Citations

48 Background: The purpose of this study is to identify differences in toxicity, quality of life (QOL), and dosimetric endpoints among patients with low-risk prostate adenocarcinoma treated with either standard fractionation or hypofractionation proton-beam therapy. Methods: We analyzed the results of the first 75 patients treated in our phase III trial comparing 38Gy relative biological effectiveness (RBE) in 5 fractions (fx) (n = 46) vs. 79.2Gy (RBE) in 44 fx. (n = 29). All patients had low-risk prostate cancer and were treated with proton radiation using fiducial markers and daily image guidance. We evaluated American Urological Association (AUA) Symptom Index, adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains at pretreatment and 3, 6, 12, 18, 24, 36 and 48 months. Doses to the prostate were selected based on similar long term effects to normal tissue based on an α/β = 3.5 for an EQD2 of 76Gy. Results: The median follow-up was 36 months for both groups; 23 (30%) patients reached a follow-up of 48 months. We observed a small difference in AUA score (3.2 vs. 8.6, p = 0.002) at 1-year favoring the 79.2Gy arm. AUA scores were not statistically different at 18 months and after. Similarly, EPIC Urinary symptoms favored the 79.2Gy arm at 1 year (92.3 vs. 84.5, p = 0.009) and 18 months (92.3 vs. 85.3, p = 0.03); bother scores were not significantly different at any other time points. G2 or higher GU toxicity was similar between arms (p = 0.8). No differences in EPIC Bowel symptoms, EPIC Sexual symptoms, or bowel G2 or higher toxicities were seen. One death was observed in the 38Gy arm due to an unrelated case of multiple myeloma. The bladder V80 (79.2Gy arm, p = 0.04) and V39 (38Gy arm, p = 0.05) were predictive for G2 or higher GU AE. There was no association observed between rectal dose and G2 or higher rectal toxicity. Conclusions: Patients treated in the hypofractionated and standard arms tolerated treatment well. A small and temporary difference in the GU domain was seen favoring the standard arm. As predicted long term effects on the GU domain and bowel were similar for both arms, suggesting that the α/β is similar to 3.5 for long term effects. Clinical trial information: 01230866.

479 Background: We and others have previously shown that the ccRCC epigenome is characterized by widespread DNA hypermethylation (CCR 2014, Nature 2014). Various important tumor suppressor genes (TSGs), such as SMAD7 (inhibitor of oncogenic TGF-β signaling), are under-expressed due to aberrantly methylated promoters or enhancers. We hypothesized that the hypermethylation in ccRCC could be due to low activity of the TET enzymes, which convert methylcytosine (5-mc) to hydroxymethylcytosine (5-hmc). Loss of function of TET enzymes can occur with an inactivating mutation (TET-2 is mutated in about 6% of ccRCC (Science Signaling 2013) or hypoactivity of normal TET enzymes, through inhibition by metabolic intermediates. AA is an essential co-factor for TET enzymes (JACS 2015). We hypothesized that high dose AA treatment of ccRCC could potentially increase the functional activity of TET enzymes leading to demethylation of the RCC genome, and enhance expression of TSGs. Methods: In vitro TET activity was performed on ccRCC cell line 769P with increasing doses of AA (L-AA). Genome wide quantitative 5-mc and 5-hmc was evaluated using mass spectrometry. SMAD7 expression was determined using qRT-PCR. Proliferation assay (MTT) was performed with AA in combination with pazopanib. Cell cycle and apoptosis assays were performed. Results: AA, at doses achieved only by the intravenous route (1-10mM), increased TET activity in ccRCC cell line 769P. Genome wide 5-mc was significantly reduced and 5-hmc was increased, correlating with increase in TET activity. SMAD7 expression was increased with AA treatment. High dose AA led to proliferation inhibition with a cell cycle arrest in the G1 phase, and had a synergistic effect with pazopanib. Since AA leads to the generation of H2O2 in-vitro, catalase was used as control. This did not reverse the effect of AA on epigenetic changes; and proliferation inhibition was seen despite catalase control. Conclusions: High dose AA causes TET mediated DNA demethylation of the hypermethylated RCC genome, resulting in the re-expression of TSGs, and proliferation inhibition. Sequencing and xenograft studies are underway.

456 Background: Renal medullary carcinoma (RMC) is a rare, aggressive malignancy for which relatively limited characterization exists to date. We evaluated clinicopathologic features, treatment patterns, and variables associated with outcomes for patients with RMC. Methods: We reviewed the National Cancer Database to identify patients diagnosed with RMC between 1998-2012. Overall survival (OS) was estimated using the Kaplan-Meier method. Clinicopathologic features associated with all-cause mortality (ACM) were assessed using Cox regression analysis. Results: We identified 153 patients with RMC, comprising approximately 0.04% of renal malignancies during this time period. Median age at diagnosis for RMC was 24 years (IQR 20, 31). The majority of RMC patients were black (135; 88%), male (108; 71%), and presented with unilateral, right-sided tumors (101; 66%). Notably, nearly half (72; 48.9%) presented with metastatic disease. A total of 92 (64.3%) patients underwent radical nephrectomy (RN), and 2 (1.3%) were treated with partial nephrectomy. Pathologic stage at nephrectomy was ≤pT2 in 30 patients (32.6%), pT3 in 43 (46.7%), pT4 in 7 (7.6%), and N+ in 50 (55.6%). Of the patients who underwent RN, 60 (65.2%) received multimodal therapy (MMT), including radiation (3; 3.3%), systemic therapy (49; 53.3%), and radiation + systemic therapy (8; 8.7%). Of the 59 patients who did not undergo surgical resection, the majority (46; 77.8%) presented with M1 disease. Median OS was 7.8 months for the entire RMC cohort, with 1- and 3-year OS of 34% and 11%, respectively. Notably, median OS for patients presenting with M1 and M0 disease was 5.2 months versus 11.2 months, respectively (p< 0.01). On multivariable analysis, treatment with RN (HR 0.40; p=0.003) or RN+MMT (HR 0.44; p<0.001) were associated with decreased ACM, whereas the presence of metastatic disease at diagnosis remained associated with an increased risk of ACM (HR 1.74; p=0.02). Conclusions: The prognosis for patients with RMC is dismal, with a median OS under 8 months. Further studies, including the development of novel therapies, are needed to establish the optimal multimodal management approach for these patients.

433 Background: Current guidelines suggest that percutaneous thermal ablation (PTA) can be utilized in those with significant comorbidity who are unable to tolerate surgery (radical or partial nephrectomy). However, the use of PTA in healthy patients, who are otherwise candidates for surgery, has been limited. Here, we reviewed our institutional experience in healthy patients electing to undergo PTA, specifically cryoablation. Methods: We identified patients ≤65 years undergoing percutaneous cryoablation for solitary, non-metastatic renal masses <7cm (cT1). We further limited our cohort to patients with an ASA score of 1 or 2, and in whom pre-operative eGFR was >60. Clincopathologic characteristics and recurrence patterns (local recurrence within the kidney versus metastatic disease) were evaluated. Results: Between March 2003 and December 2015, 705 patients underwent cryoablation, of whom 43 (6.1%) were deemed to be “healthy”. Median age of this cohort was 57 years (IQR 52−62), with pre-ablation eGFR of 75.6 (IQR 69.0-86.3). Seven patients (16.3%) had a prior partial nephrectomy, and 5 (11.6%) had a solitary kidney. The majority (40, 93.0%) of ablated masses were cT1a, with 3 (7.0%) being cT1b. Median tumor size was 2.0 cm. 27 masses (63.7%) were biopsy-proven renal cell carcinoma (RCC) and 6 (13.6%) were benign; histology was unknown in 10 (22.7%). Follow-up imaging was available for 37 patients. Median radiological follow-up was 22 months (IQR 9-42), during which time 2 patients developed metastatic disease and 1 developed local recurrence; all events were in patients with biopsy-proven RCC. No patients died from RCC during this time period. Conclusions: In this single institution cohort of “healthier” patients with cT1 solitary renal masses, cryoablation offered reasonable short term oncologic control. While longer follow-up data are needed to evaluate for durability, cryoablation in healthy patients, particularly those with challenging surgical anatomy, warrants further study.

432 Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p<0.001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range 1-3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 vs. 13.1 minutes, p<0.001). Conclusions: Computer-assisted tumor response evaluation reduced errors and time of evaluation, indicating better overall effectiveness than manual tumor response evaluation methods that are the current standard-of-care.

431 Background: While targeting VEGF improves outcomes for mRCC pts, resistance invariably develops, often within the first year. Here, we describe the efficacy and safety of atezo (anti-PD-L1) with bev (anti-VEGF) and atezo monotherapy vs sun (TKI) in first-line mRCC. Methods: Treatment-naïve mRCC pts were enrolled in a hypothesis generating Ph II study (IMmotion150; NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. Crossover to atezo + bev after disease progression was allowed for pts receiving atezo or sun. PD-L1 expression was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). Coprimary endpoints were PFS (RECIST v1.1 by independent review [IRF]) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: Baseline characteristics were comparable across arms and between ITT and PD-L1+ pts. The majority of sun and atezo pts subsequently received atezo + bev. Median survival follow up was 20.7 mo. The PFS HR in ITT pts for atezo + bev vs sun was 1.00 and 1.19 for atezo vs sun. In PD-L1+ pts, the PFS HR for atezo + bev vs sun was 0.64 and 1.03 for atezo vs sun (table). Tx-related Gr 3-4 AEs were seen in 40%, 16% and 57% of pts in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of pts, respectively. Conclusion: Atezo + bev resulted in encouraging antitumor activity in the PD-L1+ subgroup of first-line RCC pts. Atezo + bev safety is consistent with the known profile of atezo and bev individually. The clinical benefit of atezo + bev vs sun will be evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. [Table: see text]

404 Background: Testicular sarcomas represent less than 1% of all testicular tumors in adults. Because of their rarity, little is known about the features and outcomes of these tumors. We present an analysis of the prognosis and survival predictors in patients with testicular sarcomas from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: Using the SEER registry, we identified adults with testicular sarcomas between 1980 and 2013. Cases were identified using a combination of ICD-O-3 site and histology codes. The JMP and SEER*STAT 8.3.2 were used for statistical analysis. Overall survival (OS) was analyzed using the Kaplan-Meier method. The prognostic effect of variables was studied using Cox proportional hazards models. Results: We identified 264 patients with testicular sarcomas with a median follow-up time of 9.2 years. The median age at diagnosis was 55 years (range 15-94) and the median tumor size was 6.6 cm (range 0.7-45). 20% of patients with documented staging presented with de novo metastatic disease. Rhabdomyosarcomas were the most common histology (37%). The median OS was 129 months (95%; CI 85-180). OS rates at 1 year and 5 years were 85% and 62% respectively. 53% of deaths were related to cancer. 1-year OS rates for localized, locally advanced and metastatic disease were 91%, 93% and 53% (P<0.0001). Variables that were significant for survival in univariate analysis included age, histology, stage, and surgical resection. Factors that negatively affected survival in multivariate analysis were age >55 years (HR 2; 95% CI, 1.1-3.7), advanced stage (HR 4.8; 95% CI, 2.7-8.4) and surgical unresectability (HR 3.7; 95% CI, 1.1-9.3). Patients with rhabdomyosarcoma had favorable outcomes compared to other histologies (59% vs 17% alive at 10 years, P=0.01). Conclusions: Testicular sarcomas are rare entities with overall good prognosis after surgical resection. Patients presenting with distant metastases, however, have worse outcomes with only about 50% of the patients alive at 1 year. Rhabdomyosarcomas are the most common histology encountered and have relatively better survival. Younger age, earlier stage and surgical resection are factors associated with significantly better outcomes.

402 Background: AGS-003 is an autologous tumor RNA-loaded dendritic cell-based immunotherapy being tested in advanced renal cell carcinoma (RCC) patients. The immunologic specificity for the patient’s own tumor is achieved using amplified tumor RNA electroporated into monocyte derived dendritic cells. To produce AGS-003 for RCC patients the RNA is amplified from a 100 mg primary tumor sample obtained via nephrectomy. In this non treatment study we evaluated the feasibility of RNA amplification from MIBC tissue acquired by transurethral resection of bladder tumor (TURBT). Methods: MIBC tissue was obtained via TURBT. Following draining of the irrigant used during the TURBT procedure, tissue was placed into an RNA preservative solution to prevent RNA degradation until processing. Methods developed for the amplification of RCC tumor RNA and RNA quality testing were applied to the RNA extracted from the MIBC specimens. Results: This work demonstrated that the methods developed for the amplification and testing of RNA from RCC can be successfully employed for the amplification of RNA from MIBC specimens collected by TURBT. Results demonstrated that the total RNA yields obtained from bladder tissue exceed that of similar masses of primary RCC tumors. This finding enabled the reduction in the amount of starting material from 100 mg to 50 mg of bladder tissue. The amount of amplified RNA produced from the lower bladder cancer masses were sufficient to support the production of immunotherapy at full scale (17 doses average). Conclusions: These data demonstrate the feasibility of RNA extraction and amplification from muscle invasive bladder cancer tissue and supports our planned phase II clinical study. [Table: see text]

367 Background: While neoadjuvant chemotherapy (NAC) for muscle−invasive bladder cancer (MIBC) is recognized as the standard of care, the management of patients with locally advanced and/or nodal disease after NAC and radical cystectomy (RC) is not well defined. We sought to evaluate the association of adjuvant chemotherapy (AC) and overall survival (OS) among patients with adverse pathology after NAC and RC. Methods: The National Cancer Database was reviewed to identify patients with adverse pathology (pT3N0, pT4N0, or pTanyN1−3) at RC following NAC from 2006−2012. Patients were stratified by receipt of AC. Clinical and pathologic variables were abstracted. OS was the primary end−point and differences on the basis of AC were assessed by the Kaplan−Meier method and log−rank test. Multivariable Cox proportional hazards regression was used to assess the association of AC with OS controlling for age, sex, race, Charlson score, year of diagnosis, pathologic stage, and receipt of adjuvant radiotherapy. Results: Adverse pathology following NAC and RC was identified in 1,361 patients from 2006−2012, of whom 328 (24.1%) received AC. Staging was pT3N0 in 444 (32.6%), pT4N0 in 162 (11.9%), and pTanyN1−3 in 755 (55.5%). Median OS for the entire cohort was 22.9 months, which differed by pathologic stage: 34.6 months (pT3N0), 21.4 months (pT4N0), and 19.3 months (pTanyN1-3)(p < 0.01). No difference in OS was noted by receipt of AC in the overall cohort (median OS 24.6 months with AC vs 22.0 months without AC; p = 0.18), or when stratified by pathologic stage. On multivariable analysis, receipt of AC was not significantly associated with overall mortality (HR 0.86; 95%CI 0.74−1.01; p = 0.06) for all patients. When stratified by stage, AC was associated with a significantly decreased risk of mortality among patients with pT4N0 disease (HR 0.56; 95%CI 0.33−0.97; p = 0.04), but not pT3N0 or pTanyN1−3 (p > 0.05). Conclusions: Patients with adverse pathology at RC after NAC have a median OS of approximately 2 years. AC was not associated with improved survival, except in the subgroup with pT4N0 disease. Clinical trials with newer systemic therapies are warranted for patients in this setting.

364 Background: Venous thromboembolism (VTE) has been reported to occur in 2-5% of patients undergoing radical cystectomy (RC). While VTE is an important cause of perioperative morbidity, the association of these events with long-term cancer prognosis has not been established. Herein, we evaluated the association of perioperative VTE with patients’ risk of subsequent disease recurrence and mortality. Methods: We reviewed 2889 patients undergoing RC between 1980−2009 at the Mayo Clinic to identify patients diagnosed with a VTE within 90 days of RC. These cases were then matched in a 1:2 fashion to control patients undergoing RC who did not develop VTE. Matching was performed on the basis of age, BMI, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were estimated utilizing the Kaplan-Meier method and compared with the log-rank test. Results: A total of 132 patients with a VTE within 90 days of RC were identified, accounting for 4.6% of all patients analyzed. These cases were matched to 257 controls per criteria noted above, and were overall well-matched. Of the 389 patients in this study, median follow-up after RC was 9.2 years, during which time 152 (39%) patients experienced recurrence and 306 (78%) died, including 157 (40%) who died of bladder cancer. We found no significant difference in 5-year RFS (59% versus 61%; p = 0.75); CSS (57% versus 64%; p = 0.13); or OS (45% versus 50%; p = 0.15) between patients with versus without perioperative VTE, respectively. Conclusions: We found that VTE within 90 days of RC did not significantly impact long-term cancer outcomes. While these events represent an important cause of perioperative morbidity, no interaction with oncologic control was noted, and patients may be counseled accordingly.