bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of lymph node evaluation on survival for small bowel adenocaricnoma: Analysis of the Surveillance, Epidemiology and End Results (SEER) database
Authors: Overman M. J. , Hu C. , Wolff R. A. , Chang G. J.
Published: August 2020

4596

Background: Small bowel adenocarcinoma is a rare malignancy and is often associated with poor outcome. The impact that the number of positive and negative lymph nodes (LN) have upon survival following curative resection has not been studied. Methods: Patients aged 18–90 with adenocarcinoma of the small intestine diagnosed between 1988 and 2005 were identified from SEER data (ver. 2008). Disease-specific survival (DSS) outcomes were determined through 12/2005. Cox proportional hazards regression analyses were performed after adjusting for age, sex, race, T stage, grade, and primary site. Stage I-II cases were categorized by total LN examined (1–8, 9–12, and >12). Stage III cases were evaluated using cut-point analysis to determine the number of positive LN that predicted outcomes. This result was then compared to the predictive value of the ratio of positive to total LN (LNR) using the chi-square statistic. Results: 1,991 patients were identified in the SEER database. Survival among stage I/II patients (n=1,216) was dependent upon the total number of LN assessed. 5-year DSS for stage II patients was 66%, 82% (HR 0.52 95% CI .33-.84), and 88% (HR 0.38, 95% CI .23-.61) for 1–8, 9–12, >12 LN, respectively. The optimal cutpoint of positive LN for stage III disease (n=775) was <3 compard to ≥3 with 5 year DSS of 58% vs. 37% (HR 1.49, 95% CI 1.15–1.92, P=0.002), respectively. Among stage III patients, the LNR was even more predictive of survival than stratification by the number of positive lymph nodes as demonstrated by an improved chi-square statistic for the multivariate model (78.8 vs 63.1, P=0.0005). Conclusions: As noted in colon cancer, the total number of LN assessed has considerable influence upon survival in stage I, II and III small bowel adenocarcinoma. Stratifying stage III small bowel adenocarcinoma into those with <3 and ≥3 positive lymph nodes significantly improves prognostication for these patients and future staging systems should incorporate the number of positive nodes into nodal staging. The use of LNR may provide additional prognostic information.

No significant financial relationships to disclose.
A randomized phase III study of gemcitabine (G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreatic cancer (PC)
Authors: Buanes T. , Maurel J. , Liauw W. , Hebbar M. , Nemunaitis J.
Published: August 2020

4601

Background: A phase I/II study with GV1001, a telomerase peptide vaccine, showed a median overall survival (OS) of 8.6 months in non-resectable PC (Bernhardt SL et al, Br J Cancer. 2006;95:1474–1482). This phase III trial was conducted to determine the impact on overall survival of G monotherapy vs. GV1001 in sequential combination with G in unresectable and metastatic PC. Methods: Eligible patients (pts) had chemotherapy-naive, advanced PC and ECOG performance status 0–1. Pts were randomized 1:1 to receive arm A: G (1,000 mg/m2 30 min i.v.) weekly for 7 weeks (w), 1w off and then 3w during 4-weekly cycles, or arm B: GV1001 0.56 mg s.c. plus GM-CSF as immune adjuvant on days 1, 3, 5, 8, 15, 22, 36, then every 4 weeks. Patients who progressed clinically or radiologically during GV1001 continued on GV1001 and concomitant gemcitabine. CT scans were performed every 8 weeks. The primary end-point was OS. A sample size of 520 patients allowed the detection of a hazard ratio (HR) of 0.73 (B/A), with 2α = 0.05 and 90% power. Results: Between June 2006 and May 2008, 365 pts were enrolled (A / B; 182 / 183). The study was stopped prematurely due to a preliminary analysis with 178 events showing no survival benefit of GV1001. Pts were well balanced for baseline characteristics: male 59.3% / 62.8%; median age 61y / 61y; ECOG PS 0 34.3% / 36.7%; locally advanced 22.4% / 20.7%. As of August 2008, 238 pts (A / B : 114 / 124) had died. Median OS was 7.3 / 5.9 months (HR 0.8; 95% CI 0.6–1.0). Median progression-free survival (PFS) was 3.7 / 1.9 months (HR 0.5; 95%CI 0.4–0.7). Grade 3–4 AEs: gastrointestinal 6% / 8%, infection 5% / 5%, vascular disorders 2% / 3%, neutropenia 6% / 3%. Conclusions: GV1001 did not show efficacy in sequential combination with G in advanced PC. The advantage of G monotherapy over the sequential combination may be due to the delayed treatment with G in arm B.

[Table: see text]
Preclinical identification of biomarkers of response to mTOR inhibitors and subsequent application in a phase II trial of sirolimus in pancreatic cancer patients refractory to gemcitabine
Authors: Garrido-Laguna I. , Rudek M. , Tan A. , Uson M. , Iacobuzio-Donahue C. , Angenendt M. , Jimeno A. , Laheru D. , Barret M. , Hidalgo M.
Published: August 2020

4612

Background: Treatment for advanced pancreatic cancer refractory to gemcitabine has not been defined. We conducted an efficacy study in pancreatic cancer xenografts to identify biomarkers of response to mTOR inhibition and attempted to translate the results by conducting a phase II trial of sirolimus in this patient population. Methods: 19 direct pancreatic xenografts were treated with temsirolimus (20mg/Kg IP daily) for 28 days. Tumors were profiled with array CGH and gene expression arrays at baseline. TGI were calculated at 28 days. Patients refractory to gemcitabine were included in the clinical trial. Sirolimus was administered at 5mg/day for 28 days. Primary endpoint was 6 month survival rate (6mSR). Secondary endpoints included: baseline evaluation of AKT pathway activation, pharmacodynamic assessment of p-S6K in PBMC, pharmacokinetics and toxicity analysis. Results: In the preclinical study, mTOR sensitive tumors showed upregulation of genes involved in the renal cell cancer pathway. CGH identified focal gains in N-Ras and K-Ras and homozygous deletions of FHIT in sensitive cases. Overall, these genetic changes induced AKT pathway activation, and led us to explore high baseline p-S6K expression as a predictor of outcome in the clinical phase. Patient characteristics: Median age: 64 (39–77). 11 patients had received ≥ 2 prior lines of chemotherapy. 6mSR was 20%. 6mSR in the subgroup of patients who received rapamycin as first line chemotherapy after progression to gemcitabine was 34%. Baseline tumor p-S6K was not predictive for survival. Early pharmacodynamic changes in p-S6K in PBMC 6 hours after treatment initiation were correlated with survival (R2= 0.65). Treatment was well tolerated. The most common grade 3 adverse event was hyperglycemia in 10% of the patients. 7 (23%) patients achieved stable disease. Conclusions: Rapamycin is well tolerated in this setting. Early pharmacodynamic changes in p-S6K in PBMC were correlated with survival. Preclinical findings leading to activation of the AKT pathway in all sensitive cases warrants further validation studies. Efficacy data is limited by the selection of a heavily pretreated and poor prognosis population (DFS≤47 days).

No significant financial relationships to disclose.
GOFURTGO trial (GFG): An AGITG multicenter phase II study of fixed dose rate gemcitabine-oxaliplatin (Gem-Ox) integrated with concomitant 5FU and 3-D conformal radiotherapy (5FU-3DRT) for the treatment of locally advanced pancreatic cancer (LAPC)
Authors: Goldstein D. , van Hazel G. , Selva-Nayagam S. , Ackland S. , Shapiro J. , Carroll S. , Cummins M. , Brown C. , Simes R. J. , Spry N.
Published: August 2020

4616

Background: Our previous study of Gem with sandwich 5FU-3DRT for LAPC was encouraging (Br J Cancer 2007: 97, 464–471). Gem-Ox has higher response rate than Gem, improved progression free survival (PFS) but not overall survival (OS). Its use in LAPC may improve local control (LC) and delay systemic spread. GFG is a study of induction (ind) Gem-Ox, then 5FU-3DRT, then consolidation (con) Gem-Ox. Primary outcome is feasibility using proportion of patients (pts) receiving > 80% planned dose for each component. Secondary outcomes are safety, activity and QOL. Methods: Pts with previously untreated inoperable LAPC, M0, measurable disease, ECOG 0–2 were given Gem (1000mg/m2 d1 + d15 q28), Ox (100mg/m2 d2 + d16 q28) in both ind (1 cycle) & con (3 cycles), & 5FU 200mg/m2/d over 6 weeks during RT of 54Gy in 30 fractions of 1.8Gy. Results: 48 pts were enrolled, median age 61y (44–81y), PS 0/1=96%, regional lymph nodes=44%, T4=46%. Worst grade (G) for anaemia (10%); fatigue, nausea (8%); diarrhoea, vomiting, neutropenia, infection (4%); stomatitis, anorexia (2%) was G3. Thrombocytopenia was G3=2% G4=2%; liver function was G3=23% G4=6%; late radiation toxicity was G3=2% G4=2% (both gastric bleeding). Half of all pts completed all planned cycles (24 pts); 29% of pts received >80% of all treatment (14 pts); 70% of pts received >80% of all chemoradiation (33 pts). Pts ceased treatment for toxicity (16%), PD (21%) or doctor/pt preference (4/2%). Global QOL did not significantly change from baseline. Median duration of LC, PFS, OS were 15.8, 9.9, 15.4m at median follow up of 29.7m. Exploratory analysis of age, disease stage, PS, CA19–9 or WCC found no univariate predictors of PFS or treatment completion. 8/48 pts survived >24m. Conclusions: Compared to our previous study using the same radiation schedule, addition of oxaliplatin was associated with improved LC, PFS & OS (prev. 11.9, 7.1 & 11.7m) without significant offset by toxicity. The extended duration of LC and a subset who had a very prolonged benefit may be due to patient selection but equally may suggest an incremental benefit from more intensive systemic therapy requiring further study in controlled trials.

[Table: see text]
Detection of circulating hypoxia-regulated miR-210 in pancreatic adenocarcinoma patients
Authors: Ho A. S. , Huang X. , Cao H. , Koong A. C. , Le Q. T.
Published: August 2020

4624

Background: MicroRNAs (miRs) are small non-coding transcripts involved in many cellular mechanisms, including tumorigenesis. miR-210, in particular, has been shown to be induced by hypoxia, over-expressed in several different cancers, and correlated with adverse outcomes in breast cancer. Moreover, since pancreatic adenocarcinomas have been previously shown to be extremely hypoxic, we hypothesized that miR-210 may be elevated in the plasma of these patients compared to non-cancer controls. Here, we compared the circulating plasma levels of miR-210 in pancreatic cancer patients and controls using a novel miRNA extraction approach and quantitative PCR. Methods: Pretreatment EDTA plasma samples were obtained from pancreatic cancer patients and age-matched non-cancer controls. miRNA was extracted from 40ul of plasma and reverse transcribed to cDNA. A known quantity of c. elegans miR-54 was added to the sample as a normalization control. miR-210 and cel-miR-54 were then quantified using TaqMan MicroRNA Assays. The procedure was performed on the initial 11 pairs of age-matched pancreatic cancer patients and non- cancer controls, then validated with a second cohort of 12 pancreatic cancer patients and 11 controls. Results: miR-210 was reliably detected and quantified in small amounts of plasma using the approach developed in our study. There is a statistically significant four-fold increase of mir-210 expression in pancreatic cancer patients compared to normal controls (Student's t-test, p <0.0001). This difference was confirmed in the validation group (Student's t-test, p<0.05). Conclusions: Circulating miR-210 levels can be readily measured from a small quantity of plasma using a novel extraction method. Its expression is significantly higher in the blood of pancreatic cancer patients compared to controls and may potentially serve as a useful biomarker for pancreatic cancer diagnosis.

No significant financial relationships to disclose.
Pharmacodynamic (PD) study of pre-prostatectomy rapamycin in men with advanced localized prostate cancer (PC): A DOD Prostate Cancer Clinical Trials Consortium Trial
Authors: Netto G. , Armstrong A. , Wood D. , Creel P. , Partin A. , Jimeno A. , Rudek M. , George D. , Gurganus R. , Carducci M. A.
Published: August 2020

5001

Background: Rapamycin is an orally bioavailable and generic mTOR inhibitor with an MTD of 6 mg daily and anticancer activity in solid tumors. We sought to determine the optimal biologic dose (OBD) in the pre-operative setting in men with PC. Methods: We explored the safety and PD activity of 3 and 6 mg of daily oral rapamycin for 14 days prior to radical prostatectomy (RP) in cohorts of 21 men with intermediate risk localized PC. Ten untreated control subjects were included using identical inclusion criteria. Men had Gleason >6 PC involving multiple cores. PD markers in pre-treatment prostate biopsies and RP specimens included p-S6 and p-Akt, 4EBP-1, PTEN, p27, Ki-67, and cleaved caspase-3. Tissue and whole blood sirolimus levels were measured. A Simon 2-stage design using PD efficacy (tumor S6 inhibition > 60%) was utilized. Results: 32 subjects were accrued to this 2 stage pharmacodynamic trial, including 10 control subjects. Median pre-treatment PSA was 6.4 ng/dl, age 60y, Gleason 7 in 85%. 20 accrued to the 3 mg cohort without DLT. However, 2/2 men enrolled at the 6 mg dose level experienced DLT consisting of thrombocytopenia leading to a delay in surgery (<100K) and fever with grade 3 stomatitis. AEs observed in the 3 mg cohort included stomatitis (2), rash (1), post-operative ileus (2), and mild neutropenia (2). One post-operative ileus was observed among control patients. PD studies demonstrated tumor S6 inhibition in >50% of subjects (median 60% decline, p=0.026 vs. baseline) with no negative effect on the state of Akt phosphorylation (p=0.82) or p27 levels (p=0.10). Prostate sirolimus levels (range 7.1–47.2 ng/g) were two-fold higher than whole blood concentrations (range 3.2–19.2 ng/ml). There was no effect of rapamycin on rates of post-operative wound healing or bleeding. PBMC S6 activity inhibition did not correlate with tumor S6 inhibition. Conclusions: The MTD/OBD of daily rapamycin in the pre-operative or prevention setting is 3 mg. This dose demonstrated downstream mTOR inhibition in tumor tissue and achieved adequate prostate tissue levels. Additional PD and genomic studies will be presented. Conducted through the DOD PCCTC and registered at clinicaltrials.gov as NCT00311623 .

[Table: see text]
Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies
Authors: Mitsiades N. , Schultz N. , Taylor B. S. , Hieronymus H. , Satagopan J. , Scardino P. T. , Reuter V. E. , Sander C. , Sawyers C. , Scher H. I. ,   Prostate Cancer Genome Project Group
Published: August 2020

5002

Background: Androgen receptor (AR) signaling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoral androgen levels, resulting from in situ steroidogenesis. Methods: Gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumors, a transcript was considered to be overexpressed or underexpressed when its levels were >2 SDs higher or lower, respectively, than its average levels in normal tissue. Results: Metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue. In analysis involving AR and 28 steroidogenic transcripts in individual tumors, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2–14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2–16, median: 2). Conclusions: Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC. Novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials.

No significant financial relationships to disclose.
VEGF single nucleotide polymorphisms (SNPs) and correlation to sunitinib-induced hypertension (HTN) in metastatic renal cell carcinoma (mRCC) patients (pts)
Authors: Kim J. J. , Vaziri S. A. , Elson P. , Rini B. I. , Ganapathi M. K. , Ganapathi R.
Published: August 2020

5005

Background: VEGF SNPs (-634 C/C and -1498 T/T) have been associated with protection from grade III/IV HTN in breast cancer pts receiving bevacizumab plus paclitaxel (J Clin Oncol. 26:4672–4678). The aim of this study was to retrospectively evaluate the association among VEGF SNPs and the development of HTN in mRCC pts receiving sunitinib. Methods: mRCC patients receiving sunitinib (50mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. All BP measurements were recorded in clinic approximately every 4 weeks. Genomic DNA was isolated from peripheral blood lymphocytes. VEGF SNP's -634 C/G (5’UTR polymorphism, NCBI reference sequence #2010963), and -1498 C/T (promoter polymorphism NCBI reference sequence #833061) were amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data were analyzed using parametric and non-parametric methods. Results: Sixty-four patients were identified of which 63 had available SNP data; 78% were male; median age was 60 (range 35–80); 67% ECOG performance status of 0; 89% prior nephrectomy and 63% previously treated with cytokines (48%) and/or a TKI (24%). Median systolic and diastolic BPs at baseline were 139 mmHg (range, 93–190) and 80 mmHg (range, 47–103), respectively; 57% of patients were being treated with anti-hypertensive therapies at baseline. The distribution of pts for the VEGF-634 genotype was C/C (10%), C/G (33%) and G/G (57%). VEGF-634 C/C < C/G < G/G genotypes were associated with increasing frequency and duration of HTN (diastolic > 90 mmHg and/or systolic > 150 mmHg) during treatment with sunitinib (p = 0.03 and p = 0.007, respectively) and remained significant adjusting for baseline BP and use of anti-HTN meds (p = 0.05 and 0.02, respectively). Similar correlations were not found for VEGF-1498 genotypes. There was no association between VEGF SNPs and tumor volume reduction or PFS. Conclusions: VEGF SNP-634 G/G genotype is correlated with HTN during treatment with sunitinib in mRCC pts.

[Table: see text]
Outcomes of conservatively managed localized prostate cancer
Authors: Lu-Yao G. , Albertsen P. C. , Moore D. F. , Lin Y. , Shih W. , Barry M. J. , Zietman A. , O’Leary M. , Walker-Corkery E. , DiPaola R. S. , Yao S.
Published: August 2020

5010

Background: The natural history of screen-detected prostate cancer has not been well described. Methods: Cancer-specific and overall mortality, assessed through competing risk analyses, were determined for 14,516 men aged 65 years or older diagnosed between 1992–2002 and did not receive surgery or radiation within 6 months of cancer diagnosis. The population-based cohort was identified from US cancer registries, which had 98% completeness in case ascertainment. Results: Compared to earlier era studies, survival has improved considerably for conservatively managed patients diagnosed in the contemporary prostate specific antigen (PSA) era ( Table ). Conclusions: Men diagnosed with prostate cancer in the PSA era have survival outcomes significantly better than those in the past. Patients and healthcare providers may need to reassess some treatment options in light of these data.

[Table: see text]

No significant financial relationships to disclose.
Individualized intensification of treatment based on tumor marker decline in metastatic nonseminomatous germ cell testicular cancer (NSGCT): A report from the Swedish Norwegian Testicular Cancer Group, SWENOTECA
Authors: Olofsson S. , Dahl O. , Jerkeman M. , Cohn-Cedermark G. , Klepp O. , Stierner U. , Törnblom M. , Wahlqvist R. , Cavallin-Ståhl E. ,   SWENOTECA
Published: August 2020

5015

Background: From July 1995 to December 2003, 602 adult patients from Sweden and Norway with metastatic testicular NSGCT were included in a population-based multicenter SWENOTECA protocol with strict guidelines for staging, treatment and follow-up. Methods: The basic strategy of this protocol was to individualize treatment according to AFP and β-HCG decline (t1/2). Satisfactory response to treatment was defined as a t½ for AFP ≤ 7 days and/or β-HCG ≤ 3 days. Initial treatment for all patients was 2 courses of standard BEP. Tumor markers were analyzed once a week during treatment. Patients with satisfactory response went on with BEP while patients with unsatisfactory t1/2 received intensified treatment in two steps with addition of ifosfamide (BEP-if/PEI) in step 1. If still unsatisfactory response the treatment was intensified according to step 2 involving high-dose chemotherapy with stem cell rescue. Postchemotherapy surgery was performed according to protocol guidelines. Results: 99,7% (602 of 604) of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median FU was 72 months. 75% of the patients were treated with BEP, median 4 courses, without intensification, 19% according to intensification step 1 and 6% according to intensification step 2. Five year progression free survival (PFS), cancer specific survival (CSS) and overall survival (OS) grouped according to IGCCCG prognostic score are given in the Table below. There was no significant difference in PFS between the good and intermediate risk group. Death due to all causes was 10,1% (n=61) and treatment related deaths were 1,3 % (n=8). Conclusions: Our results, in a population based patient material, with individualized treatment based on tumor marker decline, are highly encouraging in all risk groups, but most notably in the intermediate risk group.

[Table: see text]

No significant financial relationships to disclose.
Randomized trial of p53 targeted adjuvant therapy for patients (pts) with organ- confined node-negative urothelial bladder cancer (UBC)
Authors: Stadler W. M. , Lerner S. P. , Groshen S. , Stein J. P. , Skinner D. G. , Raghavan D. , Steinberg G. D. , Wood D. , Klotz L. H. , Hall M. C. , Cote R.
Published: August 2020

5017

Background: Retrospective studies suggest that p53 mutation and associated immunohistochemical (IHC) detectable expression are prognostic for recurrence in pts with organ confined UBC and may be predictive for benefit from MVAC adjuvant chemotherapy. Methods: Pts with pT1–2N0M0 UBC following radical cystectomy and bilateral pelvic lymph node dissection were eligible. IHC for p53 was centrally performed and pts with ≥10% nuclear reactivity were offered randomization to 3 cycles of adjuvant MVAC vs. observation. P53 negative and p53 positive pts who declined randomization were observed. Primary endpoint was recurrence-free survival (RFS) in the randomized population. Secondary endpoints were RFS in p53 negative versus p53 positive pts and overall survival in each of these groups. Using a one-sided log-rank test with α = 0.05 and β = 0.15, 190 p53 positive patients were planned to be randomized to detect an absolute improvement in RFS at 3 years (yrs) from 50% to 70% (corresponding hazards ratio of 0.51). Results: 521 pts were registered, 499 underwent successful p53 assessment (male: 80%, <65 yrs: 57%, Caucasian: 91%, pathologic stage P1/P2: 37%/63%, lymphovascular invasion: 20% yes/28% unknown), 272 (55%) were p53 positive and 114 were randomized (42%). Further accrual was halted based on data safety monitoring board review of futility analysis on the first 100 randomized pts. P53 positive tumors were higher grade (97% vs 93% grade 3/4, p = 0.04) and less likely to express p21 (59% vs 84%, p < 0.001). Overall 5-yr RFS was 80 ± 2% with no difference based on p53 status. P53 positive patients declining were older but otherwise similar to those accepting randomization. Only 67% of pts randomized to MVAC received all 3 cycles with 12 (21%) receiving none. There was no difference in RFS in the randomized population (overall 5 yr RFS 83 ± 4%, hazard ratio = 0.88, p = 0.78). Conclusions: The prognostic and predictive value of p53 IHC were not confirmed in this prospective study, but the lower than expected event rate and failures to receive assigned therapy severely compromised the study's power. The value of p53 mutations is being assessed.

No significant financial relationships to disclose.
Circulating tumor cells (CTC) in patients with metastatic castration-resistant prostate cancer (CRPC) receiving abiraterone acetate (AA) after failure of docetaxel-based chemotherapy
Authors: Fleisher M. , Danila D. C. , Leversha M. , Rathkopf D. , Slovin S. , Anand A. , Koscuiszka M. , Haqq C. , Scher H. I.
Published: August 2020

5049

Background: Selecting targeted therapies and assessing outcome in patients (pts) with CRPC are significant unmet medical needs. A proportion of CRPC remain dependent on androgen receptor (AR) activation. AA inhibits CYP17 to decrease serum androgen to undetectable levels. Methods: AA (1000 mg QD oral) was studied in pts with metastatic CRPC who had progressed on docetaxel based chemotherapy. The primary endpoint was a >50% decline in PSA from baseline. We monitored changes in CTC number with therapy, and performed FISH for AR in CTC as previously described. Results: At MSKCC, 54 pts were screened and 48 treated; 38 pts received prednisone from the start of treatment. The median (IQR) age was 70 yrs (63–79), PSA 99.9 ng/mL (36.4–343), and CTC were 17 (4–49) per 7.5 ml of blood at baseline. Prior systemic therapy included > 3 hormonal therapies in 63%; while 71% received 1, 29% had 2 lines of chemotherapy. Metastatic sites were bone alone in 10 pts (21%), bone and lymph nodes in 21 (44%), 15 (31%) with visceral disease, 2 with soft tissue alone. Baseline CTC count was > 5 in 35 pts, whereas 13 pts had <5; CTC changes with treatment are presented in table below. Pts in Group A were treated on protocol for a median of 8.9 m, compared to 2.8 m in group B (P <0.001). Among pts with baseline CTC > 5, the CTC decline to <5 was associated with a decline in PSA by >50% (p< 0.001). From 28 pts with FISH in CTC, 13 (47%) pts had AR amplification, 8 (29%) pts had copy number gain, and 5 (10%) pts had no evident AR copy number abnormalities; FISH failed in 2 pts. PSA declined > 50% in 5 (38%) pts with AR amplification, 2 (25%) pts with gain, and 4 (80%) pts without AR abnormalities. Conclusions: Changes in CTC with treatment may represent valuable intermediary endpoints for clinical benefit. We are prospectively testing pre and post-therapy CTC, and separately AR FISH profiles and clinical outcomes in COU-AA-301, a phase III trial for CRPC patients who have received docetaxel based chemotherapy.

[Table: see text]

[Table: see text]
Sensitivity and specificity of a whole-blood RNA transcript-based diagnostic test for the diagnosis of prostate cancer (CaP) compared with prostate-specific antigen (PSA) alone
Authors: Ross R. W. , Bankaitis-Davis D. , Siconolfi L. , Katz L. , Storm K. , Magidson J. , Wassmann K. , Oh W. K.
Published: August 2020

5052

Background: Screening for CaP with PSA testing is limited by a high number of false postives, particularly in the setting of benign prostatic hypertrophy (BPH). The goal of this study was to develop whole blood RNA transcript-based diagnostic tests that improve the diagnosis of CaP over PSA alone. Methods: From August 2006 to October 2008, three prospective cohorts of men consented to the collection of whole blood in PAXgene Blood RNA tubes for gene expression analysis: men with newly diagnosed, localized, untreated CaP, otherwise healthy men without CaP, and otherwise healthy men with BPH. 168 inflammation and CaP-related genes (Source MDx Precision Profiles) were assayed using optimized Q-PCR technology. Logistic regression methods were used to develop models to optimize prostate cancer diagnosis. Results: 182 men underwent expression analysis (n = 76, 76 and 30 for CaP, normal, and BPH cohorts, respectively). The CaP and normal cohorts were age matched (median age 60 yrs); the BPH cohort median age was 70. Considering only the CaP and normal cohorts, PSA alone (using a cut-off of 4 ng/ml) had a specificity of 94.7%, but sensitivity of only 71.1% for diagnosis of CaP, or 90.8% and 77.6%, respectively, when using age-adjusted PSA criteria. A model consisting of the expression analysis of 6 genes and PSA had a higher specificity (96.1%) and a much improved sensitivity (97.4%) for CaP diagnosis. When the BPH cohort was added, the improvement of the 6-gene model remained (sensitivity and specificity of 97.4% and 92.0% vs 77.6% and 88.1% using the age-adjusted PSA criteria). Further model development using the CaP and BPH cohorts yielded a 5-gene model which, integrated with PSA and age, correctly predicted 96.1% of the CaP pts and 93.3% of BPH pts. Conclusions: These results suggest that specific whole blood RNA transcript levels can assess abnormal gene expression associated with CaP. Such a molecular CaP biomarker would be a powerful tool to reduce unnecessary biopsies in patients without CaP and detect CaP in patients with PSA values below the current cutoff. Validation of these results is ongoing and will be available at the time of the meeting.

[Table: see text]
Evaluation of the prostate-specific antigen/solvent interaction analysis (PSA/SIA) assay for prostate cancer (CaP) diagnosis
Authors: Vourganti S. , Stovsky M. , Ponsky L. , Siroky M. , Kipnis V. , Fedotoff O. , Mikheeva L. , Zaslavsky B. , Chait A. , Jones J. S.
Published: August 2020

5053

Background: We describe the clinical performance of a novel protein structural assay for prostate cancer (CaP) diagnosis. The assay uses Solvent Interaction Analysis (SIA) to accurately detect changes in PSA isoform composition that differentiate benign and malignant disease, independent of total serum PSA (tPSA). Methods: From January 2007 to September 2008, men already undergoing biopsy for accepted clinical criteria at 3 sites [University Hospitals Case Medical Center (Cleveland); Cleveland Clinic (Cleveland); and Veterans Administration Hospital (Boston)] were enrolled in an IRB approved study. Prior to standard transrectal ultrasound (TRUS) guided biopsy, patients received a digital rectal examination with systematic prostate massage followed by collection of voided urine for use in PSA/SIA. The assay determined the relative distribution of the entire heterogeneous PSA isoform population between two coexisting aqueous phases for diagnostic purposes. Results: 222 men were enrolled in the trial. Biopsy results were classified as case (malignant, n = 100) or control (benign, n = 122). Receiver operating characteristic performance results demonstrated AUC of = 0.88 for PSA/SIA and 0.58 for tPSA. At a cut-off value of the composite structural index K = 1.73, PSA/SIA displayed sensitivity = 100%, specificity = 80%, PPV = 83%, and NPV = 100%. For the same patients at tPSA cut-off level of 4 ng/ml, the sensitivity = 82%, specificity = 27%, PPV = 54%, and NPV = 87%. Conclusions: PSA/SIA uniquely exploits the inherent structural heterogeneity in PSA resulting in superior diagnostic performance over conventional biopsy selection criteria. We hypothesize that the high specificity of PSA/SIA is actually underestimated by standard prostate biopsy sampling error. Future trials will assess the utility of the assay in the surveillance of CaP patients after definitive local therapy and other applications in the diagnosis and management of CaP.

[Table: see text]
Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: A phase II study of the DOD Prostate Cancer Clinical Trials Consortium
Authors: Small E. , Harzstark A. , Weinberg V. K. , Smith D. C. , Mathew P. , Beer T. , Liu G. , Sharib J. , Rosenberg J.
Published: August 2020

5058

Background: Mitoxantrone (M) plus prednisone (P) and ixabepilone (Ix) each have modest, non cross-resistant activity as second line chemotherapy regimens in docetaxel-refractory patients with CRPC. These agents were therefore combined in a phase I study which demonstrated anti-cancer activity and defined the recommended phase II dose used in this trial. Methods: Patients with metastatic CRPC and progression after 3 or more cycles of docetaxel were enrolled in a phase II multicenter study of the combination of prednisone 5 mg BID, Ix (35 mg/m2) and M (12 mg/m2) administered intravenously on day 1 every 21 days, with pegfilgrastim (6 mg on day 2) support. Results: To date, 43 pts have been enrolled and have received a median of 4 cycles. Of 37 patients currently evaluable for response, 14 (38%; 95% CI: 22–55%) have had a confirmed ≥50% decline in PSA and 19 (51%; 95% CI 34–68%) have had a confirmed ≥30% decline in PSA. Two of 15 patients with evaluable measurable disease (13%) have had a RECIST-defined objective response. All 43 patients are evaluable for toxicity. Grade 3 or 4 neutropenia was seen in 6 pts (17%) and grade 3 or 4 thrombocytopenia was seen in 3 (8%). Nonhematologic grade 3/4 events possibly related to study drug have included grade 3 fatigue (3 pts), grade 3 pneumonia (2 pts), and grade 3 atrial fibrillation, grade 4 myocardial infarction, grade 4 prostatitis, grade 3 nausea/vomiting, grade 3 neuropathy, grade 3 elevated transaminases, grade 3 dizziness, grade 3 dehydration, grade 3 shortness of breath, and grade 4 vasovagal syncope (1 pt each). Grade 2 neuropathy has been seen in 4 patients. Conclusions: The Ix, M, P regimen is active as second-line therapy in CRPC patients with progressive disease after docetaxel therapy and is reasonably well tolerated. Further investigation of this regimen is warranted. This study was supported in part by CTEP/NCI and the DOD Prostate Cancer Clinical Trials Consortium.

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Phase II study of first-line sagopilone combined with prednisone in patients with metastatic castration-resistant prostate cancer (CRPC)
Authors: Beer T. M. , Smith D. C. , Hussain A. , Alonso M. , Wang J. , Giurescu M. , Wang Y. ,   Prostate Cancer Clinical Trials Consortium
Published: August 2020

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Background: Epothilones comprise a new class of microtubule stabilizing agents, and sagopilone is a novel, fully synthetic epothilone that has shown significant activity against a broad range of tumor models. Methods: Chemotherapy-naïve metastatic CRPC patients received sagopilone 16 mg/m2 IV over 3 hours every 21 days and prednisone 5 mg PO BID. The primary efficacy evaluation was based on PSA decline (≥50% PSA reduction confirmed at least 28 days apart). The Simon 2-Stage design required 3 responders among the first 13 evaluable patients and 13 responders among the first 46 evaluable patients to declare the agent of interest for further investigation. Results: Between August 2006 and May 2008, 53 patients were enrolled and treated. Sites of metastases were: bones, lymph nodes, and viscera in 72%, 68%, and 25% patients, respectively. Median PSA was 107.5 (6.2–1727) ng/ml. A median of 5 (2–12) cycles were delivered. The median dose delivered per cycle was 13.3 mg/m2. Two patients did not meet all eligibility criteria and were excluded from efficacy analyses; 3 additional patients were excluded from PSA decline and progression-free survival analyses due to missing baseline PSA assessment. Twenty of 48 patients (42%; 80% CI: 32%-52%) had a confirmed PSA decline in excess of 50% and 30 (63%; 95% CI: 47%-76%) had a 30% reduction in PSA within 3 months of enrollment. Of 39 patients with measurable disease by RECIST, 1 had a complete, 9 had a partial confirmed response (26%; 95% CI: 13%-42%). The median PFS was 6.4 months (95% CI: 4.7 to 10.2). All 53 patients are evaluable for safety. Toxicities occurring in ≥ 20% patients included peripheral neuropathy 74% (19% grade 3), fatigue 40% (6% grade 3, 2% grade 4), extremity pain 36% (6% grade 3), arthralgia 23% (no grade 3, 4), and constipation 21% (no grade 3, 4). Conclusions: Sagopilone is active in metastatic chemotherapy-naïve CRPC patients, with probability of PSA decline, measurable disease responses, and PFS approximating the current standard of docetaxel + prednisone. Neuropathy and fatigue are the most common toxicities, while hematologic toxicity is rare. Further evaluation of this agent in prostate cancer is warranted.

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Residual pathologic stage at radical cystectomy and risk stratification of patients with pT2N0 bladder cancer
Authors: Isbarn H. , Sonpavde G. , Shariat S. F. , Palapattu G. S. , Sagalowsky A. I. , Lotan Y. , Schoenberg M. P. , Amiel G. E. , Lerner S. P. , Karakiewicz P. I.
Published: August 2020

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Background: We hypothesized that in patients with pT2N0 transitional cell carcinoma (TCC) of the urinary bladder, residual muscle-invasive disease at radical cystectomy (RC) may confer poorer outcomes than residual non-muscle invasive disease due to larger tumor volume and/or biologically more aggressive disease. Patients with high-risk pT2N0 disease may be candidates for trials of adjuvant therapy. Methods: Patients from the BCRC database with pT2N0 stage (N = 208) at TUR (transurethral resection) whose tumors were organ-confined at RC (≤pT2N0) were analyzed. T1N0 patients (N=33) with pT2 disease at RC were also examined in order to include all pT2 patients. None of the patients had received perioperative chemotherapy. The effect of residual pT-stage at RC on outcomes was evaluated in Kaplan-Meier, as well as in univariable and multivariable Cox-regression models. Covariates consisted of age, gender, grade, lymphovascular invasion, concomitant carcinoma-in-situ (CIS), number of lymph nodes removed, and the year of surgery. Results: Among baseline T2N0 patients, residual pT-stage at RC was pT0 in 24 (11.5%), pTa in 9 (4.3%), pCIS in 22 (10.6%), pT1 in 35 (16.8%), and pT2 in 118 patients (56.7%). The median follow-up was 50.1 months. The 5-year recurrence-free survivals of patients with residual pT0/pTa/pCis, pT1 and pT2 were 100%, 85% and 75%, respectively. The 5-year cancer-specific survival rates for the same patient cohorts were 100%, 93%, and 81%, respectively. In multivariable analyses, the effect of residual stage <pT2 at RC achieved independent predictor status for recurrence (adjusted HR 0.20; p = 0.002), as well as for cancer-specific survival (adjusted HR: 0.24; p = 0.02). Initial T1 patients who were pT2 at RC did not have statistically different outcomes compared to initial T2 followed by pT2 at RC. Conclusions: Patients with pT2N0 TCC of the urinary bladder with residual non-muscle invasive disease at RC have significantly better long-term outcomes compared to residual muscle-invasive disease. With further validation, these data may facilitate the risk-stratification of patients with pT2N0 disease and enable the selection of high-risk patients for trials of adjuvant therapy.

No significant financial relationships to disclose.
SPARE: A qualitative study investigating randomization barriers in a Selective Bladder Preservation trial (SBP) (ISCRCTN: 61126465)
Authors: Moynihan C. , Hall E. , Lewis R. , Birtle A. , Mead G. M. , Huddart R. ,   on behalf of the SPARE Trial Management Group
Published: August 2020

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Background: Recruitment to randomised trials is challenging, especially when treatment strategies are complex. While studies have demonstrated barriers to recruitment, few have investigated why patients accept or refuse randomisation. The SPARE feasibility study included such an investigation to highlight difficulties that might be dealt with as the study progressed and to inform procedures for a subsequent phase III trial. Methods: Patients had newly diagnosed invasive bladder cancer and were receiving neoadjuvant chemotherapy prior to invitation to a randomised trial (SPARE) that offered the possibility of radical cystectomy or SBP. Patients allocated SBP received cystectomy or radiotherapy dependent on chemotherapy response. 15 acceptors and 10 decliners to randomisation participated in the qualitative substudy. Methods included recorded transcribed interviews and a ‘framework analysis.’ Results: Both groups experienced initial confusion, ‘muddled’ communication, information overload, and lack of time leading to misunderstandings about the trial. Perceived side effects did not necessarily inform decisions. Decision to participate was seldom made unilaterally. Individual specialist input by, and continuity between, professionals and their patients, appeared to make decision making easier. Acceptors were inclined to altruism and trust in the medical profession, often agreeing to participate with minimum understanding regarding randomisation and/or equipoise and a ‘nothing to lose’ attitude as long as withdrawal from the trial was possible. Decliners tended to opt for radiotherapy, perceived as a rational choice in the context of this trial; many abhorred the thought of surgery that was perceived as undermining and a ‘treatment in reserve.’ Conclusions: Health professionals need to consider streamlining procedures and recognise patient preferences in terms of treatments offered and information received. Recognition of the complexity of communicating equipoise and randomisation may increase ‘informed consent’ levels and recruitment rates. A further qualitative substudy investigating doctor/patient consultations in real time with confidential feedback is proposed to optimise recruitment rates.

No significant financial relationships to disclose.
Prognostic risk group classification for patients (pts.) with platinum-refractory metastatic urothelial cancer (UC) treated with second-line chemotherapy
Authors: Vaughn D. J. , Hwang W. , Munier S. , George C.
Published: August 2020

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Background: Second-line chemotherapy in pts. with platinum-refractory metastatic UC is associated with low objective response rates and short progression-free and overall survival. Prognostic risk groups in this setting have not been reported. Methods: We studied 151 pts. with platinum-refractory metastatic UC treated with second-line vinflunine (VFL) (Vaughn, GU Cancer Symposium. 2008). Using progression at 6 months as the primary endpoint, baseline patient characteristics were examined in univariate and multivariate analyses. Multivariate logistic regression was used to identify independent predictors of progression at 6 months, and the variable selection result was validated by nonparametric bootstrap. Risk scores were generated from summing the relative importance of the factors identified on multivariate analysis. Patients were classified into risk groups and compared. Results: Of the 151 pts., 80% were male, 54% were aged > 65 years, and 68% had Karnofsky performance status (KPS) > 90%. 115 pts. (76%) progressed or died by 6 months after initiating VFL. The factors associated with an increased odds ratio (OR) for disease progression at 6 months were presence of visceral metastases (OR 8.08; p < 0.001; 2 points), KPS < 90% (OR 6.63; p = 0.002; 2 points), and age < 65 years (OR 3.53; p = 0.008; 1 point). Only 41% of the low-risk group (score 0–1) progressed by 6 months compared to 74% of the intermediate-risk group (score 2) and 91% of the high-risk group (score 3–5). Compared to the low-risk group, the intermediate-risk group had OR for disease progression at 6 months of 4.01 (p = 0.006) and the high-risk group had OR of 15.5 (p < 0.001). Conclusions: We identified risk factors and developed a scoring system that classifies pts. with platinum-refractory UC treated with second-line chemotherapy into risk groups based upon probability of disease progression at 6 months. Similar to the first-line setting, the presence of visceral metastases and decreased KPS predict a worse prognosis. This system should be validated in other independent populations.

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Open versus laparoscopic retroperitoneal lymph node dissection (RPLND) in clinical stage I nonseminomatous germ-cell tumors (NSGCTs): Two contemporary series from a single institution
Authors: Nicolai N. , Biasoni D. , Piedra Aguilera J. , Necchi A. , Piva L. , Stagni S. , Torelli T. , Milani A. , Pizzocaro G. , Salvioni R.
Published: August 2020

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Background: Primary RPLND is our choice for clinical stage I (CSI) NSGCTs. Open RPLND (O-RPLND) has been our standard policy since 1985, while laparoscopic RPLND (L-RPLND) has been introduced since the late-1990s. Methods: Between June 2003-March 2008, 150 consecutive CSI NSGCT patients (pts) have been submitted to O-RPLND (n = 91) or L-RPLND (n = 59). Pts with high risk disease (vascular invasion/embryonal carcinoma > 90% in the primary tumor) were more frequently offered O-RPLND, while pts with low risk disease (none of the 2 above) were usually considered for L-RPLND. We reviewed our data focusing on: complications, operating time (OT), hospital stay (HS), number of removed nodes, occurrence of nodal metastases as well as of metastasis during follow-up and global need of chemotherapy (CT). Results: O-RPLND (91). 59/91 (64.8%) were high-risk patients. Median OT was 140 min (IQR 110–150). Five (5.5%) complications occurred: 4 lymphorrea and 1 hemorrhage. Median HS was 6 days (IQR 5–7). Nodal metastases were found in 24 (26.4%) pts. Median number of removed nodes was 20 (IQR 14–25). L-RPLND (59). 54/59 (91.2%) were low-risk patients. Median OT was 210 min (IQR 180–240). Ten (16.9%) complications occurred: 5 required conversions to open procedure due to intraoperative bleeding (4) or technical impossibility to conclude the procedure (1). Median HS was 4 days (IQR 4–5). Nodal metastases were found in 5 (8.5%) pts: 2 of them received immediate adjuvant CT. Median number of removed nodes was 14 (IQR 11–20). OT and HS were significantly better in O-RPLND and L-RPLND series, respectively (p.0001 at Mann Whitney test). After a median follow-up of 15.1 months (1–52), distant metastases were observed in 10 (0.7%) pts: 7/91 (7.7%) following O-RPLND and 1/59 (1.7%) following L-RPLND. CT was administered to 7 (7.7%) pts following O-RPLND and to 3 (5.1%) pts following L-RPLND. Conclusions: In this large case-series, no excess of recurrences but a higher rate of complications were recorded in L-RPLND pts. O-RPLND had a significant better OT while HS was shorter in L-RPLND series. Both procedures are still being applied: pts are currently offered one of the 2 modalities after counseling.

No significant financial relationships to disclose.