bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity
Authors: van Erp N. , Mathijssen R. H. , van der Veldt A. A. , Haanen J. B. , Reyners A. K. , Eechoute K. , Boven E. , Wessels J. A. , Guchelaar H. , Gelderblom H. 
Published: August 2020

5006 Background: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities; thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome and ‘any toxicity according to Common Terminology Criteria > grade 2.’ Methods: A multicenter pharmacogenetic association study was performed in 219 patients treated with single agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several non-genetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results: The risk for leukopenia was increased when the G-allele in CYP1A1 2455A/G (OR = 6.24; p = 0.029) or the T-allele in FLT3 738T/C (OR = 2.8; p = 0.008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR = 1.74; p = 0.041) was absent. ‘Any toxicity > grade 2’ prevalence was increased when the T-allele of VEGFR-2 1191C/T (OR = 2.39; p = 0.046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR = 2.63; p = 0.016) were present. The risk for mucosal inflammation was increased in the presence of the G-allele in CYP1A1 2455A/G (OR = 4.03; p = 0.021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR = 2.56; p = 0.035) was present. Conclusions: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters and drug targets are associated with sunitinib related toxicities. A better understanding of genetic and non-genetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients. [Table: see text]
The natural history of metastatic progression in men with PSA-recurrent prostate cancer after radical prostatectomy: 25-year follow-up
Authors: Antonarakis E. S. , Trock B. J. , Feng Z. , Humphreys E. B. , Carducci M. A. , Partin A. W. , Walsh P. C. , Eisenberger M. A. 
Published: August 2020

5008 Background: In men with prostate specific antigen (PSA) recurrence following radical prostatectomy (RP) and no other therapy, the natural history of metastatic progression was previously described in 1999. We now report data reflecting up to 25 years of follow-up. Methods: We performed a retrospective analysis of 774 men treated with RP between 4/1982 and 7/2008 who developed PSA recurrence (>0.2 ng/ml) and never received adjuvant or salvage therapy. We investigated factors influencing the development of metastases. Results: Mean follow-up after RP was 8.5 y (median 8 y). Of 774 men with PSA recurrence, 295 (38%) developed metastases, and 433 had data on PSA doubling time (PSADT), forming our cohort. The mean time from RP to PSA recurrence in the entire cohort was 4.2 y (median 3 y). In those who developed metastases, the mean time from PSA recurrence to metastasis was 3.1 y (median 2 y). The mean PSA at the time of metastasis was 90.3 ng/ml (median 31.4 ng/ml). In Cox regression analysis: PSADT, Gleason score, and time to PSA progression were predictive of the development of metastases ( Table ). In Kaplan-Meier survival analysis, the median actuarial time from PSA recurrence to metastasis was 10 y (95% CI 9 - 15 y). Median actuarial metastasis-free survival from PSA recurrence for men with PSADT <3 mo, 3 - 8.9 mo, 9 - 14.9 mo, and >15 mo was 1 y (95% CI 0 - 1 y), 4 y (95% CI 2 - 6 y), 9 y (95% CI 7 - 13 y), and 15 y (95% CI 12 - 20 y), respectively. Conclusions: PSADT, Gleason score, and time to PSA progression are strong independent predictors of metastasis-free survival in men with PSA-recurrent prostate cancer. These data facilitate patient counseling and logical risk-based treatment planning. They also provide the background for appropriate selection of patients, treatments, and endpoints for clinical trials. [Table: see text] No significant financial relationships to disclose.
Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC)
Authors: Scher H. I. , Beer T. M. , Higano C. S. , Taplin M. , Efstathiou E. , Anand A. , Hung D. , Hirmand M. , Fleisher M. ,   The Prostate Cancer Clinical Trials Consortium
Published: August 2020

5011 Background: MDV3100 is a novel AR antagonist selected for activity in prostate cancer model systems with overexpressed AR. In contrast to bicalutamide, MDV3100 blocks nuclear translocation of AR and DNA binding, and has no known agonist activity when AR is overexpressed. Antitumor activity of MDV3100 in a Phase I/II trial was assessed by prostate-specific antigen (PSA), soft tissue and osseous disease, circulating tumor cells (CTC), and time on treatment. Methods: Patients (pts) with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy-naïve (naïve) and 12 post-chemotherapy pts per cohort. Results: 140 pts were enrolled. 114 pts at 30–360 mg/day have been followed for >12 weeks. PSA declines (>50% from baseline) were observed at week 12 in 57% (37/65) of naïve and 45% (22/49) of post-chemo pts. Data suggest a dose-response trend particularly in post-chemo pts where PSA responses were 32% at 60 and 150 mg/day and 58% at 240 and 360 mg/day. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable soft tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. CTC counts on 101 of 114 pts showed 92% (56/61) with favorable (<5) counts pretreatment maintained favorable posttreatment counts, while 53% (21/40) converted from unfavorable to favorable posttreatment. For post-chemo pts, favorable retention was 100% (17/17) and unfavorable to favorable conversion at 240 and 360 mg/day was 60% (6/10). 87 pts at 30–240 mg/day have been followed for >24 weeks; 35 (40%) received treatment >24 weeks. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. Conclusions: MDV3100 is a promising candidate for the treatment of prostate cancer assessed by PSA, imaging, CTC, and time on treatment. The data suggest a dose-response trend and consistency across endpoints. Pt follow-up is continuing. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 240 mg/day as the recommended dose for a phase III trial in CRPC. [Table: see text]
Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer
Authors: Chi K. N. , Hotte S. J. , Yu E. , Tu D. , Eigl B. , Tannock I. , Saad F. , North S. , Powers J. , Eisenhauer E. ,   National Cancer Institute of Canada Clinical Trials Group
Published: August 2020

5012 Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of <640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR<40% vs. >60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI<13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05–12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49–87), PSA >100 μg/L in 51%, Hgb ≥100 g/L in 98%, alk phos >ULN in 44%, LDH >ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B). PSA declines at 12 weeks of any/>30%/>50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B). PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3–8.8) and 6.1 months (3.7–8.6). Median OS for Arms A and B was 27.5 (19.2-∞) and 16.9 months (12.7–26.0) (unadjusted HR = 0.60 [0.34–1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29–0.97], p = 0.04). Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society. [Table: see text]
Excision repair cross-complementing 1 (ERCC1) and survival in advanced bladder cancer: Confirmatory results using immunohistochemistry
Authors: Guix M. , Lema L. , Lloreta J. , Rojo F. , Suárez C. , Carles J. , de la Cruz J. , Sánchez-Carbayo M. , Albanell J. , Bellmunt J. 
Published: August 2020

5025 Background: DNA damaging agents are the backbone of combination chemotherapy regimens for the treatment of advanced bladder cancer. We hypothesized that levels of DNA repair genes such as ERCC1 could predict survival in patients receiving platinum based therapy. Our previous work (Bellmunt J et al, Ann Oncol. 2007) showed that survival was significantly higher in advanced bladder cancer patients with low gene expression levels of ERCC1 measured by RT-qPCR (25.4 versus 15.4 months; p = 0.03). We aimed to confirm these findings using immunohistochemistry (IHC) in an independent cohort of advanced bladder cancer patients treated with cisplatin-based chemotherapy at our institution. Methods: Formalin-fixed paraffin-embedded tumor tissue was available from 51 patients. IHC stains for ERCC1 protein levels were scored as percentage and intensity of positive cells. ERCC1 staining was considered positive if detected in ≥1% tumor cells. The Kaplan-Meier method was used to calculate survival and the Cox proportional hazards model was used to examine the prognostic value of protein expression levels. Results: ERCC1 staining was negative in 60% of patients, weakly positive (1–10% positive cells) in 21% and strongly positive (>10% positive cells) in 19%. Median overall survival for all patients was 14.4m (95% CI 6.7–16.1m). Median disease-specific survival was significantly higher in patients negative for ERCC1 by IHC (12.6m versus 8.6m; p = 0.032). Conclusions: Our results using the more simple IHC technique confirm the prognostic value of ERCC1 expression in advanced bladder cancer. Patients with high expression of ERCC1 by IHC have a worse disease-specific survival than patients with no expression. A correlative study of IHC and RT-qPCR in both sets of samples is ongoing. No significant financial relationships to disclose.
Long-term follow-up of chemotherapy-induced remissions in patients with disseminated nonseminomatous germ cell tumors
Authors: Ehrlich Y. , Brames M. J. , Beck S. D. , Foster R. S. , Einhorn L. H. 
Published: August 2020

5029 Background: There is controversy concerning management of patients (pts) with nonseminomatous germ cell tumor (NSGCT) who obtain a chemotherapy-induced complete radiographic (<1cm node diameter) and serologic remission (CR). It has been our policy not to recommend retroperitoneal lymph nodes dissection (RPLND). Proponents of mandatory RPLND cite a 20% to 30% rate of residual microscopic tumor, mostly teratoma, despite achieving CR. Methods: Retrospective analysis of 141 patients with metastatic NSGCT who obtained CR to cisplatin-based first-line chemotherapy. All were observed without RPLND. Included were 78 consecutive pts treated between Jan 1987 and Sept 1994. Additionally included were 63 pts recruited in 4 prospective trials between Oct 1984 and Apr 2005. Seven pts were lost to follow-up (FU) after <2 year. Results: At a median a FU of 15 years (range 3 months to 23.8 years), 12 pts recurred and 4 are dead of disease (DOD). The estimated 15 year recurrence free and disease specific survival was 90% and 97% respectively. The estimated 15 years recurrence free survival for 109 pts with good risk and 32 pts with intermediate or poor risk was 95% and 73% respectively (p = 0.001). Five pts recurred >2 years (range 3–13 years). All 5 are currently disease free. Six pts recurred in the RP and 2 are DOD. Six pts recurred outside the RP. Two of these 6 are DOD. Conclusions: Pts obtaining CR after primary chemotherapy can be safely observed without RPLND. Relapses are rare and potentially curable with further treatment. No significant financial relationships to disclose.
Prognostic factors in relapsed or refractory male germ cell tumors: Results from an international study of 1,593 patients
Authors: Lorch A. , Beyer J. , Mollevi C. , Guerra M. , Kramar A. ,   for the International Group on Prognostic Factors in Relapsed or Refractory Germ-Cell Tumors
Published: August 2020

5030 Background: The results of salvage treatment in male patients (pts) with relapsed or refractory germ-cell tumors (rr-GCT) depend considerably on prognostic factors. However, individual factors are not broadly accepted. Methods: Between 09/2007 and 12/2008 data on 1984 pts with rr-GCT were collected from 38 centers/groups worldwide. Inclusion criteria were (1) First line treatment for metastatic GCT after January 1, 1990; (2) Cisplatin and etoposide as part of first-line regimens; (3) No first-line high-dose chemotherapy (HDCT); (4) Relapse or progression after first-line treatment; (5) Cisplatin- based conventional-dose regimens or HDCT as salvage treatment. Data were centrally reviewed and checked for consistency. The primary endpoint was progression-free survival (PFS). Prognostic factors were identified using Cox multivariate regression analysis. Results: Overall 1593 (80%) pts fulfilled the strict inclusion criteria. Salvage treatment given as consolidation of first-line treatment in patients without progression was the most frequent cause of exclusion. Median follow-up was 58 months (range 1 to 206 months). Three-year PFS for the entire group was 38% (95% CI: 35%-40%), the overall survival was 51% (95% CI: 48%-54%). Multivariate analysis on a randomly selected 2/3 training dataset identified the following variables as the most significant ones for PFS: see Table . Cisplatin-refractory or absolute refractory disease was a confounding factor for response to first-line treatment. Conclusions: This preliminary analysis of a large dataset allowed the identification of important prognostic factors in rr- GCT. A prognostic score for first-salvage treatment based on the results of a final analysis will be presented. [Table: see text] No significant financial relationships to disclose.
Phase II study of BAY 73–4506, a multikinase inhibitor, in previously untreated patients with metastatic or unresectable renal cell cancer
Authors: Eisen T. , Joensuu H. , Nathan P. , Harper P. , Wojtukiewicz M. , Nicholson S. , Bahl A. , Tomczak P. , Wagner A. , Quinn D. 
Published: August 2020

5033 Background: BAY 73–4506 is an orally active, potent multikinase inhibitor targeting both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (RAF and p38MAPK). In tumor xenograft models, BAY 73–4506 demonstrated a broad spectrum of antitumor activity. The results of a phase I study (3 weeks on/1 week off schedule) indicated good tolerability and antitumor activity, including objective responses. Methods: Previously untreated patients with predominantly clear cell renal cell carcinoma (RCC) and measurable disease according to RECIST were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, low or intermediate risk as per Motzer score, and adequate bone marrow and organ function. Treatment consisted of BAY 73–4506 160 mg once daily on a 3 weeks on/1 week off schedule. The primary end point was overall response rate. Results: 49 patients started treatment (accrual completed October 2008): 27 male, 22 female, median age 62 years (range 40–76). All patients were evaluable for safety, 33 patients are currently available for efficacy evaluation. The most common drug-related adverse events (all grades) reported in >20% of patients were hand-foot skin reaction (HFSR) (48%), fatigue (48%), hypertension (43%), mucositis (35%), dysphonia (33%), rash (30%), diarrhea (25%), and anorexia (23%). Grade 3–4 drug related toxicities (in >5% of patients) included HFSR (13%), rash (8%), fatigue (8%), and renal failure (8%). Renal failure occurred only in patients who continued taking study medication despite having inadequate fluid intake and/or diarrhea. Preliminary efficacy data of the 33 patients evaluable for response show a 27% partial response (PR) and a 42% stable disease (SD) rate. Further tumor assessments are scheduled for the patients (n = 35) remaining on study. Conclusions: Preliminary data show promising antitumor activity and good tolerability of BAY 73–4506 in patients with RCC. The observed toxicities were typical of the drug class and were manageable. Updated results will be presented at the meeting. [Table: see text]
Activity of a multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen in metastatic renal cell carcinoma (mRCC): A phase II study of sorafenib, gemcitabine (Gem), and metronomic capecitabine (Cap) in patients with advanced mRCC (SOGUG-02–06)
Authors: Bellmunt J. , Trigo J. , Calvo E. , Carles J. , Perez-Gracia J. , Rubió J. , Virizuela J. , López R. , Lázaro M. , Albanell J. 
Published: August 2020

5040 Background: Maximal tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses administered on a frequent schedule) acts on tumor vascular endothelial cells and enhances the antitumor effect of anti-angiogenic agents (Pietras et al. J Clin Oncol. 2007). This study investigated treatment of mRCC with Gem at MTD combined with metronomic Cap and the multikinase inhibitor sorafenib. Methods: Eligible patients had cytologically or histologically confirmed mRCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and no previous targeted therapy or chemotherapy, and were unsuitable for or intolerant to immunotherapy. Treatment consisted of six 3-week cycles of Gem 1000 mg/m2 i.v. (days 1 and 8), oral Cap 500 mg/m2 b.i.d. (days 1 to 14) and oral sorafenib 400 mg b.i.d. (every day), followed by sorafenib monotherapy (at the discretion of the investigator). Study endpoints included median progression-free survival (PFS, primary endpoint), disease control rate according to Response Evaluation Criteria in Solid Tumors, and safety. Results: Forty patients were enrolled and received at least one dose of treatment (median age 63 yrs, male n = 24, ECOG 0/1 n = 18/22, 1–2/>2 metastatic sites n = 31/9). Median duration of treatment was 6 months. Among 36 evaluable patients, 17 (47%) had a partial response and 17 (47%) achieved stable disease. Median PFS was 10.2 months (95% CI 7.6, 20.5). The most common adverse events (AEs) were fatigue/asthenia (78%) hand-foot syndrome (75%) and mucositis (69%). Most AEs were grade1/2, no grade 4 toxicities occurred. One patient had grade 5 dyspnea; 6 patients discontinued treatment for AEs. Conclusions: PFS and objective responses in this study were greater than those observed in previous studies with Gem and Cap or sorafenib monotherapy in patients with mRCC, while AEs remained moderate in the majority of patients. These findings confirm the synergistic activity of the “chemo-switch” concept seen in preclinical models. The combination of sorafenib with MTD Gem and metronomic Cap warrants further investigation in mRCC. [Table: see text]
Prognostic factors for overall survival with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC)
Authors: Patil S. , Figlin R. A. , Hutson T. E. , Michaelson M. D. , Négrier S. , Kim S. T. , Huang X. , Motzer R. J. 
Published: August 2020

5042 Background: Sunitinib demonstrated superior progression-free survival (PFS; the primary endpoint) over interferon-alfa (IFN-α) as first-line mRCC therapy (NEJM 2007;356:115). Median overall survival (OS) with sunitinib compared to IFN-α was: 26.4 vs. 21.8 months (HR=0.821; P=0.051 by unstratified log-rank test; Proc ASCO 2008;26, May 20 suppl; abstr 5024). An analysis of prognostic factors for OS was performed on data from this trial. Methods: 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib or IFN-α. By Cox proportional hazards model, selected pretreatment variables were evaluated univariately and in a multivariate model for each treatment arm. Multivariate models for each treatment arm were based on a stepwise algorithm with a type I error of 0.25 for entry and 0.15 for elimination. Further elimination was applied to identify variables significant at P<0.05. Results: In multivariate analysis of sunitinib patients, factors associated with longer OS include: interval from diagnosis to treatment ≥1 yr, ECOG PS of 0, lower corrected calcium, absence of bone metastases, lower lactic dehydrogenase (LDH), and higher hemoglobin (Hgb) ( table ). For the IFN-α treatment arm, male gender, absence of bone or lymph node metastases, lower LDH, higher Hgb, lower corrected calcium, higher neutrophil count, and interval from diagnosis to treatment ≥1 yr were associated with longer OS. Conclusions: For patients in the sunitinib treatment arm, prognostic factors identified were similar to the factors previously identified in the MSKCC risk groups (J Clin Oncol 2002;20:289). Additional prognostic factors were identified for the IFN-α arm. Further studies are warranted to independently validate these findings as well as to identify tumor-specific prognostic factors. [Table: see text] [Table: see text]