bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of neoadjuvant cisplatin, gemcitabine, and bevacizumab followed by radical cystectomy (RC) in patients with muscle-invasive transitional cell carcinoma (TCC) of the bladder.
Authors: Chaudhary U. B. , Golshayan A. R. , Brisendine A. , Kraft A. S. , Clarke H. , Keane T. E.
Published: February 2017

276

Background: Cisplatin-based neoadjuvant chemotherapy has shown survival advantage in patients (pts) with muscle-invasive bladder cancer. This benefit is strongly associated with downstaging of tumor to pT0. It was hypothesized that the addition of antiangiogenic therapy bevacizumab (Avastin [A]) to cisplatin (C) and gemcitabine (G) chemotherapy may offer improved outcomes in these pts.

Methods: Patients with clinically localized, muscle-invasive, chemotherapy-naive TCC of bladder (T2-T4a), ECOG PS 0-1 received cisplatin 70 mg/m2 IV day 1, gemcitabine 1000 mg/m2 IV day 1 and 8, bevacizumab 15 mg/kg IV day 1 on a 21- day cycle for up to 4 cycles. After completion of neoadjuvant therapy all pts underwent RC. Those pts not achieving pT0 status received paclitaxel 175 mg/m2 IV day 1 and bevacizumab 15 mg/m2 IV day 1 on a 21-day cycle for up to 3 cycles. The primary objective of the trial was to achieve pT0 status.

Results: By October 2010, 15 pts were enrolled, and 13 are evaluable for response. Median age was 64 (range 47-71), 9 (70%) males, 4 (30%) females. 2/13 (15%) developed PD after neo-adjuvant therapy and were taken off protocol.11/13 (85%) underwent RC. 4/13 (31%) pts were downstaged, 3/11 (27%) achieved pTis status and none achieved pT0 status. 2/11 (18%) pts received adjuvant paclitaxel chemotherapy with bevacizumab. Dose reduction or delays were noted in 12/15 (80%) pts. Grade 3 or 4 hematologic toxicity was observed in 5/15 (33%) pts. Grade 3 or 4 nonhematologic toxicity was observed in 3/15 (20%) pts: (renal dysfunction 2 pts, pulmonary embolism 1 pt). Postoperative complications were seen in 5/12 (42%) pts: enterovesicular fistula (1), delayed wound healing (1), prolonged ileus (2), and pelvic abscess (1). With a median follow-up time of 12 months (range 3-45), 8/11 (72%) pts have remained disease free.

Conclusions: Neoadjuvant CGA is feasible in pts with clinically localized, muscle-invasive TCC of the bladder. The surgical complications rate appears rather high and close monitoring is needed. Accrual to the trial continuous and updated results will be presented.

No significant financial relationships to disclose.
Effect of the novel anti-androgen ARN-509 on response and seizure in castration-resistant prostate cancer models.
Authors: Hager J. H. , Smith N. D. , Bischoff E. , Jung M. E. , Sawyers C. L. , Heyman R. A. , Rix P. J.
Published: February 2017

28

Background: ARN-509 is a second-generation anti-androgen discovered in a screen to identify full androgen receptor (AR) antagonists in the context of AR over-expressing prostate cancer cells, a model for castration resistant prostate cancer (CRPC). It has been reported that other second-generation anti-androgens, MDV3100 and BMS-641988, can induce seizures at high dose in pre-clinical species and man and that this is mediated through antagonism of the CNS-based GABAA receptor. To define the clinical potential of ARN-509, we carried out a comprehensive assessment of its in vitro and in vivo activity in validated models of CRPC and assessed its seizure inducing potential.

Methods: ARN-509 and MDV3100 were profiled in a series of assays to monitor both on- and off-target activity. Comparative in vivo efficacy in the LNCaP/AR mouse xenograft model of CRPC and pharmacokinetics were determined. Seizure inducing potential was assessed in an acute pentylenetetrazol (PTZ) infusion model.

Results: In vivo, in the LNCaP/AR model of CRPC, an ARN-509 dose of 10 mg/kg/day exhibited tumors regressions equivalent in frequency and magnitude to a 30 mg/kg/day dose of MDV3100. Tumor re-growth following once daily dosing (30 mg/kg) for 28 days revealed that ARN-509 treated tumors exhibited a more durable response than MDV3100 treated tumors as evidenced by a significantly longer time to re-growth. At doses that yielded equivalent degree of tumor regression, the steady state plasma and brain levels were significantly lower for ARN-509 (10 mg/kg) than MDV3100 (30 mg/kg). ARN-509 and MDV3100 exhibit similar binding affinity to the GABAA receptor; IC50 3.0 and 2.7 mM, respectively. In vivo seizure potential of ARN-509 and MDV3100 was assessed in an acute PTZ infusion model in mice. MDV3100 was found to produce a dose dependant lowering of seizure threshold, while ARN-509 had no effect at any dose tested.

Conclusions: ARN-509 is a second-generation anti-androgen with significant efficacy and an appropriate safety profile that supports its clinical development in both CRPC and earlier stages of prostate cancer. ARN-509 is currently in a phase I/II study in CRPC patients.

[Table: see text]
Ability of urovysion FISH analysis to select patients with low- or intermediate-risk non-muscle-invasive bladder cancer (LI-NMIBC) for decreased surveillance.
Authors: Rosevear H. M. , Lightfoot A. J. , O'Donnell M. A.
Published: February 2017

283

Background: Recurrent LI-NMIBC is difficult to detect cytologically, requiring frequent cystoscopies. Urovysion's (Abbot Laboratories, Downers Grove, IL) fluorescent in situ hybridization assay (FISH) detects genetic changes associated with LI-NMIBC and may be useful in identifying patients for extended screening intervals.

Methods: Charts of 54 consecutive patients with LI-NMIBC who underwent cystoscopy, cytology, and FISH analysis every 3 months for the first year after resection since 2004 were retrospectively identified and reviewed. We analyzed the number of tumors or high-grade cytologies that would have been missed if surveillance cystoscopy, cytology, and FISH analysis had not been done between 3 and 12 months post-resection for patients with a normal cystoscopy, cytology, and FISH analysis at 3 months after initial resection and compared those results to patients with normal cystoscopy, cytology, and abnormal FISH analysis.

Results: Mean age of the 54 patients was 67 (range 25–89) and 41 were males. Thirty-nine patients had normal cystoscopy, cytology, and FISH analysis at 3-months follow-up. If no further surveillance was done until 1 year post-resection, 2 low-grade tumors (3 and 7 mm at 7 months post-resection) and 2 incidents of high-grade cytology would have been missed (4 of 39, 10%). Fifteen patients had normal cystoscopy and cytology but abnormal FISH analysis results at 3 months. If no further surveillance had been done until 1 year after resection, 6 tumors (6 of 15, 40%) (5, 8, 3, 3, 9, 2 mm at 5, 6, 6, 7, 9, 10 months post-resection) and no high-grade cytology would have been missed. Overall, statistically fewer patients with normal compared to abnormal FISH analysis at first follow-up developed tumors before 1 year (4 of 39 vs. 6 of 15, p=0.033).

Conclusions: FISH analysis can be used to significantly increase our ability to select patients suitable for extended screening intervals. It may be prudent to include FISH analysis at the first post-resection follow-up before selecting patients with LI-NMIBC for an extended screening interval.

[Table: see text]
Everolimus in metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients (pts) with one versus two prior vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapies enrolled in the phase III RECORD-1 study.
Authors: Figlin R. A. , Calvo E. , Motzer R. J. , Hutson T. E. , Oudard S. , Porta C. , Grunwald V. , Ravaud A. , Kpamegan E.
Published: February 2017

304

Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the only medication to have shown efficacy in a randomized, controlled, phase III clinical trial (RECORD-1) in pts with mRCC after progression on VEGFR-TKIs. Everolimus more than doubled progression-free survival (PFS) vs. placebo (4.9 vs 1.9 months) and reduced the risk of disease progression by 67%. This analysis evaluated the effect of everolimus on survival in pts who had received 1 vs 2 prior VEGFR-TKIs.

Methods: Pts with mRCC who progressed on sunitinib (SU) and/or sorafenib (SOR) were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care in the double- blind, phase III RECORD-1 study (ClinicalTrials.gov: NCT00410124 ).

Results: Before enrollment, the majority of pts received only 1 VEGFR- TKI (317 pts, 74%), with 317 pts receiving either SU or SOR (everolimus = 211; placebo = 106) and 99 pts receiving both SU and SOR (everolimus = 66; placebo = 33). Median PFS was 5.42 mo (95% confidence interval [CI]: 4.30, 5.82) in pts receiving everolimus who had received 1 prior VEGFR-TKI and 1.87 mo (95% CI: 1.84, 2.14) in those receiving placebo (hazard ratio [HR]: 0.31; 95% CI: 0.23, 0.42; p < .001). Median PFS was 3.78 mo (95% CI: 3.25, 5.13) for the everolimus group in pts who received 2 prior VEGFR-TKIs, versus 1.87 mo (95% CI: 1.77, 3.06) for the placebo group (HR: 0.37; 95% CI: 0.22, 0.63; p < 0.001).

Conclusions: Pts in all stratified subgroups derived significant clinical benefit from everolimus treatment, including pts previously treated with either 1 or 2 VEGFR-TKIs. However, there was a trend toward a longer PFS in pts treated with 1 prior VEGFR-TKI compared with 2 VEGFR-TKIs.

[Table: see text]
Phase I/II trial of concurrent sunitinib (SU) and image-guided radiotherapy (IGRT) followed by maintenance systemic therapy for patients with oligometastases.
Authors: Kao J. , Cesaretti J. A. , Sung M. W. , Stock R. , Galsky M. D. , Packer S. , Chen S.
Published: February 2017

306

Background: Preclinical data suggest that SU enhances the efficacy of radiotherapy. We tested the combination of SU and hypofractionated IGRT in a cohort of patients with historically incurable distant metastases.

Methods: Eligible patients had 1 to 5 sites of metastatic solid tumors measuring ≤ 6 cm. The most common tumor types treated were head and neck, liver, lung, kidney, and prostate cancers. Patients were treated with concurrent SU (25 to 50 qd d 1–28) and IGRT (40 to 50 Gy in 10 fractions d 8–19). Following IGRT, patients could either receive maintenance SU (50 mg daily, 4 weeks on/2 weeks off starting on d 43) or alternate forms of systemic therapy. Most patients were treated with the recommended phase II dose of SU 37.5 mg and IGRT 50 Gy. Maintenance SU was used in 40% of patients.

Results: Between 2/07 and 6/08, 43 patients with 81 metastatic lesions were enrolled with a median follow up for surviving patients was 20.1 months (range, 5–37 months). The incidence of acute grade ≥ 3 toxicities was 33%, most commonly myelosuppression, bleeding and abnormal liver function tests. The 2-year estimates for local control and distant control were 74% and 43%, respectively. The 2-year estimates for progression- free survival and overall survival were 39% and 46%, respectively. To date, 15 (35%) patients were alive without evidence of disease, 6 (14%) were alive with distant metastases, 13 (30%) were dead from distant metastases, 1 (2%) was dead from local progression, 6 (14%) were dead from comorbid illness, and 2 (5%) were dead from treatment-related toxicities. Predictors of improved progression-free survival were genitourinary primary tumor (HR 0.18; p=0.04), IGRT dose > 40 Gy (HR 0.21; p=0.005), number of metastases (HR 2.22; p=0.006) and maintenance SU (HR 0.31; p=0.06). Flow cytometry demonstrates a significant reduction in immune suppressive myeloid derived suppressor cells and T regulatory cells in SU treated patients.

Conclusions: Concurrent SU and IGRT achieves durable local and distant control in a significant subset of patients with oligometastases, particularly patients with genitourinary primary tumors with ≤ 2 distant metastases.

[Table: see text]
Phase III, randomized, placebo-controlled study of everolimus in patients with metastatic renal cell carcinoma (mRCC): Subgroup analysis of patients intolerant of prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy.
Authors: Hutson T. E. , Bracarda S. , Escudier B. , Porta C. , Figlin R. A. , Calvo E. , Grunwald V. , Ravaud A. , Kpamegan E. , Motzer R. J.
Published: February 2017

312

Background: In the RECORD-1 phase III study, the mammalian target of rapamycin (mTOR) inhibitor everolimus (ClinicalTrials.gov: NCT00410124 ) prolonged progression-free survival (PFS) versus placebo (median PFS 4.9 vs 1.9 months) in patients with mRCC whose disease progressed during or within 6 months of VEGFr-TKI (sunitinib and/or sorafenib) therapy. In this retrospective analysis, we evaluated the effect of everolimus on PFS in the subgroup of patients who discontinued prior VEGFr-TKI therapy because of adverse events.

Methods: In the randomized, double-blind RECORD-1 trial, patients with mRCC who had prior VEGFr-TKI therapy were randomized (2:1) to receive everolimus 10 mg/day (n = 277) or placebo (n = 139) plus best supportive care.

Results: Patients who were intolerant of prior VEGFr-TKI therapy included 50 patients (sunitinib = 26; sorafenib = 24) in the everolimus group and 13 patients (sunitinib = 5; sorafenib = 8) in the placebo group. The median PFS in the sunitinib group was 5.13 mo (95% confidence interval [CI]: 3.71, not available [NA]) in patients receiving everolimus vs 2.81 mo (95% CI: 1.87, 3.71) in those receiving placebo (HR: 0.28; 95% CI: 0.07, 1.18; p = 0.033). In the sorafenib subgroup, median PFS was 5.59 mo (95% CI: 3.78, NA) versus 1.91 mo (95% CI: 1.68, 3.48), respectively (HR: 0.29; 95% CI: 0.09, 0.91; p = 0.012).

Conclusions: Everolimus prolonged PFS in a subgroup of patients with mRCC who were intolerant of prior VEGFr-TKI therapy. These results suggest that mTOR inhibition with everolimus was active in patients with mRCC who were intolerant of a previous VEGFr-TKI.

[Table: see text]
A randomized, double-blind phase III study (VEG105192) of pazopanib (paz) versus placebo (pbo) in patients with advanced/metastatic renal cell carcinoma (mRCC): Updated safety results.
Authors: Sternberg C. N. , Hawkins R. E. , Szczylik C. , Davis I. D. , Wagstaff J. , McCann L. , Chen M. , Rubin S. D.
Published: February 2017

313

Background: This study evaluated the efficacy and safety of paz in 435 pts with mRCC. The primary endpoint of PFS with paz vs pbo was met with a median PFS of 9.2 vs. 4.2 mo (HR 0.46; p<0.0001) respectively. Final OS was 22.9 mos in paz arm vs. 20.5 mos in pbo (HR 0.91; p=0.224); however, OS was confounded by extensive crossover of pbo pts to paz and other therapies. Two independent analyses to adjust for crossover, IPCW (Inverse Probability of Censoring Weighted) and RPSFT (Rank Preserving Structural Failure Time) suggest an OS benefit with paz;HR 0.504; p=0.002 by IPCW and HR 0.43; p=0.172 by RPFST. At the final OS analysis, pts on the paz arm had a 30% increase or in absolute terms 70 yrs (303.7 yrs from 233.5 yrs) in cumulative exposure since analysis 2 yrs ago (Sternberg; JCO 2010). Updated safety data is reported.

Methods: Pts with clear cell mRCC and measurable disease with no prior treatment or 1 prior cytokine-based trt were randomized (2:1) to paz 800 mg QD or pbo and treated until progression (PD), death, or unacceptable toxicity. Upon PD, pts on the pbo arm could receive paz through a parallel open-label study.

Results: Median exposure duration was nearly doubled in the paz arm vs. pbo (7.4 mo vs. 3.8 mo). In the paz arm, 32% of subjects remained on treatment > than 12 mos, 15% for > 24 mos and 8% for > 36 mos. The mean daily dose of paz was 679 mg. ALT elevations >3xULN occurred in 54 pts; upon interruption of paz, or with continuation (adaptation), 85% of pts had documented recovery, 9% no recovery data and 6% not recovered. Further details regarding these and less frequent class effect AEs such as hand-foot syndrome (6%), myocardial dysfunction (<1%) will be reported.

Conclusions: This safety update reflects a 30% increase in the cumulative exposure to paz since the previous clinical cutoff. There are no significant changes to the type, frequency or severity of AEs and no differences in grade 3, 4, or 5 AEs. No new safety signals have been detected.

[Table: see text]

[Table: see text]
Efficacy of targeted drug therapy for metastatic renal cell carcinoma in the elderly patient population.
Authors: Khambati H. , Choueiri T. K. , Kollmannsberger C. K. , North S. , Bjarnason G. A. , Vaishampayan U. N. , Wood L. , MacKenzie M. J. , Rini B. I. , Heng D. Y. ,   International mRCC Database Consortium
Published: February 2017

318

Background: Targeted therapy has become the mainstay of treatment for metastatic renal cell carcinoma (mRCC). The efficacy of this therapy on the older population is poorly understood.

Methods: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 14 centers.

Results: One thousand three hundred eighty-one patients were treated with targeted therapy as their first-line treatment. Of those, 144 (10%) were seventy-five years or older (median=78 years, range=75–89). Four percent of these individuals were favorable risk, 69% intermediate risk, and 27% poor risk as per Heng et al. JCO 2009 prognostic factors. There was no statistical difference in these prognostic groups between the older (≥75) and younger populations (<75) (p=0.1779). The initial treatment for those ≥ 75 years was with sunitinib (n=98), sorafenib (n=35), bevacizumab (n=7), and AZD2171 (n=4). The older population had fewer nephrectomies (71% vs. 80%, p=0.0133) and fewer brain metastases (3% vs. 9%, p=0.0128). Only 23% of older patients went on to receive second line therapy in comparison to 39% of the younger population (p<0.0001). The overall response rate, median treatment duration and overall survival for the older vs. younger group were 18% vs. 25% (p=0.0975), 5.5 months vs. 7.5 months (p=0.1388), and 16.8 months vs. 19.7 months (p=0.3321), respectively. When adjusted for known poor prognostic factors, age over 75 years was not found to be associated with poorer overall survival (HR 1.002, 95%CI 0.781–1.285) or shorter treatment duration (HR 1.018, 95%CI 0.827–1.252).

Conclusions: Overall response rates, treatment duration, and overall survival rates are not different between the older and younger populations and age is not a prognostic factor. Thus, the decision to treat with targeted therapy should not depend on age alone.

[Table: see text]
Brain metastases in patients treated with targeted therapy for metastatic renal cell carcinoma (mRCC).
Authors: Alharbi H. , Choueiri T. K. , Kollmannsberger C. K. , North S. , MacKenzie M. J. , Knox J. J. , Rini B. I. , Heng D. Y.
Published: February 2017

326

Background: Patients with brain metastases from advanced RCC treated in the targeted therapy era are not well characterized.

Methods: Data from patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium from 6 centers.

Results: One hundred six out of 705 (15%) patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti-VEGF therapy and the rest developed metastases during follow-up. Of the patients with brain metastases, 6%, 68%, and 26% were in the favorable, intermediate and poor prognosis groups, respectively, per the Heng et al JCO 2009 criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 40% had a Karnofsky performance status (KPS) <80%, and 81% had symptoms of brain metastases. The median largest size and number of brain metastases was 1.8 cm (range 0.2–6.6) and 1 (range 1–20), respectively. Patients were treated with first-line sunitinib (n=77), sorafenib (n=23), bevacizumab (n=5), and temsirolimus (n=1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). The brain metastases of 59 patients were evaluable and based on the local treatment and/or targeted therapy achieved 7 (12%) complete responses, 23 (39%) partial responses, 14 (24%) patients with stable disease, and 15 (25%) patients with progressive disease in the brain metastases. Patients with more than 4 brain metastases vs. those with no more than 4 have an overall survival time from diagnosis of brain metastasis of 3.9 vs. 15.4 months (p=0.0051). Previous nephrectomy, sarcomatoid, and non-clear cell histology are not associated with development of brain metastases. On multivariable analysis, KPS<80% (p=0.0139), diagnosis to treatment with targeted therapy <1 year (p=0.0012), and higher number of brain metastases (p=0.0311) were associated with worse survival from diagnosis of brain metastases.

Conclusions: In patients with brain metastases from RCC, KPS at start of therapy, diagnosis to treatment time and number of brain metastases may be prognostic factors for overall survival.

[Table: see text]
Use of early primary tumor response to predict overall survival in patients with metastatic RCC undergoing treatment with sunitinib.
Authors: Abel E. , Culp S. H. , Tannir N. M. , Matin S. F. , Tamboli P. , Wood C. G.
Published: February 2017

329

Background: In metastatic renal cell carcinoma (mRCC) patients treated with sunitinib and the primary tumor in situ, there is minimal predictive data available to help guide clinicians during treatment with targeted therapy. In prior studies, early primary tumor response (PTR) was associated with improved overall PTR, but the effect on overall survival (OS) is unknown. The purpose of our study was to evaluate whether early PTR was associated with improved OS in mRCC patients undergoing treatment with sunitinib.

Methods: We reviewed our institutional database to identify patients with mRCC treated with sunitinib with primary tumor in situ. Clinical and pathological data were collected for each patient. Sequential abdominal CT or MRI scans were reviewed to evaluate PTR. Early PTR was defined as ≥ 10% decrease in tumor diameter within the first 90 days of treatment. Univariable and multivariable stepwise Cox proportional hazards regression analysis were performed to identify predictors of OS in these patients.

Results: 75 consecutive patients were identified between 2005 and 2009 with a median follow-up of 15 months. 24 patients exhibited an early PTR; median maximum response 23.1% (range: −53.4, −10.2) and decrease in primary tumor diameter at a median of 90.5 days. Early PTR was associated with a decreased risk of death on multivariate analysis (HR: 0.18; 95% CI 0.05, 0.62, p<0.01). In addition, median OS was improved in patients with an early PTR (30.2 vs. 12.7 months). Independent predictors of decreased survival on multivariate analysis included local symptoms, multiple bone metastases, clinical evidence of venous thrombus, LDH > upper limit of normal, and >2 visceral metastatic sites.

Conclusions: Early PTR ≥ 10% is associated with improved survival, better response in metastatic sites, and better overall PTR in patients with mRCC. Future studies should consider this variable when evaluating sunitinib in mRCC treatment.

[Table: see text]
Long-term survival of patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy (TT) without cytoreductive nephrectomy (CN).
Authors: Richey S. L. , Culp S. H. , Jonasch E. , Corn P. G. , Pagliaro L. C. , Tamboli P. , Patel K. , Matin S. F. , Tannir N. M.
Published: February 2017

346

Background: We recently reported on 188 patients (pts) with mRCC treated with TT without CN [Richey et al, J Clin Oncol 28:15s, 2010 (suppl; abstr 4613); Annals of Oncology- in press]. We report here outcome data on pts who survived > 24 months (mos).

Methods: We retrospectively reviewed records of patients with mRCC who received TT without CN and survived longer than 24 mos from treatment initiation. Pts did not undergo CN due to medical comorbidity, unresectable primary tumor, heavy disease burden, or patient preference. Kaplan-Meier methods were used to estimate median overall survival (OS). Long-term complications related to therapy were evaluated.

Results: 22 pts were identified meeting the inclusion criteria. Median follow-up was 30.4 mos (range, 24.1- 68.7), with median OS time of 34.1 mos (95% CI: 30.2, 37.2). Median time on therapy (TOT) was 25.3 mos (IQR: 13.7, 28.5). Six pts (27.3%) were alive at the time of analysis, with median TOT of 26.9 mos (range: 13.7, 62.5) (IQR: 24.6, 33.4). Eastern Cooperative Oncology Group performance status was 0 or 1 in 86% of pts. Ten (45%) and 12 (55%) pts had intermediate- and poor-risk disease by Heng et al criteria (JCO 2009), respectively. Patients received the following types of TT: sunitinib 14 (63.6%), sorafenib 13 (59.1%), temsirolimus 5 (22.7%), bevacizumab 5 (22.7%), pazopanib 3 (13.6%), everolimus 4 (18.2%), erlotinib 3 (13.6%), investigational targeted agent 1 (4.6%). Four (18.2%), 5 (22.7%), and 13 (59.1%) pts received 1, 2, or ≥ 3 different therapies, respectively. During treatment with TT, 6 pts (27.3%) developed hypertension, 6 pts (27.3%) developed hypothyroidism, 2 pts (9.1%) developed congestive heart failure, 1 pt (4.6%) developed stroke. No pts developed bleeding or myocardial infarction. By radiographic assessment of best primary tumor response, 4 (18.2%) pts had a partial response (≥30% decrease), 10 (45.5%) exhibited a decrease <30%, and 6 (27.3%) had stable or increased size of the primary tumor.

Conclusions: These data highlight the potential for long-term survival of patients with mRCC treated with TT without CN, and underscore the challenges in managing therapy-related long-term adverse events.

No significant financial relationships to disclose.
Hematologic toxicities in cancer patients treated with the multityrosine kinase sorafenib: A meta-analysis of clinical trials.
Authors: Schutz F. A. , Je Y. , Choueiri T. K.
Published: February 2017

352

Background: Sorafenib is a vascular endothelial growth factor receptor tyrosine-kinase inhibitor currently used in several malignancies. While not a traditional cytotoxic chemotherapeutic agent, hematological toxicities have been reported with this drug but the incidence and risk have not been formerly assessed. We performed a meta-analysis to determine the incidence and risk of hematologic toxicities associated with sorafenib use.

Methods: The databases of Medline were searched for articles from 1966 to May 2010. Abstracts presented at the American Society of Clinical Oncology meetings were also searched. Eligible studies include randomized trials with sorafenib, and adequate safety data profile reporting anemia, neutropenia, lymphopenia or thrombocytopenia. Statistical analyses were conducted to calculate the summary incidence, RR and 95% confidence intervals (CI).

Results: A total of 3,221 patients were included. The incidence of sorafenib-associated all- grade anemia, neutropenia, thrombocytopenia and lymphopenia were 43.9%, 18.0%, 25.3% and 34.1%, respectively. The incidences of high-grade events were 2.0%, 5.1%, 4.0% and 13.1%, respectively. Sorafenib was associated with a decreased risk of high-grade anemia (RR=0.62; 95% CI 0.39-0.98), an increased risk of all-grade (RR=1.69; 95% CI 1.33-2.17) and high-grade (RR=1.61; 95% CI 1.02-2.57) neutropenia, all-grade (RR=2.56; 95% CI 1.37-4.80) and high-grade (RR=3.63; 95% CI 1.98-6.66) thrombocytopenia, and high-grade lymphopenia (RR=1.84; 95% CI 1.22-2.78). Stratified analysis by the presence or not of concomitant chemotherapy demonstrated similar risks.

Conclusions: Independent of cytotoxic chemotherapy, sorafenib has significant hematologic toxicities, with a decreased risk of anemia and increased risk of neutropenia, thrombocytopenia and lymphopenia.

[Table: see text]
Likelihood of high volume renal surgeons to offer elective partial nephrectomy in high complexity tumors as classified by the nephrometry scoring system.
Authors: Weight C. J. , Kim S. P. , Crispen P. L. , Breau R. H. , Boorjian S. A. , Thompson R. H. , Leibovich B. C.
Published: February 2017

354

Background: Partial nephrectomy (PN) has demonstrated equivalent cancer control to radical nephrectomy (RN) and has been associated with lower rates of all-cause mortality. Nevertheless, there continues to be wide variability in practice pattern in the treatment of renal masses. Specifically, the decision to perform PN or RN often depends on patient, surgeon and renal mass characteristics. By quantifying the renal tumor using the R.E.N.A.L. nephrometry scoring system, collecting surgeon information, and providing defined clinical scenarios we attempt to evaluate factors important in surgeon decision-making.

Methods: In June 2009, all members of the American Urological Association with a listed email address were invited to participate in a survey evaluating the management of renal masses. Respondents were asked their preferred treatment for 8 clinical scenarios. Each of these renal masses was given a nephrometry score (NS). The propensity to offer PN was evaluated by NS and surgical volume. High volume was defined as > 50 renal cases per year and low volume was defined as £ 10 cases per year.

Results: 764 attending level urologic surgeons responded to each of the 8 scenarios providing 6112 evaluable clinical scenarios. NS ranged from 4-10; each unit increase was associated with 2-fold increased odds of a surgeon offering radical nephrectomy (OR 1.99, 95% CI: 1.93,2.06). PN was the preferred treatment for approximately 95% of patients with low complexity tumors (NS < 8) regardless of surgical volume. However, proposed treatment of high complexity tumors (NS ³ 8) demonstrated considerable heterogeneity in treatment choice. Controlling for all patient characteristics, high surgical volume significantly predicted whether PN would be offered to patients with high complexity tumors (OR 3.04 95% CI: 2.34,9.95), but not those with low complexity tumors (OR 1.95 95% CI: 0.87,4.38) compared to low volume surgeons.

Conclusions: Increasing NS correlated with increased use of radical nephrectomy, particularly after a score of 8 among all surgeons. As renal surgical volume increased, surgeons were more willing to offer PN in high complexity tumors.

No significant financial relationships to disclose.
Effect of an individualized dose/schedule strategy for sunitinib in metastatic renal cell cancer (mRCC) on progression-free survival (PFS): Correlation with dynamic microbubble ultrasound (DCE-US) data.
Authors: Bjarnason G. A. , Khalil B. , Williams R. , Hudson J. M. , Lloyd B. , Milot L. M. , Atri M. , Kiss A. , Burns P.
Published: February 2017

356

Background: Sunitinib area under the curve (AUC) correlates with response and PFS (Houk et al). Current recommendations for dose modification do not take this into account.

Methods: A single center retrospective review identified mRCC patients (pts) where individualized (individ) sunitinib dose/schedule modifications (DSM) were used to maximize dose and minimize time off therapy (Rx). Pts were started on 50 mg 28 days (d) on/14 d off. DSM were done to keep toxicity (fatigue, skin, GI) at ≤ grade-2. DSM-1 was 50 mg 14 d/7 d with individ increases in d on Rx based on toxicity. DSM-2 was 50 mg 7 d/7 d with individ increases in d on Rx. DSM-3 was 37.5 mg continuously with individ 7 d breaks. DSM-4 was 25 mg continuously with individ 7 d breaks.

Results: In 171 pts; median age was 60y; 20% good, 60% intermediate, 20% poor prognosis by Heng criteria; 80% had nephrectomy; 79% clear cell histology; 60% were previously untreated. At a median follow-up of 10.7 months (mo), overall median PFS was 7.9 mo. Of 39 pts still on therapy, 37 were on a DSM Rx. Pts were allocated to three groups based on the dose/schedule used for the longest time. The PFS/response% (PR+SD) for each group was 4.4 mo/65.6% (standard 50 mg 28 d/14 d; 43 pts), 8.0 mo/78.2% (DSM-1/DSM-2; 69 pts) and 10.4 mo/81.3% (DSM-3/DSM-4; 59 pts) with improved PFS (p=0.001) in both DSM groups vs. the standard schedule but no difference in response. 30 pts were studied by DCE-US at baseline, and after 7 d and 14 d on Rx or after 14 d and 28 d on Rx. In responding pts, tumor blood volume decreased at d 7 and again at d 14 vs. baseline but was stable or increased at d 28 vs. d 14. A rebound was seen after 14 d off Rx.

Conclusions: Based on the U.S. data, previous pharmacokinetic data (steady state at 10-14 d) and this clinical data, starting pts on 50 mg 14 d/7 d followed by individ DSM may be safe and active. This DSM strategy, was associated with a favorable toxicity profile, apparent improvement in PFS and a good PR+SD rate in a group of unselected mRCC pts, warranting confirmation in a prospective trial. Pts that tolerate 50 mg 28 d/14 d with minimum toxicity may need dose escalation and/or less time off therapy to optimize PFS.

[Table: see text]
Population-based analysis of the rising incidence of renal cancer: Evaluation of age-specific trends (1975-2006).
Authors: Nepple K. G. , Strope S. A.
Published: February 2017

357

Background: Multiple studies show an increasing incidence of renal cancer, possibly related to the rising use of cross sectional imaging. We explored if the increase in renal cancer incidence differs across age groups.

Methods: Using the Surveillance, Epidemiology, and End Results (SEER) cancer registry data for the years 1975-2006, we ascertained incident cases of renal cancer. Urothelial histology was excluded. Yearly incidence rates of renal cancer were calculated, age-adjusted to the United States 2,000 standard adult population, and stratified by age group (20-39, 40-49, 50-59, 60-69, 70-79, 80+). Age-specific trends in renal cancer diagnosis over time were evaluated with Poisson regression.

Results: 63,843 incident renal cancer cases were identified in 544,684,745 person-years of observation. From 1975 to 2006, overall age-adjusted renal cancer incidence rose 238% from 7.4 to 17.6 per 100,000 adults. The mean age at diagnosis was 61.7 years in 1975, increased to 64.7 years in 1991, and then declined to 62.7 years by 2006. Using 1991 (the year of peak renal cancer age at diagnosis) as the dividing point, the average annual percentage increase in renal cancer incidence was 3.6% from 1976-1990 and 2.9% from 1991- 2006. The age-specific incidence rates of renal cancer increased in all age groups from 1975 to 2006; however the age-specific incidence rates changed at different rates (p<0.0001). Younger age groups showed a more rapid increase in renal cancer incidence over the second half of the study than did the older age groups. For example, for patients age 20-39 years the annual percentage change increased from 4.5% in 1975-1990 to 5.2% in 1991-2006 while annual percentage change decreased from 6.7% in 1975-1990 to 0.9% in 1991-2006 in those over 79 years old. The proportion of patients diagnosed younger than age 65 increased from 45.9% in 1991 to 55.3% in 2006.

Conclusions: The incidence of renal cancer has risen steadily since 1975 and continues to increase in all age groups. In the last 15 years, mean age at diagnosis of renal cancer has decreased driven by an increased incidence in younger patients with proportionally less increase in older patients.

No significant financial relationships to disclose.
Hand–foot skin reaction, an anticipated dermatologic toxicity to pazopanib, with an unexpected low incidence: A systematic review of literature and meta-analysis.
Authors: Balagula Y. , Wu S. , Su X. , Lacouture M. E.
Published: February 2017

365

Background: Pazopanib is a novel multikinase inhibitor that has been approved for the treatment of advanced renal cell carcinoma (RCC). It shares a similar spectrum of target receptors with sorafenib and sunitinib, including VEGFR, PDGFR, and c-kit tyrosine kinases. We have performed a systematic analysis to investigate the risk of HFSR to pazopanib. Exploring the differences in the incidence of HFSR between sorafenib, sunitinib, and pazopanib may offer additional insights into underlying mechanisms of this toxicity.

Methods: Relevant studies were identified from PubMed (1998-2010) and abstracts presented at the American Society of Clinical Oncology Conferences between 2004 and 2010. Eligible studies were limited to prospective phase II-III clinical trials in which cancer patients were treated with pazopanib 800 mg orally once daily. Incidence, relative risk (RR), and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies.

Results: A total of 942 patients from 10 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 4.5% (95% CI: 2.5-7.9%) and 1.5% (95% CI: 0.7-3.1 %), respectively. The relative risks of all-grade and high-grade HFSR to pazopanib monotherapy in comparison with controls were increased, reaching statistical significance for all-grade (RR=6.05, 95% CI: 1.11-33.12, p=0.038), but not for high-grade (RR=2.51, 95% CI: 0.12-51.9, p=0.55). The incidence of all-grade HFSR was significantly higher in patients with RCC as compared to patients with non-RCC malignancies (7.8% vs. 2.4%, p value=0.015).

Conclusions: Despite sharing the same spectrum of target receptors with sorafenib and sunitinib, pazopanib is associated with an unexpectedly low risk of HFSR. Further investigations are needed to elucidate HFSR pathogenesis.

[Table: see text]
First-line sunitinib in patients with renal cell carcinoma (RCC) and von Hippel-Lindau syndrome (VHL).
Authors: Roma A. , Basso U. , Brunello A. , Maruzzo M. , Zagonel V. , Nardin M. , Bezzon E. , Zovato S. , Opocher G.
Published: February 2017

373

Background: VHL is a rare hereditary condition caused by germline alteration of VHL gene predisposing to multiple renal and other tumors. Since acquired dysregulation of VHL-dependent pathways is often present in patients with sporadic RCC treated with first-line sunitinib (SUN), there is a strong rationale to use the same drug in VHL patients with progressive disease in the kidneys or other sites.

Methods: We performed a retrospective analysis of SUN therapy in genetically confirmed VHL patients treated at our Institution for multifocal or advanced RCC.

Results: From February 2007 to October 2010, 9 VHL patients were proposed first-line SUN for RCC, mean age 44 yrs (26-60), F:M ratio 2:1. SUN was administered for a mean of 9 cycles (1-20). Eight of 9 pts received at least two cycles and were considered for response evaluation: all 8 were stable according to RECIST criteria, but decrease in radiological density of lesions was observed in 7 of 8 pts (87.5%). Density decrease was noted not only in renal and hepatic lesions but also in some pancreatic nodules; all CNS haemangioblastoma lesions remained stable (see table). Preliminary median PFS is > 13 months (8 censored, 1 deceased).

Conclusions: SUN treatment in VHL patients appears to achieve good disease control not only in renal tumors but also in synchronous VHL-related lesions, especially pancreatic solid nodules whose exact nature (metastatic RCC or neuroendocrine tumor) cannot be ruled out without invasive biopsies.

[Table: see text]

No significant financial relationships to disclose.
Surgical outcomes of gasless single port retroperitoneal radical nephrectomy for dialysis patients: A comparative analysis with nondialysis patients.
Authors: Okada Y. , Masuda H. , Saito K. , Iimura Y. , Yokoyama M. , Komai Y. , Numao N. , Koga F. , Fujii Y. , Kihara K.
Published: February 2017

376

Background: Gasless single port retroperitoneal radical nephrectomy is minimally invasive, curative and cost effective operation which we have developed since 1998 (Eur Urol Suppl 2009; 8: 392), and covered by the Japanese universal insurance system from April, 2008. Patients necessitating dialysis are considered high risk operative candidates because of their multiple comorbidities. We compared surgical outcomes of dialysis patients with non-dialysis patients to evaluate this operation as treatment for high risk group.

Methods: We reviewed 304 consecutive patients including 59 (19.4%) dialysis patients who underwent CO2 gasless single port retroperitoneal radical nephrectomy at our institute between 2000 and 2009. Complications within the first 30 days after the surgery were graded retrospectively according to the modified Clavien classification system. Patient demographics, operative outcomes, and complications were compared between dialysis and non-dialysis patients.

Results: In all patients, the median patient age and body mass index were 60 years and 23.0 kg/m2. The median length of surgical incision, operative time (OT) and estimated blood loss (EBL) were 6.5 cm, 189 minutes and 214 mL, respectively. The transfusion rate was 3.3%. The intra and postoperative complication rate were 3.9% and 10.1%. Two grade 3a (ureteral obstruction, 1; diverticulitis, 1), three grade 3b (occlusion of peripheral hemodialysis shunt, 3) and two grade 4 (pulmonary embolism, 1; acute heart failure, 1) surgical complications occurred. In dialysis patients, the mean BMI was lower (20.4 vs. 23.3, p<0.0001), the mean OT was shorter (170 vs. 201 minutes, p<0.0001) and the mean EBL was lower (216 vs. 311mL, p<0.0001) than non-dialysis patients. There was no Clavien grade 3 or 4 surgical complications except dialysis access occlusion in dialysis patients. The average time to oral feeding and walking were equivalent, but possible discharge were longer in dialysis patients (4.3 vs. 3.4 days, p<0.0037).

Conclusions: Our data supports the safety and feasibility of gasless single port retroperitoneal radical nephrectomy for dialysis patients.

No significant financial relationships to disclose.
Genomic analysis of circulating tumor cells to evaluate predictive biomarkers.
Authors: Danila D. C. , Anand A. , Yao J. , Gierszewska M. , Kramer M. , Fleisher M. , Sawyers C. L. , McCombie W. R. , Scher H. I.
Published: February 2017

38

Background: To estimate the association between molecular biomarkers detected in circulating tumor cells (CTC) and tumor sensitivity to treatment, robust assays are needed before qualification in prospective clinical trials.

Methods: To address the limitations of the current FDA cleared technology, we focused on improving our ability to isolate more purified CTC populations based on fluorescence-activated cell sorting (FACS) to capture EpCAM+, CD45−, DAPI− cells from patients with castration-resistant prostate cancer (CRPC). Androgen receptor (AR) and genes frequently mutated in CRPC have been selected from the integrative genomic profiling at MSK. We optimized the RainDance microfluidic PCR followed by targeted sequencing in low number of cancer cells, before proceeding to clinical samples.

Results: On blood samples from124 patients with progressive CRPC, FACS method isolates an average 100-fold more EpCAM+ events compared to the current FDA cleared CellSearch assay. By FACS, >10 or >50 events were isolated in 88% or 58% of patients, compared to 32% or 10% of patients by CellSearch, respectively. FACS isolated cells express prostate-specific mRNAs (PSA, AR, TMPRSS2-ERG), as detected by an analytically validated multiplex RT-PCR, indicating that these EpCAM+ events are bona fide CTC. For genomic profiling, sufficient high quality DNA was obtained from as little as 50 CTC, with a recovery rate of 89% from FACS sorted samples and adequate sequencing coverage, and 1:4 detection threshold in a heterogeneous cell population. Selected missense mutations in AR, PIK3CA and TP53 found in CTC but not in WBC from same patient are further analyzed.

Conclusions: Molecular alterations in CTC can potentially serve as predictive markers of sensitivity and clinical outcomes as surrogate tissue in clinical practice. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in a heterogeneous cell population. In the context of available samples collected from patients enrolled on AR-targeted therapies, we will generate data to qualify CTC as biomarkers under the Oncology Biomarker Qualification Initiative.

[Table: see text]
Prognostic factors in patients with advanced renal carcinoma.
Authors: Muriel C. , Esteban E. , Astudillo A. , Martinez-Camblor P. , Corral N. , Crespo G. , Berros J. , Fonseca P. J. , Luque M. , Lacave A. J.
Published: February 2017

391

Background: A retrospective cohort of 135 patients with advanced RCC treated with biological agents and/or cytokines (CK) was analysed between July 1996 and February 2010.

Methods: The expression of several biomarkers by immunohistochemistry and 2 analytical variables: thrombocytosis and neutrophilia were analysed and were correlated with prognosis.

Results: 67 patients were treated only with biological agents and 68 with CK (23 received also biological agents). The univariate statistical analysis showed that the enhanced expression of HIF-1alpha correlated with a poor prognosis in patients treated with sunitinib (PFS was 5.4 vs. 13.4 months in those with low expression, p=0.001). The overexpression of ACIX was associated to a better prognosis in patients that received biological agents (PFS was 18.3 vs. 5.2 months in those with decreased expression, p<0.001; OS was 32.1 vs. 7.8 months, p<0.001), including sunitinib (PFS was 16.8 vs. 5.5 months, p<0.001), sorafenib (PFS was 8 vs 3.5 months, p<0.001)) and CK (PFS was 6.3 vs. 2.7 months, p=0.003; OS was 32.9 vs. 5.9 months, p=0.001). Positive PTEN was related to a good prognosis in patients treated with sunitinib (PFS was 15.1 vs. 6.5 months, p=0.003) and CK (PFS was 7.5 vs. 3.8 months, p=0.037, OS was 13.7 vs 7.9 months, p=0.039). The increased expression of p21 was related to a poor prognosis in patients that received biological agents (PFS was 5.9 vs. 16.8 months with high expression, p=0.024), including sunitinib (PFS was 6.2 vs 18.9 months, p<0.001), sorafenib (PFS was 4 vs 9 months, p=0.013) and CK (PFS was 3.9 vs. 7.5 months, p<0.001). Thrombocytosis was related to a poor prognosis in patients treated with CK (PFS was 2.6 vs. 5.1 months p=0.017; OS was 5.9 vs. 14.3 months p=0.010). Neutrophilia was related to a poor prognosis in patients that received CK (PFS was 2.6 vs. 5.7 months, p=0.019; OS was 5.9 vs. 12.8 months, p=0.035). In the multivariate analysis, the overexpression of ACIX was a favorable prognostic factor independent of PFS with a HR of 0.107 (p<0.001) and OS with a HR of 0.055 (p<0.001).

Conclusions: Our experience has suggested the utility of de HIF-1alpha, ACIX, PTEN, p21, thrombocytosis and neutrophilia as prognostic factors in patients with advanced RCC. ACIX has shown to be an independent prognostic factor.

No significant financial relationships to disclose.