bluuebunny/crossref_metadata_2025 huggingface dataset:
A model for predicting overall survival in men with metastatic castrate-resistant prostate cancer (CRPC) for whom first-line chemotherapy failed.
Authors: Halabi Susan , Lin Chen-Yen , Small Eric Jay , Armstrong Andrew J. , Kaplan Ellen B. , Petrylak Daniel Peter , Sternberg Cora N. , Shen Liji , Oudard Stephane , De Bono Johann Sebastian , Sartor A. Oliver
Published: February 2017

24

Background: Several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC. The primary objective was to develop and validate a prognostic model that can be used to predict OS in men who have failed first-line chemotherapy. Methods: Data was used from a phase III trial of 755 mCRPC men who had developed progressive disease following first-line chemotherapy and were randomized to cabazitaxel plus prednisone or mitoxantrone plus prednisone (TROPIC trial). The data was randomly split into training (n=507) and testing (n=248) sets. A separate data, consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone, was used as the validation set (SPARC trial). Penalized regression method was used to identify important prognostic factors. Adaptive Lasso selected nine variables of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.29) and high (>= -1.29) risk groups in the testing datasets. The model was assessed for its predictive accuracy using time dependent area under the curve (AUC) on the testing sets (TROPIC and SPARC trials). Results: The final selected model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. In the TROPIC testing set, the median OS in high and low risk groups were 11 and 17 months, respectively, with a hazard ratio (HR)=2.47 (p-value<0.0001). Using the SPARC set, the median OS were 11 and 20 months in the high and low risk groups, respectively, with a HR=1.94 (p<0.0001). The time dependent AUC were 0.73 and 0.70 on the testing sets. Conclusions: A prognostic model of OS in the post-docetaxel mCRPC setting was developed and validated and risk groups were identified. This model can be used to select patients based on their prognosis to participate in clinical trials. Prospective validation is needed.
Post-treatment prognostic model for patients (pts) with metastatic urothelial cancer (UC) treated with first-line chemotherapy.
Authors: Galsky Matt D. , Moshier Erin L. , Krege Susanne , Lin Chia-Chi , Hahn Noah M. , Ecke Thorsten , Sonpavde Guru , Pond Gregory Russell , Godbold James H. , Oh William K. , Bamias Aristotelis
Published: February 2017

256

Background: Models to predict the outcome of pts with metastatic UC, based on pre-treatment variables, have previously been developed. However, pts often request “updated” prognostic estimates based on their response to treatment. This is particularly relevant in first-line treatment of metastatic UC, a disease state for which a fixed number of cycles of chemotherapy are typically administered. Methods: Data were pooled from 317 pts enrolled on eight trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in a Cox proportional hazards model to produce a nomogram to predict survival from end of treatment. The nomogram was validated externally using data from a trial of MVAC versus docetaxel plus cisplatin (n=148). Results: The median survival from end of treatment was 10.65 months [95% CI 9.20 – 13.24]; 69% of patients had died. Baseline (white blood count, ECOG performance status, number of visceral metastatic sites) and post-treatment (treatment response, duration of treatment, reason for treatment discontinuation) variables were evaluated. The Cox proportional hazard model is shown in the Table. The duration of treatment and reason for treatment discontinuation were not significantly associated with survival. The four significant variables were included in a nomogram. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. Conclusions: A model derived from pre- and post-treatment variables was constructed to predict survival from the end of first-line chemotherapy in pts with metastatic UC. This model may be useful for pt counseling and for stratification of trials exploring “maintenance” treatment. [Table: see text]
Survival of upper tract urothelial carcinoma: A population-based analysis.
Authors: Porten Sima P. , Gopalakrishnan Vancheswaran , Nogueras-Gonzalez Graciela M. , Kamat Ashish M. , Siefker-Radtke Arlene O. , Dinney Colin P.N. , Matin Surena F.
Published: February 2017

257

Background: Urothelial carcinoma involving the upper tract (UTUC) accounts for only 5% of urothelial malignancies; thus the majority of data are from single institution series or highly selected patient populations. We sought to examine contemporary trends in overall (OS) and disease-specific survival (DSS) for UTUC using a large, population based dataset. Methods: Patients within the Surveillance, Epidemiology, and End Results (SEER) database with de novo UTUC from 1973-2008 were included and analyzed in 5 year increments to evaluate disease trends. Univariate and multivariate for OS and DSS competing risks analysis were performed adjusting for age, gender, and race for renal pelvis and ureteral tumors. Results: A total of 14,237 patients met inclusion criteria. For renal pelvis tumors (n=9,318), overall survival was 54.4% at 3 years. On multivariate analysis factors that were significant predictors of OS were: age (HR 1.03, p<0.001), and year of diagnosis (HR 1.32, p<0.001). Competing risks regression estimated DSS of 60.5% at 5 years, with male gender, black race, and year of diagnosis remaining significant after adjusting for covariates (p<0.05). For ureteral tumors (n=4,919), overall survival was 56.1% at 3 years. On multivariate analysis, age was a significant predictor of OS (2.73, 95%CI 2.52-2.93, p<0.001). Competing risks regression estimated DSS of 61.9% at 5 years, with female race, and year of diagnosis remaining significant after adjusting for covariates (p<0.05). For both renal pelvis and ureteral tumors, the more contemporary era (1997-2002, 2003-2008) showed worse survival than prior eras (p<0.05). Conclusions: Disease-specific survival for patients with renal pelvis and ureteral UTUC appears to be worse in the contemporary era. While sociodemographic factors (age, gender, and race) appear to impact prognosis, it is unclear what factors may be contributing to this decline. This data adds to the growing literature supporting a paradigm change in the treatment of this disease.
Identification of prognostic groups in patients with hormone-sensitive metastatic prostate cancer at the present time: An analysis of the GETUG 15 phase III trial.
Authors: Gravis Gwenaelle , Fizazi Karim , Joly Florence , Oudard Stephane , Priou Frank , Latorzeff Igor , Delva Remy , Krakowski Ivan , Laguerre Brigitte , Rolland Frederic , Theodore Christine , Deplanque Gael , Ferrero Jean-Marc , Pouessel Damien , Mourey Loic , Beuzeboc Philippe , Zanetta Sylvie , Esterni Benjamin , Habibian Muriel , Soulie Michel
Published: February 2017

26

Background: Patients with upfront metastases at the time of prostate cancer (PC) diagnosis are less frequent than in the past in Western countries, but still represent 5-10% of all patients and almost one half of PC patients will eventually die of the disease. Prognostic factors (lymph node metastases/appendicular vs axial bone disease, performance status > 1, Gleason score > 8 and PSA > 65 ng/ml) have been proposed (Glass et al., 2003), leading to the definition of three subgroups with good, intermediate and poor prognosis. However, the current natural history of metastatic prostate cancer has not been well described. Methods: Patients with hormone sensitive metastatic PC were randomized to receive continuous androgen deprivation therapy (ADT) plus docetaxel (75 mg/m²/21d up to 9 cycles) and prednisone or ADT alone. Glass risk groups were used as stratification factors. Results: From October 2004 to December 2008, 385 pts were included. They were distributed into good (50%), intermediate (29%), and poor (21%) prognosis groups. The median follow up was 50 months [95% CI: 49 - 54]. The primary endpoint analysis showed no difference in overall survival (OS) (HR: 1.01 [95%CI: 0.75-1.36]) between the 2 arms but a significant PFS improvement was observed in the docetaxel group (HR: 0.75 [0.59-0.94] p=0.0147) (Gravis, ESMO 2012). The median OS in the ADT alone arm was 54 months [42-NR]. It was 69 [95% CI: 60.9-NR], 47 [95% CI: 37.7-NR, HR = 1.6] and 37 [95% CI: 28.5-58.9, HR = 2.12] months respectively in the good, intermediate, and poor prognosis groups (p=0.001) in the whole cohort. No interaction between prognosis groups and treatment was found. A detailed analysis using the Cox model will be presented. Conclusions: At the present time, median life expectancy of patients with metastatic PC seems to exceed 4 years. Subgroups with favorable or unfavorable outcome can be identified. Clinical trial information: NCT00055731.
The role of VEGF/mTOR/AKT pathway in patients with advanced urothelial carcinoma of the bladder cancer.
Authors: Moritz Rudolf , Hartmann Arndt , Giedl Johannes , Eltze Elke , Hertle Lothar , Herrmann Edwin
Published: February 2017

264

Background: Activation of the mTOR pathway can be observed in various tumor entities. In advanced urothelial carcinoma of the bladder (BCA) its role still is unclear. The aim of our study was to examine activation of the mTOR cascade in BCA and its correlation with survival data. Methods: Tissues from 268 patients undergoing radical cystektomy were collected to assess the diagnostic and prognostic value of mTOR, HIF1-alpha, p4EB-P1, pAKT and VEGF using tissue microarray-based immunohistochemistry. Results: Overexpression of mTOR pathway enzymes is frequently detected for HIF1-alpha (29.8%), pAKT (53.2%), mTOR (43.3%), p4EB-P1 (28.4%) and VEGF (58.5%). Overexpression of pAKT was a significant predictor of progression (PFS) in pT1 (p=0.026) and pT2 (p=0.018) tumors. Overall survival (OAS) was significantly shorter for patients with pT1 (p=0.021) and pT2 (p=0.026) tumors in this subgroup. HIF1-alpha overexpression leads to significant earlier recurrence of BCA following radical cystektomie in the subgroup of pT3 tumors (p=0.046). High levels of mTOR were predictive for cancer related death (p=0.021) in pT2-tumors. Conclusions: Activation of mTOR-pathway, especially pAKT is of prognostic value in patients with advanced BCA and might be useful as a target for future therapies.
Reproductive organ involvement in female patients undergoing radical cystectomy.
Authors: Djaladat Hooman , Skinner Eila C. , Miranda Gus , Cai Jie , Daneshmand Siamak
Published: February 2017

274

Background: Anterior pelvic exenteration is traditionally the treatment of choice for women with invasive bladder carcinoma. Female reproductive organ involvement is reported to be low, but there is not enough evidence to abandon this part during radical surgery. We evaluated the pathological involvement of reproductive organs (RO) in female patients undergoing radical cystectomy for invasive bladder urothelial carcinoma. Methods: 2,098 patients with bladder cancer underwent cystectomy between 1971 and 2008 at USC, of whom 458 were female. 411 (90%) had urothelial and 47 had non-urothelial bladder cancer. The cohort of female cystectomy patients with pathologic RO involvement is reviewed and their RFS and OS are discussed. Results: In the TCC group, 20 patients (4.8%) had RO involvement by urothelial cancer (UC-RO); 10 (2.5%) had vaginal, 2 (0.5%) cervical and one (0.25%) only uterus involvement with the rest (7) having a combination. In non-UC group, only two (4%) had RO involvement. In the UC-RO cohort, median age was 71 yo (38-89). Only one patient (5%) underwent orthotopic diversion. 19 cases (95%) were high grade TCC. Clinical stage T4a was diagnosed in 25% of cases preoperatively. Associated CIS, multifocality, LVI and histologic type of cancer had no significant correlation with RO involvement. Patients with a palpable mass or hydronephrosis were 5 times more likely to have RO involvement (P<0.001). RO involvement was associated with higher chance of positive lymph nodes (60%) (P=0.001). Three (15%) and seven (35%) patients underwent neo-adjuvant and adjuvant chemotherapy respectively. Urethral pathology was positive in 1 patient. 5 (25%) developed local recurrence and 9 (45%) developed distant metastasis at a median follow up of 12.2 yrs (0.1 to 35.5 yrs). Two-year RFS and five-year OS in UC-RO group were both 10%. Conclusions: The risk of RO involvement in female patients undergoing cystectomy for bladder cancer is about 5%, with the vagina being the most commonly involved organ. A palpable mass and/or hydronephrosis are a strong predictor of RO involvement, although other clinical criteria are not predictive.
A phase II multicenter study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy with pegfilgrastim support in patients (pts) muscle-invasive urothelial cancer (MIUC): Safety, pathologic, radiologic, and molecular correlates.
Authors: Choueiri Toni K. , Jacobus Susanna J. , Qu Angela Q. , Sweeney Christopher , Appleman Leonard Joseph , Tretter Christopher P.G. , Bubley Glenn J. , Elfiky Aymen , Park Rachel , Stack Edward C. , Signoretti Sabina , Walsh Meghara K. , Steele Graeme , Hirsch Michelle S. , Krajewski Katherine Maragaret , Taplin Mary-Ellen , Rosenberg Jonathan E. , Ross Robert W.
Published: February 2017

278

Background: ddMVAC is associated with high responses rate (RR) in advanced urothelial cancer (UC). We embarked on a study in MIUC to determine pathologic RR and its correlation with clinical and radiological outcomes as well as DNA excision repair pathway biomarkers (ERCC1, PAR, BRCA1, and BRCA2). Methods: Patients with cT2-T4, N0-1, M0 UC, and adequate kidney and marrow function were enrolled on a prospective multicenter phase II trial. Four cycles of ddMVAC were given followed by radical cystectomy (RC). The primary endpoint was pathologic downstaging to <pT1N0M0. The treatment would be considered effective if 17 of 37 eligible patients (46%) met the primary endpoint (85% power, 1-sided type I error 0.1). Secondary endpoints included safety, imaging response (by contrast-enhanced imaging, largely MRI), and biomarker correlates. Results: Between 12/08 and 4/12, 39 pts (cT2:42%; cT3:42%, cT4:16%, N1:45%) were enrolled. 91% had bladder primary, and 95% received 4 cycles of ddMVAC. Median follow up was 18 months. One patient developed distant metastases before RC. Of 39 eligible pts, 49% (90% CI 35-63) downstaged to Grade 3 related to chemotherapy were observed in 10% of pts and included mucositis, hand-foot skin reaction, hypokalemia and neutropenia. No neutropenic fevers were seen. Median and 18-month disease-free survival (DFS) is provided in Table. Tissue biomarker analyses will be presented. Conclusions: ddMVAC regimen is well tolerated and results in significant pathologic and radiologic downstaging in pts with MIUC. Clinical trial information: NCT00808639. [Table: see text]
Efficacy and safety of valrubicin in non–muscle-invasive bladder cancer in older and younger patients.
Authors: Cookson Michael S. , Lihou Christine Francis , Harper Samira Q. , Li Thomas , Chitra Surya , Tutrone Ronald
Published: February 2017

309

Background: Valrubicin was approved in the United States in 1998, removed from the market in 2002 because of manufacturing issues, and reintroduced in 2009. We report the effectiveness and safety of valrubicin, stratified by patient age, from a US multicenter, observational, retrospective study. Methods: Medical records of adults with non–muscle-invasive bladder cancer (NMIBC) who used valrubicin were abstracted between March and September 2011. The median age (75 [range 42–95] years) was the stratification cutoff. Kaplan-Meier analyses were performed for event-free survival (EFS), worsening-free survival (WFS), and progression-free survival (PFS). Results: 113 patients (mean age, 73.7 years) received intravesical valrubicin (median, 6 [range, 2–18] instillations). Median EFS, WFS, and PFS were similar in patients ≤75 vs >75 years old (see Table); 1-year rates were 17.8% vs 15.4%, respectively, for EFS; 16.1% vs 14.3% for WFS; and 80.2% vs 81.4% for PFS. 11 (19%) patients aged ≤75 years vs 4 (7%) aged >75 years underwent radical cystectomy; 28 (48%) vs 28 (51%), respectively, experienced ≥1 local adverse reaction; 3 (5%) vs 4 (7%) experienced ≥1 serious adverse event; and 4 (7%) vs 1 (2%) discontinued as a result. Conclusions: In patients with NMIBC treated with intravesical valrubicin, effectiveness and safety are similar in patients aged ≤75 and >75 years. Funding: Research and abstract were supported by Endo Pharmaceuticals Inc. [Table: see text]
Low-grade micropapillary urothelial carcinoma: Does it exist? A SEER analysis of management and outcomes.
Authors: Vourganti Srinivas , Harbin Andrew , Singer Eric A. , Shuch Brian , Metwalli Adam R. , Agarwal Piyush K.
Published: February 2017

315

Background: Micropapillary Urothelial Bladder Carcinoma (MPBC) is a rare aggressive variant histology of bladder cancer. Management of non-muscle invasive (NMI) MPBC is controversial, as bladder sparing strategies routinely used when managing TCC have resulted in worse outcomes. In order to better understand its behavior, we reviewed all MPBC pts in the SEER database and compared them with TCC pts. Methods: Data was collected from SEER 17. Age, sex, race, grade, stage, treatment, and cause of death were collected. Kaplan-Meier (KM) and Cox proportional hazards (CPH) models were performed. Results: From 2001-2008, 120 pts with MPBC were identified, 0.1% of all bladder cancer. Mean age was 70.3 yrs, 76.7% were male, and 90.8% were Caucasian. No difference in age, sex, or race was detected between MPBC and TCC pts. MPBC presented with more high grade (HG) disease (86.1% vs. 38.7%, p<0.0001) and with higher stage (40.8% NMI vs. 90.4% NMI, p < 0.0001). KM analysis demonstrated that NMI MPBC had significantly worse overall survival (OS) than NMI TCC (not controlling for grade, p<0.0001). Low grade (LG) NMI MPBC pts had worse OS and cancer specific survival (CSS) as compared to LG TCC pts (p=0.0037, p<0.0001 respectively), and did no better than HG NMI MPBC pts. No difference was detected between HG NMI MPBC and HG NMI TCC pts. A CPH model controlling for stage, grade, treatment, age, race, and sex detected no significant survival difference in MPBC vs. TCC (HR 1.04, p=0.7966). For NMI MPBC (n=49), only 4 pts underwent definitive therapy (2 had cystectomy and 2 received EBRT). During the median follow-up period of 31 months, no cancer specific deaths occurred in this group of pts. However, in those not receiving definitive therapy (n=45), 7 cancer specific deaths occurred (15.6%). Conclusions: MPBC is a rare variant with high stage and grade presentation. Controlling for stage and grade, no difference could be detected in survival between MPBC and TCC. However, LG NMI MPBC behaved similarly to both HG MPBC and HG TCC in regards to survival outcomes. We propose that all MPBC (regardless of grade) be managed as HG disease, and that strong consideration for definitive therapy should be given even in the setting of NMI disease.
Long-term survival rates after chemotherapy (CTx) in patients (pts) with nonseminomatous (NS) germ cell tumors (GCT) with teratoma (T).
Authors: Patil Sujata , Feldman Darren Richard , Bajorin Dean F. , Motzer Robert John , Sheinfeld Joel , Tickoo Satish , Reuter Victor E. , Bosl George J.
Published: February 2017

334

Background: Debate surrounds the clinical importance of T in NSCGT pts who receive CTx. The WHO no longer distinguishes between mature (MT) and immature teratoma (IT). Two studies suggested that immunohistologic (IHC) markers of apoptosis, p53 and Ki67 expression were independent markers of outcome in pts with embryonal carcinoma (JCO 21: 2679, 2003) and a differentiation genotype was an independent marker of worse outcome in NSGCT (JCO 27: 5240, 2009). We extend these analyses to NSGCT with and without T. Methods: In an IRB-approved study, archived pre-CTx tumor was obtained from 191 pts who received platinum-based CTx for initial treatment of NSGCT between 4/75 and 5/1996. Histology was confirmed and % cells displaying apoptosis (TUNEL assay) or expressing p53 and Ki67 (IHC) determined at MSKCC. 110 pts’ tumors had ≥ 1 NSGCT cell types without T and 81 had MT (n=39) and/or IT (n=52); 10 pts had both. Tumors with T had ≥ 1 additional NSGCT cell types. Overall survival (OS) differences were tested using Kaplan-Meier, Cox regression and log-rank test. Results: Median age was 27 years; primary site was testis (96%) and mediastinum (3%). 57% were IGCCCG good risk, 29% intermediate risk with no difference with and without T (P=0.53). With median follow-up of 7 yrs, 5-yr OS was 84% (95% CI: 75-90) without T and 72% (61-81) with T, and at 10 yrs 84% (75-90) and 65% (52-76), respectively (P=.06). OS differed by T subgroup: 5-yr OS was 80% if IT alone; 75% if both IT and MT; 61% if MT alone (P=.001). Adjusting for risk strata, this difference remained significant (P=.02). For IT, %Ki67 expression was borderline associated with OS (P=.06), but not %apoptosis (P=.56) or %p53 (P=.93). For MT, %apoptosis was associated with OS (P=.01) but not %Ki67 (P=.70) or %p53 (P=.29). Conclusions: The presence of T, particularly MT, in mixed NSGCT was associated with worse OS than tumors without T. T subtype was important: OS was associated with %Ki67 for IT and %apoptosis for MT. These data suggest that the presence of T should be considered in treatment decision-making. The absence of T subtyping in the WHO classification will likely result in a loss of prognostic information.
Phase II trial of paclitaxel, ifosfamide, and cisplatin (TIP) for previously untreated patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).
Authors: Feldman Darren Richard , Hu James , Dorff Tanya B. , Patil Sujata , Van Alstine Lindsay Joy , Momen Lamia , Carousso Maryann , Hughes Amanda , Snively-Solomon Jolie , Ketchens Charlean , Sheinfeld Joel , Bains Manjit S. , Bajorin Dean F. , Bosl George J. , Motzer Robert John , Quinn David I.
Published: February 2017

336

Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP chemotherapy. This phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with previously untreated poor-risk or modified intermediate-risk (LDH ≥3x upper limit of normal [ULN]) GCT were eligible. Four cycles of TIP were given every 21 days, consisting of paclitaxel 120mg/m2 on days 1-2; ifosfamide 1200mg/m2 (with mesna support) on days 1-5; and cisplatin 20mg/m2on days 1-5. Peg-filgrastim was given on day 6 and levofloxacin on days 7-13 for prevention of neutropenic fever. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s two-stage design was used: if ≥11 CRs were observed in the first 18 pts, a total of 41 evaluable pts would be accrued with the trial considered positive if ≥27 CRs were achieved. Results: Of 44 men (median age 27 [range 18-56]) enrolled; 38 had nonseminoma and 6 had seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, retroperitoneum in 3. Most pts had lung (n=31) and abdomen/pelvis (n=29) metastasis, and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. Markers were elevated in 42 pts. Forty pts received all 4 TIP cycles; 3 pts were withdrawn after 2 cycles for allergic reactions to paclitaxel and were inevaluable for response, and 1 pt completed only 3 cycles in order to undergo surgery for growing teratoma syndrome (evaluable). Of 41 evaluable pts, 29 (72%, 90% CI: 60% – 78%) achieved a CR and 5 (all seminoma) achieved a PR with negative markers (PR-); 7 pts had incomplete responses and 2 pts relapsed from PR- or CR. With a median follow-up of 2.1 years, estimated 1-year PFS was 79% (95% CI: 64% – 89%) and 3-year overall survival 97% (95% CI: 83% – 100%). There were no toxic deaths. Grade 3/4 toxicities were primarily hematologic but only 7 (16%) pts developed neutropenic fever. Conclusions: TIP demonstrated promising efficacy and was tolerable in intermediate- and poor-risk GCT pts. A randomized trial of TIP versus BEP is being planned. Clinical trial information: NCT00470366.
Outcomes of patients with sarcomatoid renal cell carcinoma: The Mayo Clinic experience.
Authors: Costello Brian Addis , Zhang Ben , Lohse Christine M. , Boorjian Stephen A. , Cheville John , Leibovich Bradley C. , Thompson Robert Houston
Published: February 2017

359

Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.
Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: A systematic review and meta-analysis.
Authors: Gartrell Benjamin Adam , Ying Jian , Sivendran Shanthi , Agarwal Neeraj , Boucher Kenneth M. , Choueiri Toni K. , Sonpavde Guru , Oh William K. , Galsky Matt D.
Published: February 2017

362

Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). While pulmonary toxicities are a recognized adverse effect associated with this drug class, the frequency and risk of these side effects have not been well characterized. Methods: Clinical trials of mTOR inhibitors in solid tumors were identified through a search of PubMed and ASCO abstracts. Prospective studies of temsirolimus, everolimus, and ridaforolimus in solid tumors were evaluated for inclusion. 22 eligible phase II and phase III trials that included 4,242 patients were identified and included in a systematic review and meta-analysis. Adverse event data was extracted for pulmonary complications including pneumonitis, dyspnea, and cough. The incidence rate and the incidence rate ratios were determined for these pulmonary adverse events. Results: Based on our analysis of the 20 trials that reported pneumonitis, the incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors is 0.11 (95% CI, 0.06-0.17). The incidence rate of grade 3 or 4 pneumonitis is 0.03 (95% CI, 0.01-0.04). The incidence rate ratio of any grade pneumonitis with mTOR inhibitors relative to controls is 18.9 (95% CI, 6.5-55.1), and the incidence rate ratio for the development of grade 3 or 4 pneumonitis is 7.9 (95% CI, 2.6-24.0). The incidence rates of any grade cough and dyspnea were found to be 0.23 (95% CI, 0.20-0.27) and 0.15 (95% CI, 0.10-0.21), respectively. The incidence rates of grade 3 or 4 cough and dyspnea are found to be 0.01 (95% CI, 0.00-0.01) and 0.03 (95% CI, 0.02-0.04), respectively. There was a statistically significant, but modest increase in risk of developing any grade cough (incidence rate ratio of 1.9 [95% CI, 1.6-2.4]) and grade 3 or 4 dyspnea (incidence rate ratio of 2.0 [95% CI, 1.2-3.3]) with mTOR inhibitors relative to controls. Conclusions: This study confirms that mTOR inhibitors are associated with pulmonary adverse events and provides a quantitative estimation of the risk of these adverse events in solid tumor patients treated with these drugs. The majority of pulmonary adverse events are low grade.
Adjuvant versus neoadjuvant androgen deprivation with radiation therapy for prostate cancer: Does sequencing matter?
Authors: Weller Michael A. , Tendulkar Rahul D. , Reddy Chandana A. , Stephans Kevin L. , Kupelian Patrick
Published: February 2017

37

Background: Androgen deprivation therapy (ADT) is typically given neoadjuvantly and concurrently with radiation therapy (RT) rather than adjuvantly in the management of intermediate and high risk prostate cancer. Our objective is to compare outcomes between patients who receive adjuvant ADT (ADJ), i.e. immediately after the completion of RT, with those who receive a neoadjuvant and concurrent regimen (NEO). Methods: From 1995-2002, 515 patients with CaP were definitively treated with RT and ADT. ADT was given for a duration of 6 months in all cases. NEO was given 2-3 months prior to the start of RT. ADJ was initiated immediately following the completion of RT. ADT sequencing was NEO in 311 (60%) and ADJ in 204 (40%). The distribution by NCCN risk classification for NEO was high in 67%, intermediate in 26%, and low in 7%. The risk group distribution for ADJ was high in 69%, and intermediate in 31%. RT dose was either 78 Gy at 2 Gy/fx (n=168) or 70 Gy at 2.5 Gy/fx (n=347). Kaplan-Meier analysis was used to calculate biochemical relapse free survival (bRFS, Phoenix definition), distant metastasis free survival (DMFS) and overall survival (OS). Cox proportional hazards regression was used to examine the impact of ADT timing on outcomes. Results: The median follow up for all patients was 8 years. For the entire cohort, the 10-yr bRFS, DMFS and OS rates were 61%, 80% and 66%, respectively. The 10-yr bRFS rates for ADJ vs. NEO were 63% vs. 60% (p=0.98). The 10-yr DMFS rates for ADJ vs. NEO were both 80% (p=0.60). The 10-yr OS rates for ADJ vs. NEO were 65% vs. 67% (p=0.98). There were no statistically significant differences in bRFS, DMFS or OS between the two groups after accounting for patient, tumor and treatment characteristics on both univariate and multivariate analyses. Conclusions: There is no difference between neoadjuvant vs. adjuvant ADT in the setting of dose-escalated RT for localized prostate cancer. This suggests that the synergy between radiation therapy and androgen deprivation is independent of the sequencing of both modalities and that the initiation of RT does not need to be delayed for a course of neoadjuvant ADT.
Impact of bone and liver metastases (BM, LM) in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs): Results from the International mRCC Database Consortium (IMDC).
Authors: McKay Rana R. , Kroeger Nils , Xie Wanling , Lee Jae-Lyun , Knox Jennifer J. , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Srinivas Sandy , Vaishampayan Ulka N. , Rha Sun Young , Pal Sumanta Kumar , Donskov Frede , Tantravahi Srinivas , Rini Brian I. , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2017

394

Background: The skeleton and liver are frequently involved sites of metastases in patients with mRCC. Their impact on survival outcomes of patients treated with currently approved MTAs is largely unknown. The purpose of this study was to analyze patient outcomes based on the presence or absence of BM and/or LM in the era of MTAs. Methods: We conducted a review from the IMCD of 2,027 patients with mRCC treated from April 2003 to August 2012. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: Median follow-up was 21 months. 1,978 were treated with first-line VEGF targeted therapy and 49 were treated with first-line mTOR inhibitors. Presence of BM was 34% overall and 27%, 33%, and 43% in favorable, intermediate, and poor-risk disease, respectively, by IMDC criteria (p < 0.001). Presence of LM was 19% overall and higher in poor-risk patients (23%) compared to favorable (20%) or intermediate-risk groups (16%) (p = 0.003). Other sites of metastases include lung, lymph node, adrenal, soft tissue, and/or brain. Among patients with a single metastatic site, those with BM or LM had a worse overall survival (OS) when compared to metastases at other sites (Table). Among patients with ≥ 2 sites of metastases, those with BM and LM had a shorter time to treatment failure (4.2 vs. 7.3 months, p < 0.0001) and worse OS (Table) when compared to patients with metastases at other sites. In multivariable analyses adjusting for IMDC criteria, BM and LM independently predicted poorer survival (HR=1.38 for BM vs. other metastases, 1.37 for LM vs. other metastases, and 1.82 for concomitant BM and LM, respectively, p < 0.0001). Conclusions: BM and LM in mRCC patients have significant clinical relevance and may possibly be used for risk-stratification of patients with mRCC. [Table: see text]
Metastatic non–clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Applying the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model to predict outcomes.
Authors: Kroeger Nils , Xie Wanling , Lee Jae-Lyun , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Srinivas Sandy , Vaishamayan Ulka N. , Rha Sun Young , Pal Sumanta Kumar , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , Tan Min-Han , North Scott A. , Rini Brian I. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

396

Background: The International mRCC Database Consortium (IMDC) Prognostic Model (Heng, et al. model, JCO, 2009) was defined and validated in a patient cohort that was comprised of RCC of all histological-subtypes. Clear-cell RCC (ccRCC) accounts for ~80% of RCC cases, and thus it is unknown if this model is reliable in patients with non-ccRCC (nccRCC). Therefore, we sought to evaluate the reliability of the model separately in ccRCC and nccRCC. Methods: Data on 2,215 (1,963 ccRCC/252 n-ccRCC) patients treated with 1-st line VEGF-and mTOR targeted therapies were collected from the IMDC. nccRCC included papillary, chromophobe, and other histologies. Patients were assigned to favorable, intermediate, and poor prognosis groups according to the ICDM prognostic model. The discrimination ability for overall survival (OS) was evaluated by C-index. Results: The median OS of the entire cohort was 20.9 months. nccRCC patients were of younger age (p < 0.0001), more often presented with low Hb (p = 0.014) and elevated neutrophils (p = 0.0001), but displayed otherwise similar clinicopathological features compared to ccRCC. OS (22.3 vs. 12.8 months; p < 0.0001), and TTF (7.8 vs. 4.2 months; p < 0.0001) were worse in nccRCC compared to ccRCC. The hazard ratio for death (OS) and treatment failure (TTF) when adjusted for the prognostic factors was 1.41 (95%CI 1.19, 1.67, p < 0.0001) and 1.54 (95% CI 1.33, 1.79, p < 0.0001), respectively. The IMDC prognostic model reliably discriminated three risk groups to predict OS and TTF in nccRCC; the median OS and TTF of favorable, intermediate, and poor prognosis groups were 31.4, 16.1, and 5.1 months (p < 0.0001) and 9.6, 4.9, and 2.1 months (p < 0.0001), respectively. The C-indices for OS were 0.66 and 0.64 for the IDCM and MSKCC criteria, respectively. Conclusions: Patients with nccRCC treated with targeted therapies have a significantly worse outcome than ccRCC patients. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC.
Predicting survival in metastatic RCC on sunitinib using MASS criteria: Evaluation of a large multicentered prospective phase III trial.
Authors: Smith Andrew D. , Zhang Haowei , Souza Frederico , Roda Manohar , Penman Alan
Published: February 2017

407

Background: The objective of this study is to predict progression-free survival (PFS) and overall survival (OS) in metastatic RCC on sunitinib therapy using initial post-therapy CT imaging changes as a biomarker. Methods: An IRB-approved HIPAA-compliant analysis of CT imaging and survival data from 213 randomly selected patients on sunitinib therapy from a prospective phase III trial of metastatic RCC treated with sunitinib (N=375) versus interferon-alpha (N=375) was performed. Up to 5 target lesions were identified, and response per RECIST 1.1, Choi Criteria, Modified Choi Criteria, and MASS Criteria were made in comparison with the baseline images, while blinded to clinical data. Imaging responses on the first post-therapy CT were associated with PFS and OS by log-rank test, descriptive statistics, and cox proportional hazards models. Results: All criteria had predictive capacity for PFS and OS (log-rank p < 0.0004 each). Only hazard ratios (HRs) of the best and worst response for Modified-Choi (0.60/2.60) and MASS Criteria (0.46/14.8) were both significantly different from the middle category for predicting PFS (p = 0.002/p = 0.008 and p < 0.001/p < 0.001). Only HRs of the best and worst response for RECIST (0.46/9.78) and MASS Criteria (0.56/7.18) were both significantly different from the middle category for predicting OS (p = 0.007/p < 0.001 and p = 0.001/ p <0.001). The overall accuracy for detecting a good clinic outcome (PFS > 250 days) was 51% for RECIST, 62% for Choi Criteria, 67% for Modified Choi Criteria, and 76% for MASS Criteria. The overall accuracy for detecting a poor clinical outcome (PFS<250 days) was 58% for RECIST, 57% for Choi Criteria, 58% for Modified Choi Criteria, and 58% for MASS Criteria. Conclusions: MASS Criteria had the best overall accuracy for predicting PFS and OS in metastatic RCC on sunitinib therapy.
Association of partial nephrectomy with a long-term survival advantage in patients between age 20 and 44 with renal cell carcinomas ≤ 4 cm: An analysis of the SEER database.
Authors: Daugherty Michael R. , Bratslavsky Gennady
Published: February 2017

408

Background: PN decreases the risk of developing chronic kidney disease as opposed to RN. While prior studies have demonstrated the survival advantage of PN in older patients, they have been criticized by selection bias in procedure selection due to comorbidities. We hypothesized that the long-standing effects of renal preservation would manifest in a survival advantage of a younger patient population, where this selection bias is minimized. Methods: The SEER 18-registries database was queried for patients between the ages of 20 to 44 that were surgically treated with either PN or RN for RCC between 1993 and 2003. We have excluded patients with metastatic or locally advanced disease and included patients with localized tumors ≤4 cm with known grade. The histologies selected were clear cell, papillary, chromophobe, sarcomatoid, collecting duct, and renal cell. The final cohort consisted of 222 and 494 subjects treated with PN and RN respectively. Chi-square analysis compared tumor variables and patient characteristics. Cancer-specific and overall survival rates were compared at 5 and 10 years using Kaplan-Meier analyses. Results: There were no differences between patients treated by PN or RN in demographics or tumor characteristics. Additionally, there was no difference in cancer-specific survival between the two groups at 5 or 10 years (p= 0.34 and p = 0.1 respectively). While there was no difference in 5-year overall survival (98.2% vs. 95.5%, p = 0.07), the patients treated with PN had an advantage in 10-year overall survival compared to patients treated with RN (94% vs. 89.7%, p = 0.025). Conclusions: Present SEER analyses demonstrate that when compared to RN, PN results in improved overall survival in patients treated for small, localized RCC. As expected, the survival advantage is observed late and supports the importance of long-term renal functional preservation. The present study of a younger patient population allows for minimizing selection bias in choosing surgical procedure due to comorbidities and provides further support for maximal renal preservation in patients with a life expectancy of 10 years or more.
First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: Hong David S. , Rosen Peter J. , Lockhart A. Craig , Fu Siqing , Janku Filip , Kurzrock Razelle , Khan Rabia , Amore Benny , Caudillo Isaac , Deng Hongjie , Hwang Yuying C. , Loberg Robert D. , Shubhakar Poornima , Zoog Stephen , Beaupre Darrin M. , Lee Peter
Published: February 2017

41

Background: AMG 208 is a small molecule MET inhibitor that suppresses proliferation and induces apoptosis in human tumor xenografts. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 208. We report data from the dose escalation part of the study. Methods: Key eligibility criteria: ≥ 18 yr, advanced solid tumors, ECOG ≤ 2, and evaluable/measurable disease. Using a modified Fibonacci design, 3–9 pts were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Pts received AMG 208 orally on days 1 and 4–28 once daily. If no dose limiting toxicity (DLT) was seen on days 1–28, pts received AMG 208 once daily starting at day 36 provided pts showed no evident disease progression. In cohorts 1–3, a standard 3+3 design was followed. In cohorts 4–7, a modified 3+3+3 design was followed. Results: As of July 16 2012, 54 pts (25 mg [n=6], 50 mg [n=4], 100 mg [n=4], 150 mg [n=3], 200 mg [n=16], 300 mg [n=10], and 400 mg [n =11]) had received ≥ 1 dose of AMG 208. 67% were men; 19% had prostate cancer (PC). Median (range) age: 61 (39–80) yr. ECOG 0/1: 52%/48%. 6 DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of pts had tx-related adverse events (AE). Tx-related AE occurring in > 10 pts: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of pts had grade ≥ 3 tx-related AE. AMG 208 was orally bioavailable with a 30–35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 pts with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC pt had PR after data cutoff. Of the 35 pts with available tumor response data for central reads, 26 had SD. FLT and biomarker data will be presented. Conclusions: AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer. Clinical trial information: NCT00813384.
Comparision of histologic distribution of RCC in young and older patients: Results from the SEER database.
Authors: Daugherty Michael R. , Blakely Stephen , Shapiro Oleg , Bratslavsky Gennady
Published: February 2017

419

Background: Renal cell cancer (RCC) incidence is relatively low in younger patients, encompassing 3-5% of all RCC tumors. These tumors tend to be due to hereditary syndromes and genetic mutations that predispose to cancer development. Patients with hereditary renal cancer (HRC) are at a higher risk of multiple tumors and bilateral disease. We hypothesize that there is a difference in histologic distribution in the younger patients and that the younger distribution contains more aggressive histologic subtypes. Methods: SEER 18-registries database was queried for all patients ≥20 years old that were surgically treated for renal cell carcinoma between the years 2001 and 2008. Patients with unknown race, grade, stage, or histology were excluded from the study. Histologies selected were clear cell, papillary, chromophobe, sarcomatoid, and collecting duct. Three cohorts were created with the ages 20-44, 45-64, and ≥65 year olds that contained 3,926, 19,661, and 16,323 patients respectively. Chi-square analysis was used to compare the histologic distributions between the cohorts. Results: There was no difference in the incidence of clear cell RCC between the three cohorts (p = 0.63). The histology distribution was not different in the 45-64 year olds compared to those ≥65 (p = 0.47). The non-clear cell histologies were different between the 3 age groups (p < 0.001). There were a larger percentage of patients in the younger patients that had chromophobe tumors compared to all non-clear cell histologies (p< 0.001). Conclusions: The difference in the non-clear cell histologic distribution between the groups is most likely due to genetic mutations predisposing these patients to chromophobe RCC. There has been limited data on HRCs, due in large part to its low incidence. Although the HRCs are known to have a most common histology, it is likely that this information is incomplete, as younger patients have undiagnosed genetic mutations that led to development of chromophobe tumors. [Table: see text]
Tumor shrinkage during VEGF inhibitor therapy as an independent predictor of PFS and OS in renal cell carcinoma (RCC).
Authors: Gruenwald Viktor , Busch Jonas , Weikert Steffen , Seidel Christoph
Published: February 2017

423

Background: Response to VEGF targeted therapies has been recently shown to be an important prognostic and predictive marker in metastatic RCC. However, whether the extent of tumor shrinkage (TS) correlates with distinct clinical outcome remains unknown. We investigated the role of early TS fractions on median progression free survival (PFS) and median overall survival (OS). Methods: Tumor evaluations according to RECIST 1.1 were performed within 3 months (mo) of targeted therapy with a VEGF inhibitor in 108 patients (pts). Pts were then categorized in fractions of TS: a) -100% to -60%; b) -60 % to -30% and c) -30% to 0% or gain in tumour size: d) 0% to +20% and e) > +20%. Kaplan-Meier and log-rank analyses were performed to estimate PFS and OS with a landmark set to 6 mo. Multivariate Cox proportional hazard model was utilized for evaluation of prognostic factors. Results: First-line VEGF inhibition achieved a PFS of 10.6 mo (95% CI 8.7 – 12.5) and an OS of 29.8 mo (95% CI 23.9 – 35.6) in all pts. 5 pts achieved a complete remission (4.6%), 28 pts a partial remission (25.9%), 52 pts. stable disease (48.2%), and 23 pts. had progressive disease (21.3%) as best response. In univariate analyses histology (clear cell differentiation vs. others) and TS were associated with PFS (p = 0.026; p <0.0001) and OS (p = 0.017; p = 0.009). Multivariate analyses confirmed the relevance of TS as a prognostic variable for OS (p = 0.021; HR 1.49) and PFS (p = <0.001; HR 1.91). Conclusions: TS is an independent predictive and prognostic marker in first-line treatment with VEGF inhibitors in mRCC. [Table: see text]