bluuebunny/crossref_metadata_2025 huggingface dataset:
Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and six months of combined androgen blockade.
Authors: Martin N. E. , Chen M. , Nguyen P. L. , Beard C. , Kantoff P. W. , D'Amico A. V.
Published: February 2017

191

Background: An increased duration of testosterone (T) suppression (TS) after 6 months (mo) of combined hormonal blockade (CHB) with an LHRH agonist and an anti-androgen plus external beam radiation therapy (RT) is associated with decreased mortality. We investigated whether the biopsy Gleason score (BGS) was associated with duration of TS.

Methods: The study cohort consisted of 120 men with node negative prostate cancer (PCa) treated with RT and 6 mo of CHB between 1996 and 2005 at a single academic and associated suburban center. We defined the duration of TS as the time between the last day of CHB and the date the T returned to ≥252 ng/dL (10% below the lower limit of normal on the assay used). We used Cox regression multivariable analysis to determine whether BGS was significantly associated with the duration of TS following cessation of CHB adjusting for age, PSA, baseline T, clinical tumor category, body mass index and a history of diabetes mellitus.

Results: The median age of the cohort was 70.1 years (IQR: 64.7, 73.9). The median time to T rebound (MTR) was 19.5 mo for all men (table). BGS 8-10 had an adjusted hazard ratio (AHR) of 1.85 (95% confidence interval [CI] 1.06-3.22; p=0.03) indicating a faster time to T rebound. Specifically men with BGS 8-10 had a MTR of 14.0 mo compared to 19.5 and 22.4 mo for the Gleason ≤6 and 7 respectively. Increasing age was significantly associated with a longer duration of TS [AHR of 0.95 (95% CI 0.92-0.98; p<0.001)].

Conclusions: A BGS of 8-10 is associated with a shorter period of TS following 6 mo of CHB + RT. These data are consistent with the hypothesis that a factor released from high grade PCa cells may impact T production.

[Table: see text]

No significant financial relationships to disclose.
Nomograms based on the Tyrol screening data of 2,271 patients to predict prostate cancer biopsy positivity.
Authors: Sooriakumaran P. , John M. , Bektic J. , Bartsch G. , Herman M. , Scherr D. , Tewari A.
Published: February 2017

203

Background: There are no published nomograms that predict prostate cancer in a screened population. We describe three nomograms that predict for prostate cancer on biopsy derived from a large screening population.

Methods: Patients from the Tyrol screening study of known age, total prostate-specific antigen (tPSA), digital rectal examination (DRE), prostate volume, and percent free PSA (%fPSA), and who underwent an initial prostate biopsy from January 1992 to June 2004, were included (n=2271). Multivariable logistic regression models were used to develop the biopsy positivity predictive nomograms: nomogram 1- age, DRE, tPSA; nomogram 2- age, DRE, tPSA, prostate volume; nomogram 3- age, DRE, tPSA, prostate volume, %fPSA. The predictive accuracy of the models was assessed in terms of discrimination and calibration. External validation of the nomograms was performed by comparison with a urologically referred population of patients who underwent prostate biopsy (n=599).

Results: All three nomograms discriminated well between biopsy positive and biopsy negative patients for both the screening and urologically referred cohorts (nomogram 3 better than nomogram 2 better than nomogram 1). All three nomograms were well calibrated internally, but the nomograms under-predicted the probability of a positive biopsy in the urologically referred cohort.

Conclusions: Our nomogram based on age, total PSA, and DRE has a good predictive ability to differentiate between screened patients that will show cancer on initial prostate biopsy and those that will not. Adding prostate volume and percent free PSA improves this predictive power further. All three nomograms under-predict prostate cancer in a urologically referred cohort. These simple nomograms may be of value in counseling screened men with raised PSA and/or abnormal DRE regarding the need for biopsy.

No significant financial relationships to disclose.
The knowledge and practices of urologists in the United States (US) about standardization of PSA assays.
Authors: Gupta A. , Shariat S. F. , Eastham J. A. , Scardino P. T. , Vickers A. J. , Lilja H.
Published: February 2017

207

Background: PSA assays can be calibrated to either the WHO or the Hybritech standard. Studies of PSA-based prostate cancer screening have used Hybritech-standardized assays and prostate cancer risk calculators are based on these studies. Testing of patient samples with a WHO calibrated assay gives values that are 22% lower than from those with Hybritech-calibrated assays. Up to 60% of the labs in the US use WHO calibrated assays. We evaluated whether US urologists are aware of the different calibrators and the differences in PSA values.

Methods: A random sample of 1,742 US urologists were invited by email to participate in a web-based survey of their knowledge and practices regarding PSA assay standardization. No mention was made of assays or calibration in the invitation. 419 responses were received.

Results: Many (56%) US urologists thought that different standards may lead to clinically relevant differences in PSA values. Although 62% reported awareness of the two PSA calibrators, 67% did not know the difference between the two. Only 17% correctly reported the difference between the two standards. Nationally almost 60% of the labs use WHO standardized assays, but in this survey only 5% of the urologists thought that the hospital where they practice used a WHO standardized assay. The rest reported either not knowing the standard (46%) or use of the Hybritech standard (49%). The majority of urologists did not look at the reference range (64%) or for the PSA standard (74%) in the lab reports. Only 25% reported considering the PSA-calibration in their clinical decisions about prostate biopsy, but only a third of them correctly knew the difference between the calibrators.

Conclusions: Many US urologists are unaware of the difference caused by WHO versus Hybritech based PSA-assay calibration. Although 60% of clinical laboratories use WHO-calibrated assays, only 5% of urologists are aware of this use in their practice, and a majority of urologists could not correctly explain the difference between the different calibrators. A greater awareness is needed amongst US urologists about the different PSA calibrators, the calibrator in use at their practice, and means to account for different calibrators in clinical decision making.

[Table: see text]
The influence of race and treatment choice in 16,508 men treated either conservatively, with radiotherapy, or surgically for clinically localized prostate cancer.
Authors: Sooriakumaran P. , Field T. , John M. , Leung R. , Tewari A.
Published: February 2017

210

Background: There are known variations in cancer survival based on race and treatment choices. We report the long-term survival probability, based on race, in 16,508 men with localized prostate cancer treated either conservatively or by radiotherapy or radical prostatectomy.

Methods: We extracted survival data from tumor registries of six Cancer Research Network sites in the United States. Patients were stratified into four racial groups: Caucasians, African Americans, Hispanics, and Asians. The Cox proportional-hazards regression model was used to compare long-term survival in the three treatment groups. Kaplan-Meier survival curves and competing risk analysis was also performed.

Results: Survival was improved for patients who underwent radical prostatectomy compared to radiotherapy or watchful waiting. This was true for all patients combined (Table) as well as for all races individually. Radiotherapy had at least equivalent survival outcomes as watchful waiting in all groups. The differences between treatments were greater for overall survival than for prostate cancer specific survival in all groups, though the extent of the differences varied by race.

Conclusions: Radical prostatectomy increases survival in men with localized prostate cancer compared to both radiotherapy and watchful waiting, especially for Caucasian men. Radiotherapy was at least equivalent to watchful waiting for all races. Racial disparities in outcome may influence treatment choices for men with clinically localized prostate cancer.

[Table: see text]

[Table: see text]
Physician and patient factors influencing management recommendations in stage I testicular seminoma: A survey among radiation oncologists in the United States.
Authors: Arvold N. D. , Catalano P. J. , Sweeney C. , Hoffman K. E. , Nguyen P. L. , Balboni T. A. , Fossa S. D. , Travis L. B. , Beard C.
Published: February 2017

225

Background: Post-orchiectomy adjuvant radiotherapy (RT) for stage I seminoma is associated with long-term toxicity, and management strategies with a lower treatment burden achieve the same excellent cure rate. Because studies suggest that radiation oncologists in the United States (U.S.) continue to recommend RT for these patients, we sought to identify factors associated with management recommendations.

Methods: We conducted a one-time internet-based survey among 578 randomly selected U.S. radiation oncologists specialized in genitourinary oncology.

Results: Response rate was 45% (n = 261). Forty-nine percent of respondents worked in university-affiliated practices. Sixty-two percent of respondents always/usually recommended adjuvant RT for stage I seminoma patients, whereas 21% always/usually recommended surveillance and 3% always/usually recommended chemotherapy. One-third (33%) expressed concerns that patients who relapsed during surveillance could not be salvaged, and 97% recommended against surveillance if they felt a patient was unreliable for regular follow-up. Although 88% of physicians were aware of a risk of second malignant neoplasms (SMN) after adjuvant RT, 85% underestimated the magnitude of this risk. Only 20% of physicians were aware of a possible association between sub-diaphragmatic RT and an increased risk of cardiovascular disease. Compared to physicians not typically recommending RT, physicians who always/usually recommended RT were more likely to believe that patients may not be salvaged at relapse during surveillance (p = 0.008) and were less aware of the association between RT and SMN (p = 0.04).

Conclusions: Respondents who always/usually recommend post-orchiectomy RT for stage I seminoma patients are more likely to underestimate late RT morbidity and to believe surveillance is associated with increased mortality. Given the equivalent efficacy and reduced morbidity of surveillance compared to RT, our findings underscore the need for ongoing physician education to increase appropriate clinical implementation of surveillance strategies.

No significant financial relationships to disclose.
Antitumor effects of AR-42, a novel histone deacetylase inhibitor, in embryonal carcinoma.
Authors: Bhinder A. S. , Varma V. , Abbaoui B. , Thomas-Ahner J. M. , Kulp S. K. , Chen C. , Clinton S. K. , Mortazavi A.
Published: February 2017

232

Background: Histone deacetylase inhibitors (HDACIs) modulate gene expression and induce cellular differentiation, growth inhibition and apoptotic cell death by chromatin hyperacetylation. Developmental arrest of germ cell differentiation earlier in the life is responsible for the pathogenesis of germ cell tumors (GCT). With current treatment nearly 95% of patients with GCT can be cured. Yet, effective agents with less toxicity are desired. In addition, those with relapsed/refractory disease have a dismal prognosis, indicating a clear need for new, more effective agents. Here we assess the antitumor effects of AR-42, a novel HDACI in in vitro and in vivo models of embryonal carcinoma.

Methods: In vitro effects of AR-42 and suberoylanilide hydroxamic acid (SAHA) were evaluated in NTERA-2, an embryonal carcinoma (EC) cell line derived from a human testicular cancer. Cell viability (MTS assay), apoptosis (caspase 3/7 activity and PARP cleavage), cell cycle analysis (flow cytometry) and HDAC inhibition (immunoblotting) were assessed. The in vivo efficacy of AR-42 was assessed in a NTERA-2 xenograft tumor model in male athymic nude mice. Mice were fed control diet and diet containing AR-42 at an average dose of 25 mg/kg/day. Tumor volumes and weights were used as in vivo endpoints.

Results: Treatment of NTERA-2 cells with both agents at 0.1-10 μM concentrations showed a time- and dose-dependent reduction in cell viability. Both agents significantly induced apoptosis, cell cycle inhibition and hyperacetylation of histones H-3 and H-4 in a dose-dependent manner. In vitro studies showed that AR-42 was more potent than SAHA. In our rodent model, AR-42-containing diet resulted in a significant reduction in tumor volumes and weights (50% and 56%, respectively). The results for intratumoral changes of proliferation and apoptosis are pending. There were no significant toxicities associated with AR-42, except for testicular atrophy, known to be reversible.

Conclusions: AR-42 appears to be a potent inhibitor of EC through different mechanisms, orally bioavailable and well tolerated in our rodent model. Our data indicates that AR- 42 may have clinical value in the treatment of GCT and requires further investigation in clinical trials.

No significant financial relationships to disclose.
Use of metabolomic profiling to identify potential markers and mechanism for bladder cancer progression.
Authors: Putluri N. , Vasu V. T. , Shojaie A. , Thangjam G. S. , Vareed S. , Tallman C. T. , Putluri V. , Butler C. , Giri J. G. , Sana T. R.
Published: February 2017

250

Background: Bladder cancer (BCa) is the second most prevalent urological malignancy and the fourth highest cause of cancer-related death in the United States that is known to be caused by defects in xenobiotic metabolism, which is not well understood. Using unbiased mass spectrometry we report the metabolomic profiles in BCa tissues and demonstrate its biomarker potential as well reveal a possible mechanism regulating altered xenobiotic metabolism in these tumors.

Methods: Total metabolome from clinically annotated bladder-derived tissues were examined using mass spectrometry coupled to reverse and aqueous normal phase separation of compounds. Class- specific metabolites were examined in urine specimens for their biomarker potential as well as analyzed using Oncomine Concept Map for alterations in bioprocesses. The latter was validated using a collection of molecular techniques like Q-PCR, immunoblot analysis, methylation assays and use of methyl transferase inhibitor, on bladder-derived cell lines and patients specimens.

Results: A total of 2,019 compounds were detected across the 58 bladder-derived specimens, of which 50 named compounds were differential between BCa and its adjacent benign tissue. These included aromatic compounds like aniline, catechols as well as polyamines and S-adenosyl methionine (SAM). A subset of these compounds, were detected in urine and could distinguish BCa from benign, non-muscle-invasive from muscle invasive tumors and delineate patients responding to chemotherapy and TURBT. Bioprocess mapping of BCa-specific metabolome revealed co-enriched concepts describing methylation and cytochrome P450 (CYP) driven xenobiotic metabolism in bladder tumors. The role of methylation in regulation of CYP activity in BCa was confirmed using a combination of Aza-treatment, methylation-specific PCR and bisulphite sequencing on bladder-derived cell lines and tissues.

Conclusions: Unbiased metabolomic profiling reveals potential non-invasive metabolic markers for early detection, prognosis and therapeutic response of BCa as well as describes a role for methylation induced silencing of CYP1A1 and 1B1resulting in deficient xenobiotic metabolism in BCa.

No significant financial relationships to disclose.
MC0553: A phase II safety and efficacy study with the VEGF receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer.
Authors: Pili R. , Qin R. , Flynn P. J. , Picus J. , Millward M. , Ho W. M. , Pitot H. C. , Tan W. , Erlichman C. , Vaishampayan U. N.
Published: February 2017

259

Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma.

Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle.

Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending.

Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies.

[Table: see text]
A phase 0 microdosing trial to identify chemoresistance in bladder cancer.
Authors: Pan C. , Wang S. , He M. , de Vere White R. , Lara P. , Gandara D. R. , Mack P. C. , Turteltaub K. , Henderson P. T.
Published: February 2017

264

Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS can detect carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin.

Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy.

Results: AMS detected Pt-DNA damage when cancer cells and mice with tumor xenografts were exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage were linearly proportional to the DNA damage caused by the therapeutic drug dose (R2=0.92, p<0.001); and these levels of DNA damage correlated with chemoresistance. Low DNA damage predicts chemoresistance. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some resistance mechanisms. We have opened a phase 0 microdosing trial to study patients with bladder cancer who are scheduled to receive Pt-based chemotherapy. One subtoxic microdose of 14C-carboplatin will be administered to these patients before biopsy. Pt-induced DNA damage and repair in left-over tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Molecular analysis of genes such as ERCC1 and RRM1 will be analyzed and compared with this phase 0 results. We have opened a similar phase 0 trial in dog patients with bladder cancer.

Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The clinical data of the phase 0 trial will be presented.

No significant financial relationships to disclose.
Exclusive chemoradiotherapy without TURBT for frail and elderly patients with an invasive bladder cancer: Which platin fits better?
Authors: Khoury C. , Martin E. , Gauthier M. , Crehange G. , Ladoire S. , Cormier L. , Bonnetain F. , Miny J. , Bosset J. , Maingon P.
Published: February 2017

279

Background: Frail and elderly patients (pts) with invasive bladder carcinoma (BC) are often unfit for surgery. Whether exclusive concomitant chemoradiotherapy (cCRT) without TURBT could be performed in a curative-intent remains uncertain.

Methods: From 1996 to 2007, 68 pts were treated with exclusive cCRT. Median age was 77.5 years (70-91). WHO performance status (PS) at baseline were: PS 0: 27 pts; PS 1: 36 pts; PS 2; 4 pts; PS 3: 1 pt. 31 pts (45.5%) had a Charlson's score ≥ 5. Tumors were staged T1 (5 pts), T2 (44 pts), T3 (13 pts) and T4 (6 pts). 87.5% of the pts were clinically staged N0. Transuretral resection bladder tumor (TURBT) was incomplete and thus done for a diagnostic purpose only. 58 pts had an urothelial tumor (85.29%). External radiotherapy (ERT) was delivered with 1.8-2.0 daily fractions: median total dose of 63Gy [18Gy-69.4Gy] to the bladder and 92% of the pts had a whole pelvic ERT: median dose: 37.2Gy [18Gy-46Gy]. Drug was either cisplatin (CDDP) for 40 pts or carboplatin (CBDCA) for 28 pts. Overall survival (OS) and progression-free survival (PFS) rates were evaluated.

Results: The rate of compliant pts with the full course of cCRT was 77.9% (53 pts). 5 pts stopped cCRT for acute urinary adverse events (AE) whereas 8 pts stopped chemotherapy only for hematological or renal biochemical AE. For late toxicity, 5 pts had a G3/4 toxicity (1 rectal bleeding, 1 urinary bleeding, 1 recto-urinary fistula, 1 urinary incontinence and 1 urinary retention). Median follow-up was 4.6 years [CI95%: 3.43-5.93]. Of the 68 pts, 14 are alive (13 recurrence-free) amongst the 61 evaluable pts and 47 have died (24 recurrence-free). OS rates at 2 and 5 years were 50% (CI95%: [37.45%-61.44%]) and 31% (CI95%: [13.67%-38.43%]). PFS rates at 2 and 5 years were 37.4% [CI95%: 25.89%-48.82%] and 22% [CI95%: 12.25%- 33.61%], respectively. OS and PFS rates were worse for pts treated with CBDCA in comparison with those treated with CDDP (p= 0.01 for OS and p= 0.03 for PFS). Combined 5-FU did not impact either OS or PFS.

Conclusions: cCRT for elderly pts with a BC was feasible. For selected pts with a good PS, the adequate drug that should be combined with a conventional full course of ERT remains CDDP.

No significant financial relationships to disclose.
Efficacy of immediate post-TUR mitomycin-C (MMC) instillation in high-risk non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG).
Authors: Park J. , Song K. , Jo M.
Published: February 2017

281

Background: To evaluate the efficacy of immediate post-TUR MMC instillation in high risk non-muscle-invasive bladder cancer treated with BCG.

Methods: From January 2000 to December 2007, 162 high-risk non-muscle-invasive bladder cancer patients underwent TUR and BCG instillation at our institution. Among them 76 patients received additional immediate post-TUR MMC instillation (Group A), and remaining 86 patients underwent TUR and BCG instillation only (Group B). 60mg of MMC was mixed with 50ml of normal saline and was instilled in bladder within 2 hours after TUR. Tice strain BCG 12.5mg was used with 6-week induction course followed by 3-week maintenance every 3 months. The recurrence rate, time to recurrence, and stage and grade at recurrence were investigated. The mean follow-up was 33.4 months.

Results: There were no significant differences in the characteristics of both groups, including age, sex, stage, and grade. Group A showed significantly lower recurrence rate than Group B (26.3% vs 48.8%, p=0.003). Group A showed somewhat longer time to recurrence but it was not statistically different (24.9 months vs 21.8 months, p=0.293). The change in stage and grade at recurrence were not different between 2 groups ( Table ). The 5-year recurrence free survival rate was significantly higher in Group A (72% vs 42%, p=0.003).

Conclusions: The immediate post-TUR MMC instillation significantly reduced recurrence in high risk non-muscle-invasive bladder cancer patients treated by BCG. But it did not influenced the stage and grade at recurrence.

[Table: see text]

No significant financial relationships to disclose.
Utility of quantitative fluorescent in situ hybridization (FISH) to predict non-muscle-invasive bladder cancer (NMIBC) recurrence.
Authors: Rosevear H. M. , Lightfoot A. J. , O'Donnell M. A.
Published: February 2017

286

Background: Urovysion's (Abbot Laboratories, Downers Grove, IL) FISH analysis is used to monitor bladder cancer recurrence in patients with a history of NMIBC and is often reported as a binary variable (normal/abnormal). We investigated whether the percentage of abnormal cells as determined by FISH analysis in patients with a history of NMIBC correlated with risk of recurrence.

Methods: At our institution, barbotage FISH analysis is routinely done along with cystoscopy and cytology on both high risk (Ta/T1 high grade or CIS) and low or intermediate risk patients (all others) at every 3-month follow-up for the first year post-resection. We retrospectively reviewed 241 consecutive NMIBC patients and identified 399 FISH analyses for which we had one year follow-up. Normal FISH analyses were defined as 2 or fewer abnormal cells per sample. We calculated the percentage of abnormal cells and correlated that to the number of patients who had a recurrence of NMIBC as defined by positive high grade cytology or tumor on cystoscopy during the first year of follow-up.

Results: The sensitivity, specificity, and positive and negative predictive values of FISH analysis if reported as a binary variable was 55, 43, 16 and 89%, respectively. Considering only those patients with abnormal FISH, the average percentage of abnormal cells for patients who were found to have NMIBC recurrence at 1 year was 38% (range 6–100) compared to 21% (range 6–100) for patients who were recurrence-free at 1 year (p<0.0001). High risk patients who recurred within 1 year had a statistically higher percentage of abnormal cells as compared to those who did not recur within 1 year (50% [range 6–100] vs. 25% [range 6– 100], respectively p=0.001). There was no difference in the percentage of abnormal cells for those patients with low or intermediate risk disease based on recurrence within 1 year (22% [range 6–100] vs. 20% [range 6–100], respectively p=0.25).

Conclusions: The percentage of abnormal cells in FISH analysis correlates with risk of recurrence for patients with high risk disease and can be used to guide surveillance interval decisions in patients with no other evidence of recurrence.

[Table: see text]
Could a salvage surgery after chemotherapy have clinical impact on cancer survival in patients with metastatic urothelial carcinoma?
Authors: Bekku K. , Saika T. , Kobayashi Y. , Kishimoto R. , Edamura K. , Abarzua F. , Nasu Y. , Kumon H.
Published: February 2017

287

Background: A clinical impact of salvage surgery after chemotherapy in patients with metastatic urothelial carcinoma on cancer survival is controversial. We verified a clinical role of salvage surgery with analyzing long-term outcome after salvage surgery in patients with metastatic urothelial carcinoma treated with cisplatin/gemcitabine/paclitaxel-based chemotherapy at a single institution.

Methods: From 2003 to 2010, 31 of 47 patients (66%) with metastatic urothelial carcinoma showed objective responses (CR in 4, PR in 27) after multiple courses of the chemotherapy. Twelve of 27 patients with PR underwent salvage surgeries after the chemotherapy (10 male and 2 female, median 61.0 years old). All of the patients underwent metastatectomy of residual lesions (10 of retroperitoneal lymphnodes, 2 of lung). Seven of the patients underwent radical surgeries for primary lesions as well. Progression-free survival and overall survival of the patients were analyzed retrospectively in comparison with those of patients without salvage surgery.

Results: All 12 patients could achieve surgical CR. Pathologic findings showed pathological CR in 2 patients. In median follow-up 32.5 months (range: 4.5-65.4), progression-free survival and overall survival in patients with salvage surgery were better than those in 16 PR patients without the surgery (72.9% vs 0%, and 91.7% vs 10.6% at 2 years, p=0.0005 and 0.0003; log-rank test).

Conclusions: Although there were several biases in patients backgrounds (e.g., metastatic lesion, number, age), salvage surgery in patients with residual tumor after GCP chemotherapy could have strong impact on cancer survival. Surgical CR should be achieved in an affordable patient who is responder of GCP therapy.

No significant financial relationships to disclose.
Robotic radical cystectomy: Medium-term oncologic follow-up.
Authors: Mmeje C. , Nunez-Nateras R. , Pruthi R. , Nielsen M. E. , Wallen E. , Humphreys M. , Castle E. P.
Published: February 2017

288

Background: We report our experience with robot assisted radical cystectomy (RARC) with regard to medium-term (at least 2 year) oncologic outcomes.

Methods: A total of 275 patients have undergone RARC and urinary diversion at two institutions for invasive bladder cancer between 2005-present. We performed a retrospective analysis of the 139 patients who underwent RARC with a minimum of 2 years follow-up. Medium term oncologic outcomes including recurrence rates, time to recurrence, recurrence free survival (RFS), disease specific survival (DSS) were analyzed. Follow-up was measured from time of surgery to time of most recent clinical follow-up.

Results: This cohort of patients consisted of 108 men (78%) and 31 women (22%) at a mean age of 67.3 years (range 45-86 years). Sixty-one (44%) patients had ≤ pT2 disease, 38 (27%) pT3/T4 disease, and 40 (29%) N+ disease. The mean number of lymph nodes removed was 18 (range 3-41). The average clinical follow up in this case series was nearly 3 years with a mean of 35.9 months (range 24-64 months). At this follow-up, 39 patients have recurred, 27 patients died of disease, and 5 patients died of other causes giving an overall RFS, DSS, and OS rates of 80%, 71%, and 68%, respectively. The mean (median) time to recurrence was 12.3 months (10 months). These findings are consistent with prior reports of the oncologic outcomes for open radical cystectomy.

Conclusions: The oncologic follow-up of patients undergoing RARC appears to be favorable with acceptable outcomes in the medium-term (mean – 3 years). As our follow-up increases, we should expect to truly define the long-term clinical appropriateness and oncologic success of this procedure.

No significant financial relationships to disclose.
Utilization of neoadjuvant chemotherapy in stages II and III urothelial carcinoma of the bladder.
Authors: Huang B. , Tucker T. , Bylund J. R. , Rinehart J. J. , Rowland R. G. , Strup S. E. , Crispen P. L.
Published: February 2017

292

Background: Level 1 evidence supports the use of neoadjuvant chemotherapy (NC) prior to cystectomy in patients with stage II and III urothelial carcinoma of the bladder. However, the utilization of NC in appropriate patients prior to cystectomy is unknown. Here we examine the use of and potential predictors for the use of NC prior to cystectomy.

Methods: The Kentucky Cancer Registry was reviewed from the years 2000 to 2007 for patients undergoing cystectomy for stage II and III (T2-4aN0M0) bladder cancer. Histologic subtypes of bladder cancer other than urothelial carcinoma were excluded. Multiple logistic regression was utilized to examine factors associated with the use of neoadjuvant chemotherapy prior to cystectomy.

Results: A total of 223 patients undergoing cystectomy during the study period were identified. Median age was 66 years and 74% of patients were male. The majority of patients, 66%, had AJCC stage II disease. 6.3% (14/223) of patients received NC prior to cystectomy. Bivariate analysis did not reveal significant differences in age, gender, stage, geographic location, or insurance status when comparing patients receiving and not receiving NC prior to cystectomy. Year of treatment was significantly associated with the use of NC with 2.8% and 9.6% of patients receiving NC between the years 2000–2003 and 2004–2007, respectively (p = 0.034). Year of diagnosis remained significantly associated with the use of NC on multiple logistic regression (OR 4.23, CI 1.12–15.9).

Conclusions: Although a significant increase in the number of patients receiving NC prior to cystectomy has been observed since 2003, the overall utilization of NC remains low despite the proven survival benefit noted in randomized trials. Further investigation of the low utilization of NC in this population is warranted.

No significant financial relationships to disclose.
Cessation of VEGF-targeted therapy in patients with metastatic renal cell carcinoma (mRCC): Feasibility and clinical outcome.
Authors: Sadeghi S. , Albiges L. , Wood L. S. , Black S. L. , Gilligan T. D. , Dreicer R. , Garcia J. A. , Escudier B. J. , Rini B. I.
Published: February 2017

307

Background: Standard practice in the treatment (tx) of mRCC with VEGF targeted agents is continuous tx until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for a subset of pts. It is hypothesized that a subset of pts with an initial response to tx can maintain disease control off all tx for a period of time.

Methods: A retrospective study of mRCC pts who initiated VEGF-targeted tx between January 2004 and November 2009 was conducted. Pts had achieved disease control on tx, then were taken off all tx. Pt, disease and tx characteristics were recorded. Progression free survival (PFS) was measured as the time from discontinuation of tx to RECIST PD.

Results: A total of 30 pts were identified. All pts had prior nephrectomy and had clear cell histology, and 9 patients had prior immunotherapy. At the time tx was stopped 16 pts were receiving sunitinib, 7 pts were receiving sorafenib (2 in combination with AMG 386), and 7 pts were receiving bevacizumab (6 in combination with temsirolimus, 1 with IFN-alpha). Six pts had achieved CR, 19 PR and 5 SD by RECIST. Using Heng's prognostic risk group criteria, 14 pts had favorable, 14 had intermediate, and 2 had poor risk disease prior to initiation of VEGF-targeted tx. Therapy was held for severe adverse events (5pts; 2 MIs, 3 CVAs), toxicity (16 pts; 4 diarrhea, 3 skin, 3 proteinuria, 2 cardiac, 1 fatigue, 1 stomatitis, 1 pneumonitis, 1 nausea), cost (1 pt; high co-pay), pt choice (6 pts) and interventions (2 pts; 1 angioplasty and 1 kidney stone). Median follow up is 29 months (range 11– 82). Median duration of tx prior to discontinuation was 14.6 months (range 3–79). Thirteen pts (43%) had PD off tx (lymph nodes (6), lungs (8; 3 with new lesions), bones (1), brain (2; 1 with new lesions)) with a median PFS of 10 months (range 3–27). After PD, 4 pts were offered sunitinib, 1 pazopanib, 1 everolimus, 1 local RF tx, and 6 continued expectant management. After a median follow-up to date of 7.5 months (2–28), 17 pts (57%) still did not have RECIST PD.

Conclusions: Select mRCC pts with disease control on VEGF-targeted tx can be safely observed off all tx. Further prospective investigation is needed to define the risks and benefits of this approach.

[Table: see text]
The effect of low serum sodium on treatment outcome to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma: Results from a large international collaboration.
Authors: Schutz F. A. , Xie W. , Heng D. Y. , Donskov F. , Wood L. , Vaishampayan U. N. , Tan M. , MacKenzie M. J. , Kollmannsberger C. K. , Choueiri T. K.
Published: February 2017

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Background: Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients (pts) treated with immunotherapy (Jeppesen et al, Br J Cancer. 2010). We sought to investigate the influence of baseline hyponatremia in mRCC pts treated with contemporary vascular endothelial growth factor (VEGF)- targeted therapy in a larger international and multi-institutional database.

Methods: Baseline characteristics and outcomes on 855 pts treated with first-line anti-VEGF therapy for mRCC were available from 8 Cancer Centers to study the impact of hyponatremia (defined as serum Na<135 mmol/L) on clinical outcome as measured by overall survival (OS), time to treatment failure (TTF), best response (CR, PR, SD and PD).

Results: Median OS after treatment initiation was 16.8 months (mos) (95% CI: 14.9, 18.5 mos), with 334 (39%) of patients remaining alive. Median follow-up in pts alive was 18.8 mos. Median baseline serum sodium was 138 mmol/L (range: 122–159), and hyponatremia was found in 16.7% of pts. On univariate analysis, hyponatremia was associated with shorter OS (6.5 vs. 18.8 mos; HR 2.32 [95% CI: 1.86–2.89], p<0.0001), shorter TTF (2.8 vs. 6.9 mos.; HR 2.20 [95% CI: 1.81–2.68], p<0.0001), and lower disease control rate (DCR) as defined by CR+PR+SD (51.2% vs. 74.6%, OR 0.36 [95% CI: 0.2–0.57], p<0.0001). In multivariate analysis adjusted for MSKCC or Heng's risk criteria (JCO 2009), these effects remain significant with p<0.001 for OS and TTF and p=0.01 for DCR. The results were similar (p<0.001) if sodium was analyzed as a continuous variable.

Conclusions: This is the first large multi-institutional report to show that low serum sodium is independently associated with a worse outcome in mRCC pts treated with VEGF-targeted agents.

No significant financial relationships to disclose.
Activity of tivozanib (AV-951) in patients (Pts) with different histologic subtypes of renal cell carcinoma (RCC).
Authors: Bhargava P. , Esteves B. , Al-Adhami M. , Nosov D. , Lipatov O. N. , Lyulko A. A. , Anischenko A. A. , Chacko R. T. , Doval D. , Slichenmyer W.
Published: February 2017

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Background: This phase 2 randomized discontinuation trial evaluated tivozanib, a potent and selective vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 kinase inhibitor. Median progression-free survival (PFS) in all pts was 11.8 mo, and the objective response rate (ORR) was 27%.

Methods: Pts received 1.5 mg/d tivozanib (3 wk on, 1 wk off = 1 cycle). A retrospective analysis evaluated efficacy and safety by histologic subtype. Response was evaluated by independent radiology review using standard RECIST criteria.

Results: 272 pts were enrolled: 70% were male; median age was 56 y (range, 26–79). 226 (83%) pts had clear cell (CC) RCC; 46 had non–clear cell (NCC) RCC, including 11 with papillary RCC. Of pts with CC RCC, 176 (78%) had undergone nephrectomy; of pts with NCC RCC, 23 (50%) had undergone nephrectomy. Median treatment duration was 8.5 mo (range, 0.03– 23.8) as of the data cutoff. Median PFS was 12.5 mo (range, 9.9–17.7) for pts with CC RCC, not yet reached for pts with papillary RCC, and 5.4 mo (range, 3.7–12.0) for pts with other NCC subtypes. ORR and disease control rate (DCR; ORR + stable disease), respectively, were 29% and 85% for pts with CC RCC, 18% and 100% for pts with papillary RCC, and 17% and 74% for pts with other NCC subtypes. For pts with CC RCC, median PFS, ORR, and DCR, respectively, were 14.8 mo, 32%, and 88% for those who had undergone nephrectomy and 8.9 mo, 18%, and 76% for those who had not. Among pts with NCC RCC, median PFS was 6.6 mo for pts who had undergone nephrectomy and 7.2 mo for pts without nephrectomy; ORR was 17% for both NCC subgroups, with a DCR of 78% for pts who had undergone nephrectomy and 83% for pts who had not. Common drug- related adverse events (AEs) for pts with CC and NCC RCC, respectively, included hypertension (49% and 48%), dysphonia (22% and 22%), asthenia (12% and 13%), and diarrhea (13% and 9%). The most common grade ≥3 drug-related AE was hypertension (CC, 8%; NCC, 4%).

Conclusions: Disease control was observed for pts with all RCC histologic subtypes. The rate of AEs was similar among patients with CC and NCC RCC and consistent with that of a selective VEGFR inhibitor with minimal off-target toxicities. Tivozanib is currently being tested in a phase 3 trial in pts with CC RCC.

[Table: see text]
Fatigue, quality of life, and cognitive functions in metastatic kidney cancer patients with antiangiogenic treatment.
Authors: Noal S. , Lange M. , Escudier B. J. , Sevin E. , Dauchy S. , Clarisse B. , Daireaux A. , Leger I. , Rieux C. , Joly F.
Published: February 2017

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Background: Fatigue is commonly reported by patients under anti-angiogenic therapies, with sometimes cognitive complains. However, few studies have explored these problems. A longitudinal multicentric prospective study is ongoing in France on fatigue, cognitive functions, quality of life (QoL), anxiety and depression among metastatic kidney cancer patients receiving anti-angiogenic therapies. Objectives: The main objective is to assess fatigue. Secondary objectives are to assess cognitive functions, QoL, anxiety, and depression.

Methods: Assessments are made at baseline, at 3 and 6 months. Evaluations were made by: autoquestionnaire MFI-20 to assess fatigue, FACT-G and FKSI to assess QoL, Spielberger's and Beck's questionnaires to assess respectively anxiety and depression. Cognitive functions were assessed by a neuropsychologist with the Working Memory Index (WAIS-III), Grober and Buschke test, Rey Complexe Figure test, verbal fluency and Trail Making test, exploring respectively working memory, episodic memory and executive functions. Preliminary results are presented.

Results: 35 patients were enrolled, and 20 of them had the second assessment at 3 months. Most of patients received sunitinib (51%), others received bevacizumab and interferon, or sorafenib. At baseline, 45% of patients expressed general fatigue and 50% at 3 months (p=0.04). Other domains of fatigue (physical, mental, reduced activity and motivation) did not change over time. At baseline, few patients had cognitive disorders (working memory 6%; executive functions 0%; episodic memory 11%), with no decline at 3 months. However, there was an impairment of QoL in FKSI score (p=0.01) and of FACT-G physical well-being (p=0.01). No differences were found in social, emotional or functional well-being. There was no difference on depression nor on anxiety over time.

Conclusions: Fatigue significantly increased during the first 3 months of anti-angiogenic treatment, with no impact on cognitive functions but a decline of QoL. These preliminary findings need to be confirmed by further follow-up and more patients. Final results will be provided with 120 patients.

No significant financial relationships to disclose.
Everolimus-associated pneumonitis (EAP) in metastatic renal cell cancer patients (mRCC): A single-center experience.
Authors: Cauley D. H. , Atkinson B. J. , Corn P. G. , Jonasch E. , Tannir N. M.
Published: February 2017

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Background: Pneumonitis is a known adverse effect (AE) of mammalian target of rapamycin-inhibitors, with a literature reported incidence for everolimus ranging from 4 to 45%. The goal of this review was to characterize the incidence, timing, management, and outcomes related to everolimus-associated pneumonitis (EAP).

Methods: Retrospective review of 86 mRCC patients (pts) with complete, evaluable records, given everolimus (E) between 4/2009 and 3/2010. We assessed baseline patient (pt) characteristics, previous therapies, time on E therapy, pt symptoms, physician management of AE, NCI-CTC pneumonitis grading, and survival outcomes. Radiologic CT indicated ground glass, inflammatory, and/or parenchymal opacities.

Results: (See table.) EAP occurred in 28% of pts on E therapy, confirmed radiologically. 8% of EAP patients reported no symptoms. In EAP pts, 58% reported cough, 75% dyspnea and/or SOB, 17% fever, 71% fatigue. The median number of symptoms/patient was 3. 46% of pts received steroids (median 21 days (3-120)), 38% received antibiotics, 25% received pulmonary consultation, and 8% required oxygen. In pts who developed EAP, providers discontinued E in 75%, held and dose reduced E in 8%, and continued E in 17%. The median NCI-CTC pneumonitis grade was 2 (1-3); there were no treatment-related deaths. The median time to EAP onset was 67 days (8-442). There was no statistically significant difference in outcomes between EAP pts and non-EAP pts.

Conclusions: EAP occurs often in mRCC pts treated with E. It is an important AE that can negatively affect pt symptoms, but did not adversely impact pt outcomes in our single-center experience.

[Table: see text]

[Table: see text]
Use of CDK1 and CDK2 activity to predict renal cell cancer recurrence.
Authors: Hongo F. , Takaha N. , Kimura Y. , Nakamura T. , Mikami K. , Nakayama S. , Matsushima T. , Ishihara H. , Sakai T. , Miki T.
Published: February 2017

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Background: We established original methods enabling simultaneous analysis of protein expressions and kinase activities of the CDK (cyclin-dependent kinase) molecules in lysate of tumor tissue in a clinical setting (C2P technology, Ishihara et al: Biochim Biophys Acta. 1741; 226-233, 2005). The clinical utility of the technology was first evaluated in breast cancer, and combination analysis of CDK1 and CDK2 activity was shown to be a significant prognostic indicator for relapse (Kim et al. Ann Oncol. 19;68-72,2009). The objective of our study is to evaluate the efficacy of CDK1 and CDK2 activity as a prognostic marker in human renal cell carcinoma (RCC).

Methods: Surgical specimens were obtained from 115 patients with RCC without metastasis. These patients were selected randomly for this study. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system. The system to measure the CDK specific activity (SA) is named C2Ps (Sysmex, Kobe, Japan). We then examined the specific activities of CDK1 and CDK2 and calculated CDK2/CDK1 ratio in RCC. Also, risk score (RS) was examined as described in previous study (JGH van Nes et al: Br J Cancer. 100; 494-500, 2009). Cut off value was calculated by ROC analysis.

Results: 115 cases were tested, though 32 cases were excluded of low sample quality (30 cases) and of assay failure (2 cases). 83 cases were analyzed. They included 63 male and 20 female patients, ranging in age from 19 to 83 years. At a median follow up of 33 months (1-109M), tumor with low CDK2/CDK1 ratio showed significantly better 5-year progression-free survival (PFS) than those with high CDK2/CDK1 ratio (91.2% vs. 51.6%, p=0.0016). Also, RS enabled the classification of RCCs into high-risk and low-risk groups, patients with tumors classified as low RS showed better PFS than patients with tumors with high RS (88.9% vs. 63.9%, p=0.0488).

Conclusions: CDK1 specific activity of tumors and the CDK2 specific activity are both associated with recurrence and prognosis. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting cancer recurrence and prognosis in RCC after surgery and has potential for use as a routine laboratory test.

No significant financial relationships to disclose.