bluuebunny/crossref_metadata_2025 huggingface dataset:
ECOG 8802: Phase II trial of doxorubicin (Dox) and gemcitabine (Gem) in metastatic renal cell carcinoma (RCC) with sarcomatoid features
Authors: Haas N. , Manola J. , Pins M. , Liu G. , McDermott D. , Nanus D. , Heath E. , Wilding G. , Dutcher J.
Published: August 2020

5038

Background: Patients (pts) with RCC containing sarcomatoid features have poor prognoses.Cytokine therapy is ineffective, and experience with mTor inhibitors or multi-targeted tyrosine kinase inhibitors is early. We evaluated Dox/Gem in these pts with locally advanced or metastatic disease to confirm previous activity of this regimen in a single institution trial. Methods: Pts received Dox 50mg/m2 IV push and Gem 1500mg/m2 IV over 30 minutes every 2 weeks (with G-CSF 5 mcg/kg/d days 2 or 3 to 10 or pegfilgrastim 6 mg day 2) until disease progression or unacceptable toxicity. Dose reductions occurred for low granulocytes and or platelets, mucositis, cardiac toxicity, or other grade 3 - 4 toxicities. Dox was discontinued after a cumulative dose of 450 mg/m2 unless pt had normal cardiac function. The study targeted a promising response rate (RR) of 20% vs. 5%, with 90% power and 8% Type I error. A 2-stage design was used; >4 responses were needed for efficacy. Results: From February 2004 to April 2007, 39 pts with RCC of sarcomatoid (47%) or mixed histology (53%) containing sarcomatoid features were accrued by ECOG (n = 35), NCCTG (n = 2), and CALGB (n = 2). 1 pt withdrew before treatment. Pts were mostly male (81%), with cT3/T4 (68%), node negative (61%), M1 (58%) disease at diagnosis and ECOG PS 0–1. Metastases included lung (71%) and lymph nodes (58%). Pts received a median 6.5 cycles (range, 1 - 16). Treatment was moderately tolerable: grade 4 neutropenia (3 pts, 1 with fever), grade 4 dyspnea (1 pt), grade 4 peristomal infection (1 pt). 2 of 38 pts stopped treatment due to toxicity. 1 complete and 5 partial responses (PR) were observed (16%, 90% CI 7.1–28.8%). A 7th patient had an unconfirmed PR and an eighth patient had > 50 percent decrease in tumor burden after an initial progression. 9 patients had stable disease. Two pts are alive without progression (1 with a PFS of 2.5 years), 1 is alive with progression, and 35 patients have died. Median PFS is 3.5 months (95% CI 2.8–5.2 mos). Median OS is 8.8 mos (6.1–11.1 mos). Conclusions: Dox/Gem met efficacy criteria in RCC with sarcomatoid features. A TKI/Gem regimen in ECOG is planned.

No significant financial relationships to disclose.
Phase II multicenter study of chemotherapy (chemo)-naive castration-resistant prostate cancer (CRPC) not exposed to ketoconazole (keto), treated with abiraterone acetate (AA) plus prednisone
Authors: Ryan C. , Efstathiou E. , Smith M. , Taplin M. , Bubley G. , Logothetis C. , Kheoh T. , Haqq C. , Molina A. , Small E. J.
Published: August 2020

5046

Background: AA is a potent inhibitor of the enzyme CYP17, a major contributor to androgen biosynthesis. Keto is also known to inhibit this enzyme but AA is many-fold stronger in its action. 33 pts with progressive metastatic disease, normal organ function, ECOG performance status (PS) 0–1, and no prior chemo were enrolled. Pts with prior keto treatment were excluded. AA (1000 mg qd) plus prednisone (5mg bid) were administered orally in 28 day cycles. Methods: Results: At baseline median age was 71.0 (range 52–85) yrs and median PSA was 24.7 (range 7.1–1110.0) ng/mL;19/26 pts (73%) had an ECOG PS of 0 and 7/26 (27%) had PS of 1; the median number of prior hormonal therapies was 2; all pts were on LHRHa and 73% of pts had received anti-androgen, all of whom had undergone prior anti-androgen withdrawal. Pts were evaluated at each cycle for PSA response according to PSAWG criteria. 27 pts have available data for PSA response. Total maximal PSA declines of ≥30%, ≥50%, ≥90% were observed in 89% (24/27), 85% (23/27) and 41% (11/27) pts, respectively. Week 12 PSA declines displayed a similar and sustained trend: ≥30%, ≥50% and ≥90% PSA decline in 82%, 78%, and 26% of pts. Post-treatment ECOG PS score was 0 in 24 (92%) pts: 19% experienced improvement in PS (PS 1 to 0 in 5 pts) and 19/19 pts maintained a PS of 0; Median time to PSA progression has not been reached. Majority of adverse events were grades 1–2. Incidence of hypokalemia - 12%; HTN - 6%; edema - 15%. One pt experienced a grade 3 drug-related HTN. Conclusions: Abiraterone acetate plus prednisone has significant anti-cancer activity in patients with metastatic CRPC not previously treated with ketoconazole or chemotherapy, as demonstrated by declines in PSA and improvement in performance status, and is well-tolerated.

[Table: see text]
The effect of toremifene citrate on BMD in men on ADT: A phase III clinical trial
Authors: Veverka K. A. , Malkowicz B. , Smith M. , Morton R. A. , Steiner M. S.
Published: August 2020

5055

Background: Androgen deprivation therapy decreases bone mineral density and increases fracture incidence. In a recently completed two-year randomized controlled trial of 1382 men, toremifene increased BMD and decreased vertebral fracture incidence in men receiving ADT for prostate cancer. We now describe the effects of toremifene on BMD in various subject subgroups. Methods: We conducted a randomized double blind placebo controlled trial in 1382 men with histologically confirmed prostate cancer on ADT. Key entry criteria included age ≥ 50 years, continuous ADT for 6 months or longer or intermittent ADT for 12 months or longer. Subjects on intermittent ADT at enrollment had to remain on continuous ADT for the duration of their time on study. Subjects were randomized to receive either 80mg toremifene citrate daily or matching placebo. The primary end point was the incidence of new morphometric vertebral fractures. Secondary endpoints included BMD, clinical fragility fractures, bone turnover markers, lipid profile, hot flashes, and gynecomastia. Results: In the overall study population, toremifene increase BMD of the hip and lumbar spine by 1.6% and 2% after two years compared to placebo. Similar beneficial effects of toremifene were observed in each of the subgroups ( Table ). Conclusions: Toremifene significantly increases bone mineral density of the hip and spine in every subgroup including those men who were older or had prevalent vertebral fractures, longer exposure to ADT, or lower baseline BMD.

[Table: see text]

[Table: see text]
Survival following early hormone therapy for men with rapid PSA doubling time within 2 years following radical prostatectomy
Authors: Trock B. , Han M. , Humphreys E. B. , Partin A. W. , Eisenberger M. A. , Walsh P. C.
Published: August 2020

5065

Background: Early hormonal therapy has been used in the salvage setting for men with biochemical recurrence following radical prostatectomy (RP), but no studies to date have been able to evaluate whether such treatment prolongs survival. We examined the impact of salvage hormonal therapy on overall survival (OS) in a cohort with long-term follow-up, and attempted to identify the subgroup most likely to benefit. Methods: Retrospective analysis of a cohort of 488 men undergoing RP at Johns Hopkins Hospital from 1982–2004, who experienced biochemical recurrence and received no salvage therapy (n = 386) or salvage hormonal therapy (n = 102); no one received adjuvant therapy. Survival was defined from biochemical recurrence to death from all causes, and analyzed with proportional hazards models with time-dependent covariates. Results: With median follow-up of 6 years after recurrence and 9 years after RP, there were 143 deaths (29%), including 105 from prostate cancer. After adjusting for PSA doubling time (PSADT), RP Gleason score, and year of surgery, hormonal therapy did not significantly improve OS for all men, compared to no salvage therapy: hazard ratio (HR) = 0.72 (95% confidence interval (CI): 0.45–1.17), p = 0.187. However, when restricted to men with early recurrence, i.e. within 2 years of RP, and with a rapid PSADT<6 months, hormonal therapy was associated with a large, significant improvement in OS: HR = 0.25 (95% CI: 0.08–0.71), p = 0.0095. This subgroup comprised 22% of the cohort. In contrast, there was no benefit of salvage hormonal therapy in men with early recurrence and PSADT>6 months: HR = 1.96 (95% CI: 0.89–4.31), p = 0.093, nor those who recurred more than 2 years after RP, regardless of PSADT. Conclusions: This study suggests that early salvage hormonal therapy may significantly and substantially prolong overall survival in the subgroup of men who experience an early biochemical recurrence with a rapid PSADT. These results are consistent with early recurrences being indicative of metastatic disease, while later recurrences are more likely to represent local recurrence. If validated, these results may provide useful stratification criteria for clinical trials.

No significant financial relationships to disclose.
Short-course androgen suppression therapy prior to brachytherapy for favorable-risk prostate cancer and the risk of all-cause mortality in men with or without preexisting cardiovascular disease
Authors: Hayes J. H. , Chen M. , Moran B. J. , Braccioforte M. H. , Dosoretz D. , Salenius S. , Katin M. , Ross R. , D’Amico A. V.
Published: August 2020

5066

Background: AST is used to reduce prostate size in men with favorable-risk prostate cancer who have pubic arch interference in order to enable them to undergo prostate brachytherapy. While no disease-specific benefit has been demonstrated to AST in this setting, AST use has been associated with both cardiovascular morbidity and mortality. The Objective is to determine the effect of short-course androgen suppression therapy (AST) prior to brachytherapy on all cause mortality (ACM), stratified by the presence or absence of preexisting cardiovascular disease (CVD). Methods: The study cohort included 12,792 men with previously-untreated low or intermediate risk prostate cancer (PSA < 20 ng/mL; Gleason score 7 or below on initial biopsy; clinical category T2c or below) treated between 1992 and 2005 at one of 21 community-based medical centers in Illinois, Florida, New York, or North Carolina. Men were treated with brachytherapy with or without neoadjuvant AST. Multivariate Cox regression analysis was performed to assess whether significant associations between preexisting CVD and ACM existed adjusting for age, year of treatment and known prostate cancer prognostic factors. Results: After a median follow up of 3.76 years (interquartile range, 2.03 to 5.92 years), 1557 deaths had occurred. The use of neoadjuvant AST was significantly associated with an increased risk of ACM in men with pretreatment CVD (adjusted hazard ratio (AHR) 1.62, 95% CI, 1.40 to 1.87, p < 0.001) but not in men without CVD (AHR 1.06, 95% CI, 0.91 to 1.25, p = 0.5). In men with preexisting CVD, AST use was associated with an increased risk of ACM at 5 years compared to men with CVD who did not use AST (17.5% (95%CI, 15.57% to 19.64%) vs. 14.35% (95%CI, 12.80% to 16.06%), p < 0.0001). Conclusions: Preexisting CVD is associated with an increased risk of death in men with favorable-risk prostate cancer treated with short-course AST prior to brachytherapy.

No significant financial relationships to disclose.
Cancer-related self-efficacy in African American prostate cancer patients compared to whites
Authors: Purnell J. Q. , Palesh O. , Mustian K. , Peppone L. , Morrow G. , Colman L. K. , Lord R. , Flynn P. J.
Published: August 2020

5067

Background: African American (AA) men are nearly twice as likely as white (W) men to be diagnosed with prostate cancer. Cancer-related self-efficacy (i.e., confidence in one's ability to manage cancer) has been associated with better physical and psychosocial functioning, but little is known about self-efficacy in African American prostate cancer patients. This study compared AA and W ratings of cancer-related self-efficacy for 308 prostate cancer patients (M age = 66.13, SD = 8.48; 9% AA) who participated in a group therapy intervention. Method: Independent groups t-tests were used to determine whether there were significant differences at baseline in mean scores for each group on the Stanford Self-Efficacy Scale (SSE), which asks respondents to rate their confidence in the ability to cope with cancer on a 0–100 scale, with 0 indicating no confidence. SSE subscales measure self-efficacy in the ability to: a) communicate with family, friends, and healtcare providers; b) focus and relax; and c) cope with the possibility of dying. Results: A significant difference was observed on SSE total scores (AA mean = 60.39 vs. W mean = 72.70; t = 3.30; p = 0.003). There were also significant differences on the Focus/Relax (AA mean = 68.90 vs. W mean = 77.64; t = 2.04; p = 0.011) and Cope with Dying (AA mean = 49.72 vs. W mean = 70.12; t = 4.85; p = 0.001) subscales, with a trend towards significance on the Ability to Communicate (AA mean = 62.55 vs. W mean = 70.76; t = 3.36; p = 0.095). Conclusions: Results suggest that, compared to W men, AA men have less confidence in their ability to cope with prostate cancer following diagnosis. AA men report the least confidence in their ability to cope with the possibility of death as a result of cancer, and they also report less confidence in their ability to focus and relax. They may also have greater difficulty discussing their cancer with family, friends, and healthcare personnel. As cancer-related self-efficacy has been linked to symptom-related and psychological adjustment, interventions targeting self-efficacy in AA prostate cancer patients are needed that are tailored to their unique needs.

No significant financial relationships to disclose.
Race and survival following brachytherapy-based treatment for men with localized or locally advanced adenocarcinoma of the prostate
Authors: Winkfield K. M. , Chen M. , Dosoretz D. E. , Salenius S. A. , Katin M. J. , Ross R. , D’Amico A. V.
Published: August 2020

5068

Purpose: We investigated whether race was associated with risk of death following brachytherapy-based treatment for localized prostate cancer. Methods: The study cohort was comprised of 4,880 men with clinical stage T1–3N0M0 prostate cancer and minimum follow-up of 2 years who underwent brachytherapy-based treatment at 20 centers within the 21st Century Oncology consortium. A Cox regression multivariable analysis was used to evaluate the risk of death in African-American (AA) and Hispanic (H) men as compared to Caucasian men adjusting for age, pretreatment PSA, Gleason score, clinical T stage, year and type of treatment, and comorbidity level. Results: After a median follow-up of 5 years, there were 924 deaths. AA and H race were significantly associated with an increased risk of ACM (adjusted hazard ratio [AHR] 1.42 and 1.66, [95% confidence interval (CI): 1.01 to 1.99 and 1.14 to 2.41]; p = 0.045 and 0.008, respectively). As shown in the table , other factors significantly associated with an increased risk of death included age (p<0.001), PSA (p = 0.02), Gleason score 8 to 10 (p = 0.001), year of brachytherapy (p<0.001), and presence of 2 or more significant comorbidities (p = 0.003). The risk of ACM was decreased following trimodality therapy (p = 0.02). Conclusions: African-American and Hispanic race as compared to white race appear to confer a higher risk of mortality following brachytherapy-based treatment in men with localized or locally advanced prostate cancer.

[Table: see text]

No significant financial relationships to disclose.
Impact of race on survival of prostate cancer patients treated with noncurative intent
Authors: Hatcher D. , Rose A. E. , Christos P. J. , Mazumdar M. , John M. , Taneja S. S. , Lee P. , Osman I.
Published: August 2020

5069

Background: We previously reported that African American (AA) men have a higher recurrence rate than Caucasian (CA) men treated with radical prostatectomy at the New York Veteran Administration Medical Center (NY-VAMC), an equal access to care facility (J Urol. 2006). In the current study, we attempted to examine the differences in survival of AA and CA prostate cancer (PC) patients with clinically detected localized disease treated with non curative intent. We hypothesized that comparing patients whose PC was not altered by primary treatment might give a better idea about the difference, if any, of the natural history of PC in AA compared to CA patients. Methods: Men diagnosed with PC at NY-VAMC during 1990–2005 were identified. Inclusion criteria were: 1) biopsy confirmed PC; 2) no evidence of metastatic disease within 6 months after diagnosis; 3) no curative intent treatment. Results: The study included 530 men (288 AA and 242 CA) with median follow-up of 8.1 years (range: 0.6–17.6 years). AA men presented with significantly higher PSA compared to CA patients (median 18.5 versus 11.4 respectively, p = 0.004), however, there were no differences in age at presentation (median 73 versus 74, p = 0.98) or Gleason score (23% of AA and CA had Gleason >7, p = 0.92). Of the 530 patients, 198 (37%) are alive with disease, 67 (13%) died of prostate cancer, 206 (39%) died of other causes, and 59 (11%) died of unknown causes. AA patients had shorter median overall survival compared to CA patients (8 versus 9 years, respectively), however, the difference was not significant (p = 0.29). Factors most predictive of mortality by Cox regression multivariable analysis were PSA at diagnosis (p = 0.001), Gleason score (p = 0.04), and age of patient at diagnosis (p < 0.0001). Race was not an independent predictor of mortality in this model (p = 0.37). Competing risk analysis distinguishing the types of death is underway. Conclusions: The extended follow up available for our study cohort points to non PC related mortality as the major cause of death in patients treated with non-curative intent.

No significant financial relationships to disclose.
A phase II randomized four-regimen selection trial incorporating response for sequential chemotherapy in metastatic, unresectable urothelial cancer: Final results from the M. D. Anderson Cancer Center
Authors: Siefker-Radtke A. O. , Kamat A. M. , Williams D. L. , Tannir N. M. , Tu S. , Pagliaro L. C. , Dinney C. P. , Millikan R. E.
Published: August 2020

5071

Background: We developed a clinical trial incorporating response into the treatment algorithm. Patients meeting a certain threshold of response continued with the same treatment; those with insufficient response were switched to alternative chemotherapy. We now report on final results from this trial. Methods: Patients were randomly assigned to one of four regimens: ifosfamide, doxorubicin, gemcitabine; ifosfamide, paclitaxel, cisplatin; gemcitabine, cisplatin; or cisplatin, gemcitabine, and ifosfamide. To continue with chemotherapy, patients must have had at least a 40% response after the first 6-week interval, and a >90% response after the second 6 weeks. Otherwise, they were re-randomized to alternate chemotherapy. Overall success (OSX) was defined as patients with a >90% response with either front-line or second-line therapy. Surgical consolidation was offered to patients at the discretion of their treating physician. Results: Median overall survival (OS) for 120 patients was 19.1 mo. (3 and 5-yr survival: 33% and 20%). OSX was achieved in 41 patients (median OS: 51 mo.); the median OS in the other 79 patients was 15 mo. (p = 0.0001), with a 5-yr survival of 42% and 10% respectively. Surgical consolidation was performed in 35 patients: 23 with nodal metastases to pelvic and/or RPLN, 6 with cT4b tumors, and an additional 6 patients with distant metastases. Their median OS from surgery was 23.7 months, (5-yr survival: 31%). Surgical consolidation in the setting of OSX was associated with a 42% 5-yr survival as compared to 11% in those undergoing surgery in the absence of OSX. Visceral metastases and poor performance status were associated with a worse prognosis. Conclusions: With sequential therapy, 34% of patients had a >90% response (OSX). A potential benefit in long-term survival was seen in patients who had surgical consolidation in the setting of OSX. This trial design provides a novel method for assessing the benefits of sequential chemotherapy, and enhancing the population of patients who may be offered surgical consolidation in the setting of initially unresectable, or metastatic urothelial cancer.

No significant financial relationships to disclose.
Adjuvant chemotherapy for high-risk upper tract urothelial carcinoma: Results from the Upper Tract Urothelial Carcinoma Collaboration
Authors: Hellenthal N. , Shariat S. F. , Margulis V. , Karakiewicz P. I. , Roscigno M. , Bolenz C. , Remzi M. , Weizer A. , Zigeuner R. , Koppie T. M. ,   Upper Tract Urothelial Carcinoma Collaboration
Published: August 2020

5075

Background: There is relatively little literature regarding the use of adjuvant chemotherapy following radical nephroureterectomy in the management of patients with upper tract urothelial carcinoma (UTUC). Our goal was to determine the incidence of receipt of adjuvant chemotherapy in high-risk patients and the ensuing effect on overall- and cancer-specific survival. Methods: Using an international collaborative database, we identified 1390 patients who underwent nephroureterectomy for non-metastatic UTUC between the years of 1992 and 2006. Of these, 542 (39%) patients were classified as high-risk (pT3N0, pT4N0, and/or lymph node positive). These patients were separated into two groups—those who did and did not receive adjuvant chemotherapy—and were stratified by gender, age group, performance status, tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to determine overall- and cancer-specific survival amongst the cohorts. Results: Of the high-risk patients, 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p < 0.001). Median survival in the entire cohort was 24 months (range 0–231 months). There was no significant difference in overall- or cancer-specific survival between those who did and did not receive adjuvant chemotherapy; however age, performance status, tumor grade, and tumor stage were significant predictors of both overall and cancer-specific survival. Conclusions: Adjuvant chemotherapy is infrequently utilized in the treatment of patients with high-risk UTUC after nephroureterectomy. Despite this, it appears that adjuvant chemotherapy confers minimal impact on overall- or cancer-specific survival in this group.

No significant financial relationships to disclose.
Major prognostic value of modeled AUChCG-AFP, a dynamic kinetic marker characterizing tumor marker decline of nonseminomatous germ cell tumors (NSGCT) intermediate-poor-risk patients according to the IGCCCG
Authors: Boyle H. , You B. , Fronton L. , Ribba B. , Girard P. , Tranchand B. , Tod M. , Coquelin H. , Droz J. , Flechon A.
Published: August 2020

5085

Background: The level of human chorionic gonadotrophin (hCG) and alpha-foetoprotein (AFP) serum tumor marker is well established in NSGCT as prognostic factor, the relevance of marker kinetic analysis under treatment is still unclear. This may be due to the inaccuracy of methods employed so far, simplifying complex exponential decrease curves by a median half-life (HL). We propose to model patient's AFP and hCG decline profiles in order to calculate area under the curve of marker concentrations versus time (AUChCG-AFP) and to test its prognostic value. Methods: Our retrospective study involved 65 pts treated by 4 cycles of bleomycin-etoposide-cisplatin (BEP) regimen for an intermediate-poor-risk group NSGCT in the same center between 1997 and 2008. A kinetic population approach with NONMEM software was used to model equations of hCG and AFP individual decrease profiles between day 7 (D7) and D42 after the first BEP cycle. AUChCG and AUCAFP were calculated between day D0 and D42 as: AUC0–42=AUC0–7+AUC7–42 where AUC0–7 = trapezium area between D0 and D7 while AUC7–42=integral of modeled equation. Survival univariate and multivariate analyses tested the prognostic value of AUChCG-AFP regarding PFS. Results: Mono-exponential models best fitted AFP and hCG decreases: CAFP (t) = 381*e - 0.14 *t +3.27 and ChCG (t) = 1230*e - 0.25 *t +1.22. Three prognostic groups (AUChCG-AFP) were determined according to AUCAFP median and AUChCG terciles: good if AUCAFP<=11729.4 and AUChCG0–42<=6670; intermediate if AUCAFP>11729 and/or if 6670<=AUChCG<18178 and poor risk if AUChCG>18178 whatever AUCAFP. AUChCG-AFP was a significant prognostic factor in the univariate analysis on the 2 year PFS (100% vs 73.8% vs 67.7%, p = 0.035) as well as IGCCCG score (poor/intermediate risk groups), primary site (mediastinal/other) and HLhCG-AFP. Yet AUChCG-AFP was the only significant independent factor in the multivariate Cox model (HR = 3.3, 95%CI = [1.2–9.2], p = 0.032). Conclusions: Modeled AUChCG-AFP is a dynamic kinetic marker characterizing NSGCT patient marker decline during BEP treatment. These results must be validated in a prospective cohort. It may be a major prognostic factor.

No significant financial relationships to disclose.
On the necessity for postchemotherapy surgery for residual abdominal masses in metastatic nonseminomatous germ cell tumors (NSGCT) of testis
Authors: Harland S. J. , Welch R. , Huddart R. , Stenning S. , Pollock P. , Gabe R.
Published: August 2020

5088

Background: Residual abdominal masses after chemotherapy for metastatic NSGCT of testis may contain viable tumor-derived tissue which can be a nidus for relapse of disease, particularly when the tissue is frankly malignant. This justifies routine retroperitoneal lymph node dissection (RPLND) for large masses where malignant tissue is found at an appreciable rate. Yet RPLND is often carried out for smaller, or even absent, residual masses and differentiated teratoma (TD) is commonly found. There is little data on the consequence of leaving these smaller masses in situ, which is the practice in some units in the UK. Methods: 51 patients were identified from the MRC patients entered into the TE20 trial of 3 vs 4 cycles of BEP for good prognosis metastatic NSGCT who fell into the following category: metastatic NSGCT, residual abdominal mass only, unresected post-chemotherapy, response evaluation: CR or PR marker -ve. Collaborators were asked to report on mass size, relapse status, whether an operation was ever performed and the latest CT appearance. Results: 51/51 responses were received. Follow-up from the end of chemotherapy was >3years in all but two cases and the median was 5 years. When later surgery was carried out, for persistence or enlargement of the masses, the specimens contained TD with or without necrosis. One patient suffered a relapse one year after the surgery which took place 4.5 years after chemotherapy. Of the 41 patients who did not undergo surgery, 37 were considered on subsequent CTs to have normal appearances without further treatment. Conclusions: For patients with small residual masses in good prognosis metastatic disease no short or medium term benefit from routine surgery would have been seen. Its role in this situation is therefore questionable. For larger (>14mm) masses the need for routine surgery merits further study.

[Table: see text]

No significant financial relationships to disclose.
Macroscopic versus microscopic vascular tumour invasion in patients with clear cell renal cell carcinoma: Does it make a difference?
Authors: Zigeuner R. , Hutterer G. , Chromecki T. , Rehak P. , Pummer K.
Published: August 2020

5093

Background: We evaluated the prognostic impact of macroscopic vs. microscopic vascular invasion on metastasis-free survival in a large European single centre series of patients with RCC over a period of 23 years. Methods: The pathology reports of 2333 consecutive patients operated between 01/1984 and 12/2006 were re-evaluated with regard to histological subtype, pT categories (TNM 2002), tumor grade, lymph node status, tumor size, presence of necrosis, and vascular invasion (defined as either absent, microscopic, or macroscopic). Only patients with unilateral clear cell (CC)-RCC and no distant metastases at operation were included. Metastasis-free survival probabilities for patients with absent, microscopic, or macroscopic invasion were evaluated using the Kaplan-Meier method and the log-rank test. For multivariate analysis, a Cox's proportional hazards model was used. Results: Out of 1797 CC-RCC-patients fulfilling the selection criteria, 1754 (97.6%) with complete data including follow-up were evaluated. Microscopic and macroscopic invasion was noted in 99 (5.6%) and 278 (15.8%) tumours, respectively. After a mean follow-up of 95 months, 375/1754 (21.4%) patients developed distant metastases. 10-year metastasis-free survival probabilities were 84%, 55%, and 42% in patients with absent, microscopic, and macroscopic invasion (p < 0.0001 overall; p = 0.13 for microscopic vs. macroscopic). Multivariate analysis proved pT-categories, grade, node status, size, necrosis and overall vascular invasion (p < 0.0001; RR = 2.09, 95%CI = 1.46–2.98) as independent predictors of metastatic disease. When microscopic and macroscopic invasion were differentiated, microscopic invasion remained significant (p < 0.0001; RR = 2.19, 95%CI = 1.54–3.12) whereas macroscopic invasion was not an independent predictor. Conclusions: Our data indicate that both macroscopic and microscopic vascular invasions are associated with poor outcome. Microscopic invasion was an independent predictor of metastatic disease, whereas macroscopic invasion which is directly related to categories pT3b/c was not. Vascular invasion should be considered in prognostic models for patients with RCC.

No significant financial relationships to disclose.
A randomized, open label, prospective study comparing the association between sorafenib (So) and interleukin-2 (IL-2) versus So alone in advanced untreated renal cell cancer (RCC): Rosorc Trial
Authors: Procopio G. , Verzoni E. , Bracarda S. , Ricci S. , Sacco C. , Ridolfi L. , Porta C. , Miceli R. , Zilembo N. , Bajetta E. ,   on behalf of ITMO Study Group
Published: August 2020

5099

Background: So is an orally active multikinase inhibitor with a well documented activity in advanced RCC. IL-2 is a pleiotropic cytokine with antitumoral activity depending on dose and schedule. The aim of the study is to evaluate the activity and the safety of So and IL-2 association compared to So alone. Methods: In this multicenter, randomized, open label, phase II study, 128 previously untreated metastatic RCC patients (pts) were randomized to receive 400 mg of So, orally given twice daily continuously, in combination with IL-2, 4.5 MIU administered subcutaneously, five times a week for six consecutive weeks any eight weeks (arm A), or So alone (arm B) at the same dose. Therapy continued until progression of disease or unacceptable toxicity. The primary end point was progression free survival (PFS) and the secondary endpoints were response rate, safety and overall survival. Eligible pts had histological diagnosis of RCC, ECOG 0–2, no brain metastases, measurable disease and any Motzer's score. Pts were stratified according to different histotypes and Motzer's score. Results: All pts were enrolled from October 2006 to February 2008. Response rates (all partial responses, PR) were 23 % and 10 % in arm A and B respectively. Overall disease control rates (PR + stable disease SD) were 81 % versus 74 %. Tumour shrinkage was reported in 52 % and 34 % of arm A and B therapies respectively. Median PFS was 38 weeks (range 6–104+) for So + IL-2 and 30 weeks (range 6–102+) for So alone. PFS at 1 year was 31% in the combination therapy versus 22% in arm B. The most common adverse events (AEs) were asthenia, hand foot syndrome, hypertension, fever, diarrhoea and mucositis. AE were usually low or moderate in severity and always reversible and manageable. Grade 3–4 AE were reported in 33% and 22% in arm A and B, respectively. Conclusions: The safety and efficacy data suggest that the association So + IL-2 is safe and feasible and, compared to So alone, improves tumour shrinkage, disease control rate and PFS.

[Table: see text]
A phase II trial of perifosine in patients with advanced renal cell carcinoma (RCC) who have failed tyrosine kinase inhibitors (TKI)
Authors: Cho D. C. , Figlin R. A. , Flaherty K. T. , Michaelson D. , Sosman J. A. , Ghebremichael M. , Bowers M. E. , Mier J. W. , Atkins M. B. , McDermott D. F.
Published: August 2020

5101

Background: The recently demonstrated activity of inhibitors of TORC1 in RCC has raised the possibility that even greater effects may be achieved by targeting upstream of this pathway. Perifosine is a synthetic alkylphospholipid which inhibits Akt activity and also has cell-dependent effects upon the MAP-kinase pathway. Prior single-agent trials showed disease stabilization/regression in patients (pts) with advanced RCC; however, few pts were previously treated with a TKI. Therefore, we conducted a multi-center phase II trial to determine the safety and efficacy of perifosine in pts with advanced RCC refractory to VEGFR TKI. Methods: Primary objectives were to measure the % of pts progression-free at 12 weeks (wks) and overall progression-free survival (PFS) of perifosine (100 mg qhs). Secondary objectives included overall response rate (> PR), and safety, Eligibility: ECOG PS 0–1, pts with metastatic RCC who have RECIST defined progression on either sunitinib or sorafenib. Prior Rx with immunotherapy and bevacizumab was permitted. Normal organ and marrow function required. Results: From 4/07–10/08, 24 pts were treated at four sites. Median age 67 (range 47–78) and 16 were male; 90% of pts had predominantly clear cell histology. Prior sunitinib = 12; prior sorafenib = 12 (1.5 avg prior Rx). As of 12/08, all 24 pts were evaluable for PFS, response and toxicity as follows in the table . 6/24 pts remain on treatment (range 7 - 84 wks). Therapy was well tolerated with primarily Grade (G) 1 & 2 adverse events. G 3 & 4 events were: dyspnea (8%), hyponatremia (8%), pulmonary embolism (4%) and arthalgia (4%). Conclusions: Perifosine has promising activity in pts with RCC who have failed prior TKI therapy. The favorable toxicity profile suggests potential for combinational therapies with VEGF-targeted agents. Additional studies are under consideration to evaluate perifosine for clinical benefit in pts with previously treated RCC.

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Association between treatment effects on disease progression (DP) endpoints and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC)
Authors: Delea T. E. , Khuu A. , Kay A. , Zheng J. , Baladi J. F.
Published: August 2020

5105

Background: Access to safe and effective novel therapies may be expedited if DP endpoints (progression-free survival [PFS], time to progression [TTP], or event-free survival) are established as valid surrogates for OS in pivotal studies in mRCC. While the association between DP endpoints and OS has been established in other cancers, it has not been rigorously examined in patients with mRCC. We assessed the association between treatment effects on DP endpoints and treatment effects on OS in controlled trials of patients with mRCC. Methods: A systematic literature search was conducted (Medline, conference abstracts, references of retrieved studies/ reviews) to identify studies meeting the following criteria: controlled trials in mRCC of IL-2, IFN-α, sunitinib, sorafenib, pazopanib, bevacizumab, temsirolimus, or everolimus; English language; publication date≥1997; median time to DP and OS reported for 2 or more treatment groups. For each treatment group comparison, we calculated the differences in median time to DP and median OS and analyzed the association between the differences in median time to DP and differences in median OS using weighted ordinary least-squares (OLS) regression. Results: A total of 21 studies representing 6182 patients, 52 treatment groups, and 35 comparisons were identified. The median difference between treatment groups in time to DP averaged 1.3 months; the median difference between treatment groups in OS averaged 2.8 months. The correlation between differences in median time to DP and differences in median OS was 0.69 (p < 0.0001). In weighted OLS regression, a 1 month difference in DP was associated with a 1.4 month difference in OS (p < 0.0001, adjusted R-sq = 0.46). Conclusions: In patients receiving treatment for mRCC, treatment effects on DP endpoints are predictive of treatment effects on OS.

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Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases from renal cell carcinoma: Comparison between France, Germany, and the United Kingdom
Authors: Botteman M. F. , Kaura S.
Published: August 2020

5106

Background: Zoledronic acid (ZOL) significantly reduces the risk of new skeletal-related events (SREs) in patients (pts) with bone metastases from RCC. This study assessed and compared the cost-effectiveness of ZOL in pts with RCC from French, German, and United Kingdom (UK) societal perspectives. Methods: This analysis was based on a retrospective analysis of RCC pts with bone metastases who were enrolled in a 9-mo trial of ZOL or placebo (PBO) plus concomitant antineoplastic therapy. A model was developed to simulate costs and quality-adjusted life-years (QALYs) experienced by study pts. The model included data and assumptions regarding SRE incidence, mortality, drug and administration costs, SRE costs, reduced quality of life (QOL) because of SREs and bone pain, and therapy duration. SRE costs were estimated using diagnosis-related group tariff information and published literature. Consistent with similar economic analyses, it was assumed that QOL decreased 20% to 80% (depending on SRE type) for 1 mo after each SRE experienced. Sensitivity analyses were performed to test the effects of alternate assumptions, with < 30,000/QALY considered cost-effective. Results: Compared with PBO-treated pts (n = 19), ZOL-treated pts (n = 27) experienced 1.07 fewer SREs/pt and gained discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among pts treated with ZOL vs PBO (-4,196 in France, -3,880 in Germany, and -3,355 in the UK). After including drug therapy costs, ZOL saved 1,358, 1,223, and 719 per pt in France, Germany, and the UK, respectively. In multivariate sensitivity analyses, ZOL saved costs in 67% to 77% of cases, depending on the country. ZOL resulted in a cost per QALY gained < 30,000 in approximately 93% of cases. Conclusions: Treatment with ZOL reduces SREs, improves QOL, and lowers health-related costs compared with PBO in French, German, and UK pts with bone metastases from RCC. Use of ZOL in these populations therefore provides health-related cost savings and is a cost-effective use of healthcare resources.

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Identification of baseline predictive markers of sunitinib activity using a human cytokine antibody array in patients with metastatic renal cell carcinoma (MRCC)
Authors: Perez-Gracia J. , Prior C. , Guillen-Grima F. , Gonzalez A. , Panizo A. , Segura V. , Grande-Pulido E. , Gurpide A. , Melero I. , Calvo A.
Published: August 2020

5113

Background: Several drugs are available for treatment of MRCC and predictive markers to select the most appropriate therapy for each patient are needed to improve efficacy and to avoid unnecessary toxicities and costs. Methods: Serum samples were collected prospectively in 31 patients treated with sunitinib at baseline and at the time of response evaluation by RECIST criteria. Serums of 6 patients with extreme phenotypes of marked responses (3) or clear progressions (3) were analyzed with a Human Cytokine Antibody Array (Series 2000, RayBiotech, Norcross, GA. USA) which evaluates 174 cytokines related to angiogenesis and tumor proliferation pathways and has been validated in clinical studies. Cytokine intensity levels were compared between both groups at baseline and after response evaluation and fold-change differences were calculated. Following array data normalization, the most relevant cytokines based on statistical significance and on biological plausibility, were assessed with ELISA in the whole group of patients and the results were correlated with clinical benefit (response or disease stabilization) or progression. Results: 27 of the 174 cytokines varied significantly between patients presenting response or progression. Six of them (TNF-α, MMP-9, ICAM-1, BDNF, SDF-1α and VEGF) were assessed with ELISA in 22 evaluable patients. TNF-α and MMP-9 baseline levels were significantly increased in non-responders and they were significantly associated with progression-free and overall survival respectively. The area under the ROC curves of TNF-α and MMP-9 as predictive factors of sunitinib clinical benefit were respectively 0.8287 and 0.7685, indicating good accuracy. Conclusions: Baseline serum levels of TNF-α and MMP-9 warrant further study as predictive markers of sunitinib activity in patients with MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.

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A cytokine and angiogenic factor (CAF) plasma signature for selection of sorafenib (SR) therapy in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Heymach J. , Jonasch E. , Wang X. , Du D. Z. , Yan S. , Xu L. , Herynk M. H. , McKee K. S. , Tran H. T. , Tannir N. M. , Zurita A. J.
Published: August 2020

5114

Background: SR, an oral inhibitor of Raf kinase, RET-receptor (R), VEGFR-1, 2, and 3, PDGFR-β, FLT-3, and c-KIT tyrosine kinases, has been shown to prolong progression-free survival (PFS) in mRCC after cytokine failure. In a phase II trial, mRCC pts were randomized to first line treatment with SR vs. SR plus interferon (IFN) to assess whether combination therapy improved PFS. Both treatment arms showed similar outcomes (Tannir et al, ASCO. 2008). Here we investigated predictive and prognostic biomarkers in plasma. Methods: Pts received SR 400 mg PO BID or same dose SR plus IFN 0.5 MU SC BID. Plasma was collected from 69 pts at baseline (BL; SR 34, SR+IFN 35), 59 on day (D) 28, and 57 pts on D56. We used multiplex bead suspension arrays to measure concentrations of 54 CAFs, including VEGF, PDGFbb, EGF, HGF, MMP-9, and multiple chemokines and interleukins (IL). Osteopontin (OPN), soluble carbonic anhydrase 9 (sCA9), placental growth factor (PlGF), collagen type IV (ColIV) and sVEGFR-2 were measured by ELISA. The primary objective of this analysis was to establish a CAF signature based on a set of individual markers at BL with a significant and differential impact on the association between treatment arm and PFS. Results: Among 52 CAFs available at BL, higher than median EGF concentrations associated with poor outcome independently of treatment arm, whereas low IL-2 had the opposite effect (p = 0.003 for both). Only OPN showed a significant treatment by factor interaction at BL (p < 0.01), suggesting that OPN has a differential effect on PFS in the two arms. Pts with high OPN benefitted more from single agent SR (7.74 vs. 3.93 mos for the combination; p = 0.007), but no differences were found for those with low OPN. Lower than median on-treatment increases in sCA9 (D28, p = 0.01) and GRO-alpha (D56, p = 0.04) on SR only were also associated with a better outcome. A 6-marker CAF signature at BL containing OPN, sCA9, VEGF, sVEGFR-2, ColIV, and TRAIL demonstrated predictive value on PFS. Conclusions: A CAF signature showed potential value in predicting differential benefit from single agent SR vs. SR+IFN in mRCC. Broad-based screening of circulating CAFs may identify predictive and prognostic biomarkers in the context of clinical trials.

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A translational phase II trial of celecoxib plus interferon-alpha (IFN-α2b) in metastatic renal cell carcinoma (RCC) patients (pts) with 3+ COX-2 tumor immunostaining
Authors: Schwandt A. , Garcia J. A. , Elson P. , Wyckhouse J. , Finke J. H. , Ireland J. , Triozzi P. , Zhou M. , Dreicer R. , Rini B. I.
Published: August 2020

5116

Background: Cyclooxygenase-2 (COX-2) has been correlated with RCC stage and grade, and overexpression can lead to dysregulation of dendritic cells (DC) and CD4+/CD25+/FOXP3+ regulatory T cells (Treg). A previous trial of celecoxib in combination with IFNα2b in RCC (Rini et al, Cancer. 2006) demonstrated an association between more intense COX-2 RCC tumor staining and clinical response. Methods: Pts with cytokine-naïve mRCC with at least 10% maximal COX-2 tumor staining received IFNα2b MU five times/week plus celecoxib 400 mg BID continuously. Baseline tumor tissue was stained for COX-2, CD4+ and CD8+ T cells, Treg and DC (s100 and CD208). Peripheral blood prostaglandin E2 (PGE2), DC and Treg number/function and intracellular T cell cytokine production were measured at baseline, at the end of cycles 2 and 4 and at end of treatment. Activation of DC was assessed by IL-12 and IL-10 mRNA and protein production by ELISA. The primary endpoint was objective response rate (ORR). Secondary endpoints were DC / Treg number and cytokine production changes with therapy. The trial tested a null hypothesis of ORR <20% vs. alternative hypothesis of ORR >40%; beta = 0.8 and alpha = 0.05 (n = 34). Immune parameters were analyzed using non-parametric methods. Results: Fourteen pts have been enrolled; 79% male, median age 62 (range, 43–74) and 64% ECOG performance status 0. All pts had prior nephrectomy and 36% had received prior tyrosine kinase inhibitors (TKI); MSKCC Risk Group was favorable 14%, intermediate 71%, and unfavorable 14%. The ORR was 21% and 69% of pts experienced tumor shrinkage. Median PFS is 4.4 months. Toxicity was as expected for IFN therapy. Baseline 3+ COX-2 staining was associated with elevated peripheral blood PGE2 levels (p = 0.02), reduced DC IL-12 expression (p = 0.04) and reduction in IFN gamma-producing CD3+CD4+ T-cells (p = 0.04) compared to a control group of RCC pts with <10% 3+ COX-2 staining (n = 21). No significant changes in immunomodulatory cells were observed with therapy. Conclusions: COX-2 inhibition in combination with IFNα2b in maximal COX-2-expressing mRCC pts has clinical activity. COX-2 RCC tumor expression promotes an immunosuppressive phenotype.

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