bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): Impact of crossover on survival
Authors: Eisen T. , Bukowski R. M. , Staehler M. , Szczylik C. , Oudard S. , Stadler W. M. , Schwartz B. , Simantov R. , Shan M. , Escudier B.
Published: March 2020

4524

Background: Sorafenib was approved for advanced RCC in the USA December 2005. A Phase III randomized double-blind, placebo-controlled trial demonstrated an estimated 39% improvement in survival for patients receiving sorafenib versus placebo (HR= 0.72, p = 0.018) (ECCO 2005). These data supported independently reviewed doubling of PFS to 24 weeks in RCC patients receiving sorafenib compared with placebo (12 weeks) (p < 0.000001) (ASCO 2005). Based on the statistical significance and magnitude of PFS benefit, patients were unblinded and placebo patients allowed to crossover to sorafenib in April 2005. A prospectively planned interim OS analysis reflecting impact of crossover of placebo patients is presented. Methods: OS data up to November 30, 2005, were analyzed in this interim analysis using a stratified log-rank test comparing the two treatment groups. In order to examine the effect of crossover on OS, a secondary analysis was performed censoring data from patients randomized to placebo at June 30, 2005. Results: A total of 903 patients were randomized (451 to sorafenib, 452 to placebo) and >200 placebo patients crossed over to sorafenib. Baseline characteristics were similar between treatment arms. There were 367 deaths. The median OS was 19.3 months for sorafenib versus 15.9 months for placebo (HR = 0.77; 95% CI 0.63, 0.95; p = 0.015); although this did not attain the level of significance specified for the interim analysis (α = 0.009), a continued favorable trend in survival benefit was observed. With censoring of crossover data, the median OS was 19.3 months for sorafenib versus 14.3 months for placebo (HR = 0.74, 95% CI 0.58, 0.93; p = 0.010). Conclusion: Sorafenib is the first novel, oral approved treatment for advanced RCC in more than a decade. Previous information on the effect of crossover on OS in randomized oncology studies is limited. The lower HR observed after censoring placebo patients crossed over to sorafenib suggests a continued beneficial effect of sorafenib. Final results await more mature data.

[Table: see text]
A comparison of quality of life and symptoms in kidney cancer patients receiving sorafenib versus placebo
Authors: Dhanda R. , Gondek K. , Song J. , Cella D. , Bukowski R. M. , Escudier B.
Published: March 2020

4534

Background: Results from the Phase III TARGETs study showed that sorafenib significantly prolonged progression-free survival compared with placebo in patients with advanced renal cell carcinoma. Overall survival was longer with sorafenib than placebo with a hazard ratio of 0.72. The impact of sorafenib treatment on health-related quality of life (HRQL) and symptoms was also evaluated. Methods: HRQL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G). Symptoms were measured by the FACT-Kidney Cancer Symptom Index (FKSI), in which patients used a Likert scale (0–4) to respond to each of 15 items. FACT-G and FKSI were administered at baseline, at Day 1 of each cycle, and at end-of-treatment visit. Statistical analyses used a random coefficient model over five cycles, using MSKCC risk and treatment as factors and baseline score and relative days as covariates, adjusted for multiple comparisons with Bonferroni correction. Results: A total of 903 patients were randomized. The FACT-G completion rates at baseline, and Cycles 2, 3, 4, and 5 were; 96%, 91%, 95%, 99%, and 100%, respectively. The FKSI completion rates were; 94%, 89%, 94%, 97%, and 100%, respectively. The completion rate within each patient reported outcome (PRO) measure, across all visits, was 93%. At baseline, there was no between-treatment difference in score for either FACT-G or FKSI. There was no treatment difference after adjusting for multiple comparisons in mean FACT-G total score (p = 0.96) or its domains (physical well-being [p = 0.92]; emotional well-being [p = 0.46]); social well-being [p = 0.75]; functional well-being [p = 0.94]), and no difference in total score of FKSI over time. FKSI single-item analysis showed that sorafenib-treated patients had significantly less symptoms vs placebo (e.g. cough [p < 0.0001], fevers [p = 0.0015], ‘worry that condition will worsen’ [p = 0.0004], shortness of breath [p ≤ 0.0312], and ‘ability to enjoy life’ [p = 0.0119]). Only ‘concern about treatment side-effects’ favored placebo patients (p < 0.0001). Conclusions: Sorafenib demonstrates clinical benefit without adversely impacting overall HRQL, and has a positive impact on individual symptoms.

[Table: see text]
Is intravenous (iv) IL2 superior to subcutaneous (sc) IL2 in good prognosis patients (pts) with metastatic renal cell carcinoma (MRCC) receiving a combination of IL2 and alpha interferon (IFN)? Results of the prospective randomized PERCY Duo trial
Authors: Negrier S. , Perol D. , Ravaud A. , Bay J. O. , Oudard S. , Fargeot P. , Delva R. , Deplanque G. , Gravis G. , Escudier B.
Published: March 2020

4536

Background: Pts with a single metastatic site are more likely to benefit from an IL2 and IFN combination (Negrier NEJM 1998). The French Immunotherapy Intergroup designed a multicenter trial to assess the potential benefit of iv over sc IL2 in IL2+IFN combination in this subgroup. Methods: Untreated pts, Karnofsky score ≥ 90 and a single metastatic site were randomized into this 2 arm trial. Pts received continuous IL2 infusion (18 million IU/m2/d) (arm A), or sc IL2 injections (9 or 18 million IU) twice daily (arm B). IFN was given sc (6 million IU) 3d/week in both arms. Tumor responses (OMS criteria) were assessed at weeks 12 and 27. The primary endpoint was overall survival (OS), with an expected difference of 15% at 4 yrs in favor of iv IL2. The planned sample size was 220 to have 80% power at 5% significance level with a one-sided test. One intent-to-treat analysis was performed and survivals were compared using log-rank tests. Results: From January 00 to January 05, 80 and 75 pts were randomized to arms A and B respectively. Enrollment was stopped early due to low accrual; analysis was performed at 40-month median follow up. Patient characteristics were well balanced between groups. Median age was 55, 82% pts were male, 68% had lung metastases, and 37% had more than 1 year from renal tumor to metastases. No toxic death occurred, gr 3/4 vomiting, rise in creatinine level, hypotension and neurologic toxicity were significantly higher in arm A. Response rates were 17.9 vs 21.3%, in arms A and B, respectively. Progression-free survivals were not significantly different (P: 0.285). The difference in OS was not significant: median 37.7 months [95%CI: 28.2–58.4] with iv IL2 vs. 26.3 [95%CI: 24.5–34.2] with sc IL2 (P: 0.127). Conclusions: Iv IL2 combined with IFN confers no significant advantage over a sc IL2 combination in selected pts with good prognosis MRCC. Since some toxicities were significantly more frequent with iv IL2, the use of this combination cannot be recommended. Because of premature stop, the trend in favor of iv IL2 should encourage further studies before final conclusions can be drawn.

[Table: see text]
Stage one seminoma: Evidence based guidelines for follow up
Authors: Martin J. M. , Panzarella T. , Zwahlen D. R. , Chung P. W. , Warde P.
Published: March 2020

4546

Background: Several management strategies are used following ochiectomy for stage one seminoma (SOS) of the testis. The aim of this systematic review (SR) is to provide evidence based guidelines for the follow-up (FU) schedule for each strategy regarding investigations required, frequency of assessment and overall duration. Methods: A SR of all prospective studies in SOS published since 1980 in MEDLINE, EMBASE and the Cochrane database was performed in November 2005. Data was extracted regarding the time, location and method of detection of first relapses, duration of FU, relapse free rates, and numbers of patients at risk. Five strategies were identified: Surveillance (S), Extended-field Radiotherapy (EFRT), Para-aortic Radiotherapy (PART) and either one (C1) or two (C2) cycles of Carboplatin chemotherapy. For each strategy Kaplan-Meier relapse free estimates were used to calculate weighted mean cumulative hazards of relapse over time. These were used to calculate yearly weighted mean relapse hazards. Weights used were based on numbers of patients at risk in each trial. Results: Fifteen prospective studies with a total of 5277 patients were identified. Actuarial relapse data was available in 4185 (79.3%) patients and 4850 (91.9%) had the location of relapse documented. Method of relapse detection was infrequently reported. The median time to relapse with all strategies was 12–16 months. Annual hazard ratios for relapse decreased with increasing length of FU and relapse location depended on the strategy used ( Table ). Conclusions: 1. The investigations performed need to reflect locations at risk of relapse. This should include computerised tomography (CT) of the abdomen and pelvis for Survillance and adjuvant Carboplatin, with CT of the pelvis only for Para-aortic RT. 2. Long term FU data on patients treated with Carboplatin is not available, and further FU is necessary. 3. Frequency of FU should reflect the annual hazard of relapse. We suggest 3 times per year when the risk is >5%, 2 times per year when the risk is 1–5%, and annually until the risk is <0.3%.

[Table: see text]

No significant financial relationships to disclose.
Salvage chemotherapy with high dose carboplatin + etoposide (HDCE) and peripheral blood stem cell transplant (PBSCT) in patients with germ cell tumors (GCT)
Authors: Einhorn L. H. , Williams S. , Abonour R.
Published: March 2020

4549

Background: We began studies with HDCE for patients (pts.) with recurrent GCTs 20 years ago. During the past decade, better supportive care and use of PBSCT allowed outpatient therapy and more rapid hematopoietic recovery between the 2 courses of HDCE. Methods: Retrospective review of 184 consecutive pts. treated with HDCE at Indiana University from 2–96 to 12–04. Late relapse (> 2 years from prior therapy) and primary mediastinal non-seminomatous germ cell tumor pts. were not offered HDCE. Cytoreduction with 0–2 courses of vinblastine + ifosfamide + cisplatin preceded HDCE. C dosage was 700 mg/M2 × 3 and E 750 mg/M2 × 3. A second course was given after hematologic recovery. Results: Toxicity was as previously described (JCO 18:3346, 2000). There were 3 drug- related mortalities. An additional 3 patients developed AML (2 fatal), and 1 glioma following CNS XRT for metastases. 11 pts. did not receive second course (8 due to progression or HDCE mortality). Median time to second course HDCE was 28 days (range 20 to 42). 116 of 184 pts. are alive and continuously (cont) NED (63%) with median followup 42 months (range 11 to 118). 113 (97%) of these are 12+ months NED. 5 additional pts. are currently NED with further therapy. Results are tabulated below. Conclusions: HDCE has a high cure rate with acceptable toxicity as salvage therapy for GCT pts.

[Table: see text]

[Table: see text]
Predicting recurrence following post-chemotherapy retroperitoneal lymph node dissection for residual fibrosis or teratoma
Authors: Carver B. S. , Shayegan B. , Motzer R. J. , Bajorin D. , Kondagunta G. V. , Bosl G. J. , Sheinfeld J.
Published: March 2020

4551

Background: The current recommendation for the management of patients with the histologic finding of fibrosis or teratoma at PC-RPLND is surveillance. We evaluated men at our institution who underwent PC-RPLND for metastatic non-seminomatous germ cell tumor (NSGCT) to determine predictors of disease recurrence. Methods: From 1989 through 2003, a total of 532 men underwent PC-RPLND for metastatic NSGCT at our institution. Of these, 473 (89%) had either fibrosis or teratoma present in the RPLND specimen. Following IRB approval, clinical and pathologic data were obtained from our prospective surgical database. A Cox regression model was constructed to evaluate variables that may predict for recurrence of viable NSGCT following PC-RPLND and a prognostic index was developed. Freedom from disease recurrence was analyzed using the Kaplan Meier method. Results: Of the 473 patients with fibrosis or teratoma, all patients underwent complete resection of all residual retroperitoneal masses, however 35 (7%) did not undergo a full PC-RPLND. With a median follow-up of 41 months, 47 (10%) patients relapsed with viable NSGCT. The 2- and 5- year probability of freedom from recurrent viable GCT for the entire cohort was 90% and 89%, respectively. In our multivariable model only post-chemotherapy nodal size > 5cm (p = 0.008), clinical stage III (p = 0.002), and absence of a full PC-RPLND (p = 0.002) were independent predictors for recurrence with viable NSGCT. Based on these three adverse predictors, a prognostic index was developed with favorable patients having no risk factors, intermediate prognosis patients with one risk factor, and poor prognosis patients having 2 or more risk factors. Favorable, intermediate, and poor prognosis patients had a 2-year progression free probability of 97% (95% CI 95–99%), 90% (95% CI 85–95%), and 66% (95% CI 54–78%), respectively (p < 0.001). Conclusions: This data suggests that patients who have a high risk of reucrrence with viable GCT should undergo more frequent follow-up during the first 2-years with serum tumor markers and imaging. Additionally, this data suggests that an incomlete RPLND is not sufficient surgery for men with metastatic NSGCT. These men should undergo a bilateral RPLND.

No significant financial relationships to disclose.
Prostate-specific antigen velocity and the odds of detecting gleason 8 to 10 prostate cancer at biopsy
Authors: D’Amico A. V. , Cullen J. , Chen Y. , McLeod D. G.
Published: March 2020

4567

Background: Increased detection of high-grade prostate cancer was observed in the Prostate Cancer Prevention Trial (PCPT) in men receiving finasteride that halves prostate-specific antigen (PSA) and eliminates subsequent PSA rise from benign prostatic hyperplasia. Therefore despite doubling PSA, men receiving finasteride needed a larger PSA rise to exceed 4 ng/ml and have prostate biopsy recommended compared to placebo. We evaluated whether the PSA rise during the year before biopsy (PSA velocity) was associated with prostate cancer detection. Methods: Between 1/90 and 12/03, of 2125 prostate biopsies performed for a PSA exceeding 4 ng/ml or a nodule on digital rectal examination (DRE), prostate cancer was identified in 1418. Multivariable logistic regression analyses were performed evaluating the detection of Gleason 6 or less, 7, or 8 to 10 cancer. Covariates included the continuous variables of PSA velocity and level, number of prior negative biopsies and age and the categorical variables of ethnicity, DRE findings and family history. Results: As shown in the table , PSA velocity was only associated with Gleason 8 to 10 cancers (Adjusted Odds Ratio: 1.05 [95% Confidence Interval: 1.02 to 1.08]; p = 0.001). Age, PSA level and DRE status were associated across Gleason scores (p-values 0.005 or less), whereas family history (p-values 0.02 or less) and number of prior negative biopsies (p-values 0.01 or less) were associated with Gleason 7 or less cancers. Conclusion: PSA velocity is associated with Gleason 8 to 10 cancers at biopsy providing rationale for the PCPT results and a tool to enhance detection of clinically significant prostate cancer.

[Table: see text]

No significant financial relationships to disclose.
Factors influencing prostate cancer specific mortality in patients receiving delayed androgen deprivation therapy for metastasis after biochemical recurrence following radical prostatectomy
Authors: Makarov D. V. , Trock B. J. , Humphreys E. B. , Mangold L. A. , Carducci M. A. , Partin A. W. , Eisenberger M. A. , Walsh P. C.
Published: March 2020

4571

Background: For men developing PSA failure after radical prostatectomy (RP), administration of immediate androgen deprivation therapy (ADT) has not been shown to improve survival compared to delaying ADT until evidence of metastatic disease. We evaluated factors influencing prostate cancer (PCa) specific mortality (PCSM) in a cohort of PSA era patients developing metastases after RP treated with delayed ADT. Methods: 3,658 men had RP by a single surgeon at Johns Hopkins Hospital from 4/82 until 6/05. 553 had PSA failure. 216 developed radiographically evident distant metastasis. Of these, 91 men formed the study cohort: initially treated during the PSA era (1987–2005), received ADT only after documented metastasis, and having complete data. 41 of these men died. Median failure times were estimated with the Kaplan-Meier method. Prognostic impact was estimated as the hazard ratio (HR) derived from the Cox proportional hazards model. Results: Median followup from RP was 10 yrs (range 2–18). Actuarial median failure times are: 1 yr from RP to PSA failure (range 1–11), 32 mos from PSA failure to metastasis (range 0–129), 79 mos from metastasis to death (range 7–181), and 13 yrs from RP to death (range 2–18). The following variables were significant prognostic factors for PCSM in univariate analyses: Pain at diagnosis of metastases (p < 0.01), time from RP to metastasis (p = 0.02), hematocrit at metastasis (p < 0.01) and PSADT <3 mos during the 2 years prior to metastasis (p < 0.01). A multivariable Cox proportional hazards model demonstrated the following independent predictors of PCSM: pain (HR = 10.5 p < 0.01), PSA at metastasis ≥100 ng/mL (HR = 5.3 p < 0.01) and PSADT < 3 months (HR = 7.1 p < 0.01). PSADT determined in the two years immediately after PSA failure (HR = 1.0 p = 0.37) and time from RP to bone metastasis (HR = 1.0 p = 0.80) were not independent predictors of PCSM. Conclusion: Men receiving delayed ADT for development of metastasis after RP may have a prolonged survival time (13 yrs post RP - range 2–18). Optimizing the time for ADT in these patients requires well-designed, prospective randomized studies. Our data may facilitate the selection of patients and thresholds for implementation of ADT.

No significant financial relationships to disclose.
Quality of life in young men after radical prostatectomy: Results from the CaPSURE registry
Authors: Wright J. L. , Lin D. W. , Cowan J. E. , Duchane J. , Carroll P. R. , Litwin M. S.
Published: March 2020

4576

Background: Over the past two decades, the age at diagnosis and treatment of men with prostate cancer (CaP) has steadily declined. Previous work suggests that younger men have similar or improved pathologic and clinical outcomes compared to older men. The literature on quality of life (QOL) following local treatment for CaP has primarily focused on comparing treatment modalities rather than specific age groups. This analysis explored QOL outcomes in younger men following primary curative treatment for localized prostate cancer. Methods: This was a secondary analysis of a prospectively collected cohort from the CaPSURE (Cancer of the Prostate Strategic Urologic Endeavor) registry. Men who underwent radical prostatectomy (RP) for localized disease and completed the UCLA Prostate Cancer Index (PCI) pre- and one-year post-surgery were identified. Men were grouped based on age (< 55, 55–64, ≥ 65 years). A severe decline in PCI domains from pre- to post-RP was defined as a decrease of one standard deviation from the pre-RP score. PCI scores were compared across age groups, and a multivariate model created to analyze the predictors of severe declines in PCI domains. Results: 1,143 men were identified, with 190, 526 and 427 men in the three age groups, respectively. Younger men had significantly higher mean scores one-year after RP in the urinary function (UF), urinary bother (UB) and sexual function (SF) domains of the PCI. The proportion of men with a severe decline in UF, UB and SF was not significantly different in the age groups (range 49–54%, 32–38%, 58–51% respectively). However, a severe decline in SB was more common in the youngest age group than in the oldest (54% vs. 36%, p < 0.01). With the youngest men as the reference group in the multivariate model, the oldest age group was 40% less likely to have a severe decline of SB (OR = 0.60, 95% CI 0.41–0.90, p = 0.04) but trended toward a higher risk of severe decline in UB (OR = 1.27, 95% CI 0.85–1.89, p = 0.08). Conclusions: Age predicts disease-specific QOL changes at one-year following RP. Younger men had significantly better mean UF, UB, and SF domain scores one-year after RP than did their older counterparts. Men < 55 years old are more likely than older men to experience a severe decline of sexual bother but trend toward a lower risk of a severe urinary bother.

No significant financial relationships to disclose.
Patterns of primary therapy for prostate cancer in elderly men: Analysis of data from CaPSURE
Authors: Konety B. , Cowan J. , Duchane J. , Carroll P.
Published: March 2020

4577

Background: It is generally acknowledged that men who are most likely to derive benefit from therapy for prostate cancer are those with a life expectancy of greater than 10 years. We examined the patterns of primary treatment for prostate cancer in men ≥75 years of age who would have a life expectancy of approximately 10 years. Methods: We examined data from the multi-institutional CaPSURE database on type of primary therapy received for prostate cancer in men < and ≥75 years. Primary therapy was defined as watchful waiting (WW), radical prostatectomy (RP), brachytherapy (BT), BT plus external beam radiotherapy (BT+EBRT), EBRT or primary androgen deprivation therapy (PADT). Chi square tests and multinomial logistic regression analysis were performed to identify predictors of type of primary therapy. Results: The median age of the entire population (n = 10,764) was 67 years and 18% of the dataset were patients ≥75 years. A greater proportion of patients ≥75 years were white, single, had multiple co-morbidities, had low income and low education levels and were classified as high risk (43% vs. 25%) compared to those <75 years. Men ≥75 years were more likely to have received EBRT, PADT or WW (all p < .01). In a multivariate analysis adjusted for socio-demographic factors, diagnostic risk category, and number of co-morbidities at diagnosis, patients ≥75 years were less likely to be managed with primary therapy than with WW regardless of risk category or level of co-morbidity: BT (OR 0.21, 95%CI 0.15–0.31), BT/EBRT (OR 0.21, 95%CI 0.16–0.28), EBRT (OR 0.29, 95%CI 0.22–0.37), PADT (OR 0.64, 95%CI 0.51–0.81), and RP (OR 0.01, 95%CI 0.01–0.02). Conclusions: Older patients are far more likely to received WW as primary therapy regardless of burden of co-morbidity or risk level of primary cancer. A more tailored approach to prostate cancer therapy taking into account co-morbidity and functional level to decide primary therapy may be more appropriate in elderly men. Well selected older patients with high risk disease, particularly those with low co-morbidity levels, may derive survival benefit from primary therapy other than WW.

[Table: see text]
Phase I/II study of vicinium given by intravesical administration in patients with superficial transitional cell carcinoma of the bladder: Phase I results
Authors: Fitsialos D. , Seitz S. , Wiecek E. , Rasamoelisolo M. , Entwistle J. , Jewett M. , MacDonald G. C. , Glover N.
Published: March 2020

4580

Background: Vicinium is a fusion protein comprised of a humanized scFv, specific for Ep-CAM (epithelial cell adhesion molecule), and a truncated fragment of Pseudomonas exotoxin A. Ep-CAM is highly expressed on carcinoma cells including superficial transitional cell carcinomas (TCC) of the bladder. Vicinium targets and kills Ep-CAM-positive tumors. Results from the Phase I arm of a Phase I/II trial where Vicinium was instilled into the bladders of patients with superficial TCC of the bladder showed the drug to be very well tolerated and showed promising clinical results. Methods: 64 patients with Ep-CAM positive superficial TCC of the bladder, Ta, Tis or T1, Grades 2 or 3 who were refractory or intolerant to BCG therapy were admitted into the study. Dosing comprised a minimum of 3 subjects per dose level through 12 escalating doses. Vicinium was given once/week for 6 consecutive weeks by intravesical administration into the bladder via a catheter at escalating dose levels of 0.1, 0.2, 0.33, 0.66, 1.32, 2.64, 5.28, 10.56, 13.73, 17.85, 23.2 and 30.16 mg/week. All toxicities were assessed according to the NCI CTC v3. Blood samples were collected at different times in the study to determine systemic drug exposure and to assess immunogenicity. Efficacy was explored via biopsy, cystoscopy, urine cytology and FISH. Results: Vicinium was very well tolerated at all doses. Almost all (64/65) patients were positive for the Ep-CAM antigen. Pharmacokinetic analysis showed no evidence of Vicinium in the circulation of any of the patients; however, the majority of patients developed an anti-Vicinium response. Most patients, in particular at the higher doses, showed decreased tumor cell numbers by FISH analysis by the final day of treatment with the greatest sustained effect being observed in patients with the higher percentage Ep-CAM-positive tumors. Conclusions: Vicinium dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. The early clinical benefit observed with Vicinium strongly supports its development as a promising therapy for superficial transitional cell carcinoma of the bladder. The phase II arm of the trial will confirm the safety and further assess the efficacy of Vicinium at a recommended Phase II dose.

[Table: see text]
Relationship between insulin-like growth factor-1 and human testicular cancer
Authors: Kortsaris A. H. , Diamantopoulos N. , Galaktidou G. , Andreadis C. , Boutis A. L. , Zavos C. , Mouratidou D.
Published: March 2020

4586

Background: Insulin-like growth factor (IGF) has an established role in various types of cancer inducing cellular proliferation, possessing anti-apoptotic properties, and stimulating angiogenesis. We have recently published the concept that IGF-1 system might also be implicated in the pathogenesis of testicular germ cell tumors. The present study aims to elucidate our initial concept by measuring IGF-1, IGF-binding protein (IGFBP)-3, and their molar ratio in patients with testicular cancer. Methods: We measured serum IGF-1 and IGFBP-3 using solid phase Elisa in 48 patients (mean age 31,6±8,07 years) with testicular cancer who underwent chemotherapy, and in 10 healthy male, age-matched (mean age 31.2 ± 2.54), controls. Three serum samples were obtained from patients with testicular cancer: prior to chemotherapy (baseline), before cycle 3, and 9–14 months after completion of chemotherapy. One serum sample was obtained from controls. Results: Baseline mean serum IGF-1, IGFBP-3, and molar ratio IGF-1:IGFBP-3 were 254.3 ± 242 ng/ml, 3541 ± 1740 ng/ml, and 0.293 ± 0.268 in patients, and 145.8 ± 110 ng/ml, 5440 ± 3504 ng/ml, and 0.108 ± 0.168 in controls (p = 0.048, p = 0.016, and p = 0.047, respectively). Mean IGF-1, IGFBP-3, and IGF-1:IGFBP-3 before cycle 3 were 242.4 ± 177.6 ng/ml, 3606 ± 2491 ng/ml, and 0.28 ± 0.234 (p = NS in all 3 parameters). Not all 48 patients have as yet completed chemotherapy; however, preliminary results from 10 patients show a trend for normalization in mean values of the third sample (IGF-1: 157.5 ± 129.4 ng/ml, IGFBP-3: 4500 ± 2351 ng/ml, and IGF-1:IGFBP-3: 0.141 ± 0.128), comparable to those of healthy controls. A trend for higher baseline IGF-1 values was noticed in patients with poor prognosis (n = 6, IGF-1: 367.5 ± 228.7 ng/ml) compared to those with good prognosis (n = 28, IGF-1: 211.1 ± 207.8 ng/ml). Conclusions: These results confirm our initial concept that IGF-1 system may play a significant role in testicular cancer. The trend showing that chemotherapy decreases IGF-1, IGFBP-3, and their ratio to normal, may provide evidence that these parameters can be useful surrogate markers for diagnosis and surveillance of testicular tumor growth.

No significant financial relationships to disclose.
Assessment of coronary heart disease risk in testicular cancer survivors
Authors: Palmer S. C. , Carver J. , Jacobs L. , Schmitz K. H. , Fung C. , Mohler E. , Vaughn D. J.
Published: March 2020

4592

Background: Testicular cancer survivors (TCS) who receive cisplatin-based chemotherapy (CBCT) are reported to have an increased risk of coronary heart disease (CHD) compared to chemo-naive TCS (J Clin Oncol 21:1513–1523, 2003). We hypothesized that TCS treated with CBCT would demonstrate abnormal objective measures of future CHD risk compared to chemo-naive TCS. Methods: TCS ≥ 2 years from diagnosis underwent evaluation using established objective measures predictive of future CHD risk: body mass index (BMI), Framingham relative risk (RR), flow-mediated endothelium-dependent vasodilation of the brachial artery (FMD), carotid artery intima-media thickness (IMT), serum intercellular adhesion molecule-1 (ICAM-1), and high sensitivity C-reactive protein (hs-CRP). Data were analyzed using parametric and non-parametric statistics as appropriate. Results: 30 TCS who received CBCT and 20 chemo-naive TCS were recruited. The mean age and time from diagnosis were similar between the 2 groups. Both groups demonstrated elevated BMI, increased Framingham RR, and impaired FMD, consistent with an increased risk of CHD. However, there were no statistically significant differences in these measures between the two groups. Carotid IMT, ICAM-1, and hs-CRP were not significantly abnormal and these measures also did not differ between the two groups. Conclusions: TCS demonstrate abnormal objective measures of CHD risk in both CBCT-treated and chemo-naive groups. These data suggest that behavioral interventions to modify CHD risk should target all TCS independent of chemotherapy status. All values reported are mean ± standard deviation

[Table: see text]

No significant financial relationships to disclose.
Fractional percentage of tumor volume removed is a predictor of outcome following cytoreductive nephrectomy for metastatic renal cell carcinoma
Authors: Collins S. , Pierorazio P. M. , McKiernan J. M. , Benson M. C.
Published: March 2020

4599

Background: Metastatic renal cell carcinoma, (M+)RCC, is associated with poor overall survival with only 10–20% of patients alive at 2-years. The objective of this study is to determine if the fractional percentage of tumor volume (FPTV) removed at cytoreductive nephrectomy predicts disease specific survival (DSS). Methods: The Columbia Urologic Oncology Database was reviewed and 1,016 patients were identified that underwent renal surgery from 1988 to the present. A retrospective cohort of 93 patients were identified with (M+)RCC at the time of nephrectomy. The prospective database was reviewed to determine the FPTV removed and remaining following surgery. Patients were stratified to having greater or less than 90% of their cancer burden removed. Primary outcome was defined as DSS. Kaplan-Meier analysis with log-rank test was performed to determine survival advantage between groups. A Cox proportional hazard model was fit for PTR in both univariate and multivariate models. Secondary analyses were conducted to determine if the size of primary tumor affected outcome and if FPTV affected hospitalization time. Results: 63 of 77 patients had >90% of their tumor burden removed. Median follow-up time was 8.6 months. Median DSS times were calculated to be 18.8 and 3.6 months for patients with >90% and <90% PTR respectively (p < 0.001). The hazard ratio for death was 5.73 for patients with <90% of tumor removed (p < 0.001). Those with >90% removed had larger primary tumors, 10.6cm vs. 7.2cm in the <90% removed group (p = 0.01). Outcome analysis by size of primary tumor demonstrated no difference in survival. Patients with <90% removed spent 13.6% of DSS time hospitalized compared to 6.3% for those with >90% removed (p = 0.89). Conclusions: For patients with (M+)RCC, overall survival is limited but can be extended by cytoreductive nephrectomy. FPTV expected to be removed is a simple and available method to counsel patients regarding the benefits of surgical intervention.

No significant financial relationships to disclose.
Cost-effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma
Authors: Gao X. , Reddy P. , Dhanda R. , Gondek K. , Yeh Y. C. , Stadler W. M. , Jonasch E.
Published: March 2020

4604

Background: Results from the Phase III TARGETs study showed that sorafenib plus best supportive care (BSC) significantly prolonged progression-free survival (PFS) compared with BSC alone (p < 0.000001) in patients with advanced renal cell carcinoma (RCC). In addition, at a planned interim analysis, overall survival was numerically longer with sorafenib than BSC with a hazard ratio of 0.72. The objective of this study was to evaluate the cost-effectiveness of sorafenib + BSC versus BSC alone in advanced RCC from a US payer perspective. Methods: A Markov model was developed to project the lifetime survival and costs associated with sorafenib + BSC and BSC alone. The model tracked patients with advanced RCC through three disease states - PFS, progression, and death. Transition probabilities between disease states varied for each 3-month period and were obtained from the TARGETs study. Life-years gained were used as a measure of treatment effectiveness. Resource utilization included drug, administration, physician visits, monitoring, and adverse events. Costs and survival benefits were discounted annually at 3%. All costs were adjusted to 2004 US dollars. Scenario sensitivity analyses were conducted. Results: The lifetime per patient costs were $85,571 and $36,634 for sorafenib + BSC and BSC alone, respectively. The life-years gained were higher for sorafenib relative to BSC. The incremental cost-effectiveness ratio (ICER) of sorafenib + BSC versus BSC alone was $75,354 per life-year gained. The key drivers of the model results were survival after progression and PFS probabilities for both treatment groups. Sensitivity analyses showed that the model results were robust to variance in sorafenib and BSC treatment costs. Conclusions: The incremental cost-effectiveness ratio was within the established threshold that society is willing to pay (i.e., $50,000-$100,000). Therefore, sorafenib + BSC appears to be cost-effective in the management of advanced RCC.

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Effect of obesity on PSA density (PSAD): A new clinical predictor of prostate cancer
Authors: Garzotto M. , Mongoue-Tchokote S. , Shannon J. , Peters L. , Sokoloff M. H. , Beer T. M. , Mori M.
Published: March 2020

4617

Background: The escalating rate of obesity in the Western world presents a diagnostic challenge when screening for prostate cancer. Increased body-mass index (BMI) disrupts the ability to effectively screen this population due to an associated decrease in serum prostate-specific antigen (PSA) levels and an increase in prostate volume. We therefore sought to understand how BMI impacts the probability of harboring prostate cancer. Methods: Data were collected on 647 referred men with a serum PSA of ≤ 10 ng/ml who underwent an ultrasound-guided prostate biopsy. Variables analyzed included: age, BMI, digital rectal exam (DRE), PSA, PSAD (i.e. PSA ÷ prostate volume), prostate volume, hypoechoic lesions on ultrasound and cancer on biopsy. A one-way ANOVA was performed to determine differences in log2 (PSAD) among BMI groups (<25 kg/m2 vs. 25–30 kg/m2 vs. >30 kg/m2). Multivariate logistic regression analysis was performed to estimate the odds-ratio (OR) and 95% confidence intervals (CI). Results: Prostate cancer was detected in 19.2 % of patients. ANOVA showed the mean PSAD to be significantly different in the three BMI groups (F value = 7.1, p = .0009). The mean PSAD significantly decreased as the BMI level increased (p = .0002). Independent pre-biopsy predictors of prostate cancer were tabulated (see below). Conclusions: Obesity was associated with a decrease in PSA density. The multivariate logistic regression revealed that the effect of PSAD on cancer detection was significantly modified by BMI. Specifically, the OR associated with a doubling of PSAD was 1.7 when BMI was <25 kg/m2 vs. 2.1 when BMI was ≥25 kg/m2). This interaction was an independent predictor of prostate cancer risk, along with DRE and ultrasound findings. These data underscore the need to consider BMI as a potential effect modifier of traditional clinical risk factors for prostate cancer. The dramatic rise in obesity in the United States makes this effect modification particularly relevant.

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No significant financial relationships to disclose.
Salvage prostatectomy for prostate cancer (CaP): Data from the Surveillance Epidemiology and End Results (SEER) database
Authors: Johnstone P. A. , Goodman M. , Ward K. , Assikis V. , Ogan K.
Published: March 2020

4622

Recent randomized data have established adjuvant radiation therapy (RT) as a standard of care approach for appropriately selected high-risk CaP patients after radical prostatectomy (RP). However, data on salvage prostatectomy (SP; defined here as radical prostatectomy, total prostatectomy, and cystoprostatectomy) after definitive RT are available only in single-institution reports of limited patient numbers. We analyzed data from the SEER database for the period 1988–1997. Specifically analyzed were data for patients undergoing various combinations of surgery and RT with or without hormonal therapy (HT; defined as medications, surgical castration or both) for localized (Stage I/II) CaP. Patients with multiple primary cancers were excluded. Demographic data for each case included age and diagnosis, race and year of diagnosis. Cancer-related variables included SEER summary stage and grade. Treatment information included surgery, RT, HT, and sequence of surgery with radiation. Using follow-up data through 2002, post diagnosis observed survival (OS) and relative survival (RS; defined as observed survival divided by that expected in a national age-, gender-, and race-matched cohort) was examined in four treatment groups: 44 patients with RT prior to SP, 1376 patients with RT following RP, 36344 patients with RP alone, and 30717 patients with RT alone. Mortality across treatment categories was compared using a Cox proportionate hazard model controlling for age, year of diagnosis, race, HT, SEER registry, and grade. Although infrequently performed, SP provides for 10-year relative survival of 82%. After controlling for potential confounding factors, data for RT followed by SP showed no appreciable benefit compared to RT alone.

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No significant financial relationships to disclose.
Functional heterogeneity of prostatic intra-epithelial neoplasia: Length of hormonal therapy influences response
Authors: Kang T. , Nichols P. , Skinner E. , Groshen S. , Valin G. , Ye W. , Raghavan D.
Published: March 2020

4648

Background: Prostatic intraepithelial neoplasia (PIN) is a premalignant lesion of the prostate etiologically linked to prostate cancer. While androgen deprivation therapy (ADT) has been used to reduce prostate cancer, there are controversial data regarding the effect of ADT on PIN. We hypothesized that PIN is a heterogeneous entity with respect to hormone responsiveness, that this may explain aspects of the heterogeneity in the natural history of this disease, and have used the clinical model of ADT followed by radical prostatectomy as a test of this hypothesis. Methods: We performed a retrospective study on a cohort of patients who underwent prostatectomy with biopsy proven prostate cancer. Study patients were those who must have received at least 3 months of ADT at the discretion of their surgeons. Patients from the same cohort who did not undergo ADT were used as controls. Patients were randomly selected from the database and their pathology slides were reviewed by a blinded pathologist looking for presence of PIN with an independent observer. Fisher’s exact test was used to compare the proportions of subjects who had residual PIN in the study group and the control group. Exact logistic regression was used to evaluate the duration of ADT in PIN regression. Results: Eighteen patients initially diagnosed with PIN who did not receive hormonal therapy were identified; 28 patients with PIN who underwent hormonal therapy were also studied. All patients who did not receive hormonal therapy had residual PIN whereas 7 of 28 patients undergoing ADT had no residual PIN (p = 0.043). Evaluation of hormonal therapy between responders and non-responders showed statistically significant association between PIN regression and hormone therapy duration (p < 0.001). However PIN response to ADT was not uniform as 16% of patients with ADT longer than 6 months had residual PIN, suggesting variable sensitivity of PIN to ADT. Conclusions: Our results demonstrate that ADT does cause PIN regression, and that there is heterogeneity in this effect with respect to hormonal duration. We propose for future prospective, multi-centered, randomized trials in which ADT impact on PIN is characterized further.

No significant financial relationships to disclose.
Relationship of body mass index and other anthropometric measures and prostate specific antigen, NHANES 2001–2002
Authors: Saraiya M. , Werny D. , Thompson T.
Published: March 2020

4649

Background: Obesity has been suggested to be a risk factor for prostate cancer. However, there has been limited information examining the relationship between body mass index (BMI) and other anthropometric measures such as triceps thickness (TT) and waist circumference (WC) and prostate specific antigen (PSA), a marker used in screening for prostate cancer. Methods: We analyzed data from the 2001–2002 National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey of a nationally representative sample of the non-institutionalized civilian US population. Participants in this study were limited to men aged 40 years and older without previously diagnosed prostate cancer (n = 1320). Weighted analyses were done overall and within three racial/ethnic groups [non-Hispanic whites (white), non-Hispanic blacks (black), or Mexican Americans (Mexican)]. BMI, TT, and WC were examined as both as a continuous and as a categorical variable. Three linear regression models were fit to determine the individual effect of BMI, TT, and WC on PSA within each racial/ethnic group after adjusting for age. Results: Among white men, the median PSA was 1.09 ng/mL [95% CI (0.96, 1.30)] for men with a normal BMI, 0.80 [95% CI (0.70, 0.94)] for overweight men, 0.83 [95% CI (0.74,0.95)] for obese men, and 0.74 [95% CI (0.56,1.22)] for severely obese men. Among black men, the median PSA for men was 0.83 [95% CI (0.70, 1.94)] and remained constant across BMI levels. Among Mexican men, the median PSA was 0.92 [95% CI (0.82, 1.23)] for men with a normal BMI, 0.91 [95% CI (0.81, 1.07) ] for overweight, 0.73 [95% CI (0.54,1.14)] for obese, and 0.59 [95% CI (0.39,1.06)] for severely obese men. In linear regression models controlling for age, a significant non-linear relationship was seen with BMI and PSA for both white (p = 0.010) and Mexican men (p < 0.001) but not for black men (p = 0.167). Increased TT was associated with decreasing PSA for black and Mexican men. Increased WC was associated with decreasing PSA for white and Mexican men. Conclusion: These data do suggest racial/ethnic differences of PSA across BMI categories as well as other anthropometric measures. This finding may help inform practitioners about the relationship of anthropometric measures on PSA levels.

No significant financial relationships to disclose.
Is biopsy Gleason sum an independent predictor of biochemical progression following radical prostatectomy after adjusting for the pathological Gleason sum?
Authors: Fitzsimons N. J. , Freedland S. , Presti J. , Amling C. , Kane C. , Terris M. , Aronson W.
Published: March 2020

4652

Background: Biopsy Gleason sum is a known important predictor of PSA failure following radical prostatectomy (RP). However, it is unclear whether it remains predictive of outcome after surgery when the pathological Gleason sum is known. Methods: We determined the association between biopsy Gleason sum and biochemical progression after correcting for both pre-operative and post-operative characteristics including pathological Gleason sum among 1,931 men treated with RP between 1988 and 2005 within the SEARCH Database. Gleason sum was examined as a categorical variable of 2–6, 3+4, and ≥4+3. Results: Higher biopsy Gleason sums were associated with increased prevalence of extra-capsular extension (p < 0.001), positive surgical margins (p < 0.001), seminal vesicle invasion (p < 0.001), positive lymph nodes (p < 0.001), and biochemical progression (log rank, p < 0.001). After adjusting for only pre-operative characteristics, both biopsy Gleason sums of 3+4 (p = 0.004) and ≥4+3 (p < 0.001) were associated with increased risk of biochemical progression when compared to biopsy Gleason sums of 6 or less. After further adjusting for multiple pathological characteristics including pathological Gleason sum, the association between higher biopsy Gleason sum and risk of progression was little changed in that men with biopsy Gleason sums of 3+4 (p = 0.001) and ≥4+3 (p < 0.001) were significantly more likely to progress. Furthermore, when stratified by pathological Gleason sum, higher biopsy Gleason sums were associated with increased risk of biochemical progression within each pathological Gleason sum category (log-rank, p ≤ 0.007). Conclusions: Biopsy Gleason sum remains a strong predictor of outcome even when the pathological Gleason sum is known. If confirmed at other centers, incorporation of biopsy Gleason sum into post-operative nomograms designed to predict risk of progression might improve model precision.

No significant financial relationships to disclose.