bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of prostate-specific antigen decline as a surrogate for overall survival in metastatic hormone-refractory prostate cancer (HRPC)
Authors: Armstrong A. J. , Eisenberger M. A. , Garrett-Mayer E. S. , Ou Yang Y. , Carducci M. A. , de Wit R. , Tannock I.
Published: March 2020

5009

Background: A 30% PSA decline following initiation of cytotoxic chemotherapy has been identified as a potential surrogate for overall survival in metastatic HRPC. We sought to examine whether various levels of PSA decline were surrogates for overall survival in TAX327, a randomized trial of q3w docetaxel and prednisone (DP), q1w DP, and q3w mitoxantrone and prednisone (MP). Methods: In this trial of 1006 men with HRPC, 943 men had sufficient data on 3-month post-treatment PSA decline for analysis, and 646 had sufficient data for analysis for a change in PSA kinetics with therapy. Surrogacy was examined for a range of PSA decline from 0% to 90% and PSA normalization, and for post-treatment changes in PSA kinetics. We investigated the Prentice Criteria for surrogacy using Cox proportional hazards models and calculated the proportion of treatment effect explained (PTE) by each surrogate marker. Results: In this analysis, a 30% or greater PSA decline with therapy was identified as the optimal cutoff that correlated with overall survival, based on the highest PTE point estimate (0.66, 95% CI 0.23–1.0), with 1.0 being a perfect surrogate. A 30% decline in PSA in the first 3 months after treatment occurred in 65% of subjects receiving q3w DP, 67% q1w DP, and 44% q3w MP, despite the significant survival benefits seen only with q3w DP. A 30% PSA decline was associated with a hazard ratio (HR) of 0.43 (95% CI 0.36–0.51) for overall survival after adjusting for treatment effect, while treatment effect itself lost significance, indicating surrogacy. Additionally, PSA normalization, changes in PSA kinetics, and pain response were significant prognostic variables, yet were only modest surrogates for the survival benefit seen with q3w DP therapy. Conclusions: In this trial of two schedules of DP as compared to MP for HRPC, a PSA decline of 30% in the first three months following initiation of cytotoxic chemotherapy was found to have the highest degree of surrogacy for overall survival, thus confirming data from the SWOG 9916 trial. However, given that the confidence interval for the estimate of this surrogate effect is wide, overall survival should remain the preferred endpoint for phase III trials of cytotoxic agents in HRPC.

No significant financial relationships to disclose.
Correlation of low dose tamoxifen and its metabolites plasma level with Cyp 2D6, and SULT polymorphism; a pharmacogenetics study within a chemoprevention trial
Authors: Serrano D. , Macis D. , Gandini S. , Johansson H. , Guerrieri-Gonzaga A. , Mellgren G. , Lien E. A. , Mariett F. , Sandri M. , Decensi A. , Bonanni B.
Published: March 2020

503

Background: Tamoxifen (T) is one of the most widely used drug for the treatment and prevention of estrogen receptor (ER) positive breast cancer. Individual genotype can modulate treatment efficacy. T metabolism is catalyzed by multiple enzymes: CYP2D6 is the main mediator for endoxifen, one of the most potent T metabolites. SULT may also play a role in T activation and can modulate hormone levels involved in breast cancer risk. Within a chemoprevention trial, we correlated T and its main metabolite concentration with polymorphisms (SNPs) of CYP2D6 and SULT genes. Methods: Premenopausal women (n 235) were randomly assigned in a double-blind four-arm trial to receive T 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years CYP2D6 (*4–6) and SULT1A1*3 frequencies were determined using an Allelic Discrimination Assay, following a protocol for real time polymerase chain reaction. In the subjects receiving T, we measured plasma level of the drug, and its metabolites (endoxifen, 4-hydroxy-T, N-desmethyl-T, N-desdimethyl-T and Tnoxide) using a fluorescence detector at 12 and 24 months. Results: SNPs analysis was performed in 118 women; we found 65% wild type (WT), 31% heterozygous (H) and 5% mutated (M) for CYP2D6. The SNP frequency of SULT1A was A1, 61%; SULT1A2 36% and SULT1A3 3%. At one year a positive correlation was observed between CYP2D6 M and plasma level of N- desmethyl-T, the mean plasma level being 54.6, 62.4 and 108.5 ng/ml in WT, H and M, respectively, p=.001 (p=.01 at 24 months). Endoxifen was slightly increased in the WT compared to M (15.4 vs 12.9 ng/ml). SULT polymorphisms did not show any correlation with the drug and metabolite levels. Conclusions: CYP2D6 M mediates an increased level of N- desmethylT. This observation supports the role of CYP2D6 as an important enzyme in T metabolism, but more than one cytochrome P450 isoenzymes is required. to identify good or poor T metabolizers.

No significant financial relationships to disclose.
Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT)
Authors: Hutson T. E. , Davis I. D. , Machiels J. P. , de Souza P. L. , Hong B. F. , Rottey S. , Baker K. L. , Crofts T. , Pandite L. , Figlin R.
Published: March 2020

5031

Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth & inhibits angiogenesis. This Phase II RDT determined effects of pazopanib on tumor growth in patients with adv/met RCC after 12 wks of treatment. Methods: Cytokine naïve and refractory (failed 1 prior cytokine or bevacizumab-containing regimen) patients with adv/met RCC, ECOG 1–2, were enrolled. Pazopanib 800 mg po qd was administered. Response (RECIST) assessed at wk 12: SD patients randomized to continue pazopanib or placebo (blinded); PR/CR patients continued pazopanib. Interim analysis (first 60 patients) endpoints: % randomized (SD) and % CR/PR at wk 12. Futility boundary was based on a randomization rate of <40%. Safety was analyzed in enrolled patients (n=161) at the time of interim analysis. Results: In the first 60 patients, response at wk 12 by independent review: PR in 24 (40%); SD in 25 (42%); PD in 5 (8%); unknown response in 2 (3%); and withdrawal prior to wk 12 (reasons other than PD/AE) in 4 (7%). 27 (45%) patients were randomized based on investigator review at wk 12. Total disease control rate was 82% (PR + SD). 67% of patients were treatment naïve, 33% had failed one prior treatment regimen (23% cytokine, 8% bevacizumab, 2% both). Most common AEs/lab abnormalities in all patients (n=161; 71% M, 29% F; mean 60.3 yrs; 81% Caucasian) were ALT/AST elevations, diarrhea, fatigue, nausea, hair depigmentation, & hypertension. Gr 3/4 AEs occurred in 26% of patients; most common were hypertension (8%) & ALT elevation (8%). One patient had Gr 5 AE due to large intestinal perforation. AEs led to discontinuation in 5% of patients. Conclusions: Interim analysis of this Ph II study demonstrated that pazopanib treatment resulted in a PR rate at wk 12 of 40% among patients with adv/met RCC and an acceptable toxicity profile. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of randomization to placebo. Patients without PD were offered continued treatment with pazopanib beyond wk 12. At the time of publication, efficacy and safety data will be available for all 225 patients.

[Table: see text]
Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib
Authors: Rini B. I. , Wilding G. T. , Hudes G. , Stadler W. M. , Kim S. , Tarazi J. C. , Bycott P. W. , Liau K. F. , Dutcher J. P.
Published: March 2020

5032

Background: Sunitinib and sorafenib, tyrosine kinase inhibitors (TKIs) of the VEGF and PDGF receptors (VEGFR, PDGFR), are FDA-approved treatments for advanced RCC. AG is a potent inhibitor of VEGFRs 1, 2 & 3 and showed substantial efficacy in a previous phase II study in pts with cytokine-refractory RCC (Rini et al. ASCO 2005). The activity of AG in metastatic RCC patients refractory to prior TKI therapy is of interest. Methods: Pts with sorafenib-refractory RCC were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included measurable disease, ECOG performance status of 0 or 1, controlled CNS metastases (if present) and adequate organ function. All pts received a starting dose of AG 5 mg orally BID, titrated according to tolerance. The primary endpoint was RECIST-defined objective response (OR) with a null hypothesis of OR = 8% versus = 20% under the alternative hypothesis. Pts underwent radiographic staging at baseline and every 8 weeks and were treated until progressive disease or unacceptable toxicity. Results: All planned 62 pts have been enrolled. Median age of 42 evaluable pts was 60 years (range 35–77); 29 pts (69%) were male; 41 pts (98%) had prior nephrectomy. Median number of prior therapies was 2 (range 1–8); all pts had received prior sorafenib and 9 pts also received prior sunitinib. Partial response was observed in 6/42 evaluable pts (14%; 95% CI: 5–29%), stable disease in 15 pts (36%), 12 pts (29%) experienced progressive disease, and 9 pts (21%) withdrew due to adverse events. Overall, 57% of pts experienced some degree of tumor regression. With a median follow-up of 5.3 months, the median progression-free survival (PFS) was not reached. Preliminary analysis indicates overall median PFS > 7.1 months. No ORs have yet been observed in patients with prior sunitinib treatment, although tumor regression was demonstrated in 55% of pts with median PFS > 6.1 months. Treatment-related grade 3/4 AEs included hypertension (16%), fatigue (14%) and hand foot syndrome (14%). Overall, 36 pts remain on study. Conclusions: AG has substantial antitumor activity in pts with sorafenib-refractory, metastatic RCC. Toxicity is typical of TKI VEGFR inhibitors and generally manageable.

[Table: see text]
Health-related quality of life (QoL) in patients with seminoma stage I treated with either adjuvant radiotherapy (RT) or two cycles of carboplatinum chemotherapy (CT): Results of a randomized phase III trial of the German Interdisciplinary Working Party on Testicular Cancer
Authors: Schoffski P. , Höhn N. , Kowalski R. , Classen J. , Meisner C. , Fechner G. , Dieckmann K. , Winkler C. , Bamberg M.
Published: March 2020

5050

Background: RT and CT are efficient adjuvant therapies in seminoma stage I and were compared in this trial. Clinical results will be reported elsewhere. Secondary endpoint was to assess QoL. Materials and Methods: Pts were randomized to receive RT (5x2 Gy/wk, 26–30 Gy total dose) or carboplatinum (300–460 mg/m2, 1 h iv d 1, 29). The QLQ C30 vs. 2.0 (15 QoL dimensions) and the Testicular Tumour Questionnaire (TTQ, 16 domains) were completed at randomization (0) and 1, 4, and 12 months (m) after trial entry. QoL was compared over time within the two arms (Wilcoxon) and between treatments (Mann-Whitney) by intent-to-treat. Results: 807 pts were randomized. Questionnaire compliance was 72% at 0, 75% at 1, 69% at 4 and 70% at 12m. Sign. variation (p<0.05) in QoL over time in both treatment arms (no. of Qol domains with deterioration over time): QLQ C30: RT: m1 vs 0 9, m4 vs 0 2, m12 vs 0 0 , CT: m1 vs 0 6, m4 vs 0 3, m12 vs 0 1; TTQ: RT: m1 vs 0 4, m4 vs 0 2, m12 vs 0 3, CT: m1 vs 0 1, m4 vs 0 2, m12 vs 0 1. (¼ improvement over time): QLQ C30: RT: m1 vs 0 0, m4 vs 0 6, m12 vs 0 8, CT: m1 vs 0 2, m4 vs 0 6, m12 vs 0 10; TTQ: RT: m1 vs 0 1, m4 vs 0 2, m12 vs 0 3, CT: m1 vs 0 2, m4 vs 0 4, m12 vs 0 6. Sign. variation in QoL comparing treatment modalities: QLQ C30: Better QoL in RT: at m1 in 0, at m4 in 0 and at m12 in 0 domains, Better QoL in CT: at m1 in 11, at m4 in 2 and at m12 in 5 domains; TTQ: Better QoL in RT: at m1 in 4, at m4 in 1 and at m12 in 0 domains, Better QoL in CT: at m1 in 3, at m4 in 0 and at m12 in 2 domains. Discussion and Conclusions: Adjuvant RT has a more negative impact on self-reported QoL of seminoma pts than CT, as determined by two instruments over a period of one year. RT negatively affects more dimensions of QoL as compared to CT, especially during the early phase. Pts rapidly adapt to QoL impairment, with little change persisting at m12. Not all observed differences are clinically relevant. Potential bias and methodological limitations will be discussed. Given the presumed clinical equivalence of both modalities, pts should be aware of the more negative impact of RT on the well-being. Treatment recommendation should be based on objective outcome parameters, toxicity, logistics and QoL considerations.

No significant financial relationships to disclose.
Does progression-free-survival (PFS) correlate with overall- and cancer-specific survival (OS/CSS) in randomized clinical trials (RCTs) exploring the addition of hormonal therapy (HT) to radiotherapy (RT) for early prostate cancer (EPC)? Analysis of six RCTs
Authors: Ruggeri E. M. , Bria E. , Carlini P. , Cuppone F. , Milella M. , Nisticò C. , Sperduti I. , Terzoli E. , Cognetti F. , Giannarelli D.
Published: March 2020

5056

Background: Although PFS is considered the standard primary end-point in EPC, the correlation with OS has never been explored in RCTs randomizing patients (pts) to HT plus radiotherapy (RT) versus RT. Given the relatively long prognosis in this disease setting, the correlation between PFS and CSS should be investigated as well. Methods: All phase III trials reporting all outcome’ data were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (PFS, OS and CSS rates) for all arms, and each reported Hazard Ratio (HRs). The correlation was estimated according to both the Pearson- (r) and R2-coefficient (parametric) and the Spearman coefficient (Rho, non-parametric). A sensitivity analysis in 2 subgroups (long- and short-term HT) to test for effect robustness has been accomplished as well. A model to determine the target sample size to determine CSS benefit of 3%, 4%, 6% and 7% months, respectively, was calculated as well. Results: Six RCTs (4,212 pts) were collected (follow-up range: 4.5–7.6 years). In the overall population, when considering the crude rates, a linear stronger correlation was found between PFS and CSS (r=0.71, R2=0.51, p=0.003; Rho=0.75, p=0.005), rather than with OS (r=0.55, R2=0.30, p=0.06; Rho=0.78, p=0.11). Again, when considering HRs, a linear stronger correlation was found between PFS and CSS (r=0.87, R2=0.76, p=0.02; Rho=0.94, p=0.005), rather than with OS (r=0.75, R2=0.56, p=0.08; Rho=0.77, p=0.07). Similar correlations were found whatever subgroups was explored. The sample size model (on the basis of the beta-coefficient=0.71), calculate 4,575, 2,006, 1,115 and 700 pts to improve PFS of 4%, 6%, 8%, and 10% months, which means to improve CSS of 2.8%, 4.3%, 5.7% and 7.1%, respectively. Conclusions: The correlation between PFS and CSS in RCTs exploring the benefit of adding HT to RT for EPC is significant, and suggests its further investigation as surrogate end-point. The natural history of the disease clearly explains the stronger correlation of PFS with CSS rather than with OS.

No significant financial relationships to disclose.
Circulating tumor cells in patients with castration-resistant metastatic prostate cancer
Authors: Danila D. C. , Leversha M. A. , Gonzalez-Espinoza R. , Anand A. , Gu B. , Gignac G. A. , Larson S. , Heller G. , Fleisher M. , Scher H. I.
Published: March 2020

5076

Background: Blood-based assays are urgently needed to provide molecular information on the specific targets expressed in tumor cells to optimize treatment selection. Antibody-capture technologies have been applied to isolate circulating tumor cells (CTC) from small volumes of peripheral blood from patients with progressive castrate metastatic prostate cancer. It has been demonstrated previously that CTC isolated from these patients represent authentic prostate cancer cells. Methods: CTC, positive for EpCAM (epithelial cellular adhesion molecule) and nuclear DAPI, and CD45 negative, were isolated from 120 patients with clinical castrate metastatic disease. All patients had rising PSA levels and were on stable treatment regimens at the time of CTC sampling. We tested the association between CTC counts and PSA levels, and the extent of disease to bone, and soft tissue metastasis by Wilcoxon rank sum. Fluorescence in situ hybridization was performed for AR and ERBB2 genes by an adapted method in CTC. Results: The average age in this patient cohort was 69 years, and median PSA at the time when CTC were drawn was 111 ng/mL (range 0.86–12147 ng/mL). The patterns of metastatic spread included disease in soft tissue only in 12 patients (10%), in bone and soft tissue in 67 (56%), and in bone only in 41 patients (34%). CTC counts ranged from 0 to 1958 cells per 7.5 mL of blood. A large number of patients (54, 45%) had 10 or more circulating tumor cells, while only 33 patients (27.5%) had 1 or less CTC per sample of blood. Significantly higher numbers of CTC were detected in patients with bone metastasis compared to those without bone metastasis (11 vs. 2.5, p<0.01). In patients with marked amplification of AR locus (five patients), tetraploidy was noted in the majority of cases (four cases). Two patients without AR amplification showed apparent tetraploidy, while no analyzed samples (nine) had amplification of ERBB2. Conclusions: The analysis of cancer-related gene alterations in CTC is feasible in a hospital-based laboratory. Further gene expression studies focused on the patients with higher numbers of CTC in correlation with clinical outcomes, as well as the investigation of CTC gene expression during specific treatments are under way.

No significant financial relationships to disclose.
Comparative analysis of bone marrow (BM) micrometastasis (M) with sentinel lymph node (SLN) status in early breast cancer (BRCa)
Authors: Patel M. P. , Saha S. , Ali S. , Iddings D. , Wiese D. , Sankaran H. , Arora M. , Singh T. , Branigin T. , Barber K.
Published: March 2020

508

Background: While sentinel lymph node (SLN) metastasis (mets) and bone marrow (BM) micrometastases (M) provide prognostic information in breast cancer (BRCa) patients (pts), a definitive relationship between the two has not yet been proven. We hypothesize that the presence of BMM may not infer an increased risk of SLN mets due to differences in their mechanisms of spread. Methods: We conducted a 6-year retrospective study of 251 T1/T2 BRCa pts who underwent bilateral iliac crest bone marrow aspiration, SLN mapping, and either lumpectomy, partial mastectomy, modified radical mastectomy, or total mastectomy by a single surgeon. BM samples were examined for micrometastases by Automated Cellular Imaging System using Chroma Vision Cytokeratin Detection Kit to detect cells expressing CK 8 as defined by CAM 5.2 monoclonal antibody. Pts with BMM underwent repeat BM analysis after completion of adjuvant chemotherapy. Data was collected for SLN, BM, ER/PR and HER2/neu status. Results: There were 251 consecutive pts entered into the study. Of these, 27.5% (69/251) had SLN mets and 9.6% (24/251) had BMM. Of the pts with SLN mets, 11.6% (8/69) had BMM vs. 88.4% (61/69) with no BMM ( Table ). In pts with ER/PR negative (-ve) BRCa, 7.1% (2/28) had BMM vs. 92.9% (26/28) with no BMM and 25% (7/28) had SLN positive (+ve) vs. 75% (21/28) SLN -ve pts ( Table ). Of the pts with HER2/neu +ve BRCa, 13.1% (8/61) had BMM vs. 86.9% (53/61) with no BMM and 26.2% (16/61) were SLN +ve vs. 73.8% (45/61) SLN -ve pts. After completion of adjuvant chemotherapy all pts with BMM (n=24) converted to BM -ve status. Conclusions: No correlation was identified between BMM and SLN status in T1 and T2 BRCa pts. This study suggests that BMM can occur independently of SLN status. Furthermore, (-ve) ER/PR and (+ve) HER2/neu status did not have a direct correlation with either BMM or SLN mets. Pts with BMM status may benefit from adjuvant therapy. Long-term implications of BM (+ve) have to be evaluated by larger multi- center trials.

[Table: see text]

No significant financial relationships to disclose.
Cytokine gene polymorphism: Influence in the response of bladder superficial carcinoma to the immunotherapeutic with BCG
Authors: Silva M. V. , Calais da Silva F. , Ligeiro D. , Trindade H.
Published: March 2020

5081

Background: Gene polymorphisms in key immunoregulatory molecules may contribute to the heterogeneity in outcome between individuals with bladder superficial carcinome receiving the immunotherapeutic treatment with BCG. This study aims to verify and identify cytokine gene polymorphisms that could influence the immune response to BCG and antitumoural action in those patients. Methods: We studied 90 patients, after turb and BCG intravesical, there where 72 responders (80 %), 18 non-responders (20%) all patients are multiple or recurrent except T1 G3 or Cis, the median follow up is 4,5 years The cytokines single nucleotide polymorphisms (SNP’s) (IL-1a (-889T/C), IL-1β (-511C/T), IL-1β (3962T/C), IL-1R (970 C/T), IL-1Ra (11100 T/C), IL-4 (-590 C/T), IL4-Ra (+576 G/A), IL-6 (-174 G/C), IL-10 (-1082GA/-819CT/-592CA), IL-12p35 (-916C/T), TGF-β (Codon 10 C/T), TNF-a (488GA/-238GA/-308GA), TNF-β (252 G/A), IFN-γ (+874 T/A)) genotypes were assessed by PCR with Sequence Specific Primers (PCR-SSP). Genotypes and allele frequencies of responders and non-responders (with tumour recidive) to the treatment were compared and evaluated by the two-sided Fisher’s exact test or Chi square and odds ratios (OR) were calculated as an estimate of relative risk. Results: It was found a correlation of cytokine gene polymorphisms to outcome of patients for both the genotype and haplotype TNF-a 488G/-238G/-308G frequencies, which are significantly higher in patients with tumour recidive after BCG treatment (non-responders 72,2% vs responders 42% OR=3,6; 95%CI 1.15 to 11.17 p=0.033). From the other genes studied, we could depict a weak association of the IL-1R 970 T/T genotype, with a higher frequency in non-responder patients (27,8% vs 4.2% in responders, p<0.05) and with IL-10 -1082 A allele also more frequent in non-responders to BCG (75% vs 54,8%; p<0.05). Conclusions: These results suggest that host genetics of immune regulatory molecules may play a role in predicting the antitumoural response after BCG treatment of bladder cancer. Confirmation of these findings in other populations is required.

No significant financial relationships to disclose.
A controlled prospective randomized trial of adjuvant chemoradiotherapy following radical cystectomy in advanced high risk bladder cancer
Authors: Zaghloul M. S. , Khaled H. M. , Lotayef M. , William H. , Nazmy M. , Attia G.
Published: March 2020

5082

Background: High risk locally advanced bladder cancer patients experienced low survival rates, high local recurrence and high rate of distant metastasis. Postoperative radiotherapy (PORT) improved local control and survival, yet it did not affect distant metastasis. Methods: A prospective randomized trial was performed at NCI, Cairo, Egypt including 146 patients in 2 arms. Patients who underwent radical cystectomy and pelvic lymphadenectomy had to have one or more of the following: stage P3b or P4a, G3 or involved lymphadenopathy. Arm I (74 patients) received PORT 45 Gy/30 fractions/3 weeks. Arm II (72 patients) received 2 courses of adjuvant chemotherapy (Gemcitabine 1 gm/m2 D1 and D8 and cisplatin 70 mg/m2 D2), same PORT regimen followed by another 2 courses of Gemcitabine-cisplatin. Results: Chemotherapy and radiation were tolerated with grade 1/2 toxicities. Delayed toxicity was comparable in both arms. The 45-month DFS was 51 ± 12 % in the whole group. This was affected significantly by performance status (p = 0.0001), pathological stage (p = 0.0099), nodal involvement (p = 0.004) and number of risk factors (p = 0.16). Though there was improvement of 45-month DFS from 28 ± 20% in PORT group to 70 ± 6 % in chemoradiotherapy group, yet it did not reach to the level of statistical significance (p = 0.18). Patients having one risk factor, G3 or no nodal involvement in arm II experienced better DFS than those in arm I (p = 0.17, 0.11 and 0.17 respectively). Distant metastasis-free survival (DMF) rate increased with the addition of chemotherapy from 29±21% to 75±6%. This effect was intensified in patients having one risk factor, grade 3 and negative nodes. Conclusions: Adjuvant chemoradiotherapy using Gemcitabine-cisplatin and PORT was tolerable. There was DFS improvement and higher DMF rates with the addition of chemotherapy to PORT (not statistically significant yet). Patients with one risk factor, G3 or no nodal involvement seemed to benefit more from the added chemotherapy.

No significant financial relationships to disclose.
Outcome in 41 patients with late relapse germ cell tumors (GCT) treated with high-dose chemotherapy (HDCT)
Authors: Lorch A. , Rick O. , Hartmann J. T. , Metzner B. , Glasmacher A. , Berdel W. , Schirren R. , Bokemeyer C. , Beyer J.
Published: March 2020

5086

Background: The management of patients (pts) with late-relapse GCT and unresectable tumors or very high tumor markers is controversial. Methods: A total of 41 late-relapse pts were identified among a group of 216 pts with refractory or relapsed GCT who were treated in an open, prospective, randomized, multicenter phase III trial. Late relapse was defined as any relapse occurring more than 2 years after completion of initial chemotherapy for GCT. Treatment consisted of either one cycle cisplatin 100 mg/m2, etoposide 375 mg/m2 and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE, arm A) or of three cycles of VIP plus one cycle high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2 and cyclophosphamide 6,400 mg/m2 (CEC, arm B). Each HDCT was followed by reinfusion of autologous peripheral blood progenitor cells. Results: Overall 20 pts with late-relapse GCT received sequential HDCT and 21 pts single HDCT when the study was stopped due to excess treatment-related mortality in arm B; median time to late relapse in 41 pts was 5.4 years (range 2–18 years); 8/41 (20%) pts had seminomatous GCT, 32/41 (78%) pts had nonseminomatous GCT with or without teratoma; one pt (2%) had unknown GCT histology. No non-GCT histologies were included. The retroperitonum was most commonly involved in 30/41 (73%) pts. 29 of 41 (71%) pts had unresectable, multifocal disease and 20/41 (49%) pts also had very high markers. A complete remission to chemotherapy alone was achieved in 4/41 (10%) pts, 16/41 (39%) pts achieved a partial remission with negative tumor markers. The remaining 21/41 (51%) either had a transient or no response despite HDCT. Residual tumor resections were performed in 17/41 (41%) pts. Residual tumor histology was viable cancer in 8/17 (47%) pts, teratoma in 4/17 (24%) pts and necrosis in 5/17 (25%) pts. With a minimum follow-up of 1 year and a median follow-up of 3 years the estimated Kaplan-Meier rates are 17%, 20% and 32% for event-free, progression-free and overall survival. Conclusion: Treatment outcome after HDCT was inferior in late-relapse pts compared to the group of pts who relapsed within less than 2 years. Despite an overall poor prognosis, HDCT can still result in long-term remissions in selected late-relapse GCT pts.

No significant financial relationships to disclose.
Can we improve the outcome of patients with advanced non-seminomatous germ cell tumors (NSGCT): 16 years experience of a single institution
Authors: Tryakin A. , Tjulandin S. , Fedyanin M. , Titov D. , Bulanov A. , Garin A. , Figurin K. , Kanagavel D. , Sergeev J. , Zakharova T.
Published: March 2020

5092

Background: We performed an analysis to review the outcome of patients (pts) with advanced NSGCT treated in Russian Cancer Research Center, since the introduction of modern chemotherapy (CT) at 1987. Moreover, we analyzed whether the results had improved over the last 6 years. Methods: 589 CT-naive pts with advanced NSGCT received induction etoposide- and cisplatin-based CT from 1987 to 2003. 534 (91%) pts had primary testicular tumor. Most commonly used CT regimens were EP (36%), BEP (52%), and C-BOP-3BEP (9%). Median follow-up was 60 months (range, 2–210) for the pts who survived. Pts survival was compared in accordance with two treatment periods, ‘before 1997’ and ‘after 1997’. Results: Survival rate differed significantly among the IGCCCG prognostic groups. There was a trend toward improved results over the last 6-year period (see table ). The poor prognostic group attained the most pronounced improvement in both PFS and OS (absolute benefit 14%). This fact could be explained by CT intensification (decrease in the number of reasons for treatment delay or dose-reduction on next cycle of CT) and by increase in the rate of post-CT resections of residual tumors. Conclusions: Despite the absence of major changes in advanced NSGCT treatment during the last two decades, there still exists opportunity to improve the outcome of the pts.

[Table: see text]

No significant financial relationships to disclose.
A phase I study to evaluate safety, immunogenicity and anti-tumor activity of the multi-peptide vaccine IMA901 in renal cell carcinoma patients (RCC)
Authors: Staehler M. , Stenzl A. , Dietrich P. Y. , Eisen T. , Haferkamp A. , Beck J. , Mayer A. , Walter S. , Singh-Jasuja H. , Stief C.
Published: March 2020

5098

Background: IMA901 is a therapeutic cancer vaccine based on multiple synthetic tumor-associated peptides confirmed to be naturally presented by analysis of primary RCC tissues. IMA901 consists of 9 HLA-class I-binding and 1 HLA class II-binding peptides with the capacity to activate cytotoxic T cells (CD8+ T cells) and T helper cells (CD4+ T cells). Methods: 30 patients with stage III/IV RCC were enrolled in a single arm, multi-centre study. The endpoints were safety, T-cell responses, pharmacokinetics of the intradermal application of GM-CSF and anti-tumor activity according to RECIST. Patients had to be HLA-A*02 positive and received 8 intradermal vaccinations on days 1, 2, 3, 8, 15, 22, 36 and 64 each consisting of 4.5 mg IMA901 and 75 μg GM-CSF. Results: The most prevalent adverse events (AEs) were fatigue, cough and headache. Aseptical lymphadenitis and injection site reactions such as erythema, edema and pruritus were the most frequent possibly drug-related AEs. All possibly drug-related adverse events were mild to moderate. No patient experienced any possibly drug-related serious adverse events or deaths during the study. Pharmacokinetic data provided no evidence for accumulation of GM-CSF upon repeated i.d. administration. 74% of patients showed a vaccine-induced specific T-cell response and 30% of patients responded to multiple peptides contained in IMA901. The overall tumor assessment in patients with measurable disease revealed that 8 patients (35%) demonstrated a clinical benefit (1 PR + 7 SD). Most encouraging, patients who elicited multiple T-cell responses showed a statistically significant higher clinical benefit rate. Conclusions: IMA901 is safe, very well tolerated and immunogenic. Clinically observed tumor growth control in RCC patients may imply anti-tumor activity strongly supported by two patients with tumor regression (1 PR and 1 patient with 27% shrinkage in target lesions). The mode of action is strongly supported by the finding that multiple T-cell responders were significantly more likely to have a clinical benefit. These data clearly support the further development of IMA901.

No significant financial relationships to disclose.
Combination therapy of meloxicam, a selective COX-2 inhibitor, and interferon alfa in metastatic renal cell carcinoma: A phase II study on efficacy and toxicity
Authors: Shinohara N. , Harabayashi T. , Sazawa A. , Nonomura K. , Watarai Y. , Kumagai A. , Murakumo M. , Kanagawa K. , Sakashita S.
Published: March 2020

5105

Background: Cyclooxygenase (COX)-2 plays a major role in the development of cancer through numerous mechanisms. We have previously confirmed that COX-2 is expressed in a renal cell carcinoma (RCC) and it has an important role in tumorigenesis and angiogenesis (Int J Cancer 2004). Some preclinical studies suggest that a selective COX-2 inhibitor may augment the antitumor effects of immunotherapeutic agents. We conducted a phase II trial of the combination of meloxicam, a selective COX-2 inhibitor, and interferon (IFN)-alfa 2a in metastatic RCC in order to test the hypothesis that meloxicam enhances the response to the immunotherapy. Methods: Eligible patients had metastatic RCC, no prior systemic therapy, performance status 0–2, measurable disease. Patients received IFN 3–5 MIU 3x/week and meloxicam 10 mg/daily orally. This was a single-stage trial. Primary end points were RECIST response rates and toxicity. Results: Twenty-one patients were enrolled. Patients characteristics included: median age 63 years (49–75), male/female: 16/5, PS 0/1/2: 11/6/4, prior nephrectomy: 16 (76%). MSKCC prognostic categories were good: intermediate: poor (24%: 48%: 29%). A median follow-up was 8 months (range 3–29+) and 18 of 21 (86%) patients are still alive. Toxicities were mostly grade 1 or 2 (fever, fatigue, anorexia, depression), except 1 patient with grade 3 liver dysfunction. Among 20 patients evaluable for response, complete response (CR) was observed in 3 patients (15%) and partial response (PR) in 5 (25%), yielding an overall response rate of 40% (95% CI: 17–63). An additional 5 patients (25%) had stable disease. Five of 6 patients classified as poor risk by MSKCC prognostic classification obtained a CR or PR, as did 3 of 14 patients as good or intermediate risk (p=0.038). Median time to progression for 20 patients was 6 months (1–29+). Conclusions: The overall response rate of 40% for the combination of meloxicam and IFN-alfa in metastatic RCC is greater than that of IFN-alfa alone reported previously, suggesting that meloxicam can enhance the response to immunotherapy. Further investigation with this combination is warranted.

No significant financial relationships to disclose.
Randomized phase II trial of docetaxel, with or without doxercalciferol, in advanced, androgen-independent prostate cancer
Authors: Attia S. , Eickhoff J. , Wilding G. , Blank J. , Rezazadeh H. , Shevrin D. , Glode M. , Jumonville A. , Eastman M. , Liu G.
Published: March 2020

5119

Background: Docetaxel is the standard of care for advanced androgen-independent prostate cancer (AIPC). Doxercalciferol, a vitamin D analog (1a-hydroxyvitamin D2), has single-agent activity in AIPC (Clin Cancer Res 9(11), 2003). Preclinical evidence supports combining vitamin D with chemotherapy to treat AIPC. Here we report results of a multi-institutional trial combining docetaxel and doxercalciferol. Methods: Patients with chemo-naive AIPC were randomized 1:1 to receive, on a four week cycle, docetaxel (35 mg/m2 IV; days 1, 8 and 15) with either doxercalciferol (10 mcg PO daily, days 1–28) or placebo in a double-blind fashion. The primary endpoint was to compare progression-free survival (PFS). Secondary endpoints were to assess overall survival (OS), objective response (RECIST), PSA response (consensus criteria), and toxicity. PFS and OS were analyzed on an intent-to-treat basis. Eligibility criteria included no prior cytotoxic therapy; radiographic evidence of metastasis; performance status ≤ 2 and no recent history of nephrolithiasis. Results: Seventy patients were randomized. Median follow-up time was 16.2 months (range, 0–40.5 months). Median PFS in the doxercalciferol arm was 14.9 months (95% CI: 8.7–16.6 months) versus 11.9 months (95% CI: 8.9–16.4 months) in the placebo arm (p=0.73). Median OS in the doxercalciferol arm was 18.1 months (95% CI: 14.9–26.2 months) and 17.9 months (95% CI: 12.1–24.6 months) in the placebo arm (p=0.63). Twenty-nine patients in the doxercalciferol arm and 33 in the placebo arm were evaluable for objective response. No complete responses were seen. Partial response rate was 14% (doxercalciferol) vs. 15% (placebo) (p=0.88). PSA response rate was 44% (95% CI: 29%-60%) in the doxercalciferol arm and 42% (95% CI: 27%-59%) in the placebo arm (p=0.87). Grade 3/4 toxicity rates were 38% in the doxercalciferol arm and 39% in the placebo arm (p=0.99). Conclusions: Despite encouraging data with other vitamin D analogs combined with docetaxel in AIPC, the addition of daily doxercalciferol to weekly docetaxel did not enhance median PFS, OS or tumor response. Toxicity was similar between treatment groups. Further evaluation of vitamin D analogs in combination with chemotherapy in AIPC remains of interest.

No significant financial relationships to disclose.
Cancer gene therapy with a retrovirally transduced IL2-IFNγ-secreting allogeneic tumorvaccine in patients with progressive hormone refractory prostate cancer—A phase I/II trial
Authors: Gansbacher B. , Brill T. , Eisele B. , Kuebler H. , van Randenborgh H. , Paul R. , Hartung R. , Fend F. , Pohla H. , Schendel D.
Published: March 2020

5127

Background: The purpose of this study was to determine whether immunization with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-γ (IFN-γ), would be tolerated and able to induce a prolongation of PSA doubling time in patients with progressive hormone refractory prostate cancer. Methods: 30 HLA-A0201-matched patients with progressive, hormone refractory prostate cancer, demonstrating three successive elevations in prostate specific antigen (PSA) values, received four intradermal injections on days 1, 15, 29 and 92, and then every 90 days as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, 27 patients received 15 million cells. The primary efficacy criterion was the difference in PSA doubling time (PSA-DT) determined in the pre-treatment phase (before start of vaccination) and in the trial treatment phase (during vaccination). Results: The study was completed according to protocol. Immunostimulation could be demonstrated in most of the 30 patients (histological evaluation of injection site biopsies, serial ELISPOT analysis of PBMCs). During vaccination there was a significant prolongation of the PSA-DT compared to the pre-vaccination period that came to 81% (prolongation from 63 days to 114 days (p < 0.0035; ITT)). Twenty two of 30 patients (73%) responded to the vaccine administration as judged by prolongation of PSA-DT. In the majority of patients the administration was followed by a period of PSA stabilisation that was up to 641 days (“PSA plateau”). No dose limiting or autoimmune toxicities were seen. The median overall survival time since first vaccination was 981 days (mean value: 770 days). Conclusions: This vaccine strategy showed a prolongation of PSA-DT and was found to be safe and well tolerated. The results of this trial warrant the vaccine’s further clinical development.

No significant financial relationships to disclose.
A model assessing how variable timing of outcome assessments impacts progression-free survival (PFS)
Authors: Gignac G. A. , Morris M. J. , Heller G. , Scher H. I.
Published: March 2020

5130

Background: PFS has been proposed as an endpoint in prostate cancer because tumor regression cannot be assessed easily and the significance of post-therapy changes in PSA is uncertain. There is significant variability in the frequency by which outcomes are assessed across clinical trials. We sought to create a model that would define the degree of error in estimating PFS from this variability. Methods: A simulation experiment was performed. An exponential distribution was used to generate 100 progression times for 3 hypothetical risk cohorts: rapid (median PFS of 18 wks), intermediate (36 wks) and slow progressors (72 wks). We examined how reported PFS would change depending on 3 assessment schedules: every (q) 6, 8 and 12 wks for 48 wks each, then q6 months for 2 years. The logrank statistic was used to compare PFS between schedules. If different schedules have no impact the expected type 1 error rate should be 5% (where a difference in PFS time is detected when none existed). Each simulation was repeated 1000 times. Results: Nine pairwise comparisons were performed and Kaplan-Meier PFS estimates created for the 3 assessment schedules and 3 risk cohorts (see table 1 ). In the highest risk cohort, PFS of 18 wks, 38% of the time the logrank test showed a falsely prolonged PFS for pts assessed on the q12 vs 6 wks schedule. This type 1 error rate (by simulation) was reduced to 20% and 11%, when the schedules were q8 vs 12 wks and q6 vs 8 wks, respectively, but remained above the 5% expected rate for type 1 error. For lower risk pts, PFS of 72 wks, the disparity in PFS times was diminished. Conclusions: Progression free survival is significantly skewed by the schedule of assessing treatment effects in clinical trials. This argues for uniformity in the timing of outcome assessments across trials and between arms in randomized trials. Grant support: 5T32CA09207

[Table: see text]

No significant financial relationships to disclose.
A novel androgen receptor (AR) suppressor complex (ARS)—An essential factor in androgen-independent progression of prostate cancer (PC)
Authors: Ferrari A. C. , Wang L. , Johnson E. M. , Melamed J. , Liu X. , Kinoshita Y. , Buckley M. T. , Liebes L. F. , Kurek R. , Ossowski L. , Babb J. S.
Published: March 2020

5145

Background: Increased AR level, characteristic of advanced PC, has been linked to AI growth while its down-regulation to restored androgen-dependence (AD). However, the mechanisms of AR overexpression remain in dispute. The objectives were to study the proteins comprising a novel ARS that binds to 5’-UTR of AR gene, which is partially lost in AI LNCaP cells; the status of ARS proteins in AD and AI human specimens and therapeutic modulation of ARS proteins. Methods: Parental AD LNCaP cells and its AI- derivative expressing 4 fold more AR-mRNA and protein than parental AD LNCaP were used to isolate, in vitro/in vivo characterize and therapeutically modulate ARS proteins and cell growth. NYU Tissue Bank provided human samples. Assays: column chromatography, SDS-PAGE, mass spectrometry, EMSA, Southwersten-Western, ChIP, cDNA array, real time PCR, si-RNA, immunohistochemistry. Results: Pur alpha (Pura) and hnRNP-K are part of ARS complex that binds in vitro and in vivo to a defined DNA sequence in 5’UTR of AR gene. AI cells with high AR had 3 times less Pura: its forced expression lowered AR levels. Pura knockdown in AD cells yielded higher AR levels and AI growth. Hormone-naive human PC specimens had significantly increased AR (0.0317) and lower Pura-RNA (0.0317) than hormone resistant PCs. In-vivo binding of Pura (ChIP) to 5’UTR was also reduced (p=0.0028). Histone deactetylase inibitors (HDACI) increased binding of Pura to 5’UTR, decreased AR levels and inhibited AI-growth of LNCaP cells. Conclusions: We show that AR over-expression and AI-growth of a hormone resistant PC cell line are affected by a loss of a repressor complex that binds to 5’-UTR of AR gene. Pura is a crucial part of this complex. We have convincing evidence obtained in hormone naive and resistant human samples to indicate that similar mechanism might be responsible for human PC progression. We determined HDACI can restore Pura levels and androgen-dependence.

No significant financial relationships to disclose.
Duration of the first off treatment period is associated with time to androgen independence (AI) and survival in men with localized or biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation (IAD)
Authors: Telesca D. , Higano C. S. , Yu E. Y. , Montgomery R. B. , Tam S. L. , Russell K. J. , Nelson P. S. , Etzioni R. B.
Published: March 2020

5146

Background: Patients (pts) with localized prostate cancer or biochemical relapse who are treated with AD eventually develop AI and die. In an effort to better understand the natural history of this population, various characteristics of the patients and the first cycle of IAD were analyzed. Methods: Eligible pts had histological diagnosis of prostate cancer, no evidence of bone metastases by bone scan or visceral disease by CT scan, and at least 2 consecutive rising PSA = 2 weeks apart after diagnosis, radical prostatectomy (RP), or radiation therapy (XRT). Pts were treated with IAD consisting of 9 months of leuprolide acetate and an anti-androgen. Subsequently AD was stopped and monthly PSA and testosterone levels were followed during the off treatment period (Toff) until the PSA reached a threshold value (1 ng/mL if prostate removed or 4 ng/mL if prostate intact). At that time AD was resumed as before in a new cycle. Pts were treated until AI, defined as two rising PSAs while on AD with a castrate level of testosterone. Results: To date, 57 of 88 accrued pts are evaluable for this analysis. The median age at diagnosis is 62.2 yrs (range 43.9–77.4 yrs), median Gleason sum is 7. For the 49 pts with biochemical relapse after prior RP or XRT, median time from diagnosis to PSA relapse is 3.2 yrs (0–14.7 yrs) and from diagnosis to IAD was 4.9 yrs (range 0.1–14.9 yrs). For the 8 pts with no prior therapy, median time from diagnosis to IAD is 0.2 yrs (range 0–3.9 yrs). The median PSA value for all pts at study entry is 16 ng/mL (range 4–175 ng/mL); the value at study entry or after 3, 5, or 7 months of AD is not associated with time to AI or survival. Entry PSA is predictive of length of first Toff, and the length of the first Toff is associated with both time to AI (P<0.010) and survival (P<0.01). Conclusions: The duration of the first Toff in other studies of IAD should be evaluated for similar associations with time to AI and survival.

No significant financial relationships to disclose.
Long-term effects of pre-surgical stress management for men with early stage prostate cancer undergoing radical prostatectomy (RP)
Authors: Cohen L. , Pettaway C. , Babaian R. , Pisters L. , Miles B. , Harrison-Fortier A. , Devine D. , Wei Q. , Parker P.
Published: March 2020

5148

Background: We conducted a randomized trial to examine pre-surgical stress management for men undergoing RP. We previously reported on the short-term benefits in reducing mood disturbances before and after surgery. Methods: One hundred and fifty- eight men were randomly assigned to one of three conditions. Men in the stress management (SM) group discussed their fears and concerns about the upcoming surgery and were taught diaphragmatic breathing, guided imagery, an imaginal exposure to the day of surgery, and exposure to adaptive coping skills. Men in the supportive attention (SA) group discussed their fears and concerns about the upcoming surgery and then a semi-structured interview was conducted. Men in the SM and SA groups met with a clinical psychologist two times prior to surgery, a brief session just prior to surgery, and then again prior to discharge. Men in the usual care (UC) group had no meetings with a psychologist. Men completed psychosocial and quality of life (QOL) measures including distress (BSI-GSI), intrusive thoughts (IES), and QOL (SF-36), at baseline and 6 and 12 months later. Results: Men were primarily Caucasian (78%), married (85%) and highly educated (80% some college or higher). Mixed model analyses, controlling for ethnicity, age, martial status, stage, baseline PSA, Gleason score, and the respective baseline measure, indicated a significant group main effect for SF-36 Role Physical (SF-RP)(p=0.01). Post-hoc analyses revealed significantly higher SF-RP scores for the SM (86) vs. UC (63) group and marginally higher scores for the SM (86) vs. SA (73) group. There was a marginally significant group main effect for pain scores (SF-BP) (p=0.12) with the SM group reporting significantly better pain scores than the UC group (80 vs. 71), and neither group differed from the SA group (77). There was also a group by time effect for general health scores (SF-GH) revealing by 12 months after surgery that the SM (74) and SA (76) groups both reported higher SF-GH scores than the UC group (68). There were no group differences on any of the other outcomes. Conclusions: Results suggest that even a brief pre-surgical stress management intervention is beneficial in terms of improving aspects of QOL 6 and 12 months after RP. Funding: NIMH/NCI RO1MH59432

No significant financial relationships to disclose.