bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermittent chemotherapy in metastatic androgen-independent prostate cancer (AIPC): Initial results from ASCENT
Authors: Beer T. M. , Ryan C. W. , Venner P. M. , Petrylak D. P. , Chatta G. , Ruether J. , Chi K. N. , Arroyo A. , Clow F. W. 
Published: March 2020

4518 Background: Phase III studies document a survival benefit for 10–12 cycles of docetaxel-containing chemotherapy in AIPC. Further management of patients who complete chemotherapy in response status remains ill-defined. Single-institution phase II data suggest that re-treatment with the same regimen after a treatment holiday is feasible in selected patients. This approach was prospectively tested in a multi-institutional trial. Methods: ASCENT was a multi-institution randomized clinical trial designed to compare the activity and safety of weekly DN-101 (45 μg on day 1) plus docetaxel (36 mg/m2 iv on day 2 for 3 weeks of a 4-week cycle) to placebo + docetaxel in patients with chemotherapy-naïve metastatic AIPC. ASCENT was the first large trial to prospectively evaluate intermittent chemotherapy. Patients could opt to suspend treatment if they had a confirmed ≥ 50% reduction in serum PSA and a serum PSA ≤ 4 ng/ml. PSA was monitored every 4 weeks (CT scans every 8 weeks in patients with measurable disease) during the treatment holiday. Treatment was resumed when serum PSA rose by ≥ 50% and was ≥ 2 ng/ml or for other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the two arms. Results: 250 patients were randomized 1:1. Overall PSA response rates were: DN-101: 63%, Placebo 52% (p = 0.07). Overall 18% (DN-101: 20%, Placebo: 16%) of patients entered the intermittent chemotherapy. The median duration of the first chemotherapy holiday was 16 weeks (range 4–74+) (DN-101: 15 weeks, Placebo: 16 weeks). Upon resumption of treatment after the first holiday, 50% of patients responded with a ≥ 50% reduction in serum PSA from their post-holiday baseline, 35% met criteria for stable PSA for at least 12 weeks, and 15% progressed on therapy. Conclusions: This is the first report of intermittent chemotherapy in AIPC prospectively tested in a large multi-institutional trial. This strategy results in a clinically meaningful duration of chemotherapy holidays and can be offered to a minority (18%) of patients. Upon re-treatment, most patients (85%) again respond or stabilize PSA values. [Table: see text]
Pegylated interferon alpha-2B (PEG-Intron) for metastatic renal cell cancer (mRCC): Results of a phase II clinical trial and biologic correlates of response
Authors: Kondagunta G. V. , Bacik J. , Ishill N. , Reuter V. , Schwartz L. H. , Korkola J. , Deluca J. , Sweeney S. , K. Chaganti R. S. , Motzer R. J. 
Published: March 2020

4528 Background: PEG-Intron (PEG-I) is a pegylated derivative of interferon alpha-2b (IFN), recombinant, with a single molecule of mono methoxy polyethylene glycol which increases serum half-life. Methods: A single arm, one-stage phase II trial was conducted between 6/02 and 6/04 in 32 previously untreated patients (pts) with mRCC to assess time to progression and biologic correlates (primary and secondary endpoints). Eligibility included measurable disease and fresh tumor procured at surgery for genetic and immunohistochemical (vascular endothelial growth factor [VEGF] and carbonic anhydrase IX [CAIX]) studies. PEG-I was given SC at a weekly dose of 4.5 μg/kg until progression or intolerability. Quality of life (QOL) was assessed using the FACT-BRM. Results: All 32 were evaluable, 91% had prior nephrectomy, and MSKCC risk group (JCO 20:289–96, 2002) was: 41% good, 53% intermediate, 6% poor. 10 pts (31%; 95% CI: 16%-50%) achieved a partial response (PR). Median time to progression was 5.0 mos (95% C.I. [3, 7]); median survival was 31 mos (95% C.I. [18, not reached]). There were no grade IV toxicities; primary grade III toxicities were hematologic (6/32 pts; 19%) and fatigue (4/32 pts; 13%). FACT-BRM scores showed an initial decrease in QOL at 2 weeks followed by partial recovery. Genomic profiling of tumor samples identified four novel genes that correlated with IFN resistance: ABCD3, Hs.76704, Hs.11325, and Hs.94122. Change in serum VEGF levels did not correlate with response. Tumor tissue samples are being immunohistochemically stained for CAIX. Conclusions: PEG-I treatment results in a 31% response rate and similar median time to progression as standard IFN (JCO 18:2972–80, 2000) in this population with predominantly good and intermediate risk pts. Once weekly dosing was generally well tolerated. Future investigation of PEG-I in combination with novel targeted agents in mRCC is warranted. Further study of the four identified genes may provide insight into IFN resistance. Supported by Schering-Plough, Inc. [Table: see text]
Neoadjuvant paclitaxel (P), carboplatin (Ca) and gemcitabine (G) in patients with locally advanced transitional cell carcinoma (TCC) of the bladder: A final report
Authors: Smith D. C. , Mackler N. J. , Hussain M. H. , Dunn R. , Montie J. E. , Wood D. , Lee C. T. , Petrylak D. , Quinn D. , Vaishampayan U. 
Published: March 2020

4541 Background: PCaG has activity in the treatment of TCC. Studies have shown that neoadjuvant chemotherapy may improve survival in TCC, with pathologic complete responders (pT0) having the most benefit. This study was designed to assess the pT0 rate and resectability following neoadjuvant PCaG in patients with TCC of the bladder. Methods: Patients with adequate organ function, performance status 0–2, and clinical T3 or T2 with hydronephrosis, N0, M0 TCC (Arm I) received 3 cycles of PCaG (P: 200 mg/m2, IV over 3 hours day 1, C: target AUC=5 IV day 1, and G: 800 mg/m2; IV day 1 & 8 every 21 days) followed by cystectomy with a primary endpoint of pT0. T4 or node positive (Tany, N1–3, M0) patients (Arm II) received 6 cycles with an endpoint of resectability. Each arm had a Minimax two-stage accrual with planned initial enrollment of 26 evaluable subjects in arm I (up to 54 total) and 19 in arm II (up to 33). Results: 68 patients were registered (31 arm I, 37 arm II). Median age was 65 years in arm I and 58 years in arm II. 22/31 (71%) patients in arm I are evaluable and 7 were pT0 at cystectomy. pT0 rate is 32% (95% CI: 13.9–54.9%) of evaluable, 23% (9.6–41.1%) by intent to treat (ITT). 30/37 (81%) on arm II are evaluable for response and 20 had cystectomy for a resection rate of 67% (47.2–82.7%) of evaluable, 54% (36.9–70.5%) by ITT. 5 patients resected on arm II had pT0 and 2 had only residual carcinoma in situ. A total of 252 cycles of therapy were delivered (80 in arm I, 172 in arm II) with 161 at full dose. 54/68 patients (79%) had grade 3/4 hematologic toxicity, primarily neutropenia with 4 other episodes of grade 3 toxicity (2-neuropathy, 1-myalgia, 1-fatigue). 4 patients died during chemotherapy (2-bowel obstruction, 1-coronary artery disease, 1-intracranial bleed) and 2 post-op (1-multiorgan failure, 1-enterocolitis). Only 1 death was clearly chemotherapy related, but the study was halted early due to these deaths. Conclusions: Neoadjuvant PCaG has demonstrated activity in locally advanced TCC of the bladder, but has considerable toxicity. The pT0 rate with this combination is comparable to the rates reported in the literature for other regimens. Support from Bristol-Myers Squibb, Eli Lilly, and 2P30 CA 46592–14 from the National Cancer Institute [Table: see text]
Phase II trial of epothilone B analogue BMS-247550 in advanced carcinoma of the urothelium (E3800): A trial of the Eastern Cooperative Oncology Group
Authors: Dreicer R. , Li S. , Manola J. , Haas N. , Roth B. , Wilding G. 
Published: March 2020

4543 Background: Patients (pts) with advanced urothelial carcinoma who progress following first line therapy have limited effective therapeutic options. The epothilones are a class of antineoplastics with a broad range of antitumor activity. We evaluated BMS-247550 in pts with advanced urothelial cancer having received 1 prior systemic therapy regimen. Methods: Pts with TCC or mixed histologies containing TCC received BMS-247550 40 mg/m2 IV over 3 hours on day 1 of a 3-week cycle. Dose modifications occured for low granulocytes and/or platelets, mucositis, sensory neuropathy, and other Grade 3 or 4 toxicities. Pts remained on treatment until disease progression or unacceptable toxicity. Standard ECOG response criteria were used. Results: Total accrual (allowing for ineligible pts) was 45 pts, of whom 17 had received prior taxanes. One pt was ineligible (2 prior regimens) and was excluded from this analysis. Sixteen pts are still being evaluated for eligibility. The pt cohort was 82% male and 86% Caucasian. The median age was 63 (range 37–81), 70%, 7% and 23% had 1, 2 and 3 MSKCC risk factors respectively. Eighty-two % of pts had distant metastatic disease at study entry. A median of 2 cycles were administered (range, 1–8). The most common reasons for discontinuing treatment were progressive disease (65%) and toxicity (25%). Twelve pts experienced grade 4 toxicity, including leukopenia (n = 5), neutropenia (n = 9), ventricular arrhythmia, hypotension, DIC, stomatitis, elevated bilirubin, dyspnea, febrile neutropenia, hypoxia, acidosis, and elevated creatinine (n = 1 patient each). One pt died of cardiac failure following numerous grade 4 toxicities, including neutropenic infection. Two other deaths due to progressive disease occurred while pts were receiving treatment. Response information is available for 37 of 44 potentially eligible pts. There have been 5 partial responses, 3 among pts who had previously received taxanes, 17 pts had stable disease for at least 6 weeks. Conclusions: BMS-247550 has modest activity in pts with previously treated advanced TCC of the urothelium, but at the cost of modest-significant toxicity. Activity in pts previously treated with paclitaxel is of interest, however its ultimate utility remains undefined. [Table: see text]
Adjuvant chemoradiotherapy after radical cystectomy in advanced high risk bladder cancer: A prospective randomized trial
Authors: Zaghloul M. S. , Khaled H. M. , Lotayef M. , William H. 
Published: March 2020

4545 Background: High risk locally advanced bladder cancer patients experienced low survival rates, high local recurrence and extensive distant metastasis. Postoperative radiotherapy (PORT) though improved the survival through improving local control. Methods: A prospective randomized trial was performed at NCI, Cairo, Egypt including 142 patients in 2 arms. Patients who underwent radical cystectomy and pelvic lymphadenectomy had to have one more of the following: P3b or P4a stage, G3 or involved lymphadenopathy. Arm I (71 patients) received PORT 45 G/30 fractions/3 weeks. Arm II (71 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 was tolerated with grade 1/2 toxicities. Early radiation reactions were also tolerable in both arms, slightly more in arm II. Delayed toxicity was comparable in both arms. The 2-year DFS was 67.6 ± 5.9% in the whole group. This was affected significantly by performance status (p = 0.009), pathological stage (p = 0.001), tumor cell type (p = 0.053), nodal involvement (p = 0.07) and number of risk factors (p = 0.09). Though there was improvement of DFS from 61.5 ± 7.4% in PORT group to 70.9 ± 6.1% in chemoradiotherapy group, yet it was not statistically significant (p = 0.2). Patients having one risk factor, low pathological stage or no nodal involvement in arm II experienced better DFS than those in arm I (p = 0.07, 0.08 and 0.09 respectively). Conclusions: Adjuvant chemoradiotherapy using Gemcitabine-cisplatin and PORT was tolerable with minimal severe toxicities. There was DFS improvement with the addition of chemotherapy to PORT (not statistically significant yet). Patients with one risk factor, lower pathological stage or no nodal involvement seemed to benefit more from added chemotherapy. No significant financial relationships to disclose.
Expression of the endothelin axis and microvessel density in bladder cancer
Authors: Herrmann E. , Bierer S. , Boegemann M. , Eltze E. , Hertle L. , Wülfing C. 
Published: March 2020

4583 Background: Endothelin-1 (ET-1) and its receptors ETAR and ETBR, referred to as the Endothelin (ET)-axis play an emerging role in cancer. The ET-axis has been shown to be involved in proliferation, angiogenesis and metastasis. We investigated the effect of the ET-axis on microvessel density (MVD) and on the clinical prognosis in patients with invasive carcinoma of the bladder. Methods: Archival tumor tissue of 157 consecutive patients was reviewed and representing tumor blocks were selected. Paraffin sections were assessed immunhistochemically using mono- and polyclonal antibodies for ET-1, ETAR,ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Results: Overexpression of ET-1, ETAR and ETBR was identified in 26.8%, 58.8% and 76.9% of cases, respectively. Normal urothelium was constantly negative. No association with TNM staging and histologic grading was found. However, patients with ETBR expression tended to have organ-confined tumors (P = 0.16) and no vascular invasion (P = 0.09), the latter being statistically significant in the subgroup of G3 tumors (P = 0.02). T1 and T2 (MVD = 32,2) tumors had greater MVD compared to T3 and T4 tumors (MVD = 21,2) (P = 0.02), showing an association of MVD and overexpression of ET-1 (P = 0.027). ETBR-positive tumors were associated with favorable disease-free survival (P = 0.04). In urothelial carcinomas the MVD was 23,7, whereas squamous cell carcinomas had a MVD of 17,8 (P = 0.04). Conclusion: The ET-axis is overexpressed in invasive bladder cancer. Urothelial carcinomas are significantly greater vascularized compared to squamous cell carcinomas. Organ-confined tumors showed more MVD than T3 and T4 tumors, which is related to ET-1 expression in this subgroup. ETBR appears to predominate in bladder cancer and is associated with a more favorable prognosis. No significant financial relationships to disclose.
Antitumor effects of sorafenib and sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) who had prior therapy with anti-angiogenic agents
Authors: Tamaskar I. , Shaheen P. , Wood L. , Hodnick S. , Nemec C. , Garcia J. , Dreicer R. , Rini B. , Bukowski R. 
Published: March 2020

4597 Background: Sorafenib and sunitinib are multi-targeted kinase inhibitors (TKI’s) with clinical activity in mRCC. Their effect in mRCC pts refractory to prior anti-angiogenic agents is unclear. We investigated the anti-tumor effect of sorafenib and sunitinib in patients with mRCC who failed prior treatment with anti-angiogenic agents. Methods: Pts with mRCC receiving sorafenib and sunitinib on compassionate use trials were identified. Those pts who had received prior treatment with anti-angiogenic agents defined as thalidomide, lenalidomide, M200 (anti-α5β1 integrin monoclonal antibody), bevacizumab, AG013736, sunitinib or sorafenib were selected and their treatment response to current sorafenib or sunitinib evaluated. Results: Seventy-two pts (39 receiving sorafenib and 33 receiving sunitinib) were identified. Of these 72 pts, 23 pts (32%) had received prior anti-angiogenic therapy as defined above. Demographics included: 19 male and 4 female, median age 61 years (range 44 to 77). Thirteen pts (57%) are currently evaluable; the remainder are too early for assessment. Twelve pts (92%) demonstrated tumor reduction including 4 pts with objective partial response (PR); 8 pts had stable disease with tumor shrinkage ranging from 4 to 27% and 1 pt had disease progression. Of the 4 PR pts, prior therapy included M200 (1 pt), lenalidomide (2 pts) and sorafenib (1 pt). Of the 13 evaluable pts 4 had failed a prior TKI and received a subsequent TKI and all had evidence of tumor shrinkage to subsequent therapy (sunitinib followed by sorafenib, 1pt - 16% shrinkage, sorafenib followed by sunitinib 2 pts - 33.4% and 24% and AG013736 followed by sunitinib 1 pt - 12% ). Conclusion: Sorafenib and sunitinib have anti-tumor activity in mRCC pts who have received prior anti-angiogenic agents. [Table: see text]
Predicting the histology of renal masses using pre-operative Doppler ultrasonography
Authors: Raj G. V. , Iasonos A. , Bach A. , Hann L. , Russo P. 
Published: March 2020

4598 Background: Traditional imaging techniques cannot differentiate between benign, indolent and malignant renal neoplasms. Since conventional clear cell carcinomas are highly vascular, we evaluated the association between vascular flow within a renal mass on pre-operative color and/or power Doppler ultrasonography (CDUS) and surgical pathology. Methods: Nephrectomies performed at our institution between 1/2001 and 12/2004 were retrospectively evaluated. Detection of flow within the renal mass on CDUS was defined as vascular flow. A prospective validation study was performed from 1/2005 to 10/2005, and a nomogram predicting clear cell histology created using vascular flow along with clinical and radiologic parameters. Results: Of 299 renal lesions in the retrospective cohort, 210 (70%) had evidence of vascular flow, including 156 of 169 (92%) conventional clear cell carcinomas (p < 0.0001). On logistic regression analyses, vascular flow was associated with conventional clear cell histology with an odds ratio of 16.9, CI: 8.7–32.8, p < 0.0001. These findings were validated prospectively in 97 patients; CDUS detected vascular flow in 54 of 65 (83%) renal masses with conventional clear cell histology (p < 0.0001) and was associated with an odds ratio of 10.8 (95% CI 4.0–29.0; p < 0.0001). On multivariable analyses, vascular flow was still a statistically significant predictor of conventional clear cell histology. A nomogram incorporating vascular flow along with clinical and radiologic variables (clinical size, patient gender and age) to predict conventional clear cell histology was constructed on the retrospective cohort and validated on the prospective data set (concordance index 0.82 and 0.76 respectively). Conclusions: Vascular flow within a renal mass detected by CDUS is strongly associated with conventional clear cell histology with an odds ratio of 10.8–16.9. A nomogram incorporating vascular flow on CDUS and clinical and radiographic parameters may aid in the non-invasive characterization of renal lesions. [Table: see text] No significant financial relationships to disclose.
Anti-proliferative effects of sorafenib in clear cell renal cell carcinoma (CCRCC) cell lines: Relationship to von Hippel Lindau protein (pVHL) expression and hypoxia
Authors: Al Hazzouri A. , Vaziri S. A. , Lynch M. , Schwartz B. , Rini B. I. , Bukowski R. , Ganapathy R. 
Published: March 2020

4601 Background: Sorafenib, a multikinase inhibitor targeting raf kinase and several receptor tyrosine kinases including VEGFR-2 and PDGFR, has demonstrated clinical activity in the treatment of metastatic CCRCC. To further characterize the molecular basis of response to this agent, we tested the functional role of pVHL and hypoxia in the anti-tumor activity of sorafenib in a panel of CCRCC cell lines. Methods: CCRCC cell lines CAKI-1 (wild-type pVHL), CAKI-2 (mutant VHL) and the isogenic pair, 786–0-neo (vector control) and 786–0-VHL (pVHL expressing) cells were treated with sorafenib (2.5 - 20 μM) for 24 - 96 hours at 37°C in a atmosphere of either normoxia (21% oxygen) or hypoxia (1% oxygen), 5% carbon dioxide and remainder nitrogen. Gene expression analysis of control and sorafenib treated CCRCC cell lines was carried out using a custom cancer cDNA array containing probes to 9240 cDNA clones corresponding to 4900 Unigenes or unclustered ESTs relevant to cancer or kidney development. Results: Anti-proliferative effects of sorafenib were both concentration and time of treatment dependent; the IC50 of sorafenib (inhibitory concentration for 50% cell kill) ranged from 7.5-10 μM and required continuous treatment for at least 48-72 hours for maximal cell kill. In contrast to CAKI-2 and 786–0-neo cells harboring mutant VHL, both CAKI-1 and 786–0-VHL cells expressing wild type VHL were ∼2-fold more resistant to the anti-proliferative effects of sorfaenib when treated under hypoxic conditions. No difference in resistance was observed under normoxic conditions. In contrast to 786–0-neo cells, there were ∼40 genes overexpressed (>5-fold) under hypoxia in control 786–0-VHL cells, that were predominantly related to anti-apoptosis (e.g. bcl2-associated athanogene) or angiogenesis (e.g. PDGF beta). Bcl2-associated athanogene and PDGF beta were down regulated >2-fold in hypoxia with sorafenib treatment. Conclusions: CCRCC with wild type VHL under hypoxic conditions can promote overexpression of anti-apoptotic and angiogenesis genes that attenuate the anti-proliferative effects of sorafenib. pVHL and hypoxia related genes may be important biomarkers for assessing the clinical efficacy of sorafenib in CCRCC. [Table: see text]
Phase 2 trial of 177Lutetium (177Lu) radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 (177Lu-J591) in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Morris M. J. , Milowsky M. I. , Pandit-Taskar N. , Divgi C. , David K. A. , Rozario C. P. , Vallabhajosula S. , Goldsmith S. J. , Scher H. I. , Nanus D. M. 
Published: March 2020

4613 Background: J591 is an anti-PSMA mAb targeting the extracellular domain of PSMA, a highly PC restricted glycoprotein. 177Lu linked to J591 via a DOTA chelate was evaluated in a phase 1 trial in pts with metastatic AIPC demonstrating acceptable toxicity (MTD = 70 mCi/m2), excellent targeting of metastatic sites and biologic activity. Methods: Pts with progressive metastatic AIPC receive a single dose of 177Lu -J591 in two cohorts (65 and 70 mCi/m2). Cohort 1: 15 pts; Cohort 2: 17 pts. The primary endpoint is PSA and measurable disease response assessed at wk 12. Secondary endpoint is to evaluate toxicity. One 177Lu imaging study is done at 1 week post-treatment to confirm tumor targeting. Results: 14 pts, median age 73 (5 chemo-naïve), have been treated on this ongoing 2-center study. One pt with bone-only metastases achieved an 87% decline in PSA by day 85 with resolution of bone pain. Bone scan at wk 12 revealed a flare response. As of day 222, the pt has not required additional therapy. PSA stabilization (< 25% PSA rise above baseline) has been seen in 4 pts lasting 16 wks in 2 pts, 18 wks (1 pt) and 23 wks (1 pt), respectively. One pt withdrew at wk 56 without PSA progression. Of 5 pts with measurable disease, no objective responses were seen. Grade 3 and 4 thrombocytopenia occurred in 6 and 4 pts, respectively. 12/14 pts recovered plt counts to ≥ 150 x 109/L (median time to recovery = 22 d). Grade 3 and 4 neutropenia occurred in 7 and 1 pts, respectively. 13/14 pts had ANC recovery to ≥ 2 x 109/L (median time to recovery = 13 d). No significant drug-related non-hematologic toxicity has occurred. Excellent targeting of known sites of PC metastases has been observed in all pts. Conclusions: 177Lu-J591 demonstrates anti-tumor activity in pts with AIPC with one pt achieving the primary endpoint (≥ 50% PSA decline) and 4 pts with PSA stabilization at a dose of 65 mCi/m2. Support: NIH CA102544 , NCRR M01RR00047, DOD PC031175 , David H. Koch Foundation, Cancer Research Institute, MSKCC Experimental Therapeutics Ctr, McCoey Fund, BZL Biologics, Inc. and Millennium Pharmaceuticals, Inc. No significant financial relationships to disclose.