bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gefitinib (G) plus prednisone (P) versus placebo (pl) plus prednisone in the treatment of hormone-refractory prostate cancer (HRPC): A randomized phase II trial
Authors: Boccardo F. , Rubagotti A. , Tacchini L. , Lapini A. , Cruciani G. , De Rubertis G. , Battaglia M. , Conti G. 
Published: March 2020

5070 Background: In spite of EGF-R overexpression in 40%-80% of pts with HRPC, the results achieved so far with G, a selective EGF-R tyrosine kinase inhibitor have been dismal. This trial was designed to investigate the activity of G when combined with P, a common therapeutic option for HRPC pts. Methods: HRPC pts unresponsive to antiandrogen withdrawal were given P (10 mg/d) plus G (250 mg/d) or pl. On progression, pts initially assigned to pl were offered the possibility to receive G. This was a one-stage trial, and 37 pts per arm were required. Best PSA response (any decrease = 50% in baseline PSA confirmed 4 wks apart) was the primary end-point. Time to disease progression, OS and toxicity were secondary end-points. Results: 82 pts were enrolled (GP: 38; plP: 44). Groups were well balanced in respect to median age (75 vs 74 yrs); WHO PS (0 in both); baseline PSA (52 vs 44 ng/ml); bone disease (87% vs 84%) Gleason score 7 (58% vs 52%); prior treatment. At a median follow-up time of 29 mos (26–32), overall 77 pts progression and 51 died. PSA resp was recorded in 16% and 11% of pts in GP and plP groups. Median time to progression was 4.0 (3.5–4.5) and 4.5 (3.5–5.0) mos, respectively. In both groups, median PSA level increased during the first 8 wks of treatment (GP:13%; plP: 32%) while it decreased thereafter. Median time to death was 26.5 (16–37) and 20.5 (14–27) mos in the GP and plP groups, respectively (HR: 0.69, 0.39–1.23; p=.2). However, OS of pts given either early or delayed treatment with G was significantly longer (26.5 vs 17.5 mos; HR: 0.49, 0.28–0.87, p=.01). This advantage was maintained also after multivariate analysis by Gleason score, baseline PSA, Hb and PAL, WHO PS and pain score. AEs (any grade) occurred in 19 pts in each arm. However diarrhea and skin rash were more common in the GP group (12% vs 0% and 14% vs 2%, respectively). Conclusions: G when combined to P showed a moderate toxicity, achieved PSA control and prolonged pts survival. The efficacy of GP in HRPC warrants to be further investigated. [Table: see text] No significant financial relationships to disclose.
Radium-223 in the treatment of metastatic hormone refractory prostate cancer (HRPC): Results from a randomized, placebo-controlled, phase II study
Authors: Nilsson S. , Franzén L. , Tyrrell C. , Blom R. , Tennvall J. , Lennernäs B. , Johannessen D. C. , Sokal M. , Parker C. , Bruland Ø. S. 
Published: March 2020

5071 Background: The alpha emitter radium-223 is a bone-seeking radionuclide studied as a novel treatment for patients with HRPC and bone metastases. Ra-223 showed minimal toxicity in a phase 1 study (Nilsson S, et al., Clin Cancer Res 2005;11 (12): 4451–59). Here we present outcome data from a randomised phase II study. Methods: Patients with HRPC and bone pain requiring external beam radiotherapy were randomized to treatment with 4 injections of either Ra-223 (50 kBq/kg b.w.) or saline (placebo) every 4 weeks. The primary endpoints were change in bone-alkaline phosphatase (ALP) levels from baseline to 4 weeks after last injection (previously reported (Bruland ØS, et al. Clin Cancer Res 2006;12:6250s-57s), and time to occurrence of Skeletal Related Events (SREs). Secondary endpoints included toxicity, PSA progression and overall survival. Results: 33 patients were randomised to Ra-223 and 31 to placebo. The two groups were well balanced with respect to standard prognostic factors. Mild, transient haematological toxicity was seen after Ra-223. Long term toxicity was not observed. SAEs were observed in 8 patients in the Ra-223 group versus 14 in the placebo group. Based on intention to treat analysis, the median time to PSA progression was 26 versus 8 weeks (p=0.047) for Ra-223 versus placebo, respectively. The median time to first SRE was 28 versus 26 weeks (p= 0.164). The median overall survival was 65.3 weeks versus 46.4 weeks (p = 0.066). The hazard ratio for overall survival, adjusted for baseline PSA, albumin, LDH and performance status was 2.11 (95 % CI: 1.08 - 4.13, p=0.029). At 18 months, 15 (45%) versus 8 (26%) patients patients were still alive. Conclusions: Alpharadin was extremely well tolerated, with minimal myelotoxicity, and with encouraging evidence of efficacy. Larger clinical trials are warranted to study the impact of Alpharadin on the prevention of SREs and on overall survival in HRPC. The bone targeting properties of Alpharadin, may also be applicable to the treatment of skeletal metastasis from other primary cancers. [Table: see text]
Changes on endorectal MRI during neoadjuvant hormonal therapy for prostate cancer and biochemical outcome in men managed using radiation therapy: A prospective phase II Cancer and Leukemia Group B study
Authors: D’Amico A. V. , Halabi S. , Tempany C. , Vollmer R. , Loffredo M. , Sanford B. , Small E. J. 
Published: March 2020

5072 Background: We prospectively determined whether changes in tumor volume (TV) on 1.5 Tesla endorectal magnetic resonance imaging (eMRI) during neoadjuvant androgen suppression therapy (AST) were associated with biochemical outcome after radiation and 6 months of AST. Methods: Between May, 1996 and April, 2001,180 men with T1c-T3c non-metastatic adenocarcinoma of the prostate cancer were registered. Fifteen were found to be ineligible leaving 165 men who had a eMRI TV measurement at baseline and following 2 months of neoadjuvant AST. An eMRI response was defined as > 10% reduction in the volume of all lesions consistent with prostate cancer. In 32 men, the institutional MR radiologist could not completely assess the TV leaving 133 for analysis. A proportional hazards model was used to assess whether a significant association existed between eMRI response and time to prostate-specific antigen (PSA) failure following registration adjusting for PSA level (continuous), Gleason score (8 to 10 or 7 versus 6 or less) and stage (T3 versus T1, 2). PSA failure was defined as 2 consecutive rises of 0.2 above 1.0 ng/ml (PSA fail) and according to the 1997 and the 2006 American Society of Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Results: The median age and PSA level of the study cohort were 70 years and 10.7 ng/ml respectively. An eMRI response was noted in 112 (84%) men and 85, 47, and 47 men experienced PSA failure based on the 1997, 2006 ASTRO consensus and PSA fail definitions respectively. After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a statistically significant association between eMRI defined tumor response and time to PSA failure using the 1997 (p = 0.04) and 2006 (p = 0.009) ASTRO consensus definitions and a near significant association (p = 0.08) using PSA fail. Conclusion: Men lacking a > 10% reduction in the eMRI defined TV during neoadjuvant AST are at increased risk for recurrence following radiation and AST. Therefore, eMRI enables the early documentation of androgen insensitive disease and identifies men for trials evaluating outcome when non-AST based approaches are combined with radiation and AST. No significant financial relationships to disclose.
Intra vesical gemcitabine (G) single agent as adjuvant chemotherapy in superficial transitional cell carcinoma (TCC) of the bladder: Final results
Authors: Bounedjar A. , Ferhat R. , Smaili F. , Bouzid K. 
Published: March 2020

5078 Background: Systemic intravenous G is usually used in advanced bladder carcinoma. A phase I study of intravesical G has shown safety profile in pts refractory to BCG therapy (Dalbani G et al JCO 2002; 20:3193–98). In this study we evaluate the toxicity and the efficacy of intravesical G in patients (pts) with superficial bladder carcinoma. Methods: The study population criteria were: age = 18 years old, histological diagnosis of transitional cell carcinoma (TCC) of bladder (Cis and pT1) confirmed by transurethral resection (TUR), no prior chemotherapy, a performance status (PS) < 2, good bone marrow reserve, adequate renal and liver function and informed consent. Three weeks after a total TUR, pts receive intravesical instillation of 2,000 mg G every wk for 6 wks, than every month for six months. Evaluation is performed 3–4 wks after the last instillation (CT scan and/or US pelvis, urinary cytology and cystoscopy with biopsy). Results: From February 2003 to June 2004, 60 pts (57M/3F) were enrolled in the study (M/F = 57/3). The median age was 59,5 years old (24–84). Nine pts had a carcinoma in situ (Cis) and 51 had pT1 lesions. They received a total of 720 instillations. All pts were evaluable for toxicity and response Toxicity (CTC/NCI scale) is evaluated over the 720 instillations. Non haematological toxicity was grade 1: irritate bladder reaction (4.7%), asthenia (2.9%), nausea and vomiting (1.8%) and hot flashes (2%). Grade 1 haematological toxicity: anaemia (6.8%), leucopenia (4.5%) and thrombocytopenia (0.4%). After a follow-up time of 30 to 48 months, all pts were evaluable for tumor response: 53 patient had a persistant complete remission after TUR. Five patients (8.3%) had a superficial relapse of TCC (one at six months, 2 at 9 months and 2 others at 12 months). Two patients had progressive disease at 18 months and 27 months. Conclusion: Intravesical G is an active and well tolerated treatment even after repeated instillation in pts with superficial TCC carcinoma of the bladder. No significant financial relationships to disclose.
Chemotherapy for poor prognosis non seminomatous germ cell tumors (NSGCT): Should doses be reduced at first cycle to prevent acute respiratory distress syndrome (ARDS) in patients with multiple lung metastases?
Authors: Fizazi K. , Massard C. , Postel-Vinay S. , Escudier B. , Culine S. , Raynard B. , Blot F. , Antoun S. , Nitenberg G. , Plantade A. 
Published: March 2020

5087 Background: Patients with multiple lung metastases from NSGCT and dyspnea at presentation are at high risk of ARDS and death in the first days after chemotherapy induction. This entity has been designated the “choriocarcinoma syndrome” or “very high risk NSGCT”. It is linked to acute intra-alveolar hemorrhage related to early tumor necrosis, which in turn, may be complicated by pulmonary infection promoted by neutropenia. To try to avoid this complication, The policy to manage these patients was changed at Institut Gustave Roussy in 1997. Methods: Data from all patients with lung metastases from NSGCT and dyspnea or a pO2 < 80 and treated between1980–2006 in our institution were collected. Patients were treated in a specialized intensive care unit. From 1980–1997, the first cycle of chemotherapy consisted in a full dose regimen. After 1997, it consisted in a 3-day reduced induction regimen of EP (cisplatin 20 mg/m2/day and etoposide 100 mg/m2/day), with bleomycin and two additional days of EP being postponed to day 15, and the regular BEP regimen being started at day 21. Results: 25 patients with a poor risk NSGCT according to the IGCCCG classification had extensive lung metastases plus either dyspnea at presentation (n=6) or a pO2<80 (n=2), or both criteria (n=17). Median age was 30 years (range 18–49). Median hCG was 200,000 UI (range 11–8,920,000) and 18/25 (72%) patients also had non-pulmonary visceral metastases. During the 1980–1997 period, 13/15 patients (87%) developed ARDS, of whom 10 died, and only 4/15 (27%) patients were long-term survivors. In contrast, during the 1997-2006 period, only 3/10 patients (30%) developed ARDS, of whom 2 died, and 4/10 (40%) survived. Conclusions: Reducing doses of chemotherapy during the first cycle of chemotherapy for poor-prognosis NSGCT with extensive and symptomatic lung metastases seems to prevent the risk of early death due to ARDS and should therefore be recommended. No significant financial relationships to disclose.
A phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab in patients with metastatic renal cell carcinoma (mRCC)
Authors: Garcia J. A. , Rini B. I. , Mekhail T. , Triozzi P. , Elson P. , Nemec C. , Bukowski R. M. 
Published: March 2020

5103 Background: Interleukin-2 and bevacizumab, a VEGF ligand-binding antibody, have each demonstrated antitumor activity in mRCC. Increased VEGF levels can lead to immunosuppression and resistance to immunotherapy through inhibition of dendritic cell (DC) differentiation and increase in immunosuppressive regulatory T cells (Tregs). To further evaluate the clinical and immunomodulatory effect of low-dose IL-2 and bevacizumab in mRCC, a phase II trial was conducted. Methods: Previously untreated good and intermediate risk mRCC pts received 8-week cycles of IL-2 (250,000 U/kg/d SC D1–5 during week 1 and 125,000 U/kg/d SC D1–5 during weeks 2–6, followed by a 2 week break). Bevacizumab 10mg/kg was administered IV every 2 weeks starting on day -14. Eligibility included RECIST-defined measurable disease, clear cell histology, normal organ function, and prior nephrectomy. A Simon 2 stage phase II design was employed to test the hypothesis of a 40% improvement in the 3-month PFS vs. historical IL-2-treated controls. Overall response rate (ORR) and toxicity were recorded. Exploratory endpoints included activation of circulating DC’s, Tregs and VEGF levels. Results: To date 16 of a planned 35 pts are enrolled. Median age is 59 years (range, 44–67); Eight patients have >1 site of metastasis; median treatment duration is 8 weeks (8–32+). Among 11 pts evaluable for response, 1 PR and 3 SD lasting >3 months have been observed. All pts with SD have demonstrated some degree of tumor shrinkage. Seven pts have discontinued therapy (5 PD, 2 withdrew consent). Most common treatment-related toxicity included fatigue, nausea, diarrhea, and fever. When comparing immune correlates at day 56 of therapy vs. baseline, all pts had an increase in the number of Tregs (median increase 1.65, range; 0.76–10.4; p= 0.008). Similarly, all pts had a decline in VEGF levels (median decline 164.38 pg/ml, range; 2.20–393.04 pg/ml; p= 0.008). No differences in DC activation have been observed. Conclusions: The combination of LD IL-2 and bevacizumab produces antitumor activity and moderate toxicity. Preliminary correlative data demonstrates inhibition of VEGF and increase in Tregs without effect on DC activation. No significant financial relationships to disclose.
Sequential therapy with sorafenib and sunitinib in renal cell carcinoma
Authors: Dham A. , Dudek A. Z. 
Published: March 2020

5106 Background: Sunitinib and sorafenib are two small-molecule tyrosine kinase inhibitors (TKI) that have been shown to have antitumor activity in advanced renal cell carcinoma (RCC). However, the optimal sequence of first- and second-line therapies with sunitinib and sorafenib is still unclear. The purpose of this study was to assess whether an objective disease response could be identified in patients after receiving sequential treatment with these two agents. Methods: Patients who had progressed or experienced unacceptable toxicity after first-line therapy with either sunitinib or sorafenib and then subsequently received second-line therapy with the other TKI agent were evaluated for their response to sequential treatment using RECIST criteria. Results: Thirty-seven patients were identified (29 male and 8 female) with a median age of 62 years (range 32–75). Twenty-three patients received sorafenib followed by sunitinib (Group A), and 14 patients received sunitinib followed by sorafenib (Group B). According to Memorial Sloan-Kettering prognostic model, 35% of patients in Group A had favorable risk, 52% had intermediate and 13% had poor risk, whereas 50% of patients in Group B had favorable risk, 43% had intermediate and 7% had poor risk. Three patients (13%) in Group A and two (14%) in Group B switched TKI due to toxicity, while all remaining patients switched due to disease progression. For patients in Group A, median duration of stable disease after starting sunitinib was 32 weeks (range 6–37 weeks)(median follow up 266 days); 9% were not evaluable for response to treatment; 34% had disease progression; and four patients (17%) had an objective partial response of 31%, 36%, 27% and 50%, respectively. For patients in Group B, median duration of stable disease after starting sorafenib was 8 weeks (range 4–10 weeks) (median follow up 179 days); 7% were not evaluable for response to treatment; 50% had disease progression; and one patient (7%) had no evidence of disease after tumor resection. The median duration of disease control in Groups A and B was 42 weeks (range: 10–113 wks) and 30.5 weeks (range: 4–56 wks), respectively. Conclusions: While disease control was observed in both sequences, the duration of response was longer in patients receiving sorafenib followed by sunitinib. [Table: see text]
Clinical and molecular factors predictive of outcome with first-line sorafenib-based therapy in advanced renal carcinoma (RCC): An analysis of SWOG 0412
Authors: Goldman B. H. , Lara Jr. P. N. , Beer T. M. , Mack P. C. , Drabkin H. A. , Holland W. S. , Crawford E. , Ryan C. W. 
Published: March 2020

5108 Background: SWOG 0412 was a phase II study of sorafenib and interferon-a2b (IFN) as first-line therapy for RCC. Response rate was 19%, median PFS was 7 months, and estimated median OS was 17 months (Ryan ASCO 2006). We investigated several potential risk factors among participants in SWOG 0412. Methods: Hemoglobin (hgb), LDH, number of metastatic sites, grade, gender, time from diagnosis to treatment, and MSKCC risk category were analyzed in 62 patients. Von Hipel-Lindau (VHL) gene status was determined by direct sequencing of DNA amplified by PCR methods from archival tumor. Immunohistochemistry for p-MAPK, p-p38, and p- AKT was performed to assess for enhanced signaling through the RAS-RAF and related pathways. Survival differences between subgroups were assessed by the logrank test. Results: Clinical factors associated with improved PFS and OS: favorable MSKCC risk category, time from diagnosis to treatment = 1 year, normal hgb. Fewer metastatic sites was also associated with improved OS but not PFS. No association was found with gender, grade, or LDH. VHL mutations were detected in 4 of 18 (22%) archival tumor specimens. P-p38 was overexpressed in all tumor specimens and p-MAPK was absent in all but one specimen. p-AKT was overexpressed (>20% staining) in 18 (82%) of patients. In this limited subset analysis, none of these tumor markers was found to be significantly predictive of survival. Conclusions: Time from diagnosis, hgb, and MSKCC risk grouping were predictive of PFS and OS in patients receiving sorafenib + IFN. The median PFS of 18 months for favorable MSKCC risk patients is higher than the 8 months expected for first-line patients treated with IFN-based therapy, while the median PFS of 4 months for intermediate and poor risk patients is similar to the expected 5 months (Motzer JCO 2002). This observation is consistent with a hypothesis that the benefit of first-line sorafenib-based therapy may be most profound in or limited to favorable MSKCC risk patients. [Table: see text] [Table: see text]
A phase II trial of thalidomide, bevacizumab, and docetaxel in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Ning Y. M. , Arlen P. , Gulley J. , Latham L. , Jones E. , Chen C. , Parnes H. , Wright J. , Figg W. D. , Dahut W. L. 
Published: March 2020

5114 Background: Angiogenesis plays a vital role in the progression of prostate cancer. Antiangiogenic agents thalidomide (T) and bevacizumab (Bv) may enhance docetaxel (Doc) activity in metastatic AIPC. However, T and Bv have different antiangiogenic mechanisms. Since tumor angiogenesis is a complex interplay of multiple angiogenic factors, we reasoned that combination of mechanistically different antiangiogenic agents T and Bv with Doc might be associated with an adequately high and durable PSA response to merit further study. Methods: Pts are required to have progressive metastatic AIPC and no prior chemotherapy for AIPC. Treatment consists of Doc 75 mg/m2 plus Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus T 200 mg qhs and prednisone 10 mg qd. Enoxaparin is used for thrombosis prevention and pegfilgrastim initiated after detection of grade ≥3 neutropenia. PSA is assayed q C and staging studies are done at C 0, C 2, & then q 3 Cs. Results: 39 pts were enrolled, median age 66 [54–79], Gleason score 8 [74% Gs 10∼8, 26% Gs 7∼6], on-study PSA 92 ng/ml [5.9–4399] and pre-study PSA doubling time 1.6 months [0.3–18.2, 87 % <3 months]. Median treatment Cs is 14 [1- 28]. 34 pts (87%) had PSA declines of ≥50%, with median ≥50% PSA-duration 12 Cs [0∼28]. 3 pts have PSA declines around 40% and 2 stable. 26 pts (67%) had >80% PSA declines. 17 pts with measurable disease were evaluable: 1 CR, 9 PR, & 7 SD, with 59% ORR. Significant toxicities: febrile neutropenia (5/39), syncope (4/39), colon perforation or fistula (2/39), grade 3 bleeding (2/39), thrombosis (2/39). Conclusions: This trial is the first study to combine antiangiogenic agents of different mechanisms with Doc in metastatic AIPC. Most of the accrued patients have unfavorable characteristics as evidenced by a high Gleason score and a short PSA doubling time. However, the combination of T and Bv with Doc appears to result in both a high durable PSA decline rate (87%) and a high response in measurable disease (59%) with acceptable toxicities. No significant financial relationships to disclose.
Pharmacogenetics of organic anion transporting peptides (OATP): An association of a SLCO1B3 polymorphism with the overall survival in white Caucasian patients with androgen independent prostate cancer
Authors: Hamada A. , Price D. K. , Sissung T. , Venzon D. , Duhut W. L. , Figg W. D. 
Published: March 2020

5118 Background: Steroid hormone have been implicated in playing a fundamental role in pathogenesis of prostate cancer and several studies have reported an association between clinical outcome and polymorphism of genes involved in steroid metabolism. Recently we observed that polymorphic enzyme CYP17 which influences the rate-limiting steps in androgen biosynthesis was associated with overall survival. However, the effect of genetic variation on the transport of steroid hormones remains unknown. The purpose of this study was to evaluate the association between clinical outcomes in patients with androgen independent prostate cancer, and polymorphism in the SLCO1B3 gene that are potentially important in the differential uptake of steroid hormones. Methods: One hundred seventy nine white Caucasian patients with androgen independent prostate cancer were enrolled in this study. The duration of survival was computed from the date of prostate cancer diagnosis until the date of death or last follow-up. The SLCO1B3 polymorphism (-334 T>G) was analyzed using an automated sequencer. Results: The T allele (TT or TG) and G allele (GG) frequency of SLCO1B3 among all patients was 0.16 and 0.84, respectively. The frequency of the SLCO1B3 genotype was similar in patients and healthy volunteer. No significant differences were observed in the frequencies of the SLCO1B3 genotype in relation to categorized Gleason scores and age at diagnosis. Interestingly, the median survival was significantly longer in 134 patients with the SLCO1B3 G allele (8.4 years) genotype than 45 patients carrying at least one T allele (6.4 years) genotype (hazard ratio=1.58, 95%CI: 1.13 - 2.26, p=0.0105 by Logrank test). Similarly, the survival probability at ten years (22.9% in T allele vs 41.1% in G allele) is observed. Conclusions: Our results indicate that the SLCO1B3 polymorphism is associated with overall survival in white Caucasian patients with androgen independent prostate cancer. Large population-based studies are needed to confirm these results. No significant financial relationships to disclose.