bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing chemotherapy in patients with metastatic transitional-cell carcinoma: High rate of complete response with two sequential dose-dense regimens of cisplatin, gemcitabine, paclitaxel, followed by MVAC.
Authors: Passalacqua Rodolfo , Giganti Maria Olga , Brighenti Matteo , Perrucci Bruno , Donini Maddalena , Negri Federica , Tomasello Gianluca , Toppo Laura , Liguigli Wanda , Poli Rossana , Ratti Margherita , Benecchi Luigi , Prati Andrea , Arnaudi Roberto , Potenzoni Michele , Panni Stefano , Lazzarelli Silvia
Published: February 2017

303

Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active regimens in transitional-cell carcinoma (TCC). We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a phase II, single institutional trial, including patients (pts) with bladder, renal pelvis, or ureteral TCC. Primary end point was the rate of complete response (CR) after two sequential DD regimens. Primary analysis was carried out in the intention to treat (ITT) population.Patients with histological diagnosis of TCC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP DD followed by 4 cycles of M-VAC DD. All received peg-filgrastim after chemotherapy. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: 44 consecutive pts followed in the same oncology institution were included. Males were 73%; median age was 66 years; median PS ECOG was 1; Bajorin risk factors was 0 in 36%, 1 in 48%, 2 in 16%. After the first 4 cycles of CGP DD, we observed 6.8% CR, 43.2% PR, 38.6% SD, and 11.4% PD. After the 4 sequential cycles of M-VAC DD, we observed a global 27.3% of CR, 15.9% of PR, 18.2% of SD, and 13.6% of PD. Median TTP was 9.66 months (95% CI, 6.7-13) and median OS was 18.6 months (95% CI, 12-30). Main grade 3–4 toxicity included asthenia (26%), anemia (26%), neutropenia (9.5%), febrile (7%), thrombocytopenia (12%), and neurological toxicity (5%). No toxic deaths were seen. After a median follow up of 50 months, 4 of 12 patients who obtained a complete response are free of disease since more than 3 years. Conclusions: This sequential use of these two DD regimens leads to a 4-fold increase in CR, an increase in survival, and a possible cure for some patients. A phase III trial is warranted.
Incidence and predictors of upgrading and upstaging among 10,000 contemporary patients with low-risk prostate cancer.
Authors: Dinh Kathryn Tindell , Mahal Brandon Arvin Virgil , Ziehr David R. , Muralidhar Vinayak , Chen Yu-Wei , Viswanathan Vidya Bhavani , Nezolosky Michelle Daniel , Beard Clair , Choueiri Toni K. , Martin Neil E. , Orio Peter F. , Sweeney Christopher , Trinh Quoc-Dien , Nguyen Paul Linh
Published: February 2017

32

Background: To inform decisions about active surveillance, we determined the incidence of upgrading and upstaging for a contemporary cohort of low-risk prostate cancer patients who received radical prostatectomy and identified clinical predictors of advanced disease. Methods: We studied 10,273 patients in the Surveillance, Epidemiology, and End Result (SEER) database diagnosed with low-risk prostate cancer (cT1c-T2a, PSA<10 ng/mL and Gleason 3+3=6) in 2010-2011. Upgrading was defined as pathologic Gleason score 7-10 and upstaging as pathologic T3-T4/N1 disease. Regression coefficients were used to evaluate the predictive value of clinical factors for upgrading or upstaging. Significant factors were used to develop a risk stratification table to evaluate individual patients. Results: At prostatectomy, 44% of patients were upgraded and 9.7% were upstaged. Multivariable analysis showed age, PSA, and percent total cores positive were associated with advanced disease (all p<0.001). When these variables were dichotomized by the median, age >60 (Adjusted Odds Ratio [AOR] 1.39), PSA>5.0 (AOR 1.28), and >25% total cores positive (AOR 1.76) were significantly associated with upgrading (all p<0.001). Similarly, age>60 (AOR 1.42), PSA>5.0 (AOR 1.44), and >25% total cores positive (AOR 2.26) were associated with upstaging (all p<0.001). Sixty percent of low-risk patients with PSA 7.5-9.9 and >25% total cores positive were upgraded. Conclusions: A significant proportion of low-risk patients eligible for active surveillance were harboring more aggressive or locally-advanced prostate cancer. Age, PSA and percent total cores positive should be used to assess risk of upgrading or upstaging and can guide decisions to pursue further evaluation or treatment. [Table: see text]
Predicting survival after radical cystectomy: Validation of the SPARC score.
Authors: Hu Brian Robin , Eisenberg Manuel S , Boorjian Stephen A. , Frank Igor , Dalag Leo , Movassaghi Kamran , Thapa Prabin , Miranda Gus , Daneshmand Siamak
Published: February 2017

326

Background: The Survival Prediction After Radical Cystectomy (SPARC) score (Eisenberg et al, J Urol 2013) incorporates clinical and pathologic features to predict cancer specific survival (CSS) for urothelial carcinoma of the bladder. Validation of this model would improve its generalizability. Methods: Using the IRB-approved bladder cancer database at the University of Southern California (USC), we identified patients who underwent radical cystectomy (RC) for urothelial carcinoma of the bladder for curative intent from 1971-2009. Clinical factors (Charlson comorbidity index, ECOG performance status, hydronephrosis, adjuvant chemotherapy, smoking status) and pathologic factors (pathologic T stage, nodal status, multifocality, and lymphovascular invasion) included in the SPARC score were obtained. Patients were excluded if there were missing variables or if they underwent neoadjuvant chemotherapy. Associations between clinicopathologic factors and CSS were evaluated using Cox proportional hazards. Calibration plots were generated comparing actuarial CSS with SPARC predicted CSS by deciles. A c-index was generated to determine accuracy of the prediction. Kaplan Meier curves estimated CSS stratified by SPARC score and were compared with the log rank test. Results: A total of 2,045 patients underwent RC and 1,123 (55%) met inclusion criteria with a median follow-up of 4.7 years (IQR 2.0-8.9 years). Of the 1,123 patients, 332 (30%) died of bladder cancer. All the clinical and pathologic variables used in the SPARC scoring model were associated with CSS except for smoking status and tumor multifocality. Calibration plots demonstrated concordance between the SPARC-predicted and actuarial CSS with a c-index of 0.75. Kaplan Meier curves demonstrated significant differences in CSS based upon SPARC score, p<0.001. Conclusions: The SPARC score represents a valid instrument for predicting bladder CSS after RC. The model can be utilized to better tailor adjuvant therapy and surveillance.
Molecular profiling of small cell bladder cancer.
Authors: Wang Jue , Arguello David , Gatalica Zoran , Reddy Sandeep K.
Published: February 2017

338

Background: Small cell bladder cancer (SCBC), a malignancy indistinguishable from small cell lung cancer (SCLC), is a rare and aggressive subtype of bladder cancer. Response to chemotherapy in SCBC is poor, yet the standard therapy remains cisplatin and etoposide. Novel therapies based on a better understanding of the underlying mechanisms of transformation are needed. The purpose of this study is to identify potential targets and therapeutic options for this disease, using multiplatform tumor profiling. Methods: In total, 19 small cell bladder cancer specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). Results: Loss of RRM1 (22.2%, 4/18), MGMT (83.3%, 15/18), and TS (26.3%, 5/19) by IHC are associated with potential benefit to traditional chemotherapy. High expression of ERCC1, associated with resistance to platinum-based therapy, was 37.5% (3/8). MRP1, a drug pump associated with resistance to various chemotherapies, was present in 100% (5/5) of specimens. PD-L1 (0%, 0/6) was not expressed. EGFR amplification was detected in 25.0% of patients (1/4). NGS aberrations included TP53 (90.0%), cMET (20.0%, 2/10), RB1 (11.1%), FBXW7 (10%, 1/10), PTEN (10%, 1/10). Sanger sequencing also detected KRAS (100%, 1/1) and PIK3CA (33.3%, 1/3) mutations. Conclusions: Multiplatform tumor profiling identified biomarkers which may clarify treatment dilemmas with this rare cancer. MRP1 overexpression and TP53 loss help explain this cancer’s resistance to traditional chemotherapy and its aggressive course. This approach identified potential therapies, some of which are not typically considered, like temozolomide. Immunotherapy may not be as beneficial in SCBC based on absent PD-L1 expression. NGS and Sanger sequencing identified cell surface receptors and downstream molecules that could be candidates for therapeutic strategies.
Carboplatin-based sequential chemotherapy for aged patients with advanced bladder cancer.
Authors: Yoneyama Takahiro , Tobisawa Yuki , Yoneyama Tohru , Yamamoto Hayato , Imai Atsushi , Mori Kazuyuki , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

342

Background: We retrospectively evaluated the feasibility and effectiveness of carboplatin based chemotherapy for the patients 65 years or older with advanced bladder cancer. Methods: We treated 86 patients with advanced bladder cancer at our clinic between August 2004 and June 2014. 56 patients (40 men and 16 women) with the age of 65 years or older were enrolled. Their average age was 75.8 years old (65–86), average Ccr was 54.4 ml/min (14.5–113.0), and an average follow-up period was 21.7 months (2–81). There were 18 recurrent cases after radical surgery and 38 inoperable cases. The therapeutic regimen consisted of 2 lines: gemcitabine/carboplatin (GCarbo) therapy as the first line, with two courses as a set; GCarbo/docetaxel (GCarboD) therapy as the second line if the response in the first line was insufficient. GCarbo consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. If this regimen was effective, another 2 courses of GCarbo was performed. If this regimen did not induce any tumor size reduction, we switched to GCarboD, which consisted of 800mg/m2 gemcitabine on days 1 and 8, 70mg/m2 docetaxel on day 1, and carboplatin(AUC 3) on day 2. Treatment efficacy was checked every 2 course. Results: Of the 56 subjects who had undergone the GCarbo therapy, the response rate was 37.5% (CR+PR) with 4 and 17 subjects exhibiting CR and a PR, respectively; the average response duration was 10.0 months (2–78). The response rates of 12 instances of GCardoD was25.0 %; the overall median survival was 14.0 months throughout the carboplatin-based sequential chemotherapy. Adverse events (AE) of grade 3 or higher occurred in 33 of those who had undergone the GCarbo therapy (58.9%). In GCarboD regimen, there were 11 (91.7 %) of G3/4 AEs. Conclusions: Although the present study is small and preliminary, the present carboplatin-based sequential chemotherapy is safe and active for advanced bladder cancer of the patients 65 years or older. GCarbo regimen achieved acceptable response rate (37.5%) in advanced bladder cancer. The median overall survival of 14.0 months is acceptable when average age of 75.8 year for the subjects is took into consideration. However, GCardoD had limited effectiveness for non-responder of GCarbo.
Validating a local failure risk stratification for use in a prospective study of adjuvant radiation in bladder cancer.
Authors: Baumann Brian C. , He Jiwei , Hwang Wei-Ting , Tucker Kai , Bekelman Justin E. , Herr Harry W. , Lerner Seth P. , Tangen Catherine M. , Guzzo Thomas J. , Malkowicz S. Bruce , Christodouleas John Paul
Published: February 2017

347

Background: To inform the design of trials of adjuvant radiation (RT) for bladder cancer, a local failure (LF) risk grouping has been proposed and externally validated that stratifies radical cystectomy (RC) pts into 3 groups based on pathologic factors. This stratification was developed using historical surgical databases and may not reflect outcomes in the observation arm of a modern trial. The purpose of the study is to assess whether trial accrual bias or improving surgical techniques over time impact the validity of the stratification or reduce the LF risk estimates for each subgroup. Methods: The LF stratification was developed using 2 cohorts treated with RC +/- chemo: a single-institution cohort of 442 pts (1990-2008) and the multi-center SWOG 8710 cohort of 264 pts (1987-1998). To assess the impact of trial accrual bias, we excluded pts who developed LF, DM, died, or were lost to follow up <90 days from surgery or completing post-op chemo as these pts are very unlikely to be enrolled in an adjuvant RT trial. 3-yr LF rates were estimated using Gray’s test. The stratification was considered valid if all 3 risk groups had significantly different LF rates. To assess the impact of improving surgical techniques over time, a Fine-Gray regression estimated the association of LF and year of RC while controlling for risk group. Results: Using the stricter criteria, 10% of SWOG pts and 14% from the other cohort were excluded. Analysis of the remaining pts confirmed 3 subgroups with significantly different LF risk: low risk (stage ≤pT2), intermediate risk (≥pT3 with negative margins and ≥10 nodes identified at surgery), and high risk (≥pT3 with positive margins OR <10 nodes identified) with 3-yr LF rates of 7%, 17%, and 36%, respectively (p<0.01), nearly identical to the rates when not accounting for accrual bias. Year of RC was not associated with LF risk on univariate analysis or after controlling for risk group in the SWOG, single-institution, or combined cohorts. Conclusions: These results suggest that neither trial accrual bias nor improvements in surgical techniques over time invalidate the LF risk stratification or substantially affect LF estimates. The proposed stratification is promising for use in adjuvant RT trials.
Measuring success after radical cystectomy: Feasibility of a novel composite endpoint ("poor recovery") to quantify outcomes after surgery.
Authors: Wood Erika L. , Baack Kukreja Janet E. , Porten Sima P. , Ezeagu Raphael , Qiao Wei , Navai Neema , Kamat Ashish M. , Dinney Colin P. N. , Shah Jay Bakul
Published: February 2017

357

Background: Given the predilection of invasive bladder cancer toward older sicker patients and the complexity of radical cystectomy (RC), it is not surprising many patients experience prolonged, difficult recoveries. There is growing interest in identifying ways to improve recovery after RC. To date, studies have focused on inpatient length of stay (LOS) as the primary measure of recovery improvement efforts. Given that many patients suffer complications after discharge and require hospital readmission, inpatient LOS may not be the most useful measure. We propose a novel endpoint – “Poor Recovery” – as a more encompassing measure of outcomes after RC. Methods: A comprehensive perioperative multidisciplinary algorithm known as the Optimized Surgical Journey (OSJ) has been in development at our institution over the last 18 months. We selected 50 patients who underwent RC with the OSJ algorithm and 50 patients who underwent RC with usual care during the same time period. Poor Recovery was defined by inpatient LOS > 7 days or hospital readmission within 30 days. Statistical analyses included Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables. Results: Patients in the OSJ group had significantly shorter times to first flatus, bowel movement, ambulation, and resumption of regular diet (Table). There were no differences between the groups in operative time, blood loss, opioid use, or rate of ICU admission. Mean LOS was significantly shorter in the OSJ group (5.6 and 8.5 days, p<0.01). Poor Recovery was experienced by 18% of the patients in the OSJ group and 70% of the patients in the non-OSJ group (p<0.01). Conclusions: We define a novel composite endpoint, Poor Recovery, that can help measure outcomes after RC. For future prospective studies of accelerated recovery pathways, the poor recovery endpoint may be a useful metric by which to determine the efficacy of various interventions. [Table: see text]
Institutional retrospective review of presurgical cisplatin-based chemotherapy (chemo) in patients with urothelial carcinoma (UC): Gemcitabine+cisplatin (GC) versus dose-dense methotrexate, vinblastine, doxorubicin, cisplatin (ddMVAC).
Authors: Harshman Lauren Christine , Jacobus Susanna J. , Mullane Stephanie A. , Feldman Hope , Hirsch Michelle S. , Kantoff Philip W. , Choueiri Toni K. , Bellmunt Joaquim
Published: February 2017

365

Background: Neoadjuvant cisplatin-based chemo is the standard of care for muscle invasive UC. ddMVAC and GC are frequently used regimens but have not been directly compared. The choice is often based on physician preference and toxicity profile. We interrogated a pre-existing database of UC patients (pts) for differences in efficacy and toxicity among them. Methods: From 2007-2013, consecutive pts who had received presurgical chemo prior to primary tumor resection for muscle invasive, non-metastatic UC were identified. Tolerability, toxicity and efficacy were evaluated. Rates were calculated by regimen and compared using Fisher’s exact test. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by regimen using logrank test. Cox regression estimated hazard ratios (HR) in univariate and adjusted models. Results: Of the96 patients eligible for analysis (GC: 40, ddMVAC: 56), 42% of GC pts had ≥cT3 and 23% had cN+ compared to 62% and 39% with ddMVAC. pCR rate was 18% for GC and 27% for ddMVAC (p=0.33). With a median follow-up of 28 mo., 2-yr OS probabilities were 59% [95% CI:(39-74)] on GC and 77%[95%CI:(60-87%)] on ddMVAC (p=0.1). Conclusions: Despite having more clinical ≥T3 and node positive disease at baseline, ddMVAC is at least as active as GC and achieved a numerically higher rate of pCRs/≤pT1 than GC in our cohort. No unexpected toxicities surfaced. Dose delays, discontinuations, and most selected toxicities appeared higher with GC. Neither DFS or OS significantly differed between the two regimens, however, there was a trend to greater benefit with ddMVAC. [Table: see text]
Outcomes of progression on surveillance for clinical stage I nonseminomatous germ cell tumours (NSGCT).
Authors: Hamilton Robert James , Nayan Madhur , Anson-Cartwright Lynn , Bedard Philippe L. , Moore Malcolm , Chung Peter W. M. , Warde Padraig Richard , Sweet Joan , O'Malley Martin , Atenafu Eshetu G. , Jewett Michael A. S.
Published: February 2017

377

Background: Active surveillance (AS) is universally accepted for clinical stage (CS) IA and favoured by most centers for CSIB. Patients progressing on AS are typically treated with chemotherapy, but there is no consensus. We describe patterns and mode of detection of progression and treatment of progression in our NSGCT AS cohort. Methods: From Dec 1980 to Aug 2011, 466 CSI NSGCT patients were managed with AS and 133 (28%) had disease progression while on AS. Treatment upon progression was physician choice but based on site of progression (e.g. retroperitoneum vs. extra-retroperitoneal), size or multifocality, and markers (S0 or stable, low level S1 vs. ≥ S1). Mode of detection of progression, characteristics at progression and primary treatment of progression (chemotherapy vs. retroperitoneal lymphadenectomy (RPLND)) were explored. Multivariate logistic regression was used to explore factors associated with receipt of more than one therapy in treatment of progression after surveillance. Results: Median time to progression was 7.3 months and detected by routine imaging (47%), routine serum tumour markers (37%), or both (12%). Progression most frequently occurred in the retroperitoneum (67%). Following progression, first-line treatment was chemotherapy for 71 (53%), RPLND for 51 (38%) and 11 (8.3%) underwent other therapy. In 59%, only one modality of treatment was required: chemotherapy only in 42/71 (59%); RPLND only in 36/51 (71%). For those treated with chemotherapy, pure embryonal carcinoma in the orchiectomy pathology (OR 0.11; p=0.05) was inversely associated with requiring further therapy. For those treated with RPLND, elevated markers pre-RPLND (OR 7.31; p=0.01) was associated with requiring further therapy. Overall, a second relapse occurred in 25/133 (19%) patients. With a median follow-up of 8.2 years, there were 5 deaths from testis cancer (3.8% of AS progressors; only 1.1% of overall AS cohort). Conclusions: The majority of patients progressing on surveillance do so in the retroperitoneum and within the first year. Of those that progress, most will achieve complete response with single modality treatment. In particular, RPLND can be utilized as monotherapy in select cases.
The use of radiation for stage I seminoma: Analysis of the National Cancer Database.
Authors: Waingankar Nikhil , Handorf Elizabeth , Smaldone Marc C. , Plimack Elizabeth R. , Wong Yu-Ning , Haseebuddin Mohammed , Horwitz Eric M. , Uzzo Robert G. , Kutikov Alexander
Published: February 2017

385

Background: Primary radiotherapy has historically been the preferred treatment for stage I seminoma. However, there is emerging consensus that observation or primary chemotherapy may be preferred in order to reduce overtreatment and risk of secondary malignancy. Hypothesizing that the use of radiotherapy has decreased in the modern era, our objective was to assess temporal practice patterns in stage I seminoma using a large national cancer registry. Methods: The National Cancer Database (NCDB) was queried for all patients diagnosed with stage I seminoma from 1998 to 2011. Temporal trends for receipt of systemic chemotherapy, radiation, and observation (defined as no treatment) were assessed. Following adjustment for patient, demographic, and clinicopathologic characteristics, generalized estimating equations were used to assess for associations between covariates and receipt of primary radiotherapy. Results: Of the 34,251 patients identified with stage I seminoma in the NCDB, 20,627 were treated with radiation (60.2%), 2,278 were treated with chemotherapy (6.7%), and 11,346 were managed with observation (33.1%). Radiation use significantly declined from 73.5% in 1998 to 29.6% in 2011 (p<0.0001), while utilization of chemotherapy (1.9% to 16.5%, p<0.0001) and observation (24.6% to 53.9%, p<0.0001) increased. Following adjustment, age categories 30−39 years (OR 1.06 [CI 1.01−1.13]) and 40−49 years (OR 1.10 [CI 1.03−1.17]), and stage T2 (OR 1.25 [CI 1.17−1.32]) and T3 (OR 1.21 [CI 1.04−1.41]) were associated with increased utilization of radiotherapy. Uninsured patients (OR 0.78 [CI 0.71−0.86]) and those with Medicaid (OR 0.82 [CI 0.73−0.92]) or Medicare (OR 0.62 [CI 0.55−0.69]) were less likely to undergo primary radiotherapy, while those with non-Medicare/Medicaid government insurance were more likely to receive radiation (OR 1.40 [CI 1.13-1.75]). Conclusions: In the largest known cohort of patients with Stage I seminoma reported to date, these data demonstrate that utilization of radiation therapy for stage I seminoma is on the decline. Coinciding with shifts in evidence−based guidelines, observation is now the most commonly employed management strategy for patients with Stage I seminoma.
Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.
Authors: Haas Naomi B. , Manola Judith , Uzzo Robert G. , Atkins Michael B. , Wilding George , Pins Michael , Jewett Michael A. S. , Kane Christopher J. , Cella David , Wagner Lynne I. , Coomes Bob , Wood Christopher G. , Dutcher Janice P. , Flaherty Keith , DiPaola Robert S.
Published: February 2017

403

Background: Patients (pts) with locally advanced renal cell carcinoma (RCC) are not uniformly cured by resection. The pursuit of tolerable and effective adjuvant therapies led to this investigation of two oral agents that are widely effective in the metastatic setting. Methods: 1,943 pts with completely resected RCC (pT1b high grade to pT4 any grade N any) were stratified on risk (intermediate-high or very high), clear/non-clear histology, ECOG PS, and resection approach, and randomized equally to sunitinib daily for 4 of 6 wk cycle, sorafenib daily, or placebo, then treated for up to 1 year. The primary endpoint was disease-free survival (DFS). The study was designed to detect a 25% reduction in the hazard rate, corresponding to an improvement from 5.8 to 7.7 years median DFS. After accrual of 1322 pts, the starting dose was reduced and then individually titrated to mitigate the effect of pt discontinuation from treatment intolerance. Results: At an interim analysis conducted with 62% information, although no efficacy or futility boundaries were crossed, the Data Safety Monitoring Committee recommended release of results. Using a stratified log-rank test, there were no significant differences in DFS or overall survival between either of the experimental arms and placebo. The redesign reduced the discontinuation rate on the experimental arms from about 26% in pts starting at full dose to about 14% in pts starting at reduced dose. Most common grade ≥3 adverse events were hypertension (16%/16%/4%), hand-foot reaction (15%/33%/1%), Rash (2%/15%/<1%), and fatigue (17%/7%/3%) on sunitinib, sorafenib and placebo, respectively. (See Table.) Conclusions: In pts with locally advanced, resected RCC, adjuvant treatment with sorafenib or sunitinib should not be pursued. Dose titration reduced the treatment discontinuation rate; this finding may have relevance in other settings. Clinical trial information: NCT00326898. [Table: see text]
A phase II trial of sunitinib and gemcitabine in sarcomatoid and/or poor-risk patients with metastatic renal cell carcinoma.
Authors: McKay Rana R. , Choueiri Toni K. , Werner Lillian , Atkins Michael B. , Olivier Kara M. , Song Jiaxi , Signoretti Sabina , McDermott David F. , Michaelson M Dror
Published: February 2017

408

Background: Sarcomatoid renal cell carcinoma (sRCC) is associated with aggressive biology and poor prognosis. Poor-risk RCC, as defined by established risk factors, demonstrates similar aggressive behavior. Though vascular endothelial growth factor (VEGF) therapy is the standard initial therapy for RCC, insufficient data exist in sRCC and efficacy is limited in poor-risk disease. The objective of this study was to investigate the efficacy of anti-angiogenic therapy and cytotoxic chemotherapy in clinically aggressive RCC. Methods: We conducted a phase II single arm trial at 3 institutions of sunitinib (37.5 mg PO daily, 2-weeks on, 1-week off) and gemcitabine (1,000 mg/m2 IV day 1 and 8 of every 21-day cycle) in patients (pts) with sarcomatoid or poor-risk RCC (NCT00556049). The primary endpoint was objective response rate (ORR) defined by RECIST. Secondary endpoints included overall survival (OS), safety, and biomarker correlatives. Results: Overall, 39 pts had sRCC and 33 had poor-risk RCC. Of the 32 sRCC pts with evaluable disease, the ORR was 26% (n=10) and stable disease rate (SDR) was 38% (n=15). Of the 31 evaluable poor-risk RCC pts, ORR was 24% (n=8) and SDR was 39% (n=13). OS for pts with sRCC was 10 months (95% CI 6, 24) and 15 months (95% CI 9, 29) for pts with poor-risk RCC. The most common ≥ grade 3 treatment-related adverse events included neutropenia (n=20), anemia (n=10), and fatigue (n=7). Of the 27 sRCC pts with tissue for central review, increased sarcomatoid histology (>10%) correlated with an improved clinical benefit rate (CBR, ORR + SDR) compared to pts with ≤10% sarcomatoid histology (CBR 100% for >10% versus 55% for ≤10% sarcomatoid, p=0.04), suggesting that sRCC was sensitive to combination therapy. Pts with clear-cell histology were more likely to experience an OR compared to those without clear-cell histology (32% versus 16%, p=0.23). Of 11 pts with tumor DNA sequencing data, no actionable gene mutations were identified. Conclusions: Our results suggest that VEGF targeted therapy and cytotoxic chemotherapy are an active combination in pts with rapidly progressive RCC. The combination may be more efficacious than either therapy alone and this is under further investigation (NCT01164228). Clinical trial information: NCT00556049.
Patients' preferences for adjuvant sorafenib after resection of intermediate or high-risk renal cell carcinoma in the SORCE trial: What makes it worthwhile?
Authors: Blinman Prunella Louise , Davis Ian D. , Martin Andrew , Troon Simon , Sengupta Shomik , Hovey Elizabeth J. , Coskinas Xanthi , Kaplan Richard S. , Ritchie Alastair W. S. , Meade Angela M. , Eisen Tim , Stockler Martin R.
Published: February 2017

415

Background: SORCE is an international, double-blind, placebo-controlled, phase 3 trial comparing adjuvant sorafenib for 1 year, for 3 years, or observation after resection of intermediate or high risk (as per the Leibovich score), localised renal cell carcinoma (RCC). We determined the survival benefits that SORCE participants judged necessary to make adjuvant sorafenib worthwhile 3 months after starting study treatment. Methods: Participants recruited to SORCE from Australia and selected UK sites completed a validated, self-administered questionnaire 3 months after starting study treatment to determine the minimum survival benefits they judged necessary to make adjuvant sorafenib worthwhile. Scenarios used baseline survival times (without adjuvant sorafenib) of 5 and 15 years; and baseline survival rates (without adjuvant sorafenib) of 65% and 85% at 5 years. Preferences were determined for 1 year of adjuvant sorafenib (versus none) and for 3 years of adjuvant sorafenib (versus 1 year). All tests were 2-sided and non-parametric. This substudy of SORCE was conducted by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Results: The 179 participants were mostly male (72%) with a median age of 57 years (range 29 to 78). Participants allocated sorafenib judged larger benefits necessary to make 1 year of adjuvant sorafenib worthwhile than those allocated placebo: median benefit of an extra 1 year versus an extra 1 month for baselines of 5 years (p=0.004) and 15 years (p=0.02); median benefit of an extra 5% versus an extra 1% for baseline of 65% (p=0.03), and an extra 3% versus an extra 1% for a baseline of 85% (p=0.07). Larger survival benefits were judged necessary to make 3 years of adjuvant sorafenib worthwhile (versus 1 year) regardless of treatment allocation: median benefit of an extra 2 months to 1 year for baselines of 5 years (p=0.02) and 15 years (0.02). Conclusions: Experienced toxicity and duration of treatment are important determinants of patients’ preferences for adjuvant sorafenib in RCC.
Association of PD-1 and PD-L1 protein expression in matched primary and metastatic renal cell carcinoma tumors.
Authors: Rini Brian I. , Yearly Jennifer , Dhakal Hari , Przybycin Christopher
Published: February 2017

418

Background: Therapy targeting programmed death (PD)-1 and PD-L1 proteins has activity in metastatic renal cell carcinoma (mRCC). Expression of these proteins on tumor and infiltrating immune cells is associated with a higher response to drugs inhibiting this pathway. However, these associations have been made based on primary tumor expression, while therapy is directed against metastatic deposits. Methods: Patients with mRCC and metastases (all clear cell; 3 with sarcomatoid changes) who had undergone resection of both the primary and at least one metastatic tumor were included. Samples were evaluated for PD-1 and PD-L1 expression by immunohistochemistry using anti-PD-1 clone NAT105 and Merck proprietary anti-PD-L1 clone 22C3. Stained sections were scored for PD-1 and PD-L1 using a semi-quantitative 0 to 5 scale (0 = negative, 1 = rare, 2 = low, 3 = moderate, 4= high, 5 = very high). PD-1 expression was limited to cells with lymphoid morphology, PD-L1 expression was evaluated for both tumor and non-tumor (inflammatory, endothelial) cells. Linear regression analysis was performed to assess significance of correlations. Results: Fifty matched primary and metastatic RCC tissue sets were analyzed with 48 evaluable matched pairs. PD-1 score greater than 3 (considered positive) was detected in 9 primary tumors (18%) and 9 metastatic sites (18%). PD-L1 score greater than 3 was detected in 9 primary tumors (18%) and 12 metastatic sites (24%). There was a correlation between PD-1 scores for primary and metastatic pairs (R2=0.194; p<0.002) and between PD-L1 scores for primary and metastatic pairs (R2=0.319; p<0.0001). There was an association between PD-1 score and PD-L1 score for primary tumors (R2=0.513; p<0.0001) and for metastatic sites (R2=0.449; p<0.0001). For PD-1 score, there were 10 pairs (21%) in which either the primary or metastatic site score was ≥3, but the matched pair was < 3. For PD-L1 score, there were 9 pairs (19%) in which either the primary or metastatic site score was ≥3, but the matched pair was < 3. Conclusions: The expression of PD1 and PD-L1 in primary clear cell RCC tumors is correlated with metastatic site expression, although there are a substantial percentage of tumors with discordance.
Temporal trends in the management of localized prostate cancer: From 2004 to 2011.
Authors: Gray Phillip John , Lin Chun Chieh , Jemal Ahmedin , Efstathiou Jason Alexander
Published: February 2017

42

Background: The management of localized prostate cancer (PC) is evolving. We sought to analyze recent management trends using a large national database. Methods: Data on patients presenting with a new diagnosis of PC between 2004 and 2011 were extracted from the National Cancer Data Base. Patients with nodal or distant metastases were excluded. Patients were categorized as low risk (LR), intermediate risk (IR) or high risk (HR) according to the National Comprehensive Cancer Network’s (NCCN) guidelines. Multivariate logistic regression was performed to identify factors associated with the receipt of surgery or radiotherapy. Results: 823,977 patients met the study criteria; 38.5% were LR, 42.7% IR and 18.9% HR. Between 2004 and 2011, for LR patients, rates of observation after diagnosis increased from 12.4% to 18.5% and receipt of radical prostatectomy (RP) increased from 40.3% to 54.4% (p for trend both <.001). In contrast, receipt of brachytherapy decreased from 24.4% to 11.4% and receipt of external beam radiation therapy (EBRT) decreased from 18.2% to 13.4% (p both <.001). For IR patients rates of observation increased from 6.1% to 7.3% and RP from 48.1% to 58.5% (p both <.001) while receipt of brachytherapy decreased from 12.1% to 6.4% (p <.001) and receipt of EBRT plus androgen deprivation therapy (ADT) fell from 14.7% to 8.7%. For HR patients, receipt of RP increased from 30.6% to 41.3% (p < .001) while receipt of EBRT plus ADT decreased from 30.4% to 28.0% (p <.001). On multivariate analysis factors predicting for a lower odds of receiving RP vs. radiotherapy (p all <.001) included black race (OR 0.52 vs. white), lack of insurance or insurance through Medicaid (OR 0.66 and 0.50 vs. private insurance) and residing in low income level areas (OR 0.85 for areas in the lowest national quartile vs. the highest). Conclusions: Utilization of radical prostatectomy for patients with localized PC increased significantly across risk groups from 2004 to 2011 while utilization of radiotherapy decreased. Rates of observation have increased in LR disease but remain low overall. Markers of poor socioeconomic status appear associated with receipt of radiotherapy. Further work is needed to elucidate the causes and appropriateness of these trends.
Randomized phase II trial of sunitinib four-week on and two-week off versus two-week on and one-week off in metastatic clear cell type renal cell carcinoma: RESTORE trial.
Authors: Lee Jae-Lyun , Kim Min Kyoung , Park Inkeun , Ahn Jin-Hee , Lee Dae Ho , Ryoo Hun-Mo , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuck , Ahn Hanjong
Published: February 2017

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Background: Standard sunitinib schedule, 4-week on followed by 2-week off (schedule 4/2), is associated with troublesome toxicities, and maintenance of sunitinib dose intensity has been challenging, especially in patients with Asian ethnicity. To determine the efficacy and safety of an alternative dosing schedule, 2-week on and 1-week off (schedule 2/1), we conducted a randomized phase II study. Methods: Treatment-naïve patients ≥18 years with clear cell type, mRCC were randomly assigned 1:1 to schedule 4/2 or schedule 2/1 after stratification for MSKCC risk group. The primary endpoint was failure-free survival (FFS) at 6 months. Results: From November 2007 to February 2014, 76 patients were enrolled (38 to schedule 4/2 and 38 to schedule 2/1). Two patients in schedule 4/2 were later found to be ineligible due to brain metastases and excluded from the analysis. FFS at 6 months was 44% in schedule 4/2 and 63% in schedule 2/1. Patients with schedule 2/1 were treated for a median of 7.7 months (95% CI, 3.0-12.3) of initial assigned schedule, while patients with schedule 4/2 were treated for a median of 5.7 months (95% CI, 5.0-6.5) (HR=0.54, 95% CI, 0.32-0.91, p=0.021). Seven patients in the schedule 4/2 crossed over to the schedule 2/1. Neutropenia (all grade 61% vs. 37%; grade 3-4 28% vs. 11%, p=0.0368) and fatigue (all grade 83% vs. 58%, p=0.0167) were more frequently observed with schedule 4/2. There is a strong tendency of lower incidence of mucositis (all grade, 86% vs.71%, p=0.116), and hand-foot syndrome (grade 3-4, 33% vs. 18%, p=0.143) and rash (all grade, 56% vs. 34%, p=0.0648) with schedule 2/1. Eighteen patients (ORR, 47%) in the schedule 2/1 achieved a partial response (PR) while one patient had a complete response and 11 patients had a PR (ORR, 36%, 95% CI) in the schedule 4/2. With a median follow-up duration of 47 months, the median time-to-progression was 15.1 months in the schedule 2/1 and 10.1 months in the schedule 4/2 (HR=0.69, 95% CI, 0.39-1.20). Conclusions: Sunitinib given with the schedule 2/1 is associated with less toxicity and longer FFS than the schedule 4/2 without compromising the efficacy in terms of ORR and PFS (NCT00570882). Clinical trial information: NCT00570882.
Surgical management for local retroperitoneal recurrence after radical nephrectomy in the targeted therapy era.
Authors: Thomas Arun Z. , Adibi Mehrad , Borregales Leonardo , Hoang Ly N , Tamboli Pheroze , Matin Surena F. , Karam Jose A. , Wood Christopher G.
Published: February 2017

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Background: Isolated local retroperitoneal recurrence (RPR) after radical nephrectomy (RN) for renal cell carcinoma (RCC) poses a therapeutic challenge. We examined the role of aggressive surgical resection of localized RPR in the modern era of targeted therapy for metastatic RCC. Methods: We retrospectively reviewed clinico-pathological data of patients from our RCC database from 2004-2014. We identified 67 patients with localized RPR after radical nephrectomy (RN) who underwent surgical resection. We assessed patient demographics, clinical and pathological features, location of RPR, perioperative complications and outcomes, recurrence free, cancer-specific and overall survival. Results: Median follow up after RPR resection was 33 months (range 3-120). Median recurrence free survival after RPR was 20 months (range 1-120). One, 3 and 5-year cancer specific survival was 95% 77% and 50%, respectively. Neoadjuvant and salvage targeted therapy were administered in 29 (43.3%) and 28 (41.8%) patients, respectively. Multivariate analysis identified that pathological tumor stage and nodal stage at nephrectomy, maximum diameter of RPR mass and abnormal lactate dehydrogenase levels were associated with an increased risk of cancer specific death. Patients with 0, 1, and greater than 1 adverse risk factors demonstrated cancer specific survival of 100%, 74%, 50% at 3 years and 100%, 57%, 19% at 5 years. Conclusions: This study is the largest series of patients to undergo RPR resection in the targeted therapy era. We found that clinic-pathological factors at the time of nephrectomy as well as RPR resection are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with RPR.
Impact of statins and survival outcomes in patients with metastatic renal cell carcinoma.
Authors: McKay Rana R. , Lin Xun , Albiges Laurence K. , Fay Andre Poisl , Kaymakcalan Marina Dusevic , Mickey Suzanne S , Ghoroghchian Paiman Peter , Bhatt Rupal Satish , Simantov Ronit , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

435

Background: A growing body of evidence has demonstrated the antineoplastic activity of statins. The objective of this study was to investigate the impact of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era. Methods: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for age, sex, race, histology, prior therapy, body-mass index, and other known prognostic factors and the Kaplan-Meier method. Results: We identified 4,736 patients treated with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (n=457), temsirolimus + interferon-alpha (n=208), bevacizumab + temsirolimus (n=393), bevacizumab + interferon-alpha (n=391), or interferon-alpha (n=560), of whom 511 were statin users. Overall, statin users demonstrated a statistically significant improvement in overall survival (OS) but not progression-free survival (PFS) compared to non-users (OS: 25.6 versus 18.9 months; p=0.015; adjusted hazard ratio [aHR] 0.787; 95% CI, 0.648-0.955; PFS: 7.9 versus 6.9 months; p=0.823, aHR 1.018; 95% CI, 0.867-1.196). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, p=0.023; aHR 0.749; 95% CI, 0.584-0.961) or mammalian target of rapamycin (18.6 versus 14.0; p=0.035; aHR 0.657; 95% CI, 0.445-0.972), but not in those receiving interferon-alpha (15.6 versus 14.8 months; p=0.410; aHR 1.292; 95% CI 0.703-2.275). Adverse events were similar between statin users and non-users. Conclusions: In the largest RCC analysis to date, we demonstrate that statin use improved survival outcomes in patients with mRCC treated in the targeted therapy era. Statins could represents a potential adjunct therapeutic option for patients with metastatic RCC; however, this hypothesis needs to be corroborated with preclinical work exploring the mechanisms underlying their anti-cancer effects and well-designed clinical trials investigating the clinical benefits of adding statins to modern therapies.
Active surveillance in asymptomatic or minimally symptomatic renal cell carcinoma: Retrospective analyses of a cohort of three oncological centers from Spain.
Authors: Jove Maria , Etxaniz Olatz , Sala Nuria , Font Albert , Jimenez Colomo Laura , Saigi Maria , Recalde Sabela , Navarro-Perez Valentín , Barretina Ginesta Maria Pilar , Ochoa de Olza Maria , Mulet Nuria , Garcia del Muro Xavier
Published: February 2017

441

Background: Some patients (pt) with metastatic renal cell carcinoma (mRCC) have an indolent course. Treatment toxicities can worsen quality of life. Active surveillance (AS) in paucisymptomatic pts is an option often used but few data is available. Our aim is to analyze the impact of initial AS in a sequential therapy strategy in terms of overall survival (OS). Methods: Data frompt diagnosed with mRCC from January 2005 to December 2013 in 3 centres of Spain were retrospectively analyzed. AS subgroup was defined as pt with ≥6 months (m) between diagnosis and first-line (L) treatment (tto) start. A descriptive analysis and median OS (mOS) were performed comparing pt with or without AS (AS vs. tto <6m). OS curve and medians were estimated using Kaplan Meier Method. A multivariate cox regression analyses with different prognostic factors was also realized. Results: From a cohort of 277 pt with mRCC, 69 pt (25%) were on initial AS and 208 pts on tto <6m (75%). Median time on observation until systemic tto was started on pt on AS was 14 m 95%CI (17.6-26.02). Pt characteristics of AS vs tto <6 m were: median age 63/60; males 70/72%; histology: 94/76% clear cell, 3/12% papillar, 0/4% chromophob; M1 at diagnosis: 22/48%; prognosis (Heng risk criteria): 0/17.% poor, 38.5/57% intermediate, 61.5/25% good; prior nephrectomy: 93/73%; number of metastatic locations (loc): 87/68% ≤2 loc, 12.5/32.5% ≥3 loc; lines of treatment: first L 46/53%, second L 38/23%, and third L 16/24%. When comparing exposure in months to each tto L, pt on AS had longer period of tto in second L (10.06/4.14 m, p=0.014). mOS were: 62 m 95%CI (52.97-71.03) vs. 22 m 95% CI (19.87-24.12) for AS/tto <6 m respectively (p<0.001) with statistical significance after multivariate analysis (Cox regression, HR=0.39; 95% CI, 0.25-0.63). Factors that independently influence on OS were: ≥2 M1 sites and papillar histology, negatively, and prior nephrectomy and >1 year from diagnosis to M1, positively. Conclusions: Our results suggest that AS before starting first L of tto is not a detrimental action in a selected population of mRCC pt with good risk characteristics allowing them to remain free of therapy’s toxicity during a long time period.
Twenty-year trends in survival for metastatic kidney cancer.
Authors: Macleod Liam Connor , Holt Sarah , Wright Jonathan L. , True Lawrence D. , Tykodi Scott S. , Lin Daniel W. , Gore John L.
Published: February 2017

454

Background: Since the 1990s, the therapies for metastatic renal cell carcinoma (mRCC) expanded from immunotherapies to survival-extending targeted therapies. Targeted therapy is most efficacious in clear cell RCC. Trial results likely overestimate population norms. Population-based studies on histologically limited cohorts omit a large proportion of patients, giving an overly optimistic prognosis. To clarify the changing prognosis of mRCC we examine a heterogeneous RCC cohort from the Surveillance Epidemiology and End Results (SEER) registry. Methods: mRCC patients were identified from SEER diagnosed calendar years 1990-2009. Cases were primary renal tumors confirmed by histology/cytology, not diagnosed on autopsy. Survival was analyzed by treatment era (cytokine 1990-2005, targeted 2006-2009) and classified by histology. Multivariate Cox regression identified factors independently associated with overall survival (OS). Results: Of 14,521 mRCC patients identified, clear cell mRCC represented 4,136 (median OS 12 months). Non-clear cell RCC represented 10,385 cases (median OS 4 months) of which 8,860 were designated NOS. For clear cell mRCC unadjusted median OS improved from 11 to 14 months pre/post targeted era (p<0.001). For non-clear cell mRCC there was no improvement pre/post targeted era (p=0.56). However, when RCC NOS was removed, median OS improved slightly from 6 to 7 months pre/post targeted era (p<0.001). On multivariable analysis cases diagnosed 2006-2009 were associated with improved OS compared to 1990-2005 (HR 0.90, 95% CI 0.86, 0.94). Female gender (HR 1.06 95%CI 1.02-1.10), unmarried status (HR 1.12 95%CI 1.08-1.15), non-receipt of surgery (HR 1.46, 95%CI 1.44-1.49), T3/4 primary tumor (HR 1.25, 95%CI 1.18-1.32), and higher grade (HR 1.43, 95%CI 1.25-1.63) were also significantly associated with decreased OS. Conclusions: Median mRCC OS in SEER in the targeted therapy era is lower than survival reported in clinical trials, but has improved. These discrepancies are likely related to variation in the availability of optimal treatment strategies including cytoreductive nephrectomy and biopsy-based implementation of targeted therapies in a heterogeneous health care delivery environment.