bluuebunny/crossref_metadata_2025 huggingface dataset:
Denosumab for prevention of fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer (PC)
Authors: Saad F. , Smith M. R. , Egerdie B. , Tammela T. L. , Feldman R. A. , Heracek J. , Szwedowski M. , Ke C. , Leder B. , Goessl C.
Published: August 2020

5056

Background: ADT increases bone resorption, reduces bone mineral density (BMD), and increases fracture risk. Previously, we reported that denosumab, a fully human monoclonal antibody against RANKL, increased BMD and reduced the incidence of vertebral fractures in men with PC on ADT. We now describe in further detail the effects of denosumab on fractures at other skeletal sites. Methods: Men receiving ADT for nonmetastatic PC were randomized to receive subcutaneous denosumab 60 mg every 6 months (n = 734) or placebo (n = 734), with daily calcium and vitamin D supplements for 3 years. Men < 70 years old were required to have low BMD or a history of osteoporotic fracture. The primary endpoint was percentage change in lumbar spine BMD at 24 months. Key secondary endpoints were subject incidence of new vertebral fractures and fractures at any site (excluding fractures from severe trauma or pathologic fractures) over 3 years. Here, we evaluate the frequency of all fractures and fractures at key osteoporotic sites. The planned sample size (N = 1226) provided power to differentiate effects of denosumab from placebo for the primary and key secondary endpoints. Results: As previously reported, denosumab reduced the incidence of new vertebral fractures by 62% (p = 0.006), fractures at any site by 28% (p = 0.10), and multiple fractures at any site by 72% (p = 0.006) over 3 years. In a post-hoc analysis, we found a consistent trend showing a positive effect of denosumab on nonvertebral fractures. The occurrence of any fractures (counting all fractures within a subject) over 3 years was lower with denosumab than placebo (43 vs 77, p < 0.01). The subject incidence of fractures at 6 high-risk sites (wrist, humerus, hip, pelvis, leg [excluding patella], and clavicle) was numerically lower with denosumab (15 vs 24 placebo; p = 0.12). Also, fewer subjects in the denosumab arm than in the placebo arm reported fractures at key osteoporotic sites (e.g., 2 for denosumab vs 10 for placebo at the radius). Overall rates of adverse events were balanced between treatment arms. Conclusions: Denosumab significantly reduced the incidence of new vertebral fractures and in a post-hoc analysis, showed a trend toward a positive effect on nonvertebral fractures in men receiving ADT for nonmetastatic PC.

[Table: see text]
Phase I/II study of docetaxel and 153Sm for castrate metastatic prostate cancer (CMPC): Summary of dose-escalation cohorts and first report on the expansion cohort
Authors: Morris M. J. , Pandit-Taskar N. , Stephenson R. D. , Hong C. , Slovin S. F. , Rathkopf D. , Solit D. , Carrasquillo J. , Larson S. , Scher H. I.
Published: August 2020

5057

Background: We previously reported (ASCO 2008) that full doses of docetaxel (Tax) and Sm can be repetitively delivered safely using a schedule of q 3 week (wk) Tax and q 6–9 wk Sm. Here we summarize the dose-escalation cohorts and safety/efficacy data from the expansion cohort of 24 pts. Methods: Cohorts of 3–6 pts with CPMC were defined by: 65, 70, 75, 75, 75 mg/m2 of Tax and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle was 6 wks. The expansion cohort used 75 mg/m2 Tax (q 3 wk) and 1 mCi/kg Sm (q 9 wk). Pts with an ANC of grade 0–1 and platelet count of > 100,000/mm3 at the end of cycle 1 received additional cycles until progression or toxicity. Results: 52 pts have been treated. 28 pts were taxane naïve, 11 received previous taxanes but were not refractory, and 13 were taxane refractory. As anticipated, side effects were primarily hematologic. However, the leading cause for treatment termination was disease progression, involving 16/52 (31%) pts, rather than toxicity. 12/52 (23%) pts came off for thrombocytopenia, and 2/52 (4%) pts experienced neutropenic fever. Cohort 3 tolerated the highest cumulative dose and total number of doses of docetaxel (mean of 8 doses, range 4–12; mean total dose 600 mg/m2, range 300–900 mg/m2). Cohort 5 tolerated the highest exposure to Sm (mean of 3 doses, range 1–5). 50 pts are evaluable for response; 22 (44%) achieved a ≥ 50% decline in PSA. 50% of the taxane naïve patients achieved a significant PSA decline, as did 55% of the taxane exposed, and 23% of the taxane refractory pts. Mean time to progression in the taxane naïve, treated, and refractory groups were: 7.5 (range 1.4–22.6), 5.8 (range 0.7–13.7), and 4.3 (range 0.7–11.2) months. Conclusions: This regimen is safe and appears to be active both in taxane naïve and taxane refractory patients, as reflected by favorable toxicity profiles, and rates of significant PSA declines and times to progression. The optimal phase II dose may differ by the population treated. For studies involving taxane naïve patients, the regimen of cohort 3 maximizes docetaxel exposure; for studies of taxane refractory patients, cohort 5 maximizes Sm exposure. Support: EUSA, NIH CA102544.

[Table: see text]
A phase II study of neoadjuvant chemotherapy with docetaxel and bevacizumab in patients (pts) with high-risk localized prostate cancer: A Prostate Cancer Clinical Trials Consortium trial
Authors: Oh W. K. , Febbo P. G. , Richie J. P. , Fennessy F. M. , Scibelli G. , Hayes J. H. , Choueiri T. K. , Tempany C. M. , Taplin M. E. , Ross R. W.
Published: August 2020

5060

Background: Treatment options for high-risk localized prostate cancer remain inadequate, with the majority of pts relapsing despite surgery or radiation therapy. We conducted a phase II multicenter trial of neoadjuvant docetaxel and bevacizumab prior to radical prostatectomy in pts with high risk localized prostate cancer. Methods: Eligibility included any of the following: PSA > 20 ng/ml or PSA velocity > 2 ng/ml/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. Also, >50% biopsy cores involved and either Gleason 7 or PSA >10 or cT2 disease were eligible. Pts were treated with docetaxel 70 mg/m2 q 3weeks x 6 cycles and bevacizumab 15 mg/m2 q 3 weeks x 5 cycles. The primary endpoint was erMRI partial response (PR, defined here as >50% decrease in tumor volume) in a single target lesion after chemotherapy. Results: 42 pts were registered and treated with 220 cycles so far. Median age was 55 yrs (range 41–67). Median Gleason score was 8 (69% with Gleason 8–10 cancer). Median PSA was 10.5 ng/ml (range 2.1–72.5). Clinical stage was T2 in 46% and T3 in 32%. Of 23 evaluable pts to date, the median decline in the maximal tumor volume by erMRI was -45% (range -84% to 110%). 9/23 (39%) patients had PR, and only 1 pt had radiographic progression. Any PSA decline was noted in 22/34 (65%) evaluable pts, with 18% having a >50% decline. Treatment was well-tolerated: 2 pts had grade 3 allergic reactions requiring discontinuation, 3 had febrile neutropenia and 1 had grade 3 hyperglycemia. Mild fatigue was common. Only 1 pt stopped treatment because of a rising PSA. To date, 31 pts have had radical prostatectomy. One had intraoperative bladder neck injury and was treated instead with radiation + hormone therapy. A second pt had an intraoperative rectal injury but completed surgery. Conclusions: Neoadjuvant docetaxel and bevacizumab demonstrates clinical evidence of activity in men with high-risk localized prostate cancer, with a 39% PR rate by erMRI and PSA declines noted in 65%. Treatment was well-tolerated. The study is ongoing and updated data on response, toxicity and pathology will be presented.

[Table: see text]
An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)
Authors: MacVicar G. R. , Greco A. , Reeves J. , Maleski J. , Holmlund J. , Leopold L.
Published: August 2020

5062

Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing.

[Table: see text]
A phase I study of CNTO328, an anti-interleukin (IL)-6 monoclonal antibody combined with docetaxel in subjects with metastatic castration-resistant prostate cancer (CRPC)
Authors: Hudes G. , Tagawa S. , Whang Y. , Qi M. , Qin X. , Puchalski T. , Prabhakar U. , O’Brien K. , Eisenberger M.
Published: August 2020

5063

Background: IL-6 is a potential mediator of prostate cancer morbidity and mortality and may protect prostate cancer cells from chemotherapy-induced apoptosis. CNTO328, a chimeric anti-IL-6 antibody, has been shown to inhibit prostate tumor growth in xenograft mouse models. Methods: Chemotherapy-naïve patients with metastatic CRPC were administered CNTO328 in combination with T (75 mg/m2 q3w) in 3 dose-escalation cohorts (6 mg/kg q2w, and 9 and 12 mg/kg q3w) following an initial run-in cycle of T alone to examine the effect of CNTO328 on T pharmacokinetics (PK). Safety was evaluated prior to each dose escalation. Prostate specific antigen (PSA), radiological response, and C-reactive protein (CRP), the best-known surrogate of serum IL-6 bioactivity, were also assessed. Results: This study is fully enrolled December 2008 with 38 patients. 36 patients with KPS ≥70, median age 66 (range 43–82) received 6 (median) cycles of T (range 1–37). 32 patients received at least one dose of CNTO328 in combination with T and are evaluable. Baseline patient characteristics included: median PSA of 59 ng/mL (range 12–1430) and median CRP was 3.85 mg/L (range <1 to 91.3). One DLT was observed in each cohort (grade 4 neutropenic infection, grade 3 syncope and dehydration, grade 3 GI bleeding), though MTD for the combination was not reached. Most frequent ≥grade 3 adverse events (AE) were neutropenia (69%); leukopenia (63%); lymphopenia (31%); dyspnea (19%); fatigue (16%). One patient died due to AE (sepsis) reported as possible related to T and unlikely related to CNTO328 by investigator. Preliminary data show CNTO328 does not appear to have a major effect on T PK. Preliminary efficacy data is shown in the table . Ongoing evaluation indicates 3/12 partial responses in patients with measurable disease reported thus far. Conclusions: CNTO328 with T is well tolerated and demonstrates biological and clinical activity in CRPC that warrants further study.

[Table: see text]

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A phase II study of sunitinib on a continuous dosing schedule in patients (pts) with relapsed or refractory urothelial carcinoma (UC)
Authors: Gallagher D. J. , Milowsky M. I. , Gerst S. R. , Tickoo S. , Ishill N. , Ishill N. , Regazzi A. , Trout A. , Bajorin D. F.
Published: August 2020

5072

Background: Suntinib has demonstrated activity in the second-line setting for pts with advanced UC when administered on a 4 week on/2 week off schedule. This study was designed to evaluate an alternative 37.5 mg/day continuous dosing schedule for sunitinib in the same setting. Methods: The primary objectives of this single institution phase II study of sunitinib in pts with UC who have failed prior chemotherapy were: 1) to determine the response rate (by RECIST); and 2) to evaluate toxicity. Secondary endpoints include: 1) correlation of response and toxicity with HIF and mTOR pathway marker expression; and 2) phamacokinetics. Pts may not have received >4 prior cytotoxic agents. Pts received sunitinib 37.5 mg/day continuous dosing.. Response was assessed after each of the initial 4 cycles and every other cycle thereafter. A minimax 2-stage design was used (maximal 32 pts). Results: 31 pts (21 M, 10 F) with a median age of 68 yrs and median KPS of 90 were enrolled between 10/15/07 and 12/18/08. Primary sites included bladder (28), and renal pelvis (3). Prior therapy included 1 pt with 1 drug, 19 pts with 2, 7 with 3 and 4 with 4. 25 pts had visceral metastases and 6 pts had lymph node only metastases. 25 pts were evaluable for response after completing at least 1 cycle. One pt achieved PR, 12 pts had SD, 12 had PD, 2 are too early to assess for response, and 4 patients did not complete cycle 1 (2 related to toxicity, and 2 related to non-treatment-related deaths). Radiographic regression was seen in liver, lung, soft tissue and lymph nodes. With a median follow up of 4 months, median progression free survival was 2 months (95% CI, 1 - 4 months) and median overall survival was 7 months (95% CI, 4 months - not achieved). Clinically significant toxicity (Grade 3/4) included: abdominal pain (1), anorexia (1), diarrhea (1), fatigue (4), hand and foot syndrome (2), hemorrhage (2), hypertension (2), mucositis (2), thrombosis (2), and emesis (1). Conclusions: Sunitinib has modest activity when administered on a 37.5 mg continuous dosing schedule to patients with relapsed or refractory UC with a similar toxicity profile to the 50 mg in the 4 /2 schedule. Upcoming trials will evaluate sunitinib in combination with standard chemotherapy in pts with UC.

[Table: see text]
Maintenance sunitinib postchemotherapy (CT) in patients (pts) with advanced urothelial carcinoma (UC): A randomized placebo controlled phase II trial
Authors: Bradley D. , Daignault S. , Smith D. C. , Nanus D. , Tagawa S. , Stadler W. M. , Garcia J. , Dreicer R. , Al-Hawary M. , Hussain M.
Published: August 2020

5073

Background: Although response to CT is common in pts with advanced UC it is rarely durable. Sunitinib is an oral small molecule inhibitor of receptor tyrosine kinases regulating angiogenesis including VEGFR-1, -2, -3, and PDGFR-α, -β with demonstrated antitumor activity in a variety of solid tumors. Inhibition of angiogenesis following CT may delay disease progression. Therefore, we are evaluating maintenance sunitinib in a phase II study. Methods: Pts with advanced UC, > stable disease (SD) after 4–6 cycles of CT, a performance status (PS) 0–2, adequate organ function and < 42 days from last CT dose were randomized to sunitinib 50 mg or placebo; 4 weeks (wks) on 2 off in 6 wk cycles. Pts were stratified by response to CT. Disease was assessed every 12 wks. Pts were unblinded for progression or unacceptable adverse events (AEs), with placebo pts offered open label sunitinib. The primary end point is 6 month progression rate using a modified version of the randomized selection design (Simon 1985). 42 pts/arm are to be accrued to allow selection of the superior arm with 90% probability. Other endpoints include safety, response rate (RR), time to progression, median survival, RR to open label sunitinib and correlation of changes in serum VEGF and sVEGFR-2 levels with outcome. Results: To date, 28 pts have been registered and 26 have completed > 12 wks of therapy. Median age is 69 years (48–81) and PS is 1 (37% PS 0, 52% PS 1). 12% had a complete response (CR) to prior CT, 46% a partial response (PR) and 42% SD. 14 pts have progressed after a median of 2 cycles (range 1–12). 7 pts received open label sunitinib at progression, 1/7 remains on treatment. Median duration on open label therapy is 2.2 months (11 days-15 months). Best response to open label therapy to date is progressive disease (2 pts), SD (2 pts) for 24 wks, PR in 1 pt through 60 weeks and 2 pts have not reached first assessment. Grade 3 AEs on open label sunitinib included: bladder hemorrhage, increased creatinine, fatigue, thrombocytopenia and hand-and-foot syndrome. No grade 4 or 5 AEs were observed. Conclusions: Preliminary results indicate that maintenance sunitinib post CT is feasible in advanced UC pts and is associated with clinical activity. Supported by Pfizer.

[Table: see text]
Vascular thromboembolic events in patients (pts) with advanced urothelial cancer (UC) treated with carboplatin/gemcitabine alone or in combination with bevacizumab
Authors: Apolo A. B. , Regazzi A. M. , Milowsky M. I. , Bajorin D. F.
Published: August 2020

5074

Background: Vascular thromboembolic events (VTE) occur in 13% of UC pts treated with cisplatin-based therapy ( J Urol 160:2021, 1998). Carboplatin-based therapy is used in UC pts intolerant of cisplatin but the frequency of VTE is unknown. Bevacizumab added to chemotherapy increases VTE in non-small cell lung cancer (NSCLC; 5% vs 3%) (Oncologist 12:713, 2007), breast cancer (7.4% vs 5.5%) and colorectal cancer (19% vs 16%) (JAMA. 2008;300:2288). This study evaluated VTE in UC pts treated with carboplatin/gemcitabine alone or with bevacizumab. Methods: Pts with advanced UC treated on a Memorial Sloan-Kettering Cancer Center protocol from June 2006 to September 2008 were analyzed prospectively. Therapy included > 3 cycles of bevacizumab (15 mg/kg on day 1) plus carboplatin (AUC 5 or 4.5 on day 1) and gemcitabine (1000 mg/m2 on days 1,8) every 21 days. Evaluation for VTE on a contemporary UC control group of pts receiving carboplatin plus gemcitabine alone during the exact same time period was conducted retrospectively. VTE were defined as pulmonary embolism (PE), deep venous thrombosis (DVT), myocardial infarctions (MI) and cerebral vascular accidents (CVA). Pts with simultaneous PE and DVT were considered to have one VTE. Results: 89 pts were evaluated. Of the 25 pts treated with bevacizumab plus chemotherapy, 4 pts (16.0%; 95% CI 5–36%) had a VTE of which there were 2 PE alone, 1 DVT alone, and 1 DVT and PE. No MI was observed in bevacizumab-treated pts. Of the 64 contemporary control pts treated with gemcitabine plus carboplatin alone, there were 11 pts (17%; 95% CI 9–29%) who had a VTE of which there were 4 PE alone, 4 DVT alone, 2 DVT and PE, and 1 MI. No CVA were seen in either group. Conclusions: Pts with advanced UC receiving carboplatin plus gemcitabine have a very high rate of VTE (17%). The VTE incidence is similar to colon cancer (16%) and greater than NSCLC (3%) and breast cancer (5.5%). The VTE rate is similar for both cisplatin and carboplatin, suggesting that it is intrinsic to the UC disease state. In this study, the addition of bevacizumab to carboplatin/gemcitabine was not associated with an increase in VTE over that seen for carboplatin/gemcitabine alone.

No significant financial relationships to disclose.
High-dose chemotherapy (HDCT) as second salvage treatment in patients with multiple relapsed or refractory germ cell tumors
Authors: Beyer J. , Hackenthal M. , Lorch A. , Neubauer A. , Dieing A. , Rick O. , Hartmann J. T. , Bokemeyer C.
Published: August 2020

5082

Background: To determine the activity of high-dose chemotherapy (HDCT) as intensification of second salvage treatment (SST) in patients with multiple relapsed germ-cell tumors (GCT). Methods: Databases in Berlin and Marburg (Germany) on patients treated with HDCT between 1989 and 2008 for germ-cell tumors were screened. Among 534 patients overall, 71/534 (13%) patients were identified as scheduled for HDCT having failed at least one previous conventional-dose first-line and first-salvage chemotherapy regimen. Forty-nine patients who had received at least cisplatin- and etoposide as first-line as well as conventional-dose cisplatin as first-salvage treatment and were diagnosed after January 1, 1990, were further analyzed. Results: Median age at SST was 32 years (range 19 to 52 years). Median follow-up for surviving patients was 4 years (range 1,7 to 8,5 years). Histology was pure seminoma in 5/49 (10%) patients and non-seminoma or mixed histologies in 44/49 (90%). The median number of cisplatin-based treatment cycles prior to SST was 7 (range 5 to 11 cycles). Three of forty-nine (6%) patients either progressed or died prior to scheduled HDCT, the remaining 46/49 (94%) received either single or sequential HDCT. The rate of favorable responses to HDCT as intensification of SST was 27/49 (55%). Ten patients are alive without progression. One additional patient is lost-to-follow at four years without progression. The projected overall survival rate at five years after initiation of SST was 17%. Conclusions: HDCT can induce long term remissions even in patients with multiple relapsed GCT.

No significant financial relationships to disclose.
Preliminary evaluation of chemotherapy plus residual tumor excision for testis conservation to provide justification for a randomized trial versus orchidectomy to reduce metabolic syndrome in patients with germ cell cancer
Authors: Oliver R. , Shamash J. , Nargund V.
Published: August 2020

5087

Background: There is evidence that early andropause due to testicular atrophy may be playing a role in the increased metabolic syndrome and cardiac deaths seen with follow up of GCC patients even those on surveillance. In a randomized trial of 1,477 stage I seminomas a single course of carboplatin produced a 78% reduction of contra lateral testicular GC. This, has increased awareness of the effectiveness of chemotherapy on primary tumours This abstract updates our experience.assessing chemo-response of primary GCC in past 30 years. Methods: Testicular GCC patients receiving chemotherapy with primary tumour in situ during 1978–2001 have been reviewed. 62 had advanced disease and 20 had stage I. Results: In 30/82 (37%) the testis normalised and was retained. Median follow-up is 132 months. 7 of these patients developed second GCC. Actuarial 5, 10, and 15 year relapse free survival was 81% and 76%. All relapses are new tumours without evidence of metastasis and are disease free after orchidectomy alone (15, 17, 35, 45, 48, 72, and 156 months). 22 additional patients (28%) who underwent orchidectomy for apparent treatment failure had necrotic tissue/mature teratoma involving less than 50% of the testis and could have been candidates for tumour enucleation. Patients with stage 1 tumours and seminoma histology showed significantly higher preservation rate that approached 100% if one included those showing necrosis or mature teratoma involving less than 50% of the testis. There have been 6 pregnancies to date in wives of 3 patients. 5 of 6 patients studied in detail have recovered sperm, the highest count (100x106) being the only patient who was successfully treated for bilateral testis tumours. Conclusions: This preliminary study suggests that up to 50% of all cases and 90% of stage I seminoma cases with tumours small enough for tumour enucleation for incomplete responders could have successful testis preservation after chemotherapy safely up to 10 years though in the future a randomized patient preference driven trial is needed to establish its acceptability, safety and value in reducing androgen deficiency.

No significant financial relationships to disclose.
Histopathology in surgically treated renal cell carcinoma: Is there a survival difference when stratified by stage?
Authors: Keegan K. A. , Hellenthal N. J. , Chamie K. , Koppie T. M.
Published: August 2020

5089

Background: The impact of renal cell carcinoma histopathology (RCC) on survival has been conflicting and limited to retrospective institutional studies. Therefore, we sought to determine the role of RCC histopathology on stage-specific survival rates in a population-based cohort. Methods: We utilized the National Cancer Institute's Surveillance, Epidemiology, and End Results database and identified 21,258 patients who underwent partial or radical nephrectomy for RCC between 1996 and 2004. Patients were stratified based on histopathologic diagnosis (clear cell, papillary, chromophobe, sarcomatoid, and collecting duct) and pathologic stage. We performed Cox-proportional hazard modeling and Kaplan-Meier survival analyses to determine overall- and cancer-specific survival. Results: Using univariate analysis, histopathology significantly impacted overall- and cancer-specific survival (p< 0.001). Specifically, patients with papillary and chromophobe variants had lower stage disease at the time of surgery and had improved survival compared to clear cell subtypes, (HR: 0.50; 95% CI, 0.42–0.60 and HR: 0.31; 95% CI, 0.22–0.44, respectively). When controlled for stage, improved outcomes for chromophobe and papillary histologies persisted, although it did not achieve statistical significance at all stages. On the other hand, patients with sarcomatoid disease were more likely to present with high stage disease and invariably had worse survival compared to clear cell carcinoma (HR: 8.74; 95%, CI 7.70–9.91). When controlled for stage, this difference achieved statistical significance across all stages (p< 0.001). Conclusions: Histopathologic subtype in patients with RCC does predict overall- and cancer-specific survival. Patients with sarcomatoid RCC, even those presenting with low-stage disease, have poor survival. These findings may give further value to recent data suggesting the increased utility of percutaneous renal biopsy and its potential impact on management.

[Table: see text]

No significant financial relationships to disclose.
Use of chromosome 9p status to identify a subset of high-risk localized renal cell carcinoma
Authors: LaRochelle J. C. , Dastane A. , Rao N. , Klatte T. , Shuch B. , Kabbinavar F. , Said J. , Belldegrun A. , Pantuck A.
Published: August 2020

5090

Background: We investigated whether deletion of chromosome 9p in clear cell renal cell carcinoma (ccRCC) predicts worse disease-specific (DSS) and recurrence-free survival (RFS), and if it is associated with worse prognosis in tumors < 4 cm. Methods: 316 patients undergoing nephrectomy prior to 2001 were included on a tissue microarray in whom FISH analysis using the LSI p16/CEP 9 Dual Color Probe was performed to assess chromosome 9p deletion status. An additional 389 patients undergoing nephrectomy after 2001 had 9p status determined by standard cytogenetics. Tumor grade, stage, size, 9p status, nodal involvement, and the presence of metastasis were recorded. Disease-specific and recurrence-free survival were determined, and independence was assessed using Cox proportional hazards models. Results: 9p deletions were detected in 14% of tumors. 54% of 9p-deleted tumors were high grade (G3–4) vs. 38% without 9p deletions, and 60% of 9p-deleted tumors were T3–4 vs 38% without 9p deletions (p < 0.01). 55% of those with 9p deletions had positive nodes or metastases vs. 34% of those without 9p deletions (p < 0.01). Median DSS for those with and without 9p deletions was 80 months and 37 months, respectively (p < 0.01). In localized disease, median RFS for those with 9p deletions was 53 months and was not reached in those without 9p deletions (p<0.01). In 188 patients presenting with localized RCC < 4 cm, loss of 9p occurred in 3/7 (42.9%) of patients with post-nephrectomy recurrence vs. 13/168 (7.2%) of patients without disease recurrence (p = 0.001). DSS for patients with 9p deletion in tumors < 4 cm was significantly worse than DSS in those without 9p deletions (HR 6.18; p = 0.02), and an independent effect on RFS was seen for 9p deletions in localized RCC (HR 2.3, p < 0.01). 9p status was not a significant predictor in metastatic RCC. Conclusions: Deletion of chromosome 9p in ccRCC occurs in 14% of patients and is associated with higher grade and T stage, presence of nodal and distant disease, worse prognosis, and in patients with small NOMO tumors, 9p deletions but not tumor size was independently associated with RFS. Identifying high risk patients with 9p deletions will allow better risk stratification for surveillance protocols and for adjuvant trials.

No significant financial relationships to disclose.
A nomogram predicting disease-specific survival after nephrectomy for papillary renal cell carcinoma
Authors: Klatte T. , Remzi M. , Said J. W. , Haitel A. , Kabbinavar F. F. , Waldert M. , de Martino M. , Marberger M. , Belldegrun A. S. , Pantuck A. J.
Published: August 2020

5091

Background: Whereas multiple nomograms have been developed to assess outcomes of patients with clear cell renal cell carcinoma, a model to assess prognosis of papillary renal cell carcinoma (PRCC) has not yet been developed. After data collection and slide review of a large cohort of patients, the aim of this study was to develop and to internally validate a nomogram for prediction of disease-specific survival for PRCC. Methods: Out of 2,687 patients who underwent surgery for a renal tumor between 1989 and 2008 at two institutions, 258 (10%) were found to have PRCC. H&E slides were reviewed by one uro-pathologist at each institution for papillary sub-type, tumor grade, microvascular invasion, sarcomatoid features, collecting system invasion and presence and extent of tumor necrosis. A nomogram was constructed as a graphical representation of significant variables of disease-specific survival in multivariate Cox proportional hazards regression analysis. The discrimination and calibration of the nomogram were assessed, both utilizing bootstrapping to obtain relatively unbiased estimates. Results: After a median follow-up of 35 months, 49 PRCC-related deaths (19%) had occurred. In univariate analysis, incidental detection, T, N, M stage, grade, microvascular invasion, collecting system invasion, papillary sub-type, sarcomatoid features, and necrosis were all associated with prognosis. Multivariate Cox proportional hazards analysis, however, identified incidental detection, T stage, M stage, microvascular invasion, and necrosis, but not papillary sub-type as independent prognostic factors of disease-specific survival. These variables formed the basis of the nomogram that predicted 5-year disease-specific survival probability. The nomogram predicted well, with a bootstrapped corrected concordance index of 0.93, and showed good calibration. Conclusions: A highly accurate tool utilizing basic clinical and pathological information for predicting disease-specific survival was developed specifically for PRCC. This tool should be helpful for identification of the subset of PRCC patients with aggressive clinical behavior, and may contribute to the ability to individualize postoperative surveillance and therapy.

No significant financial relationships to disclose.
Association of percentage of tumor burden removed with debulking nephrectomy and progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC) patients (Pts) treated with VEGF-targeted therapy
Authors: Barbastefano J. , Garcia J. A. , Elson P. , Wood L. S. , Lane B. S. , Dreicer R. , Campbell S. , Rini B. I.
Published: August 2020

5095

Background: Debulking nephrectomy is a standard of care in mRCC, although data in patients subsequently treated with targeted therapy is lacking. The objective of this study was to determine if fractional percentage of tumor volume (FPTV) removed with debulking nephrectomy is associated with PFS on subsequent VEGF-targeted therapy. Methods: The Cleveland Clinic Urologic Oncology database from 2005–2008 was retrospectively reviewed to identify mRCC patients who had undergone debulking nephrectomy followed by VEGF-targeted therapy, defined as treatment with sunitinib, sorafenib, bevacizumab or sunitinib + bevacizumab. FPTV was determined by the diameter of the primary tumor divided by the total tumor burden (per RECIST criteria) by investigator re-review of imaging studies. PFS was defined from the start date of systemic therapy to disease progression per RECIST criteria. Results: Seventy-five Pts were identified; 76% male, median age 60 years (range, 34–84), 95% clear cell histology and 69% ECOG PS 0. Pts received treatment with bevacizumab (28 pts), sunitinib (23), sorafenib (20), or sunitinib + bevacizumab (4). Lung (76%) and lymph node (48%) were the predominant sites of metastasis. The median diameter of the primary tumor was 9.3 cm (range, 3.3–21 cm). The median FPTV removed was 95% (range, 80–99%). The median PFS was 12 months. In univariable analysis, the FPTV removed was associated with prolonged PFS (p < 0.001), as were low nuclear grade (p = 0.009), longer interval from diagnosis to treatment (p = 0.05), normal hemoglobin (p = 0.02), number of metastatic sites (p = 0.05), and lack of lung (p = 0.05) and brain (p = 0.05) metastasis. In multivariable analysis, the FPTV removed, as well as the interval from diagnosis to treatment (p = 0.03), were found to be independent predictors of PFS (< 0.001). Conclusions: Improved PFS on targeted systemic therapy is significantly associated with a greater percentage of tumor burden removed at debulking nephrectomy.

No significant financial relationships to disclose.
Dosing patterns in patients with renal cell carcinoma treated with sorafenib or sunitinib: A retrospective claims database analysis
Authors: Keefe S. , Moyneur E. , Barghout V. , Flaherty K. T.
Published: August 2020

5097

Background: Tyrosine kinase inhibitors (TKIs; sorafenib [SR], sunitinib [SU]) are FDA approved for the treatment of advanced renal cell carcinoma (RCC). Dose reduction may be needed for management of treatment-related adverse events. We analyzed the dose reduction patterns in pts with RCC treated with SR, approved Dec 05, or SU, approved Jan 06. Methods: A retrospective analysis was conducted using data from a US claims-based database (MarketScan MedStat) covering ≥18 million lives for 2002–2008 in all US census regions. Inclusion criteria were ≥2 claims for RCC (ICD9 189.0 or 198.0), continuous healthcare coverage, >180 days of coverage before RCC diagnosis, no claim for SR or SU prior to RCC diagnosis, initial standard daily RCC dose per package insert recommendation (800 mg for SR or 50 mg for SU), and ≥2 consecutive dispensings. Initial episode was defined as the time from the date of the first drug dispensing (index date) to the first switch to another TKI, end of healthcare coverage, end of treatment, or March 31, 2008. Pt and pt-time level analyses for dose reductions between treatments were conducted. Results: SR- (n = 189) and SU-treated (n = 304) pts met the inclusion criteria. No significant differences in baseline demographics existed between the groups except for a higher incidence of stroke (7.9% vs 3.6%, p = 0.037) and other cancer site (93.7% vs 87.8%, p = 0.036) in the SR group. Significantly more pts who received SU (23%) required dose reductions during the first 3 months of therapy and for all initial episodes than did pts who received (4.2%) SR (p < 0.001 for both). For all episodes, the mean time to dose reduction was 104 days for SU versus 162 days with SR (p = 0.0028). The majority (65%) of dose reductions with SU occurred within the first 3 months, whereas dose reduction with SR was 25% during this time (p < 0.001). After controlling for different lengths of exposure time, 2 to 6 times more dose reductions were observed in pts who received SU than with SR (p < 0.001). Conclusions: This US retrospective claims analysis showed more dose reductions, including number of patients and total number of days, in pts who initially received sunitinib compared with those who received sorafenib.

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Final 10-year analysis of prospective multicenter Chemo N0 trial for validation of ASCO-recommended biomarkers uPA/PAI-1 for therapy decision making in node-negative breast cancer
Authors: Harbeck N. , Schmitt M. , Meisner C. , Friedel C. , Untch M. , Schmidt M. , Lisboa B. , Sweep C. , Jänicke F. , Thomssen C.
Published: August 2020

511

Background: Based on interim results of the prospective, randomized, multicenter Chemo N0 trial and an EORTC pooled analysis (n = 8,377), ASCO and AGO guidelines recommend invasion markers uPA/PAI-1 for risk assessment in N0 breast cancer. Methods: We present final analysis of the Chemo N0 trial (recruitment 1993–1998; n = 647; 12 centers) with 113 (5–167) months median follow-up. Patients (pts) with low tumor levels of uPA and PAI-1 (n = 283) were observed. Of 364 patients with high uPA and/or PAI-1, 242 were randomized to CMF chemotherapy (n = 117) vs. observation (n =125); 122 pts decided for or against CMF on their own. External quality assurance provided good ELISA standardization in 5 participating laboratories. Results: The actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high uPA/PAI-1 pts in the combined (randomized and not randomized) observation group was 23.0%, in contrast to only 12.9% in those with low uPA/PAI-1 (p = 0.011, log rank). High-risk pts randomized for CMF had a 26.0% lower estimated probability of disease recurrence than high-risk pts randomized for observation (intention-to-treat analysis: HR 0.74 (0.44–1.27); p = 0.28, log rank). In per-protocol analysis, the treatment benefit was significant: HR 0.48 (0.25–0.88), p = 0.019, adjusted for tumor stage and grading in Cox regression for DFS; for OS, HR was 0.64 (0.35–1.19); p = 0.162, adjusted for tumor stage and grading in Cox regression. Conclusions: Chemo N0 is the first prospective biomarker-based therapy trial in early breast cancer defining a patient group achieving good long-term DFS without any adjuvant therapy. This trial demonstrates that, using a standardized uPA/PAI-1 ELISA, about half of N0 pts, classified as low-risk, could be spared chemotherapy, while high-risk pts benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic and predictive impact of uPA/PAI-1 at highest level of evidence (LOE I) and support their guideline-based routine use for risk-adapted individualized therapy decisions in N0 breast cancer. The ongoing NNBC-3 trial is evaluating optimal chemotherapy for uPA/PAI-1 high-risk patients.

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A phase I study of temsirolimus (TEM) and bryostatin (BRYO) in patients with metastatic renal cell carcinoma (RCC)
Authors: Plimack E. R. , Wong Y. , Von Mehren M. , Malizzia L. , Roethke S. K. , Li T. , Litwin S. , Hudes G. R. , Haas N. B.
Published: August 2020

5111

Background: TEM, an inhibitor of mTOR complex 1 (TORC1), is approved for the treatment of metastatic RCC. BRYO inhibits protein kinase C, a downstream effector of mTOR complex 2 (TORC2). We observed additive effects of TEM and BRYO against RCC in vitro. Methods: Four cohorts of 3–6 patients (pts) received weekly BRYO (20 mcgm/m2) and TEM (10, 15, 25, or 37.5 mg,) in 28 day cycles. DLT was defined as 1st cycle toxicity ≥ grade 3. Results: Twenty-three pts have been enrolled. Eighteen pts had RCC: clear cell (12), papillary (3), clear cell with sarcomatoid/spindle features (2), unclassified (1), Among RCC pts, 3 had no prior therapy. 15 had a median of 2 prior therapies (immunotherapy, TKIs, and/or bevacizumab). To date, 22 pts have received 103 cycles across 4 dose levels. Five non-RCC pts (4 sarcoma, 1 paraganglioma) received up to 3 cycles of treatment. Two of these pts (both had prior cytotoxic therapy) experienced DLT at 15 mg (Gr 3 neutropenia and Gr 3 hypophosphatemia) Subsequently, pts with prior cytotoxic therapy were excluded. One additional non-RCC pt (prior radiation) experienced DLT (Gr 3 neutropenia) at TEM 37.5 mg. Among RCC pts, there were no 1st cycle DLT's. Significant toxicities during later cycles included Gr 3/4 thrombosis at TEM 37.5 mg (2), Gr 4 thrombus/Gr 4 LV dysfunction at TEM 15 mg (1), and Gr 3 dyspnea/Gr 3 pneumonitis at TEM 10mg (1). Gr 4 hypercholesterolemia (1) and Gr. 4 triglyceride elevation (1) were seen at TEM 37.5 mg, both reversed with treatment. One RCC pt withdrew prior to receiving treatment. Of the 17 remaining RCC pts, 3 had PRs and 9 had SD. One treatment naïve pt (TEM 15 mg) continues with PR for 2+ years after discontinuing treatment. One pt (had progressed on sunitinib) continues in a PR at 14+ months. Twelve pts received ≥4 cycles and 3 received >10 cycles. PR was seen in both clear cell and papillary histologies. Median PFS was 7.8 months for all pts and 5.7 months for previously treated pts. Two pts, both with PR, remain on treatment, having received 18 and 8 cycles. Conclusions: The TEM/Bryo combination is feasible for multiple cycles on a weekly schedule at full doses of each agent with durable PR and SD in RCC refractory to other therapies. Enrollment continues to further characterize safety and efficacy.

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Survival gains needed to justify the side effects of treatment for localized prostate cancer
Authors: King M. T. , Viney R. , Hossain I. , Smith D. , Savage E. , Stockler M. R. , Armstrong B.
Published: August 2020

5119

Background: Men diagnosed with localized prostate cancer face difficult treatment decisions. Evidence about the relative survival benefit of treatment options is lacking or piecemeal. Side-effects can vary widely with treatment, affecting some fundamental aspects of quality of life (QOL). Little is known about patients’ views of the relative tolerability of these side-effects or the survival gains needed to justify them. Methods: QOL data were collected prospectively 3 years post-diagnosis in a population-based cohort of men treated for localized prostate cancer (n=1642); these data were used to identify common side-effect profiles. A patient preference survey was conducted in a subset (n=357, stratified by treatment); hypothetical treatment alternatives were described in terms of side-effects and survival. Random parameter logit models were estimated. We adapted the concept of compensating variation from welfare economics to derive a parameter function for the value of changes in QOL in terms of survival time; i.e., the survival gains needed to justify persistent side-effects. Bootstrap confidence intervals (CI) were constructed. Results: The table shows the survival gains needed for a range of common treatment profiles, relative to the base case of active surveillance (in which men typically experienced mild loss of libido and mild fatigue). For example, radical prostatectomy often resulted in severe impotence and mild urinary leakage; men required an extra 8.0 months (95% CI 7.4–8.7) of life to make this worthwhile. Generally, urinary dysfunction and bowel symptoms were considered the least tolerable, hormonal symptoms and fatigue came next, and sexual dysfunction was considered relatively benign. This pattern was relatively consistent across treatment groups. Conclusions: These results highlight the need for better evidence about the actual survival benefits of alternative treatments. They also help to target supportive care to optimize patient QOL after treatment for localized prostate cancer.

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No significant financial relationships to disclose.
The 70-gene profile and chemotherapy benefit in 1,600 breast cancer patients
Authors: Bender R. A. , Knauer M. , Rutgers E. J. , Glas A. M. , de Snoo F. A. , Linn S. C. , Van 't Veer L. J.
Published: August 2020

512

Background: The 70-gene expression profile (MammaPrint) is validated as an independent prognostic indicator for breast cancer patients with T1–2 node-negative and positive disease regardless of estrogen receptor status. Here we present the relationship between MammaPrint outcome and chemotherapy benefit in the adjuvant setting. Methods: We performed a pooled analysis of 1,637 patients with MammaPrint outcomes (T1–2, node-negative and positive invasive breast cancer and median FU 7.1 yrs) to determine the chemotherapy benefit of patients treated with adjuvant chemotherapy in addition to endocrine therapy. Patients were collected from 7 large datasets at multiple institutions across Europe. Results: In this meta-analysis, MammaPrint assigned 772 patients (47%) to “low risk” and 865 (53%) to “high risk”. In total 349 patients were treated with endocrine therapy alone, whereas 226 were treated with both chemo- and endocrine therapy. Patients with poor prognosis MammaPrint profile had a substantial benefit from chemotherapy: At 5 years, distant disease-free survival was improved from 69% to 88% (HR 0.28 (95% CI 0.14–0.56, p<0.001) when chemotherapy was added to hormonal therapy. The results remained significant in multivariate analysis including stratification by standard clinico-pathologic prognostic factors. Patients classified by MammaPrint as good prognosis (“low risk”) had no significant benefit from chemotherapy (p=0.962). Conclusions: The 70-gene MammaPrint profile is not only a strong and independent prognostic indicator for patients with early stage breast cancer, but it may also be predictive for the benefit of chemotherapy. While MammaPrint “high risk” classified patients demonstrate a clear benefit from adjuvant chemotherapy added to hormonal therapy, patients classified by MammaPrint as “low risk” for recurrence do not appear to benefit from the addition of chemotherapy to hormonal treatment alone.

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Defining the role of patient navigators for men with an abnormal prostate cancer screening test result in an urban setting
Authors: Hamer S. , Nonzee N. J. , Simon M. A. , Liu D. , McKoy J. M. , Byer P. J. , Feinglass J. , Rademaker A. , Calhoun E. A. , Bennett C. L.
Published: August 2020

5120

Background: Though several navigation programs have aimed to reduce cancer health disparities, few have evaluated the role of patients’ race/ethnicity on patient navigator activities. We report preliminary data on types of encounters and actions taken to prevent delays in prostate cancer diagnosis or treatment for 82 veterans enrolled in the NCI-funded Patient Navigation Research Program in Chicago. Methods: Male lay patient navigators and a social worker recorded encounter types, perceived or patient-identified barriers, and actions taken to prevent or resolve patient barriers to follow-up after identification of an abnormal finding for prostate cancer. Results: Of our study participants, half were African-American, 57% had an annual income of less than $30,000, 68% were unemployed, 43% were married, and the mean age was 66 years old. The most common type of patient navigator encounters included phone calls with the patient and in-person visits at the hospital, 64% and 32% respectively. Two-thirds of encounters on behalf of the patient lasted less than 15 minutes. Almost all patient navigator actions resulted from proactive case management. The most common navigator actions taken were providing support, making referrals to health providers or community resources, and verifying appointments, 32%, 29%, and 15%, respectively. There was a significant difference between African-American versus White patients with respect to type of encounter and length of encounters (p=0.002 and <0.0001, respectively) but not actions taken. Conclusions: Patient navigator activity for our study thus far largely consisted of proactive management of patient- and system-related barriers as opposed to reactive response to patient-identified barriers. Future navigation programs should consider tailoring gender- and culturally-matched interventions for their patients.

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No significant financial relationships to disclose.