bluuebunny/crossref_metadata_2025 huggingface dataset:
Inguinal lymph node dissection for penile cancer: Predictors of lymph node metastasis.
Authors: Luchey Adam , Espiritu Patrick , Gopman Jared , Agarwal Gautum , Pow-Sang Julio M. , Sexton Wade Jeffers , Spiess Philippe E.
Published: February 2017

386

Background: Inguinal lymph node dissection (ILND) for lymph node metastasis (LNM) of squamous cell carcinoma of the penis (SCCP) can be a curative surgical treatment. Having the potential to identify clinical and pathological factors that predict LNM is important because of the poor prognosis this diagnosis carries. Methods: A retrospective review of 51 patients that underwent inguinal plus pelvic lymph node dissection from 1999 to 2012 was preformed. Age, race, body mass index (BMI), significant lymphadenopathy on preoperative imaging (nodes > 1 cm), palpable lymphadenopathy, and pathologic depth of invasion and diameter of the primary penile tumor along with associated lymphovascular invasion (LVI) were recorded and analyzed as potential predictors of LNM. Results: Median patient age was 65 and the median BMI was 29.3. Thirty-nine patients (76.5%) were white, 3 (5.9%) African American, and 9 (17.6%) were Hispanic. Median primary penile tumor diameter was 3.2 cm with 7, 29, and 15 patients having well, moderate, and poorly differentiated tumors. Pre-operatively, 32 patients (62.7%) had palpable lymphadenopathy on physical exam and 26 (51.0%) had significant lymphadenopathy on imaging (93% CT, 7% MRI), with 24 (47.1%) having both findings. Thirty-one patients (60.8%) who underwent ILND had pathological LNM. On univariate analysis, palpable nodes (p < 0.001), nodes on imaging (p <0.001), having both palpable nodes and nodes on imaging (p < 0.001), age (p = 0.02), and LVI (p = 0.04), were significantly associated with LMN. On multivariate analysis, having nodes on imaging (p = 0.001) and age < 65 years (p = 0.049) were significant for predicting LNM. Conclusions: In evaluation of patients with T1-T3 penile cancer, multiple factors were predictive of LNM in our series: palpable and radiographic nodes, younger than age 65 and LVI. Inguinal adenopathy defined as more than 1 cm appears to better predict occult nodal metastasis, however, this must be weighed in terms of the additional cost and clinical yield provided by widespread adoption of pelvic (CT or MRI) imaging in all patients with aggressive primary penile tumor phenotypes.
Surgical management of testicular cancer patients with complex postchemotherapy residual masses: Aachen University experience.
Authors: Heidenreich Axel , Porres Daniel , Piper Charlotte , Thissen Andrea K. , Pfister David J. K. P.
Published: February 2017

387

Background: Post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) represents the treatment of choice in patients with residual masses following chemotherapy for advanced non-seminomatous testicular germ cell tumors (NSGCT). Involvement of the abdominal aorta, the inferior vena cava or the thoracic/lumbar spine are rare but need complete resection for curative intent. We report on our single center experience in the management of such complex cases. Methods: Between January 2009 and September 2014 post-chemotherapeutic retroperitoneal lymph node dissection (PCRPLND) was performed in 162 patients (pts) with advanced NSGCT. Fourteen pts (4.9%) fulfilled the criteria of a GTS: enlarging metastatic mass in the retroperitoneum or visceral organs during systemic chemotherapy with normalized or regredient tumor markers. In all cases of GTS a complete radical bilateral PCRPLND including the resection of adjacent visceral and vascular structures was performed. Results: Median patient age was 24.5 (18 to 52). All patients exhibited NSGCT with a good or intermediate prognosis according to IGCCCG; 10 and 4 patients presented with clinical stage IIC and III, resp. Median tumor diameter at time of surgery was 6.5 (3,0-35)cm. Tumor markers were normalized in 12 out of 14 patients and markers plateauted in 2 out of 14 patients. Tumor masses were localized in the retroperitoneum in 12 pts; two pts had additional pulmonary metastases which were resected in a second approach. Median time from start of chemotherapy to surgery was 4.8 (1.5 to 26.5) months Median surgical time was 265 (165 to 585) minutes, median blood loss 650 (450 to 2,000) ml. Four pts required resection of the inferior vena cava or abdominal aorta with implantation of a prosthetic graft; adjunctive nephrectomy was performed in three pts. After a median follow-up of 4.2 years two pts developed recurrent disease; the remainder are alive without evidence of disease. Conclusions: Involvement of vascular structures and/or bone is a rare phenomenom among pts with advanced NSGCT and necessitates complete surgical resection of all masses with curative intention. Due to the complex surgery, treatment should be performed at specialized centers.
Clinical characteristics and outcomes of patients with primary mediastinal germ cell tumors.
Authors: Sakdejayont Siwat , Sathitruangsak Chirawadee , Sunpaweravong Patrapim , Dechaphunkul Arunee
Published: February 2017

389

Background: Mediastinal germ cell tumors (MGCTs) account for 20% of all mediastinal tumors. Cisplatin-based chemotherapy followed by surgical resection of residual tumor remains the standard of care. To prevent pulmonary complications secondary to extensive thoracic surgery, non-bleomycin containing regimen is generally preferred. This study aims to review clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients with MGCTs treated in our institution between 1993 and 2013. Results: A total of 40 patients were enrolled with a median age of 24. Only one patient is female. Stratified by histology; eight patients (20%) had pure seminoma, 25 patients (62.5%) had pure non-seminoma, four patients (10%) had mixed seminoma and non-seminoma, and three patients (7.5%) had malignant transformation (two adenocarcinoma, one sarcoma). Median tumor size was 13 centimeters. Ninety-two percent of patients received chemotherapy as a first treatment modality, whereas 8% underwent upfront surgery. All patients received cisplatin-based chemotherapy: Eighty seven percent bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin. Seventy-two percent of patients completed four planned cycles of chemotherapy. Thirty-one patients were able to assess radiological response: 3.2% complete response, 58.1% partial response, 29.0% stable disease, and 9.7% progressive disease. Forty-four percent of patients achieved completely serological response with chemotherapy. Seventeen patients underwent surgical resection of residual tumor. Among these, viable tumor was seen in 35% (6 out of 17 patients). No patients complicated with clinically significant pulmonary complications after thoracic surgery. The five year overall survival (OS) of patients with seminoma was 72.9% as compared with 19.9% in those with non-seminoma (p=0.012). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected (N=11), the five year OS was 64.9%. Conclusions: Our study confirmed the importance of multi-modality approaches with primary chemotherapy followed by surgical resection of residual tumor. Bleomycin-containing regimen can be safely used in this setting.
Cytoreductive nephrectomy (CN) in patients with synchronous metastases from renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Heng Daniel Yick Chin , Rini Brian I. , Beuselinck Benoit , Lee Jae-Lyun , Knox Jennifer J. , Bjarnason Georg A. , Pal Sumanta Kumar , Kollmannsberger Christian K. , Yuasa Takeshi , Srinivas Sandy , Donskov Frede , Bamias Aristotelis , Wood Lori , Ernst D. Scott , Agarwal Neeraj , Vaishampayan Ulka N. , Rha Sun Young , Kim Jenny J. , Kanesvaran Ravindran , Choueiri Toni K.
Published: February 2017

396

Background: The role of cytoreductive nephrectomy is unclear in patients with synchronous metastases from renal cell carcinoma (RCC) in the age of targeted therapy. Methods: Comparisons were made between patients treated with targeted therapy who had a CN versus not and adjusted using proportional hazards regression for known poor prognostic criteria (IMDC criteria Heng et al JCO 2009). Results: 2569/3245 (79%) mRCC patients received a nephrectomy. Patients who had nephrectomy before the diagnosis of metastatic disease were excluded (n=1634). Among the remaining patients, 935 patients had a CN and 676 patients did not have nephrectomy. All patients received targeted therapy with the majority receiving first-line sunitinib 72%, sorafenib 15%, temsirolimus 5%, bevacizumab 3%, pazopanib 3%. Patients who had CN had better IMDC prognostic profiles versus those without (favorable/intermediate/poor in 9%/63%/28% vs 1%/45%/54% p<0.0001). The median overall survival of patients with CN vs without was 20.6 vs 9.5 months (p<0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95%CI 0.52-0.69, p<0.0001). The Table demonstrates the increasing benefit of CN if a given patient has a longer survival time. Conclusions: CN can be beneficial in patients with synchronous metastatic RCC even after adjustment for prognostic factors. Patients who are estimated to survive less than 9-12 months may have a marginal benefit compared to those with longer estimated survival. This may aid in patient selection as we await results from randomized controlled trials. [Table: see text]
Ten- and 15-year prostate cancer-specific survival in patients with nonmetastatic high-risk prostate cancer randomized to lifelong hormone treatment alone or combined with radiotherapy (SPCG VII).
Authors: Fossa Sophie D. , Widmark Anders , Klepp Olbjorn Harald , Wiklund Fredrik , Angelsen Anders , Damber Jan-Erik
Published: February 2017

4

Background: After a median observation time of 7.6 years, Scandinavian Prostate Cancer Group VII randomized trial showed a significant 12% reduction of prostate cancer-specific mortality in patients with locally advanced or histologically aggressive prostate cancer who received three months of total androgen blockade followed by radiotherapy and continuous antiandrogen therapy compared to patients with hormonal treatment only (Widmark et al :Lancet [2009]; 373,1174). Here we provide the 10 (15)-year survival results after a median observation time of 10.7 years. Methods: Between February 1996 and December 2002, 875 patients with locally advanced prostate cancer were randomized (Randomization ratio 1:1). Primary endpoint was prostate cancer-specific survival analyzed by intention to treat. This updated analysis is based on death registry data of the Norwegian patients (2/3 of the population), and on data recorded in CRF database available for the Swedish patients. A Swedish death registry analysis is underway, and will be included in the final analysis at the meeting. Results: Prostate cancer death occurred in 118 out of 439 of the antiandrogen treatment group and in 45 out of 436 men in the combination treatment group (p< 0.0001), with death due to any cause in 210 out of 439 and 161 out of 436 men (p=0.0006), respectively. The 10 (15) year cumulative prostate cancer-specific mortality was more than halved after combined treatment: 18.9% (30.7%) and 8.3% (12.4%) (HR=0.35;[p<4.1E-10 for 15 year results]), and overall mortality was 35.3% (56.7%) and 26.4% (43.4%) (HR=0.70; P=0.0006 for 15 year results), respectively. Conclusions: Addition of local radiotherapy to hormonal treatment in patients with non-metastatic locally advanced or high-risk prostate cancer more than halved the 10 and 15 year prostate cancer-specific mortality and substantially decreased overall mortality.
Impact of follow-up imaging on overall and cancer specific survival after radical and partial nephrectomy.
Authors: Strope Seth A. , Sutcliffe Siobhan , Vemana Goutham , Sandhu Gurdarshan Singh , Schootman Mario
Published: February 2017

401

Background: While imaging after radical and partial nephrectomy has been shown to detect recurrent disease, impacts on mortality are unclear. We assessed effects of imaging on overall-survival (OS) and cancer specific survival (CSS) in Medicare patients. Methods: From linked SEER-Medicare data we defined a cohort of patients treated with radical or partial nephrectomy from 1992 to 2007. All post-operative imaging was collected and stratified as abdominal (CT or US) or chest (CT or CXR). Ascertainment of imaging tests was stopped at the time of possible recurrence based on an algorithm of cancer directed therapy, surgery, or visit to a medical or radiation oncologist. After limiting the cohort to patients treated in hospitals with at least 30 cases, we developed a hospital level average rate of scans per patient for the first five years of patient follow up. The rates were then stratified into three groups for abdominal imaging (Scans less frequent than every 24 months, every 18 to 24 months, more than every 18 months) and chest imaging (Scans less frequent than every 18 months, every 12 to 18 months, more than every 12 months). These categories were then applied in survival analyses at the patient level for OS and CSS and then stratified by final cancer stage. Results: Our cohort included 3,167 patients treated in 62 hospitals. Patients treated in hospitals with higher rates of chest imaging had marginally better OS (HR 0.77 and 0.83, CI 0.60 to 1.01 and 0.63 to 1.08 for scans 12-18 and <12 months respectively), but no effect was found for CSS. Treatment in hospitals with higher rates of abdominal imaging had no impact on OS or CSS. The OS benefit of treatment in hospitals with higher rates of chest imaging appeared limited to patients with stage 1 cancer (HR 0.53 and 0.57, 95% CI 0.38 to 0.76 and 0.40 to 0.80 for scans 12-18 and <12 months respectively). Conclusions: With the exception of chest imaging for stage 1 patients, we found no evidence that higher rates of imaging are associated with better OS or CSS after radical or partial nephrectomy. These results suggest more conservative follow-up imaging protocols can be used in this patient population.
AUA and NCCN surveillance guidelines for RCC: Do they effectively capture recurrences following nephrectomy?
Authors: Stewart Suzanne B. , Lohse Christine M. , Psutka Sarah P. , Cheville John C. , Boorjian Stephen A. , Thompson Robert Houston , Leibovich Bradley C.
Published: February 2017

402

Background: The American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) are highly utilized sources for surveillance strategies following surgical treatment for renal cell carcinoma (RCC). However, the duration of follow-up may be inadequate to capture the majority of recurrences. Herein, we assess the ability of these guidelines to effectively capture recurrences of RCC following primary surgical resection. Methods: We reviewed our institutional database of 3,725 patients treated with radical or partial nephrectomy for M0 sporadic RCC between 1970-2008. For comparison to the AUA guidelines, patients were stratified into low risk following partial nephrectomy (LRp) or radical nephrectomy (LRr) = pT1N0, and moderate/high risk (M/HR) = pT2-4 N0-1. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods given for site-specific recurrence: AUA—LRp: 3yrs for all sites; LRr: 1yr for abdominal and 3yrs for chest/bone/other sites; M/HR: 5yrs for all sites; NCCN—6 months for abdominal/chest sites and 5yrs for bone/other sites. Results: Of the 3,725 patients, 2721 (73.1%) underwent radical nephrectomy, 2,210 (59.3%) were classified as pT1 NX-0 and 2,910 (78.1%) as clear cell RCC. Median postoperative follow-up was 8.9yrs (IQR 5.5-14.2) during which 1,114 (29.9%) patients developed recurrence. Of these recurrences, 760 (68.2%) would have been detected using the AUA guidelines and 432 (38.8%) by NCCN recommendations. Within AUA risk groups, 37.2% recurrences were captured in LRp, 31.4% in LRr and 80.2% in M/HR. Capture of 90% of recurrences in the abdomen and chest would require surveillance for 9yrs and 8 yrs, respectively in LRp, 15yrs and 12yrs in LRr and 11yrs and 10yrs in M/HR. Conclusions: Duration of follow-up recommended by current surveillance algorithms by the AUA and NCCN do not adequately capture many recurrences in RCC following radical or partial nephrectomy. Guidelines using risk stratification and site-specific recurrence parameters to assign length of surveillance may allow providers to better individualize surveillance regimens.
Understanding treatment disconnect and mortality trends in renal cell carcinoma using tumor registry data.
Authors: Smaldone Marc C. , Egleston Brian , Hollingsworth John M. , Hollenbeck Brent K. , Miller David Christopher , Kim Simon , Handorf Elizabeth , Wong Yu-Ning , Uzzo Robert G. , Kutikov Alexander
Published: February 2017

403

Background: Previous research has demonstrated a rise in overall and cancer specific mortality over time despite increased detection and treatment of kidney cancer, termed “treatment disconnect.” Our aim was to assess the impact of missing data and rising incidence on mortality trends using national tumor registry data. Methods: Using Surveillance, Epidemiology, and End Results (SEER) data, we identified all patients with a kidney cancer diagnosis from 1973-2009. We estimated overall mortality rates by tumor size after accounting for lags from diagnosis to death and using multiple imputation for missing data. Mortality rates for all patients irrespective of tumor size were also estimated after adjustment for prior cumulative incidence using ridge regression. Results: 73,647 patients met inclusion criteria, of which 22.7% had missing tumor size data. Compared to observed rates, significant decreases in the change in mortality rate per 100,000 US population from 1983 to 2009 were noted for 2-4cm (Δobs1.58 versus Δimp1.34; p=0.003), 4-7cm (Δobs1.61 versus Δimp0.79; p<0.001), and >7cm (Δobs1.55 versus Δimp0.19; p<0.001) tumors following missing data imputation, while no differences in change of rate were noted for tumors <2cm (Δobs0.29 versus Δimp0.25). In a separate analysis, holding the incidence of kidney cancer constant over time, the temporal increase in overall mortality for all patients was attenuated (p<0.001 for test of difference in slope) when comparing observed (3.9 to 6.8) and estimated (5.9 to 7.1) rates, suggesting that rapidly rising incidence may also influence reported mortality trends. Conclusions: Missing data and rising incidence rates may contribute substantially to the “treatment disconnect” phenomenon when examining mortality rates in kidney cancer using tumor registry data.
The effect of sunitinib on biomarkers and tumor heterogeneity in metastatic clear cell renal cancer.
Authors: Stewart Grant , Laird Alexander , O'Mahony Fiach , Eory Lel , Lubbock Alexander , Nanda Jyoti , O'Donnell Marie , Mackay Alan , Mullen Peter , McNeill Alan , Riddick Antony , Aitchison Michael , Berney Daniel , Bex Axel , Overton Ian , Harrison David James , Powles Tom
Published: February 2017

408

Background: The purpose of this work was to investigate the effect of sunitinib on tumour biomarkers and assess intratumoural heterogeneity in metastatic clear cell renal cancer (mRCC). Primary tumours and metastatic sites were examined. Methods: Multiple fresh frozen tissue samples (median=4) were taken from sunitinib naive (n=23) and sunitinib treated (18 weeks at sunitinib 50mg) patients (n=27) with mRCC. Tissue was taken from the primary renal tumours. Multiple analysis of DNA (aCGH), mRNA (Illumina Beadarray) and protein lysates (reverse phase protein array) were performed on each tumour sample. Analysis of metastatic tissue occurred where possible (n=4). A cohort of matched untreated and sunitinib/pazopanib treated paraffin embedded mRCC samples from 3 clinical trials was used for validation with automated quantitative analysis. Results: Treated and untreated patient had similar patient characteristics. Significant intratumoural heterogeneity in DNA, RNA and protein occurred. Sunitinib was associated with increased intratumoural heterogeneity in protein expression (p<0.05), but not DNA or RNA. Despite this heterogeneity, significant changes to protein expression with sunitinib occurred. Four proteins changed significantly in terms of both expression and variance with sunitinib (BCL2, MLH1, CAIX and mTOR; p<0.05 for each). Elevation of CAIX expression in sunitinib treated patients was confirmed in the validation cohort (p=0.01). Low levels of CAIX correlated with poor outcome in treated samples (HR=0.26, 95% CI: 0.11-0.61, p=0.001). A positive correlation between protein expression in the primary tumour and metastatic sites occurred. Individual metastasis within patients exhibited a variable radiological response to therapy, which was equally marked in the genetically more homogeneous primary tumours. Conclusions: Intratumoural heterogeneity occurs on many levels in mRCC. Sunitinib is associated with increase in protein heterogeneity. Despite this, upregulation of CAIX is a potential prognostic biomarker.
Correlation between patient-reported fatigue and hemoglobin (Hgb) levels in metastatic renal cell carcinoma (mRCC) patients (pts) receiving sunitinib (SU).
Authors: Davis Mellar P. , Matczak Ewa M. , Chen Connie , Korytowsky Beata , Bhattacharyya Helen , Lin Xun , Rini Brian I.
Published: February 2017

418

Background: Low Hgb is linked with fatigue in cancer pts; however, the onset and severity of fatigue is multifactorial. The approved SU dosing schedule in mRCC is 4 weeks on treatment, 2 weeks off, and quality of life (QoL) when examined on day 28 is significantly worse than on day 1 of each cycle. The relationship between pt-reported fatigue and Hgb levels with SU in mRCC was investigated. Methods: Two randomized clinical trials of SU were combined to examine the pt-reported fatigue item from FKSI-15 which asks pts to indicate their level of fatigue on a 5-point Likert scale from 0=“not at all” to 4=“very much”. Data were collected at baseline (BL; cycle 1, day 1) and on days 28 and 42 of each 42-day cycle. For each visit, only pts who had data for both fatigue and Hgb at BL were included in the analysis. Results: 481 pts were included. Fatigue and Hgb levels at BL and over cycles 1–6 are shown in the table. Pts reported worse fatigue (higher score) at day 28 of each cycle than on day 42. Fatigue scores typically ranged from 1= “a little bit” to 2=“somewhat”. Changes in Hgb levels, however, were modest and opposite to fatigue changes i.e. were higher on day 28 of each cycle and lower on day 42. Findings were similar beyond cycle 6. Conclusions: Pts indicated less fatigue on day 42, after the 2-week break, than on day 28 of each cycle, consistent with previous overall QoL findings. Low Hgb is not associated with worse fatigue in mRCC pts receiving SU.This may be due to the multifactorial nature of fatigue. The ‘on’ and ‘off’ periods in intermittent dosing are important considerations of patients’ full experience of QoL. [Table: see text]
Utility of 2-(18F) fluoro-2 deoxy-D-glucose PET/CT in advanced papillary renal cell carcinoma.
Authors: Shuch Brian , Stamatakis Lambros , Chen Clara , Gautam Rabindra , Merino Maria , Choyke Peter L. , Linehan W. Marston , Srinivasan Ramaprasad
Published: February 2017

419

Background: 2-(18F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is used infrequently in renal cell carcinoma (RCC) based on modest sensitivity in patients with clear cell kidney cancer. We evaluated the ability of FDG PET/CT to identify metastatic kidney cancer in patients with the second most common variant, papillary RCC. Materials and Methods: Patients with papillary RCC who underwent FDG PET/CT in conjunction with anatomic imaging were identified in a review of our clinical database. The ability of FDG PET/CT to detect malignant lesions (categorized by radiographic criteria) was evaluated. Results: Imaging studies from 42 patients with metastatic papillary RCC were reviewed. A total of 215 lesions were characterized as metastatic based on radiologic features. The median lesion size and lesions per patient were 2.0 cm and 5, respectively. Of these, 200 lesions were correctly classified as malignant by PET/CT (sensitivity, 93.0%, 95% confidence interval (CI) 88.8-95.7%). Of histologically confirmed lesions, 35 of 39 were PET positive (sensitivity, 89.7%, CI-76.4-95.9%). FDG PET/CT sensitivity did not appear to differ by lesion size, site, or papillary subtype. In a patient based analysis, all 42 patients had evidence of at least one FDG PET/CT avid lesion (sensitivity 100%, (95% CI 91.6-100%). Conclusions: FDG PET/CT is a highly sensitive modality for identifying extra-renal disease associated with papillary RCC. These data suggest that FDG PET/CT might be a clinically useful modality in the staging and surveillance of this patient population.
Active surveillance as a treatment option for metastatic or recurrent renal cell carcinoma.
Authors: Park Inkeun , Lee Jae-Lyun , Ahn Jin-Hee , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: February 2017

426

Background: Metastatic renal cell carcinoma (MRCC) often presents with very indolent course without any symptom, and treatment (Tx) for MRCC is mostly palliative rather than curative in a molecular target agents era. There exist several Tx options for MRCC, but all available agents have considerable toxicities, cause economic burden to patients (pts), and impair quality of life. We retrospectively evaluate outcomes of active surveillance for asymptomatic MRCC pts. Methods: We enrolled MRCC pts who was followed-up with deferred treatment in our institution between 2000 and 2012. Clinical characteristics, response to active surveillance, predictive factor for time-to-progression (TTP), and response to succeeding first line VEGFR TKIs were analyzed. Results: Of 58 pts, 42 had recurrent disease and 14 had initially metastatic disease. Most pts had good Karnofsty PS (KPS), 100% for 39 pts and 90% for 14 pts. Lung (47 pts) and lymph nodes (18 pts) were most common site of metastasis. During active surveillance, 83% of patients had stable disease (SD) as their best response. Only 17% of patients had progressive disease (PD) as their initial response. Ultimately, 47 pts had PD finally until data cut-off date. With a median F/U period of 31.4 months, 47 patients experienced disease progression with a median TTP of 12.4 months (95% CI, 8.4~16.5). A median OS was 91.1 months (95% CI, 30.7-151.6). Multivariate analysis revealed that KPS < 100, presence of liver metastasis, time from diagnosis to active surveillance less than 1year, and neutrophilia were independent predictive factors for worse TTP. After PD, 30 pts proceeded to systemic treatment (14 sunitinib, 11 pazopanib, 4 immunotherapy, and 1 temsirolimus). Objective response rate were 71% for sunitinib, and 46% for pazopanib. Conclusions: This study suggests that active surveillance without any intervention could be a viable treatment option for the first-line approach in asymptomatic MRCC pts, especially for those who have good performance status without neurtrphilia or liver metastases. The possibility of disease stabilization should be considered before initiation of any active treatment and when assessing the activity of any treatment in terms of time to progression.
Phase II clinical trial of bevacizumab plus ixabepilone in renal cell carcinoma.
Authors: Burotto Pichun Mauricio Emmanuel , Acquavella Nicolas , Edgerly Maureen , Bates Susan Elaine , Balasubramaniam Sanjeeve , Fojo Antonio Tito
Published: February 2017

427

Background: Metastatic renal cell carcinoma (mRCC) remains incurable. Seven targeted agents are approved for mRCC, five targeting VEGFR and two m-TOR inhibitors. Most approvals have been based on improvements in progression free survival (PFS). Preclinical data indicates synergism of ixabepilone and bevacizumab. Methods: Patients with histologically confirmed mRCC with at least one previous therapy received ixabepilone [6mg/m2/d X 5d] plus bevacizumab [15 mg/kg] every 21 days. The primary endpoint was PFS by RECIST. Secondary endpoints were response rate, overall survival, and safety. In addition to “conventional” efficacy assessments, we calculated the growth rate constant as a measure of efficacy. Results: Thirteen patients have been enrolled. The median number of prior therapies was two (range 1-5). Nine (69%) have stable disease as best response with two (15%) partial responses. Median time to progression (TTP) was 6.39 months. The growth rate constant (g) was 0.0021/day and the regression rate constant (d) was 0.0032/day. Six patients discontinued treatment due to progression; one patient died. Principal toxicities including hypertension, fatigue, anemia and thrombocytopenia led two patients to discontinue therapy. One continues on study after 25 cycles. Accrual continues. Conclusions: Ixabepilone plus bevacizumab has activity in mRCC. A median TTP of 6.39 months compares favorably with 3.9-4.8 months for approved second line therapies. The calculated growth rate of 0.0021/day in this refractory population is indistinguishable from a value of 0.0022/day with single agent bevacizumab in treatment-naive mRCC. However, we cannot discern if this reflects bevacizumab activity even in refractory disease or a beneficial ixabepilone effect. Clinical trial information: NCT00923130.
Does nonsurgical management for localized kidney cancer equate to active surveillance in the SEER-Medicare population?
Authors: Smaldone Marc C. , Egleston Brian , Kim Simon , Handorf Elizabeth , Geynisman Daniel M. , Wong Yu-Ning , Uzzo Robert G. , Kutikov Alexander
Published: February 2017

444

Background: Differentiating between patients with small renal tumors not selected for treatment from those who choose elective active surveillance (AS) using administrative data is a significant challenge. Using active treatment as a benchmark, our objective was to compare survival outcomes between all patients with localized kidney cancer who received non-surgical management (NSM) with those meeting more stringent NSM criteria who are more likely to clinically resemble AS. Methods: Using linked SEER-Medicare data, we identified all patients ≥66 years old with localized T1 (<7cm) Renal Cell Carcinoma from 1995-2009. Treatment groups were defined as active treatment (partial or radical nephrectomy), all NSM (no treatment within 6 months of diagnosis), and stringent NSM (further exclusion of patients with lack of imaging or presence of hospice claims). Patients undergoing ablative treatment were excluded from analyses. Overall and cancer specific mortality were assessed using Cox and Fine and Gray proportional hazard models with propensity score based weighting. Results: Of 15,450 identified patients, 2,089 (13.5%) underwent NSM. Of these, 1,182 (56.6% of NSM, 7.7% of overall sample) met stringent NSM criteria. Following adjustment, the all NSM group demonstrated significant increases in cancer specific (sHR 1.91 [CI 1.26-2.88]) and overall (HR 1.49 [CI 1.16-1.92]) mortality compared to patients undergoing active treatment. In contrast, for patients meeting stringent NSM criteria, these differences in cancer specific (sHR 1.48 [CI 0.82-2.68]) and overall (HR 1.33 [CI 0.998-1.77]) mortality were attenuated and no longer met statistical significance. Conclusions: Compared to active treatment, patients meeting stringent NSM criteria demonstrated improved survival outcomes when compared to all-comers with localized kidney cancer who were managed non-surgically. Our findings support that a validated, claims-based algorithm that more accurately identifies patients undergoing elective AS is needed to objectively assess the safety and effectiveness of this clinical strategy.
Active surveillance of pulmonary metastases in renal cancer patients.
Authors: Abdul Rahman Rozana , Teo MinYuen , Osman Noorsyakira , Jayaram Anuradha , o'Donnell Dearbhaile M. , McDermott Raymond
Published: February 2017

445

Background: Biology of pulmonary metastases (PM) in renal cancer (RCC) patients (pts) is variable and not all pts require immediate treatment. We examined the role of active surveillance in PM predominant metastatic RCC pts. Methods: Pts with a diagnosis of RCC and presence of PM were identified. PM had to be ≥ 5mms (solitary) or 2mms (multiple), classified as metastatic by the treating physician, and definitive local therapy was deemed not possible. Metastatic disease could also be present elsewhere if small volume. Pts, disease and treatment details were extracted from chart review. Kaplan-Meier method was used to perform time-to-event analyses. Primary endpoint was time on surveillance. Also studied were time from PM appearance to treatment initiation and duration of treatment. Results: Between Nov 2005 and Sept 2013, 48 pts were identified. Median age at PM diagnosis was 66 years (39 – 88 yrs), 81% were male, 94% had prior nephrectomy and were of clear cell histology. 31/45 pts (69%) had pT3 tumours with median Fuhrman grade of 3. Median MSKCC score was 1. PMs were present at diagnosis in 20 pts and developed subsequently in 27 pts at a median of 19.4 months (interquartile range (IQR) 9.5 - 64.3). Twelve (25%) of PMs were biopsy proven. 14 pts had solitary PM while 31 were multiple. Median size of metastases was 9mm (2 – 32mm). Metastases elsewhere were present in 10 pts. Median follow-up duration for all pts was 24.5 mos (IQR 12.9 – 44.1). 28/48 pts (58%) remain on surveillance at median 18.6 mos (IQR 10.6 - 28.5). In 11 pts there had been no progression while 17 pts have experienced RECIST progression of PM but remain on surveillance due to lack of symptoms/slow growth. 20/48 pts commenced on treatment. Median time from PM diagnosis to treatment was 12.5 mos (IQR 7.9 – 19.3). 18/20 pts started on VEGF TKI (Sunitinib 12 pts, Pazopanib 5, Sorafenib 1), while 2 pts had mTOR inhibitors. Median duration of follow-up on treatment was 13.4 mos (IQR 5.4 – 35.8), with 2 patients having died at 40.1 mos and 37.5 mos. Number of pts who received 2nd/3rd/4th/5th line of treatment were 7/2/2/1 respectively. Conclusions: Active surveillance of PM in RCC pts is safe and may avoid unnecessary treatment related toxicity. Once treatment is commenced, outcomes do not appear to be adversely affected.
Prognostic value of flare-up phenomenon after discontinuation of sunitinib (SU) or pazopanib (PA) in metastatic renal cell carcinoma (mRCC).
Authors: Iacovelli Roberto , Massari Francesco , Albiges Laurence , Escudier Bernard
Published: February 2017

448

Background: SU and PA are VEGFR inhibitors, approved for the treatment of mRCC. Cessation of treatment has been reported to induce flare-up, with increased tumor growth rate (TGR). We aimed to investigate this phenomenon and its prognostic role in mRCC. Methods: Patients who discontinued first line SU or PA with available data about CT scans performed before (t-1), at the time of discontinuation (t0) and after (t+1), were included in this analysis. TGR was evaluated as the difference between the sum of longest diameters (SLD) of the target lesions during the interval time between the CTs (TGR1=SLD0–SLD-1/t0-t-1 and TGR2=SLD+1-SLD0/t+1-t0) and expressed in cm/month. Flare-up was evaluated as the difference between the TGRs. Median overall survival was evaluated from t0 (OS0) to death by the Kaplan-Meier method and correlation with variables was evaluated with Cox model. Results: Sixty-three patients treated from Oct 2006 to Nov 2012 at the Institut Gustave Roussy were eligible. Median age was 57.1 y, 81% were males, 89% had SU and 11% PA. Heng prognostic groups were good in 33% and intermediate in 67% of the pts. Median OS0 was 24.1 months (95%CI, 8.3 – 40.0). Major reasons for discontinuation were durable partial/complete response (16%), severe toxicity (22%) and progression of disease (62%). The median TGR1 and TGR2 were 0.2 and 0.7 cm/month, respectively (p=0.001), no correlation was found (p=0.33) and no differences were found between SU and PA in TGR1 (p=0.95) and TGR2 (p=0.53). Median flare-up was 0.5 cm/month (IQR: 0.1 – 1.2); in pts who discontinued for response, toxicity, or PD it was 0.1 (IQR: -0.2 – 0.6), 0.5 (IQR; 0.2 – 2.0) and 0.8 (0.1 – 1.7), respectively. At the univariate analysis flare-up was a prognostic factor for OS0 (HR: 1.13, 95%CI: 1.02 – 1.24; p=0.018). When compared to Heng criteria in the multivariate analysis, it was confirmed to be an independent prognostic factor: each increase of 1 cm in flare-up increases the risk of death by 11% (HR: 1.11, 95%CI: 1.00 – 1.23; p=0.048). Conclusions: Flare-up is an independent prognostic factor present in patients affected by mRCC who discontinued SU or PA. This is independent by the reason for discontinuation and the type of therapy.
Using biologic knowledge to discover molecular correlations between human renal cell carcinoma pathways.
Authors: Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Veiga Francisco Gomez , Valladares Ayerbes Manuel , Quindós Varela Maria , Fernandez Nunez Natalia , Molina Diaz Aurea , Santamarina Cainzos Isabel , Anton Aparicio Luis Miguel
Published: February 2017

451

Background: Renal cell carcinoma (RCC) is known to be resistant to chemotherapy. There is need for the identification of biomarkers capable to determine RCC prognosis factors and metastatic potential obtainable from non-invasive or minimally invasive techniques. Our aim was to derive predictive models which could predict more accurately than any one factor alone. Methods: To studythe cascade of events leading to the formation and progression of RCC, we assessed 29 markers by immunohistochemistry and qRT-PCR using tissue micro-array (TMA). Results: Multivariate logistic regression showed the best proteins combination for node status (NOTCH1 and GLUT5) and pelvis invasion (EGFR and DLL3). ROC curve analyses were made to analyse the accuracy of the best candidate proteins; it should be noted NOTCH1 and GLUT5 for node status prediction (AUC=0.833, 95% CI, 0.744-0.922; p<0.001) and EGFR and DLL3 for pelvis invasion (AUC=0.777, 95% CI, 0.631-0.922; p=0.007). Furthermore, we carried out the correlation between these candidate proteins and all mRNA measured in order to deepen in the cellular transcripts traffic associated with them. To highlight the correlation between high DLL3 protein levels and low Hif1-β expression, and the negative correlation between GLUT5 protein and low levels of Baxβ. Conclusions: In the age of individual therapy, the approach to percutaneous image-guided RCC biopsy procedures plays an expanded role. Applying a 2 mm punch needle for constructing a TMA we could describe for the first time how are combined and correlated 29 markers in regression equations to predict in the most optimal way a number of pathological variables associated with RCC. [Table: see text]
Treatment (tx) patterns and drug (Rx) costs for patients (pts) with metastatic renal cell carcinoma (mRCC) in the United States.
Authors: Geynisman Daniel M. , Shih Ya-Chen T.
Published: February 2017

457

Background: The tx paradigm for mRCC has rapidly morphed from cytokine-based and cytotoxic tx to targeted therapy (TT). Five oral (O) and two intravenous (IV) TTs are approved for mRCC. No consensus exists on the sequence of TT use. This study aimed to examine the evolution of 1st through 3rd line tx patterns since 2004 and their associated costs. Methods: LifeLink Health Plan Claims Database (October 1, 2003-March 31, 2011), a commercial claims database, was used to create a cohort of age ≥ 18 yo, mRCC pts with at least 12 months of continuous enrollment. We examined tx patterns and sequences by year. When evaluating cost, we limited analysis to pts <65 yo because the database does not have information on claims paid by Medicare. We described pt characteristics and tx patterns over time and applied a nonparametric bootstrapping method to compare costs. Results: 1,561 mRCC pts met the inclusion criteria with 71% men and a mean age of 62 yo (SD=11); 39% were from the South; 57% had a modified Charlson comorbidity score of zero. In 2010: 9 unique Rx regimens were used for 1st line tx, 8 for 2nd, 8 for 3rd; most common 1st/2nd/3rd line tx was sunitinib (44%)/temsirolimus (24%)/everolimus=sunitinib (26%); most common sequence was VEGF->mTOR for the 1st switch and VEGF->VEGF->VEGF for 2nd switch. From 2004 to 2011, 1st line cytotoxic tx decreased from 47% to 6%, IFN-α from 47% to 3%, bevacizumab from 33% to 9%. Over time, more pts were able to go from 1st to 2nd line tx (p=0.01) and 2nd to 3rd line tx (p=0.025). Median time to switch (TTS) from 1st to 2nd line was 175 days (SD 103) with a longer TTS if started on O vs. IV tx (188 vs. 143 days) (p<0.001). For 959 pts <65 yo, stratifying by whether the 1st line tx was O or IV, mean total 1st-yr tx cost/pt was $130,962 (IV) vs. $121,676 (O) (P=0.18) and total 1st-yr Rx cost was $36,636 (IV) vs. $54,596 (O) (p<0.001). Also, costs increased by the number of switches, from $108,428 for no switch to $190,976 for > 1 switch. Conclusions: The results support a drastic shift in the tx of mRCC with wide heterogeneity in tx patterns, reflecting a lack of clear guidelines. Over the years, more pts are able to receive more lines of tx, TTS was longer with initial O tx, but 1st-yr Rx costs were lower with initial IV tx.
Significance of preoperative butyrylcholinesterase as an independent predictor of overall survival in patients with renal clear cell carcinoma treated with nephrectomy.
Authors: Koie Takuya , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: February 2017

458

Background: Prognostic factors for overall survival (OS) of the patients with clear cell renal cell carcinoma (cRCC) treated with nephrectomy are still not defined well. Butyrylcholinesterase (BChE) is an α-glycoprotein found in the nervous system and liver. Advanced cancer is a condition with mild to moderate inflammation and interacts with various degree of protein-energy malnutrition. In this study, we analyzed the potential preoperative prognostic significance of BChE in patients with cRCC undergoing nephrectomy. Methods: etween 1992 and 2013, we treated 551 patients with renal cell carcinoma. Of these 400 patients with cRCC who underwent radical or partial nephrectomy were enrolled. Serum BChE was routinely measured before operation in all patients. Covariates included age, gender, performance status (PS), preoperative laboratory data, clinical T stage, and distant metastasis status. Univariate analyses were performed using the Kaplan-Meier and log-rank methods. Multivariate analysis was performed using a Cox proportional hazard model. Univariate and multivariate analyses were performed to determine clinical factors that associated with OS. Results: Of these, 302 patients had an organ-confined disease (T1-2N0M0) and 56 patients had a distant metastasis (any T, any N, and M1). The median BChE level was 250U/L (normal range from 168 to 470U/L). The median follow-up period was 34 months. At the time of analysis, 26 patients (6.5%) had alive with recurrent cRCC and 38 patients (9.5%) had died from cRCC. The 3-year OS rate for our entire cohort of 400 patients was 88%. The 3-year OS rates were 89.3% and 77.7% in the BChE ≥100 and <100U/L groups (p= 0.004). In the univariate analysis, PS, anemia, hypoalbuminemia, BChE, corrected calcium, C-reactive protein, and distant metastasis status were significantly associated with OS. Multivariate analysis revealed that BChE and distant metastasis status were significantly associated with OS. Conclusions: These data suggest a possible role of pre-operative BChE as an independent predictor of OS after nephrectomy for cRCC.
DNA hypermethylation biomarkers to predict therapy response of antiangiogenic therapy in metastatic renal cell carcinoma patients.
Authors: Peters Inga , Dubrowinskaja Natalia , Abbas Mahmoud , Seidel Christoph , Kogosov Michael , Scherer Ralph , Gebauer Kai , Merseburger Axel S. , Kuczyk Markus A. , Gruenwald Viktor , Serth Juergen
Published: February 2017

459

Background: Antiangiogenic therapy has demonstrated to increase progression-free (PFS) as well as overall survival (OS) in RCC patients. Clinical scoring systems like the Memorial Sloan Kettering Cancer Center (MSKCC) help to stratify patients for treatment options. However, identification of molecular phenotypes of RCC patients would improve stratification of specific targeted therapies. We investigated whether DNA hypermethylation based markers can predict the PFS following first-line therapy. Methods: We examined primary tumors from formalin-fixed paraffin embedded tissue specimens obtained from 18 patients receiving anti-VEGF based targeted therapy. Quantitative methylation-specific PCRs were carried out following bisulphite conversion of DNA for CpG island methylation analysis of the five candidate genes, CST6, GATA5, LAD1, hsa-miR124-3 and hsa-miR9.1 identified in advance as potential prognosticators for RCC. For Kaplan Meier survival analysis relative methylation values were uniformly dichotomized and logrank statistics calculated. The analyses of sensitivity and specificity were carried out using a cutoff of 6 months for PFS to categorize for therapy failure and response, as described in the literature. Results: Hypermethylation of CST6 and LAD1 shows a highly significant association with a shortened PFS following first-line therapy (p=0.009, p=0.004, logrank test). The median survival observed for the high and low methylation group was 2.0 and 11.4 months for CST6 and LAD1. Moreover, LAD1 methylation showed a specificity of 1.0 (0.65-1.0, 95%CI) and a sensitivity of 0.73 (0.43-0.90, 95%CI) for detection of therapy failure. For CST6 methylation analysis a specificity of 0.86 (0.49-0.97, 95%CI) and a sensitivity of 0.82 (0.52-0.95, 95%CI) was detected. Conclusions: The analysis of our discovery cohort revealed that CGI methylation of CST6 and LAD1 predicts a shortened PFS of patients after anti-VEGF therapy. Provided, these results can be confirmed in an independent larger evaluation cohort, detection of hypermethylated loci in primary RCC would allow, to our knowledge for the first time, a molecular-based clinical management of patients.
Comparison of radical treatment and mortality in patients with nonmetastatic prostate cancer in England and the United States.
Authors: Sachdeva Ashwin , van der Meulen Jan , Cathcart Paul
Published: February 2017

46

Background: Prostate-cancer mortality in the U.S. is amongst the lowest globally. Given historical differences in management between England and the U.S., this paper aims to determine if risk-adjusted prostate-cancer mortality is inferior amongst men in England compared to the U.S. Methods: Patients diagnosed with non-metastatic prostate-cancer between 2004 and 2008 were identified using English hospital admission records linked to national cancer registry data, and the American Surveillance, Epidemiology and End Results program. Complete data were available for 222,163 patients. Patients were stratified into low-, intermediate-, and high-risk groups according to disease characteristics. Patient demographics from the two countries were compared using the Chi-square test. Competing-risks survival analyses were used to estimate relative six-year prostate-cancer mortality. Results: In comparison to patients in the U.S., English patients were more likely to present at an older age (70 to 79: England 44.2%, USA 29.3%, p<0.001), with higher clinical tumour stage (cT3-4: England 25.1%, USA 8.6%, p<0.001) and higher Gleason score (GS 8-10: England 20.7%, USA 11.2%, p<0.001). They were also less likely to receive radical therapy, with greatest disparity amongst patients with high-risk disease (England 30%, U.S. 83%, p<0.001). After adjusting for age, ethnicity, year of diagnosis, Gleason score, and tumour stage, English patients were more likely to die of prostate cancer (all risk groups: HR 1.9, 95% CI 1.7-2.0, p<0.001). However, this difference was no longer statistically significant on adjustment for radical therapy (all risk groups: HR 1.0, 95% CI 1.0-1.1, p=0.336). Conclusions: After risk adjustment, prostate-cancer mortality is significantly higher in England compared to the U.S. for men with intermediate- and high-risk disease. This difference appears to be explained by decreased use of radical therapy in England.