; range 1.2-26.303; r2 = 0.24; p = 0.17) with REMARK score. Conclusions: Despite several published manuscripts on RCC prognostic biomarkers, most poorly adhere to the REMARK guidelines; this may be the cause for the paucity of a validated RCC biomarker to help supplement or supplant current clinical prognostic criteria. Better designed studies and appropriate reporting of methods, results and interpretation are required to address this urgent unmet need.