bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerability of neoadjuvant chemotherapy with gemcitabine plus cisplatin in elderly (older than age 65) patients (pts) with muscle-invasive urothelial cancer.
Authors: Niedersuess-Beke D. , Gruenberger B. , Puntus T. , Bauer W. , Lamche M. , Schramek P. , Meran J. G.
Published: February 2017

296

Background: Urothelial cancer (UC) is a common tumor with a peak in the seventh decade. Locally advanced disease has a significant risk for developing metastases. Neoadjuvant, platinum-containing, combination chemotherapy improves survival over radical cystectomy (RC). Chemotherapy with gemcitabine plus cisplatin (GC) shows equivalent efficacy with less toxicity to methotrexate-vinblastine-doxorubicin- cisplatin (MVAC) in metastatic setting.

Methods: We prospectively evaluated 23 elderly pts (8 female, 15 male) with a median age of 72 years, WHO performance status 0/1, with muscle invasive UC who received neoadjuvant GC (gemcitabine 1,000 mg/m2 days 1, 8, 15 and cisplatin 70 mg/m2, day 2 q28) for 3 cycles between 2006 and 2010 prior to RC. Assessments included toxicity of GC, pathologic response, progression free survival (PFS) and overall survival (OS).

Results: 21 (91.3%) out of 23 pts finished intended chemotherapy. Two refused chemotherapy due to personal reasons. According to CTCAE guidelines 43.5% developed grade 3 hematologic toxicities; 13% developed grade 4 thrombopenia. Grade 3 non-hematologic toxicities included nausea in 2 patients. In 2 (8.7%) pts grade 4 thromboembolic events occurred. There was no treatment related febrile neutropenia or death. 15 (71.4%) of the pts underwent RC. 5 (23.8%) pts refused RC due to personal reasons. 1 of them agreed second look TURB. 1 patient underwent palliative radiotherapy due to progression of disease. Out of the 16 pts 43.75% achieved pathological response (18.75% pT0 stage and 25% pT1 stage). 56.25% had muscle invasive UC. 18.75% of them nodal positive disease. All 7 pts achieving < pT2 pathologic stage remained progression-free at a median follow up of 16 months. Pts > pT2 stage had a median PFS of 14 months. Median OS was not reached yet.

Conclusions: Neoadjuvant GC is a well tolerated regiment in elderly pts and it seems to be less toxic than MVAC. Prophylactic anticoagulation during treatment should be considered. Although pathologic response is lower than in previously published retrospective data we recommend neoadjuvant treatment with GC in elderly pts.

[Table: see text]
Planning outcomes and acute toxicity of intensity-modulated radiotherapy (IMRT) for treatment of bladder and pelvic lymph nodes.
Authors: Harris V. , McDonald F. , Hansen V. , Taylor H. , Huddart R. A.
Published: February 2017

297

Background: We implemented an IMRT protocol for simultaneous treatment of bladder and pelvic lymph nodes (LN) and report the planning outcomes and acute toxicity of patients treated using this technique.

Methods: 13 patients were treated with a 5-field step and shoot IMRT technique. Inclusion criteria were: radiological evidence of pelvic LN metastases; stage T3/T4; high risk pathology or post-cystectomy with persistent/recurrent disease. Anisotropic margins were applied to the whole bladder CTV (0.5 cm laterally/inferiorly, 1 cm posteriorly, 1.5 cm superiorly/anteriorly) to create PTV1. 0.5 cm margins were applied to the pelvic LN CTV to create PTV2. PTVs 1/2 were prescribed 52 Gy in 32 fractions. 1 cm margins were applied to the involved bladder to create PTV3 (prescribed 64Gy). 0.5 cm margins were applied to the involved LN volumes to create PTV4 (prescribed 60 Gy). Post cystectomy patients were planned using PTVs 2/4 only. Dose volume histograms for organs at risk (rectum, femoral heads and other bowel) were calculated and compared with local dose constraints. Acute toxicity was assessed according to common toxicity criteria v3.0 and recorded weekly during treatment. Treatment verification was performed by cone beam CT.

Results: All treatment plans achieved target coverage of > 95% volume to > 95% prescription dose for each PTV. All patients achieved rectal and femoral head dose constraints. 2 patients did not meet V45 other bowel constraints but proceeded with treatment as all other dose limits were achieved. At the time of abstract submission 13 patients had completed treatment. 2 were treated for relapse post-cystectomy and did not have GU toxicities recorded. Maximum experienced acute toxicities were recorded. 9/11 patients experienced acute GU toxicity (G1=3, G2=1, G3=5). 6/13 patients experienced acute GI toxicity (G1=3, G2=3). 9/13 patients developed other acute toxicities (G1=7, G2=2). No patients developed ≥G3 non-GU toxicity.

Conclusions: Bladder and pelvic LN IMRT allows patients with high risk locoregional bladder cancer to meet preset dose constraints, appears feasible and has a comparable rate of acute toxicity to conventional bladder-only radiotherapy treatment.

No significant financial relationships to disclose.
Contrast enhanced CT (CE-CT) changes and nephrometry down-scoring of unresectable primary renal cell carcinoma (RCC) tumors in patients (Pts) treated with neoadjuvant sunitinib.
Authors: Salem M. , Shah S. N. , Wood L. S. , Elson P. , Medsinge A. , Campbell S. , Rini B. I.
Published: February 2017

299

Background: The impact of neoadjuvant sunitinib on CE-CT parameters and nephrometry score of primary RCC tumors remains unknown.

Methods: Retrospective review of baseline and prenephrectomy CE-CT from a prospective phase II trial of neoadjuvant sunitinib (50 mg sunitinib continuous dosing) in unresectable primary RCC tumors with or without metastatic disease. CE-CT parameters and R.E.N.A.L. nephrometry score for each lesion were determined in pts who underwent subsequent surgery. RECIST and MASS criteria were used to assess primary tumor radiographic response. CT changes were analyzed using the sign test and Wilcoxon signed rank test.

Results: Twenty nine pts were enrolled, of which 13 pts (85%M; median age 63y) underwent post-sunitinib resection of 16 primary tumors (3 pts had multifocal RCC). Post-therapy, 88% of tumors had decreased long diameter (median 32% decrease, p<0.001 vs. baseline), 88% decreased attenuation (median 30 HU reduction, p=0.006) and 69% increased necrosis (p=0.001). 56% of tumors had a decrease in nephrometry score (median 1 point decrease; 10 to 9, p=004). At baseline, 81% of tumors were highly complex by nephrometry score; following therapy 46% of the highly complex tumors became moderately complex. At baseline 13 tumors abutted renal hilar vital structures, whereas following treatment 4 tumors demonstrated abutment. Adenopathy decreased (range, 23%-83%) in 4/4 patients with enlarged baseline lymph nodes, with complete resolution in 1 patient. RECIST objective response was seen in 38% and SD in 56% of primary tumors; 1 tumor had PD based on size despite > 95% necrosis. MASS criteria response was favorable 38%, intermediate 62%. Two of four pts had reduction in extent of venous thrombus (1 pt from level 0 to resolved and 1 pt from level IV to II).

Conclusions: Neoadjuvant sunitinib resulted in decreased size/attenuation, increased necrosis of the primary tumor and reduction in lymphadenopathy and venous thrombus in pts who underwent subsequent surgery. Sunitinib reduced the RENAL nephrometry score and facilitated nephrectomy, notably due to impact on tumor proximity to vital structures in the renal hilum.

[Table: see text]
The relationship of HIF2 and the progression of PTEN-deficient mouse prostate tumors.
Authors: Kim W. Y. , Zhou B. , Thomas G.
Published: February 2017

30

Background: The hypoxia-inducible factor (HIF) transcription factor has already cemented its oncogenic role in the development of renal cell carcinoma (RCC). However, its role in the tumorigenesis of other solid tumors remains unspecificed. Our studies focus on a novel link between HIF and prostate carcinogenesis.

Methods: Using both in vitro cell culture studies as well as in vivo studies (orthotopic xenograft and genetically engineered mouse models) we investigate the role of HIF in prostate cancer cell proliferation, invasion, and progression.

Results: Both HIF1 and HIF2 appear to be necessary for the proliferation and invasion of prostate cancer cell lines in vitro. Preliminary analysis of a PTEN deficient mouse model of prostate cancer suggests that expression of a stabilized form of HIF2 promotes the development of a larger prostate tumor burden and a more aggressive histology (high grade prostate intraepithelial neoplasia [PIN] at earlier stages). Moreover, PTEN-deficient prostate tumors producing HIF2 are more proliferative and vascular and express increased levels of genes associated with epithelial to mesenchymal transition (EMT).

Conclusions: There has been much interest in the role of angiogenesis and hypoxia in prostate cancer progression. Our preliminary data suggest that HIF2 is able to promote PTEN-deficient prostate cancer progression in mice by increasing proliferation, angiogenesis, and EMT.

No significant financial relationships to disclose.
Postoperative complications from cytoreductive nephrectomy after neoadjuvant targeted therapy for metastatic renal cell carcinoma.
Authors: Chapin B. F. , Delacroix S. E. , Culp S. H. , Gonzalez G. , Wood C. G.
Published: February 2017

300

Background: Neoadjuvant treatment of metastatic renal cell carcinoma (RCC) with targeted systemic therapies is under investigation. Postoperative complications that occurred after cytoreductive nephrectomy (CRN) preceded by neoadjuvant systemic therapy were assessed.

Methods: A retrospective review of all patients with clinical evidence of metastasis that underwent CRN was performed. Of 683 surgical patients with metastatic disease, 67 had received preoperative targeted therapy. Preoperative, operative, and postoperative characteristics were evaluated for each patient. Surgical complications were assessed using the modified Clavien system. A multivariate was sued to determine preoperative variables in an attempt to predict surgical complications within 1 year of CRN.

Results: Complications occurred in 64% (43/67) of patients within 365 days of CRN. Clavien grade ≥ 3 complications occurred in 30% (20/67) patients. The most common occurrences were superficial wound dehiscence (25%), and wound infection (15%). On univariate analysis there were no statistically significant differences between groups in regards to age, race, gender, smoking history, follow-up, Charlson comorbidity index, MSKCC risk groups, or time from cessation of targeted therapy to surgery. Significant predictors of complications included BMI ≥ 30 (p=0.007), EBL (p=0.019), matted nodes (p=0.043), and surgical approach (p=0.001). Clinical T-stage and N-stage (p=0.068, p=0.073) approached significance. On multivariate analysis Charlson comorbidity index ≥ 8(OR 5.2, 95% CI 1.23, 21.99) and clinical N-stage (OR 5.11, 95%CI 1.21, 21.66) were significant predictors of postoperative complications.

Conclusions: In this series of patients treated with neoadjuvant targeted therapy, a majority of patients experienced a postoperative complication after CRN. A Charlson comorbidity index ≥ 8 or clinical node positivity predicted for an increased risk of postoperative complications. The use of neoadjuvant systemic targeted therapy prior to CRN is investigational and adequate assessment of operative morbidity is needed prior to wide spread adoption.

No significant financial relationships to disclose.
Comparison of low-temperature-sensitive liposome encapsulated docetaxel and doxorubicin in a murine model of prostate cancer.
Authors: Chokshi S. , Ranjan A. , Benjamin C. J. , Chung P. H. , Rastinehad A. , Dreher M. R. , Wood B. J. , Pinto P. A.
Published: February 2017

31

Background: Low-temperature-sensitive liposomes (LTSLs) release their encapsulated drug into targeted tissue when activated by a source of hyperthermia. The efficacy of an LTSL formulation of docetaxel (DOC) or doxorubicin (DOX) was compared against prostate cancer in a xenograft mouse model.

Methods: Under an approved IACUC protocol, Luciferase transfected human prostate PC-3M-luciferase cells were inoculated (3x106 cells) subcutaneously in the right hind leg of 8 wk old female athymic nude mice. When tumors reached a volume of 200–300 mm3, mice were randomized to receive one intravenous injection of saline, Stealth liposomal DOX (5 mg/kg), LTSL DOX (5 mg/kg), or LTSL DOC (15 mg/kg), with or without hyperthermia treatment (LTSL DOX and LTSL DOC were supplied by Celsion Corp., Columbia MD). Mice undergoing hyperthermia treatment were anesthetized and stabilized in a holder that allowed for only the leg with tumor to be heated to 41–42°C that triggered LTSL drug release. Mice were monitored daily for tumor volume and body weight. Study end-points included growth of tumor to 5x the initial treatment volume or monitoring of survival for 60 days.

Results: The LTSL DOC delayed tumor growth longer (> 14 days) than DOX (0 day) and LTSL DOX (1 day) with hyperthermia (P<0.05). Mice treated with LTSL DOC and hyperthermia survived longest (60 days) compared to all other mice (range 6–8 days, P<0.05). LTSL in the setting of hyperthermia demonstrated complete regression of tumor in 57% of mice.

Conclusions: LTSL DOC with hyperthermia delayed tumor growth more than all other treatments. Survival studies suggest LTSL DOC is a more effective temperature sensitive delivery system against PC-3M prostate tumors.

No significant financial relationships to disclose.
Everolimus in patients with metastatic renal cell carcinoma (mRCC) who are intolerant of or have progressed after prior vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy: An international expanded access program (EAP).
Authors: Grunwald V. , Bodrogi I. , Miller K. , Machiels J. H. , Lee S. , Chowdhury S. , Yuan R. , Rosamilia M. , Booth J. L. , Karakiewicz P. I.
Published: February 2017

314

Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the first agent to show efficacy in a randomized, controlled phase III trial in patients with mRCC after progression on VEGFr-TKIs (RECORD-1). Progression-free survival (PFS) was significantly improved (4.9 vs 1.9 months) and the risk of disease progression was reduced by 67% with everolimus compared with placebo. To fulfill an unmet medical need, everolimus was offered globally in this EAP. Presented here are preliminary results on 605 patients.

Methods: The program began in July 2008 (ClinicalTrials.gov: NCT00655252 ; EudraCT: 2007-005460-28), and since then over 1,000 patients in 34 countries have been enrolled. Patients with clear cell and non–clear cell mRCC who failed or became intolerant of VEGFr-TKIs received daily oral doses of everolimus with investigator assessment every 3 months.

Results: Data were collected for 605 patients who had discontinued treatment as of January 15, 2010. Evaluable patients had a mean age of 63 years, and most (94%) had progressed after prior VEGFr-TKI therapy. The adverse event (AE) profile did not differ significantly from that reported in the RECORD-1 trial. Most frequently reported grade 3–4 AEs were anemia (6.1%), stomatitis (4.6%), fatigue (4.6%), hyperglycemia (4.0%), and infection (3.6%). Grade 3–4 noninfectious pneumonitis was reported in 2.8%. Best overall response was stable disease, which was evident in 42% of patients.

Conclusions: The EAP has allowed patients with mRCC access to everolimus before marketing approval. The rapid enrollment rate of this EAP confirms the unmet medical need after failure of VEGFr-TKIs. Everolimus has shown good tolerability, and no new safety issues have been identified. The investigator-assessed response rate is consistent with that reported in the RECORD-1 trial. The EAP provides an efficient framework for the development of other programs for innovative anticancer agents in patients without satisfactory therapeutic options.

[Table: see text]
Incidence and risk of congestive heart failure risk in renal cell cancer (RCC) and non-RCC patients treated with sunitinib.
Authors: Richards C. J. , Je Y. , Schutz F. A. , Dallabrida S. M. , Moslehi J. J. , Choueiri T. K.
Published: February 2017

316

Background: Sunitinib is a multitargeted receptor tyrosine kinase inhibitor that is widely used in the treatment of renal cell cancer (RCC) and several other malignancies. Congestive heart failure (CHF) has been reported with sunitinib, but the overall incidence and relative risk (RR) remain undefined. We preformed an up-to-date comprehensive meta-analysis to determine the risk of developing serious CHF in patients with both RCC and non-RCC tumors treated with sunitinib.

Methods: Medline databases were searched for articles from January 1966 to September 2010. Eligible studies were limited to phase II and III trials of sunitinib in cancer patients with any primary tumor type and adequate safety profile reporting. Statistical analyses were conducted to calculate the summary incidence, RR and 95% confidence intervals (CI), using random-effects models.

Results: A total of 5,497 patients were included. Overall incidence for all-grade and high-grade CHF in sunitinib-treated patients was 4.9% (95% CI, 1.6–14.1%) and 1.8% (95% CI, 0.8–3.9%), respectively. The RR of all-grade and high-grade CHF in sunitinib-treated patients compared to placebo-treated ones was 1.81 (95% CI, 1.30–2.50; p<0.0001) and 3.17 (95% CI, 1.12–8.97; p=0.030), respectively. On subgroup analysis there was no difference observed in the CHF incidence for RCC vs. non-RCC patients. No evidence of publication bias was observed.

Conclusions: This is the first comprehensive report to demonstrate that sunitinib use is associated with an increased risk of significant heart failure in cancer patients.

[Table: see text]
Effect of angiotenstin system inhibitors (ASIs) on the outcome of sunitinib treatment (tx) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Keizman D. , Huang P. , Eisenberger M. A. , Pili R. , Kim J. J. , Hammers H. J. , Carducci M. A.
Published: February 2017

317

Background: The VEGFR inhibitor sunitinib is a standard tx for mRCC. ASIs include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). ASIs are used in the tx of hypertension (HTN), kidney disease, and heart failure. Preclinical and clinical studies in several cancer types have shown that they may inhibit tumor growth. Their effect on the outcome of sunitinib in mRCC is poorly defined. Aims: to study the effect of ASIs on the outcome sunitinib tx for mRCC.

Methods: We performed a retrospective study of an unselected cohort of pts with mRCC, who were treated with 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest. Pts were divided into 2 groups: (1) ASIs users and (2) ASIs naive. The effect of ASIs use on objective response, time to progression (TTP), and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from cox model.

Results: Between 2004–2010, 124 pts with mRCC were treated with sunitinib. There were 44 ASIs users (group 1) and 80 nonusers (group 2). With regard to sunitinib tx initiation time, 39 users started ASIs before, 3 within 1 month, and 2 after 5 months. The groups were balanced regarding the following known clinical prognostic factors: past nephrectomy, RCC histology, time from diagnosis to tx, ≥ 2 metastatic sites, lung/liver/bone metastasis, ECOG performance status, Hb level, corrected ca > 10 mg/dL, platelets count, prior cytokines/ targeted tx, sunitinib induced HTN, % pts that had dose reduction/tx interruption, and mean dose/cycle. Objective response in group 1 vs. 2 was partial response (PR) 48% vs 38% (p=0.24), stable disease (SD) 38% both, and progressive disease (PD) 14% vs. 24% (p=0.19). Median TTP was 12 vs. 6 ms (HR 0.635 in ASIs users, p=0.034). Median OS was 25 vs. 22 ms (p=0.3).

Conclusions: ASIs may improve the outcome of pts with mRCC that are treated with sunitinib. This should be investigated prospectively, and if validated, applied in clinical practice and clinical trials.

No significant financial relationships to disclose.
Stimulation of prostate cancer cell proliferation by bone-derived factors.
Authors: Sluka P. , Whitty G. , Davis I. D.
Published: February 2017

32

Background: Interactions between cancer cells and their microenvironment affect the establishment and metastasis of cancer. The most common site of prostate cancer (PC) metastasis is bone. This study examined the effects of selected factors known to be produced by bone stroma (EGF, aFGF, HGF, β-NGF, TGF-β, and TNFα) on the proliferation of PC cells. The effect of cell culture medium (CM) conditioned by osteoblasts (OBCM) was also examined.

Methods: The PC-derived cell lines PC3, LNCaP, and DU145 were used. Expression of receptors for the above-mentioned cytokines was assessed using real-time RT-PCR. After 5 days of continuous cytokine treatment, proliferation was assessed by MTS conversion, and cell survival and apoptosis was assessed by 7-AAD staining and flow cytometry. OBCM was generated using the HOS, MG63, and SaOs2 cell lines. CM from the HT1080 fibrosarcoma cell line was used as a non-bone control.

Results: The PC cell lines expressed receptors for all of the cytokines examined at the mRNA level. LNCaP cell proliferation was increased by aFGF and decreased by TGF-β. Treatment with TNFα decreased proliferation of all PC cell lines. These effects were not due to apoptosis. EGF, HGF, and β-NGF did not affect proliferation of any line despite receptor expression. OBCM increased proliferation of PC3 and DU145 cells but not LNCaP cells, while HT1080 CM did not affect proliferation of any line.

Conclusions: PC cells are able to respond to defined bone-derived factors and that the nature of this response varies between individual cancers. Acidic FGF increased proliferation of LNCaP cells while TGF-β and TNFα decreased proliferation of LNCaP and all cell lines, respectively; an effect not mediated by apoptosis. Current studies are examining the effect of these cytokines on other functional parameters (cell survival, adhesion and migration) and on primary PC epithelial cells.

No significant financial relationships to disclose.
Comparison of partial nephrectomy for tumors greater than 7 cm to radical nephrectomy and effect on overall survival.
Authors: Vourganti S. , Linehan W. , Bratslavsky G.
Published: February 2017

323

Background: As growing evidence indicates the importance of renal functional preservation, there is an increased utilization of partial nephrectomy (PN) performed for small renal masses (SRM). The optimal cutoff size for PN has been based on historical observation of low metastatic rates for SRM and increasing metastatic potential with increase in size of the primary tumor. We aim to evaluate the outcomes of patients treated by PN or radical nephrectomy (RN) for tumors greater than 7 cm.

Methods: SEER 17 database was queried to identify patients treated for kidney tumors between 1983 and 2007. We excluded cases treated for non-RCC histology, not treated surgically, and those without specified size. Patients were included if treated by PN or RN with tumor size between 7 and 20 cm. Demographic information included age, gender, and race. The comparison of RCC-specific and overall survival was performed for the entire cohort and stratified by SEER stage (localized, regional, or distant). The survival was compared using Kaplan-Meier method with log rank test to identify significant differences.

Results: We identified a total of 18,927 patients treated for RCC that included 18,575 cases of RN and 352 treated with PN. There were no differences in age, gender, or race (Caucasian vs. non-Caucasian) between patients treated by RN or PN (p>0.05). The mean size for tumors treated by PN was 9.7 cm vs. 10.2 cm for RN (p<0.01) and there was more localized disease in the PN group (p<0.01). The overall median survival for patients treated with PN was 108 months vs. 80 months for patients treated with RN (p<0.01). The cancer-specific survival for the entire cohort treated with PN was 195 months vs. 145 months for RN (p<0.01). When stratified by stage, there were no differences in the cancer specific survival between PN and RN groups (p>0.05).

Conclusions: PN for tumors 7 to 20 cm is not associated with inferior oncologic outcomes but may provide survival advantage. While patient selection may have influenced overall survival outcomes, PN may provide survival advantage by maximizing renal reserve. These findings may be best answered in a randomized trial to establish if there should be a size cutoff for nephron sparing surgery.

No significant financial relationships to disclose.
Effect of routine ipsilateral adrenalectomy on cancer-specific survival and risk of adrenal insufficiency for patients with pT3/4 renal cell carcinoma.
Authors: Weight C. J. , Kim S. P. , Thompson R. H. , Boorjian S. A. , Leibovich B. C.
Published: February 2017

324

Background: The indications for the removal of the ipsilateral adrenal gland in patients with renal cell cancer (RCC) have not been well defined. Most continue to advocate ipsilateral adrenalectomy in patients with risky features such as a tumor thrombus, large, locally advanced tumors, and/or upper pole tumors. We evaluated the oncologic outcomes of concurrent adrenalectomy with either partial (PN) or radical nephrectomy (RN) in a large single institution cohort.

Methods: From 1970–2006, 4,019 consecutive patients with RCC treated by RN (n=3,107) or PN (n=912) from Mayo Clinic were studied for adrenal involvement. Risk of asynchronous adrenal metastasis and cancer specific survival (CS) were also compared between those who underwent concomitant adrenalectomy (n=1,464) and those who did not (n=2,555) using multivariate cox models.

Results: Median postoperative follow-up was 6 years. Synchronous ipsilateral adrenal involvement was rare even for those with large (>7cm) tumors (2.5%), upper pole (1.3%), and locally advanced (pT3/4) tumors (3.5%). The development of asynchronous adrenal metastasis occurred in 109 patients (2.7%) at a median of 3.7 years after initial surgery. The risk of developing an ipsilateral (1.4% 95% CI 0.8, 2.0) vs. contralateral (1.8% 95% CI 1.0, 2.6) asynchronous adrenal metastasis was equivalent at 10 years, in those who did not undergo adrenalectomy at initial surgery. At 10 years, 7.3% (99% CI: 4.4, 10.2) of patients with higher stage tumors (pT3/4) are predicted to develop a contralateral adrenal metastasis. On multivariate analysis, routine adrenalectomy was associated with a decreased risk of subsequent adrenal metastasis (HR 0.88: 99% CI 0.81, 0.95), but did not significantly impact CS (HR 1.15: 99% CI 0.99, 1.34).

Conclusions: Asynchronous metastasis can usually be salvaged without apparent effect on CS. Ipsilateral adrenal involvement from RCC was uncommon even in large, locally advanced, and/or upper pole tumors. Routine adrenalectomy in these high risk patients may lead to an unacceptably high rate of adrenal insufficiency when a significant subset develops a contralateral adrenal metastasis.

No significant financial relationships to disclose.
Multicenter prospective phase II study of sunitinib in non-clear cell type renal cell carcinoma.
Authors: Lee J. , Ahn J. , Lim H. , Lee S. , Kim T. , Lee D. , Cho Y. M. , Hong J. , Kim C. , Ahn H.
Published: February 2017

325

Background: Sunitinib has been shown to produce a high response rate (RR), and improved progression-free survival (PFS) in patients (pts) with clear cell RCC. Retrospective data suggest sunitinib may be effective in papillary and chromophobe RCC. We conducted a multicenter phase II trial of sunitinib in non-clear cell RCC (nccRCC).

Methods: Eligibility criteria included PS 0-1, measurable disease, and adequate organ function. Pts with brain metastases were not excluded if controlled without steroid dependence. Response assessment was performed every 6 weeks. Primary endpoint was RR. Secondary endpoints were TTP, safety and OS.

Results: Between 6/2008 and 7/2010, 29 pts with nccRCC were enrolled (total accrual 35: P0=5%, P1=20%, alpha=0.05, beta=0.2, drop-out rate 15%). Median age was 52 (18–76). Twenty-four pts (84%) had prior nephrectomy. Seven pts (24%) had poor risk and 13 (45%) had intermediate risk disease by MSKCC criteria. Twenty-one pts had papillary RCC (type II in 11 and type not- specified in 10), and 4 patients had chromophobe RCC. Two pts discontinued protocol treatment due to toxicity prior to completion of cycle 1 (one pt had cardiogenic shock 27 days after start of therapy and the other refused further treatment 5 days after therapy). Eleven pts out of 29 had partial response with a RR of 38% (95% CI, 20.2%–55.6%) and additional 15 patients (52%) had SD with a disease control rate of 90%. Response rates were not significantly different according to the histologic type (43% in papillary type and 25% in chromophobe type). Median duration of response was 12.7 months (95% CI, 2.3∼23.1) and median TTP was 6.4 months (95% CI, 4.5∼8.3). With a median FU duration of 16 months (95% CI, 8.6∼23.4), 10 pts have been dead resulting in an estimated median OS of 17.9 months. Toxicity profiles were commensurate with prior reports on Korean patients (Yoo, et al. Jpn J Clin Oncol 2010). However, there was one treatment-related death caused by acute heart failure in patient without relevant risk factors for heart disease.

Conclusions: Although our study is ongoing, the primary endpoint has been met and these data suggest that suntinib has promising activity in patients with nccRCC.

No significant financial relationships to disclose.
C-reactive protein kinetics superior to radiographic response as a surrogate endpoint for survival in patients with advanced renal cell carcinoma.
Authors: Tatokoro M. , Saito K. , Fujii Y. , Komai Y. , Koga F. , Masuda H. , Kawakami S. , Kihara K.
Published: February 2017

333

Background: As cytokines and targeted agents against advanced renal cell carcinoma (aRCC) are considered to achieve high stable disease (SD) rate rather than objective response (OR) by radiographic measurement, we often face the therapeutic dilemma in deciding whether to continue the ongoing treatment and when to change it. Therefore, other valid surrogate endpoints have been desired. We have previously demonstrated C-reactive protein (CRP) kinetics could predict prognosis of pts with aRCC (Eur Urol. 2009:1145-53).

Methods: This study was performed on 56 pts with aRCC (metastatic: 54, unresectable: 2) enrolled in a phase II trial of interferon-alpha, cimetidine, COX-2 inhibitor and renin-angiotensin-system inhibitor (I-CCA; Cancer Sci. in press). CRP levels were measured at pretreatment, thereafter almost every visit. Pts were divided into 3 groups according to CRP kinetics. Pts whose pretreatment CRP levels were < 5 mg/l were assigned to nonelevated group. Pts whose pretreatment CRP levels were > 5 mg/l but normalized (< 5 mg/l) at least one time during I-CCA were assigned to normalized group. Pts whose CRP level never decreased to normal level were assigned to non-normalized group. Radiographic response was assessed by WHO criteria; survivals were estimated by Kaplan–Meier method and prognostic factors were assessed by Cox's proportional hazard model.

Results: Median follow-up was 26 mo. An OR and clinical benefit rate to I-CCA were 20 and 64%, respectively. The median progression-free and overall survival (OS) was 12 and 45 mo, respectively. The median OS was 74, 83 and 13 mo in in non-elevated (n=26), normalized (n=16) and non-normalized (n=14) group, respectively (p<0.0001). Of the 25 pts achieving SD, CRP kinetics was independent prognostic factor for OS (p<0.0001). Of the pts whose pretreatment CRP was elevated, all pts achieving OR had CRP normalization and multivariate analysis revealed CRP normalization was independent prognostic factor for OS (p=0.0008), whereas achieving OR was not (p=0.19).

Conclusions: CRP kinetics compares favorably with objective response to systemic therapy as a valid surrogate endpoint for survival.

No significant financial relationships to disclose.
Tyrosine kinase inhibitors and development of brain metastasis in metastatic renal cell carcinoma: A retrospective review.
Authors: Verma J. , Jonasch E. , Allen P. , Tannir N. M. , Mahajan A.
Published: February 2017

340

Background: Tyrosine kinase inhibitors (TKIs) have been shown to improve overall survival (OS) in metastatic renal cell carcinoma (mRCC) but their effect on brain metastasis (BM) development is unclear. The purpose of our study is to evaluate the impact of TKIs on incidence of BM and OS in patients with mRCC.

Methods: Searched the M. D. Anderson Cancer Center (MDACC) tumor registry for patients who presented with mRCC in 2002-2003 and 2006-2007 with no BM at initial staging. The following items were retrospectively collected: age, sex, Fuhrman grade, sites of disease, nephrectomy, systemic therapy including TKIs (sorafenib or sunitinib), MSKCC risk category, BM treatment, and vital status. Interaction between OS and incidence of BM and these variables was estimated using the Cox proportional hazards model. OS and incidence of BM were estimated using the Kaplan-Meier (K-M) method.

Results: 338 patients were identified; 154 (46%) were treated with a TKI prior to BM, and 184 (54%) were not. There were no significant differences in age, histology, involved sites of disease other than lung, nephrectomy, or MSKCC risk category between the groups. A higher proportion of the nonTKI group received other systemic agents and had lung metastasis at initial staging (p=0.03). Median OS was longer in the TKI-treated group (25 months versus 12.1 months, p<0.0001). In Cox multivariate analysis, TKI treatment (HR=0.53, 95% CI 0.38-0.74, p<0.001) was associated with improved OS and lung/mediastinal involvement and ECOG performance status > 2 (HR 1.87, 95% CI 1.28-2.71, p=0.001) were associated with poor OS. Median OS after BM was not significantly different between TKI treated and untreated groups. 44 patients (13%) developed a BM, including 29 (15.8%) of the nonTKI group and 15 (9.7%) of the TKI group. In K-M analysis, the 5-year incidence of BM was 40% versus 17% respectively (logrank p<0.001). In Cox multivariate analysis, TKI treatment was associated with lower incidence of BM (HR=0.39, 95% CI 0.21-0.73, p=0.003). Lung metastasis increased the risk of BM (HR=9.61, 95% CI 2.97-31.1, p<0.001).

Conclusions: Treatment with TKI agents reduces the incidence of BM in mRCC. Lung metastasis is a risk factor for BM development.

No significant financial relationships to disclose.
Impact of pathologic tumor characteristics in patients with sarcomatoid renal cell carcinoma.
Authors: Shuch B. , Bratslavsky G. , Shih J. H. , Finley D. , Castor B. , Linehan W. , Pantuck A. J. , Said J. , Belldegrun A. S.
Published: February 2017

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Background: Patients with sarcomatoid renal cell carcinoma (sRCC) are known to have a poor prognosis and response to therapy. We sought to determine the influence of pathologic tumor characteristics on outcome in order to aid clinical management.

Methods: A single center database was reviewed from 1989-2009 to identify all patients with sRCC. Clinical and staging variables were collected and pathologic information including histology, necrosis, percentage of sarcomatoid features (PSF), and microvascular invasion (MVI) was recorded. Influence of clinicopathologic variables on outcome was assessed.

Results: A total of 104 patients had confirmed sRCC. The median size of tumors was 9.5 cm (range 2.5-30), 65% of patients had areas of clear cell RCC, and 69.2% had metastatic disease at presentation. The PSF did not influence tumor size, stage, necrosis, MVI, nodes, or metastasis. A total of 85 patients (81.7%) died during the follow-up period with a median survival of 5.9 months. In the overall cohort poor performance status, metastatic disease, and MVI were independent predictors of poor survival. Increased PSF was associated with worse outcome, but it failed to reach significance on multivariate analysis. In a subset analysis of those with non-metastatic disease, MVI and non-clear histology influenced prognosis, but only PSF was the only predictor of outcome.

Conclusions: The PSF has limited influence on pathologic characteristics. However, increased PSF amounts may impact survival, especially in those with non-metastatic disease. The presence of MVI is an independent predictor of poor outcome while carcinoma grade and subtype have limited impact on survival. When counseling patients or designing clinical trials for these patients, PSF and MVI, not carcinoma grade or subtype should be considered.

No significant financial relationships to disclose.
Use of preoperative erythrocyte sedimentation rate (ESR) to predict overall survival in localized renal cell carcinoma following radical nephrectomy.
Authors: Master V. A. , Kucuk O. , Harris W. , Cross B. , Abbasi A. , Michigan A. , DeRosa A. , Johnson T. V. , Marshall F. F.
Published: February 2017

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Background: Systemic inflammation has been associated with increased tumor grade and disease progression in renal cell carcinoma (RCC). Erythrocyte sedimentation rate (ESR) reflects systemic inflammation in other disease states. However, the relationship between ESR and survival remains unclear in localized RCC following potentially curative nephrectomy. We hypothesized that preoperative ESR would be a prognostic indicator of overall survival in localized RCC following radical nephrectomy.

Methods: 167 patients undergoing nephrectomy for localized RCC had ESR measured preoperatively. Receiver operating characteristics (ROC) curves were constructed and used to determine the area under the curve (AUC) and relative sensitivity and specificity of preoperative ESR in predicting overall survival. From this curve, cut-offs for low risk (0.0-20.0 mm/hr), intermediate risk (20.1-50.0 mm/hr), and high risk (> 50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based risk groups on overall survival. Finally, univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics.

Results: 55.2%, 27.0% and 17.8% were in the low, intermediate, and high risk groups, respectively. Median (95% CI) survivals for these groups were 44.1 (42.6-45.5), 35.5 (32.3-38.8), and 32.1 (25.5-38.6) months, respectively. After controlling for patient age, race, gender, Charlson Comorbidity Index, T-Stage, Fuhrman Nuclear grade, and tumor size, intermediate risk and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735-27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117-162.228) increased risk of overall mortality, respectively.

Conclusions: Preoperative ESR values represent a robust categorical predictor of overall survival following nephrectomy in localized renal cell carcinoma in this cohort. Clinicians may consider including ESR measurements in counseling patients before nephrectomy, as well as managing patients according to their ESR-based risk category.

No significant financial relationships to disclose.
Econimic burden of reoperative renal surgery: Do the means justify the ends?
Authors: Agochukwu N. , Linehan W. , Bratslavsky G.
Published: February 2017

364

Background: Despite the high morbidity of reoperative renal surgery (RRS) most patients are able to preserve adequate renal function to obviate the need for dialysis. Nevertheless, the economic burden of RRS has not been evaluated so far. We aim to provide cost analysis for patients requiring RRS on a solitary kidney and patients needing completion nephrectomy and dialysis.

Methods: We reviewed the charts of patients treated at the NCI requiring RRS from 1989 to 2010. The data extracted included total time in the OR, ICU stay, total hospital stay, need for additional procedures, blood products, laboratory evaluation, and surveillance imaging until the next intervention on the operated unit or most recent follow up. The hospitalization cost was calculated based on current Medicare reimbursement rates based on current procedural terminology (CPT) codes. Those costs were compared to the estimated cost of completion of uncomplicated nephrectomy, AV fistula placement, and hemodialysis.

Results: We identified 30 patients treated with RRS on a solitary renal unit. The average procedure lasted 7.76 hours (4.25-11 hours) requiring an average of 7.16 units of blood transfused (0-32 units). The average time of hospitalization was 9.56 days (6-30 days), with the average ICU stay of 4.03 days (range 1-12 days), and an average floor stay of 6.64 (2-18 days). The estimated cost for hospitalization per patient was $52,058, while the estimated cost for uncomplicated nephrectomy, AV fistula placement, and a year of dialysis was $59,572. The financial benefit of RRS is reached at 0.9 years. At our median follow up of 4 years, the average cost saving per patient is estimated to be greater than $100,000 with the numbers likely to increase as these patients continue to avoid dialysis.

Conclusions: While associated with high morbidity, the RRS on the solitary unit may provide an opportunity for the majority of patients to retain their native renal remnants, preserve quality of life, and allow for savings for the healthcare system. These benefits are in addition to savings not included in our analysis that are associated with the morbidity and complications associated with dialysis in addition to the costs of care required for patients on dialysis.

No significant financial relationships to disclose.
Single-fraction radiosurgery for the treatment of renal tumors in singular renal units.
Authors: Staehler M. D. , Nuhn P. , Karl A. , Bader M. , Stief C. , Wowra B. , Muacevic A.
Published: February 2017

368

Background: High-dose local radiation treatment (stereotactic radiosurgery [SRS]) was added for selected patients to improve local control and overall survival in metastases. We report on toxicity and local tumor control in patients with renal tumors who were treated with aggressive local irradiation using a single fraction SRS with the Cyberknife in singular renal units to avoid hemodialysis.

Methods: n=18 patients with renal tumors and an eastern cooperative oncology group (ECOG) status of 0 or 1 were treated with SRS. Patients with surgically removable renal lesions were not included. Prior to SRS gold markers were planted into the renal parenchyma under ultrasonographic guidance.

Results: Nine patients had transitional carcinoma of the renal pelvis, six patients had renal cell carcinoma and three had other tumor entities. No skin toxicity occurred after SRS, and SRS did not induce other side effects. Local tumor control 9 months after SRS was 98% (95% CI: 89-99%). There were no treatment related deaths, and late complications after SRS were not noted so far. Renal function so far remained stable without a change in serum creatinine.

Conclusions: SRS for selected patients with renal tumors is safe and effective. Single-fraction delivery as an outpatient procedure allows for convenient integration of SRS into various oncological treatment concepts. Further studies are needed to determine the limits of SRS in this setting.

No significant financial relationships to disclose.
A novel web-based tool for risk quantification and objectification of treatment of renal cell carcinoma.
Authors: Canter D. , Kutikov A. , Bland J. , Sterious S. , Rozenfeld B. , Chen D. , Uzzo R.
Published: February 2017

382

Background: Despite the development of treatment guidelines, the management of renal cell carcinoma (RCC) remains overly subjective. Nomograms and statistical algorithms promise more objective decision making by patients and physicians by quantifying risk. Unfortunately, these tools remain underutilized in daily clinical practice because they are both cumbersome and time-consuming. We sought to create a novel website where all the available and relevant nomograms for RCC could be easily accessible for patients and practitioners, minimizing the subjectivity associated with clinical risk stratification and decision-making.

Methods: The existing literature was reviewed to identify published nomograms relevant to RCC. Nomograms were grouped by defining characteristics (preoperative versus postoperative predictive models, predictive models for metastatic disease, etc). Additional operationalized models included staging tools, surveillance models and cancer statistics. Nomograms were selected based on predictive accuracy, applicability, and ability to objectify risk stratification. Only nomograms with an AUC of greater than 0.7 were operationalized. The times required to extract clinical metrics for four hypothetical clinical scenarios were compared between the original paper version and our web-based model.

Results: www.cancernomograms.com organizes and operationalizes interactive predictive models for RCC for both physicians and patients. Each model was developed as an independent software program and deployed as an interactive flash object embedded in an HTML page allowing point of care risk calculation. In an initial sample of 15 subjects, the website decreased nomogram metric output from minutes to seconds, proving that utilization of a computer-based platform for these nomograms is faster (p=0.0003).

Conclusions: www.cancernomograms.com is a novel website that allows point of care risk quantification and objectified decision making using published statistical models. This web tool may help improve physician and patient communication and clinical care.

No significant financial relationships to disclose.
Can contemporary targeted therapies provide clinically meaningful changes in renal cell carcinoma venous tumor thrombi?
Authors: Delacroix S. E. , Chapin B. F. , Cost N. , Karam J. A. , Culp S. H. , Abel E. J. , Gonzalez G. , Margulis V. , Wood C. G.
Published: February 2017

390

Background: Renal cell carcinoma (RCC) tumor thrombus regression has been reported after treatment with contemporary targeted therapies. We sought to identify clinically meaningful changes in tumor thrombi in a series of patients treated with targeted therapies.

Methods: A University of Texas M. D. Anderson institutional database was queried for patients treated with targeted therapy while the primary RCC remained in situ. The subset of patients with a vascular tumor thrombus was assessed for radiographic responses of tumor thrombi. Pathology was obtained from a percutaneous biopsy or the surgical specimen. The modified Clavien system was used to grade complications within 12 months of surgery. Clinically meaningful changes were defined as changes in the anatomic thrombus level or changes altering surgical approach.

Results: A total of 178 patients were treated with targeted therapy with the primary tumor in situ. Venous tumor thrombus was present in 27% (n=48) and comprised our study cohort. The primary histology was clear cell in 75% of cases and 47/48 patients presented with metastatic disease. Prior to treatment, the tumor thrombus was within the renal vein (RV) in 60% (29/48-Level 0), the first 2 cm of the inferior vena cava in 10% (5/48-Level 1), > 2 cm above the RV in 21% (10/48-Level 2), at the level of the hepatics but below the diaphragm in 6% (3/48-Level 3), and above the diaphragm in 2% (1/48-Level 4). After a median duration of therapy of 2.75 months, clinically meaningful changes occurred in 25% of patients (12/48). Of these, progression occurred in 58% (7/12) while 42% (5/12) had regression of tumor thrombus. Fourteen patients (30%) received surgery after targeted therapy. Clavien categorized complications ≥ grade 3 occurred in 50% of surgical cases. No patient experienced a pulmonary embolism with treatment or during follow up.

Conclusions: To our knowledge,this is the largest reported series of RCC patients with an in-situ venous tumor thrombus treated with targeted therapy. Although no patient experienced a pulmonary embolism, the use of targeted therapy with the primary goal of obtaining clinically meaningful reductions in tumor thrombi does not appear to be a promising therapeutic option.

No significant financial relationships to disclose.