bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics (PK), safety and tolerability of atrasentan (ABT-627, ATN) in combination with docetaxel (DOC) in men with hormone refractory prostate cancer (HRPC)
Authors: Petrylak D. P. , Mohile S. G. , Shelton G. , Carr R. A. , Steinberg J. , Sleep D. , Melia J. , Rieser M. J. , Nanus D. , Milowsky M. I. 
Published: March 2020

14512 Background: ATN (Xinlay) is an oral selective endothelin A receptor antagonist in Phase III clinical development for the treatment of HRPC. ATN is extensively metabolized by oxidation and glucuronidation. In vitro, CYP3A is the predominant isozyme involved in oxidative metabolism of ATN and DOC; ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). Methods: 11 men with HRPC received DOC 75 mg/m2 by 1-h IV infusion on day (D) 1 of each 21-D cycle (C), and ATN 10 mg po qd starting D8C1 and prednisone(Pred) 5 mg orally twice daily.Three oral doses of dexamethasone 8 mg were administered starting 12 hours before DOC. On coadministration days, ATN was taken at the start of the DOC infusion. PK were to be determined over 24 h following DOC alone (D1C1) and in combination with ATN (D1C2), and following ATN alone (D20C1) and in combination with DOC (D1C2). Plasma concentrations of ATN and DOC were determined using a validated LC/MS/MS method. Results: Preliminary PK results are summarized (N = 10, mean ± SD) in the table below. Some patients (pts) had D1C2 PK performed D1C4 (N = 4), D1C5 (N = 3) or not at all (N = 1). No unexpected adverse events (AE) were observed. One subject experienced neutropenic fever related to DOC. This resolved with treatment and ATN/DOC was resumed. Efficacy: 3/5 DOC naive and 2/6 DOC resistant pts had a >50% post treatment PSA decline. One DOC resistant pt demontrated post treatment calcicfication of liver metastases accompanied by a >45% PSA decline. Conclusions: No PK interaction was observed between ATN and DOC when coadministered at full standard single agent dosages implying 10 mg QD ATN did not alter CYP3A4 activity in gut or liver. Treatment with ATN/DOC was well tolerated and demonstrated activity in DOC resistant pts, further justifying a planned Southwest Oncology Group phase III study comparing ATN/DOC/Pred to DOC/Pred. [Table: see text] [Table: see text]
Phase II trial of weekly docetaxel (D) and complete androgen blockade (CAB) prior to radical prostatectomy (RP) in high-risk localized prostate cancer (PC) patients (pts)
Authors: Mellado B. , Font A. , Aparicio L. A. , Gallardo E. , Mel J. R. , Alcaraz A. , Areal J. , Gómez Veiga F. J. , Hannaoui N. , Gascón P. 
Published: March 2020

14515 Background: Pts with high-risk localized PC have an increased risk of positive margins and recurrence after RP or radiotherapy alone. Neoadjuvant hormonotherapy (HT) has not shown a survival benefit prior to surgery, while outcomes are improved when HT is combined with radiotherapy. D-based chemotherapy improves survival in metastatic PC. These data support the investigation of multi-modality approaches to improve the aggressive behavior of high-risk localized PC. The main objective of this study was to assess the pathologic complete response (pCR) rate of the study combination. Secondary objectives were clinical activity, toxicity profile, time to progression and survival. Methods: Pts with clinical stage T1–2 (+ Gleason ≥ 7 (4+3) and/or PSA≥20 ng/mL) and T3 PC received 3 cycles of D (35 mg/m2 i.v. days 1, 8 and 15, every 28 days) concomitant with a depot goserelin (10.8 mg sc) plus flutamide (750 mg po daily for 3 months). RP was performed 2–4 weeks after the end of neoadjuvant therapy. Results: Fifty six pts have been included into the trial. Available data from 32 pts receiving neoadjuvant therapy were analyzed for this presentation. Median age was 69 years (53–75). Median follow-up was 3.6 months. Clinical stage was T1 (20%), T2 (53%) and T3 (27%); Gleason was ≥ 7 (4+3) in 25 (78%) pts. Eight (28%) pts had a PSA ≥ 20 ng/ml. A total of 85 cycles were administered (median 3) with a 100% median relative dose intensity for D. Grade III/IV toxicities per patient were liver toxicity (15.6%) and diarrhea (9.4%). Among the 16 pts who underwent RP to date, one (6%) achieved pCR, 11 (69%) had negative surgical margins and 9 (56%) had organ-confined disease. Conclusions: Neoadjuvant weekly D plus 3-month CAB is well tolerated and induces pCR in high-risk localized PC pts. Updated results will be available for the meeting. These results are encouraging while the true impact of neoadjuvant chemo-HT in this group of pts has to be determined in randomized trials. No significant financial relationships to disclose.
Degarelix: A gonadotropin-releasing hormone receptor (GnRH) blocker, tested in two one-year multicenter, randomized, dose-finding studies in prostate cancer patients
Authors: Gittelman M. , Pommerville P. , De La Rosette J. , Persson B. E. , Jensen J. K. , Olesen T. K. 
Published: March 2020

14516 Background: The GnRH receptor blocker degarelix has immediate onset of action in suppressing gonadotropins (LH and FSH), testosterone (T) and prostate specific antigen (PSA) and does not cause T surge. Its long-term efficacy and safety in different maintenance dosing regimens were evaluated in prostate cancer (CaP) patients. Methods: Degarelix was investigated in two multicenter, one-year studies in North America and Europe/South Africa. Degarelix initiation doses of 200 and 240 mg administered subcutaneously, followed by three maintenance doses (80, 120 and 160 mg). Therapeutic effect was assessed by measuring T and PSA levels. 314 patients (age 47–93, median 73 years) with histologically confirmed CaP, PSA ≥2 ng/mL received degarelix subcutaneously every 28 days. Median baseline T was 4.1 ng/mL and PSA was 20 ng/mL. 19% of patients had metastatic, 24% had locally advanced and 30% had localized CaP. 27% were M0/MX and not T-staged. Tumour grade was well differentiated (Gleason 2–4) in 13%, moderately differentiated (5–6) in 38%, and poorly differentiated (7–10) in 49% of the patients. Results: T levels ≤0.5 ng/mL were achieved in 92% of patients at Day 3 and 95% of patients at Day 28 among those treated with 240 mg (40 mg/mL) degarelix. From Day 28 until Day 364, 100% of patients receiving maintenance doses of 160 mg had T levels consistently ≤0.5 ng/mL. No evidence of T surge was detected. PSA decreased by 90% at 8 weeks after starting therapy, 94% at 12 weeks and 96% at 24 weeks. Twelve patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. There were no cases of systemic allergic reactions. Conclusion: Degarelix treatment for one year resulted in fast, profound and sustained suppression of T (≤0.5 ng/mL) and fast, profound and sustained reduction of PSA levels. Degarelix was well tolerated without evidence of T surge or systemic allergic reactions. [Table: see text] [Table: see text]
Phase I study of interleukin 2 (IL2) maintenance after induction with weekly docetaxel and estramustine in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: Jiang P. , Higano C. S. 
Published: March 2020

14526 Background: Patients with HRPC commonly respond to docetaxel, but many develop asthenia and other docetaxel related toxicities that impair quality of life and hence, many clinicians prescribe a “chemotherapy vacation”. IL2 exerts its anti-tumor effect through activation of T cells and NK cells and at high dose has been shown to have efficacy (and toxicity) in men with HRPC (Maffezzini, The Prostate 1996). Low dose IL2 and 13-cis-retinoic acid given as maintenance after cytoreduction of advanced solid tumors was associated with increased numbers of circulating NK cells as well as further tumor responses (Recchia, Proc ASCO 2001). A phase I trial of low dose IL2 maintenance after chemo induction was undertaken. Methods: Chemotherapy naive pts with metastatic HRPC were induced with weekly docetaxel 35 mg/m2 on day 2 and estramustine 280 mg/M2 TID on days 1 and 2 for 3 wks followed by 1 wk off for a total of 12 doses of chemotherapy. Responding pts received maintenance IL2 for 5 days/wk for 3 wks, followed by 1 wk off. During the 3rd wk, a boost dose was administered on days 2 and 3. Level 1 maintenance was 0.5 x106 IU/m2 SC bid, level 2 was 0.75 × 106 IU/m2 SC bid. Level 1 boost was 3 × 106 IU/m2, level 2 was 4.5 × 106 IU/m2 SC bid. Cohorts of 3 patients were treated at a given dose level according to standard dose escalation schemes for toxicity. IL2 was continued until objective progression was documented. Results: 15 pts, median age of 70 (range 46–78), median PSA 32.7 (range 2.28 to 1248) were enrolled. After chemotherapy, 12 pts had > 50% (7 had > 75%) decline in PSA, 3 pts had < 50% decline. 13 pts went on to receive IL2. The MTD for maintenance IL2 was 0.5 × 106 IU/m2 SC bid (4 pts at level 1 had no toxicity but 3 of 4 at level 2 had grade 2 toxicity requiring a drop to level 1). MTD for the boost was 3 × 106 IU/m2 (4 with no toxicity at level 1, 3 of 3 with grade 2 toxicity at level 2 requiring a drop to level 1). The most common toxicities were fatigue, nausea, chills, edema. One pt has received IL2 maintenance for 25 months. Conclusions: IL2 maintenance can be safely administered at the MTD. Immunological studies before/after chemotherapy and during IL2 are pending. No significant financial relationships to disclose.
Ultrasensitive PSA nadir on testosterone inactivating pharmaceuticals accurately predicts early prostate cancer progression
Authors: Scholz M. C. , Lam R. , Guess B. , Strum S. , Johnson H. , Jenrrich R. 
Published: March 2020

14531 Background: Prostate cancer has a variable natural history. Researchers and clinicians sorely need a marker identifying men destined for early progression to bone metastasis (EPBM). Prostate cancer is uniquely sensitive to testosterone inactivating pharmaceuticals (TIP) especially when TIP is initiated prior to the onset of bone metastasis. Moul 1 reported 10 year median response in men with a rising PSA after surgery. With such effective therapy, predicting EPBM requires a marker signaling TIP resistance. Elevated PSA nadir is a likely candidate. Methods: Retrospective chart review of 159 men with prostate cancer started on TIP before 1/1/00 with negative bone scan and PSA < 100. The predictive value of Gleason score, initial PSA, PSA doubling-time (DT), clinical stage, and ultra-sensitive PSA nadir were evaluated for their ability to predict EPBM within 72 months of starting TIP. TIP consisted of an antiandrogen and LHRH agonist. Results: Median follow was 9.25 years. Median values for patient age, initial PSA, PSA nadir, and PSA doubling time were 65.9, 9.6, 0.03 and 10 months respectively. Sixty men were staged as: T1c-T3b, 46 PSA relapse, and 53 stages T3c, D0 or D1. Thirty-five men developed EPBM. PSA nadir was the most accurate predictor of EPBM (see Table). Only 8% of men with PSA nadir ≤0.05 had EPBM compared to 78% with high nadirs. Cox regression analysis indicated that PSA nadir, Gleason score, and PSA doubling time < 12 months independently predicted EPBM. Median and maximum time to PSA nadir were 4 and 8 months respectively. Conclusions: Ultra-sensitive PSA nadir is a more accurate indicator of early progression to bone metastasis (90%) than Gleason score (75%) as well as being more sensitive and specific (72% vs. 37%) and (95% vs. 86%) respectively. This prognostic information provided by PSA nadir is obtainable within the first 8 months of starting TIP in virtually all patients (97%). 1. Moul JW et al. J Urol 2005, 171: 1141–7. [Table: see text] No significant financial relationships to disclose.
Cytoreductive nephrectomy for metastatic renal cell carcinoma in the presence of nonconventional histology
Authors: Kassouf W. , Sanchez-Ortiz R. , Tamboli P. , Matin S. , Swanson D. 
Published: March 2020

14535 Background: While randomized trials show a survival benefit for cytoreductive nephrectomy in the setting of metastatic conventional (clear cell) renal cell carcinoma (mRCC), the benefit of cytoreductive surgery for patients with mRCC of nonconventional histology (papillary, chromophobe, unclassified) is unknown. We evaluated our experience with cytoreductive nephrectomy for nonconventional mRCC at M. D. Anderson. Methods: From 1990–2004, 464 patients with mRCC underwent cytoreductive nephrectomy; of these, 89 patients had nonconventional mRCC and form the basis of this report. The remaining 375 patients with conventional mRCC formed a comparative group. Overall survival (OS) and disease-specific survival (DSS) data were evaluated by Kaplan and Meier analysis, with univariate and multivariate log rank tests. Results: Compared to patients with conventional histology, patients with nonconventional mRCC were younger (p < 0.045), more likely to have nodal metastases (p < 0.0001), and more likely to have sarcomatoid dedifferentiation (21.2 versus 13.2%, p = 0.056). In multivariate analysis, the median survival for nonconventional histology was significantly worse than for conventional mRCC (11.1 versus 19.5 months, p = 0.0081), even after adjusting for stage, grade, performance status, age, and presence of sarcomatoid dedifferentiation. Although positive nodal status was associated with a decreased survival in nonconventional histology (p < 0.0001) in our multivariate analysis, even node negative patients demonstrated a worse survival when compared to those with conventional histology (p = 0.03). Interestingly, patients with nonconventional mRCC who had complete resection of their retroperitoneal nodal metastases with cytoreduction showed a trend towards improved survival, as has been reported in patients with conventional mRCC and nodal disease. Conclusions: Patients with nonconventional mRCC have a higher incidence of nodal metastases and demonstrate a worse prognosis than those with conventional histology, who undergo cytoreductive surgery. Aggressive cytoreduction with removal of all nodal disease may improve outcomes. More effective systemic therapies are needed to improve upon the results seen with aggressive surgery. No significant financial relationships to disclose.
Upper urinary tract cancer: Prognostic factors for bladder tumours development and systemic relapse
Authors: Merlin F. , Riolfi M. , Sava T. , Consoli F. , Griso C. , Manno P. , Porcaro A. B. , Ghimenton C. , Comunale L. , Cetto G. 
Published: March 2020

14560 Background: Transitional cell carcinomas (TCC) of the renal pelvis and ureter are relatively uncommon. An important characteristic of TCC is multifocality throughout the all urinary tract simultaneously and/or subsequently. To clarify the association between UTTCC and bladder tumors, we retrospectively analysed 86 patients with UTTCC in order to evaluate prognostic factors for recurrence and to identify risk factors for development of bladder cancers. Methods: All 86 upper tract transitional cell carcinoma patients (pts) were treated surgically between January 1988 and July 2005. Median age was 69 years (range: 34–91). We observed a male predominance (71%) and 78% of patients were heavy smokers. Forty-five (52.3%) patients had a diagnosis of bladder transitional carcinoma. The median age of this group of patients was 70 range 40–87). In fifteen cases (17%), bladder tumour occurred first than upper tract neoplasia; in 14 patients bladder and upper tract tumours were synchronous. Results: Median survival was 97 months; 49 (57%) patients are alive and 43 are disease-free. Grading, stage T, lympho-vascular invasion and squamous differentiation were significant prognostic factors for systemic relapse (p < 0.05). Twenty-eight pts (32.5%) developed subsequent transitional bladder cancer after a median time of 12 months; multifocality of primitive tumours was significant predictive factor. Invasive UTTCC were less likely associated with bladder cancer. We observed that superficial bladder cancer developed more frequently in pts with well differentiated (G1–2) primitive cancer (90% of cases), without lympho-vascular invasion and with history of heavy smoke exposition. Conclusions: In our study, T, N and G confirmed to be the most important prognostic factors for systemic relapse. Lympho-vascular invasion highly predicts metastasis. Our analysis highlights that upper urinary tract cancers seem to have different history and different pattern of association with bladder tumours, according to specific prognostic factors. The development of recurrent superficial bladder cancer is more frequently associated with small well differentiated multifocal upper tract tumours.Therefore follow-up should be oriented according to these characteristics. No significant financial relationships to disclose.
Non-seminomatous retroperitoneal histology in patients with a pure testicular seminoma and an elevated serum alpha feto-protein
Authors: Karanikolas N. T. , Secin F. P. , Stasi J. , Carver B. S. , Dotan Z. , Sheinfeld J. 
Published: March 2020

14561 Background: There is controversy regarding the management of patients with pure testicular seminoma (PTS) and elevated alpha-fetoprotein (AFP) level (Nazeer, Oncol Rep 1998;5:1425). Our objective was to determine the retroperitoneal histology and clinical outcome of patients with pure testicular seminoma and elevated serum AFP level. Methods: Between 1989 and 2004, 15 patients with PTS and elevated AFP level underwent post chemotherapy retroperitoneal lymph node dissection (PC-RPLND) at MSKCC. All diagnoses of PTS were confirmed by a MSKCC uropathologist. Clinical and pathologic data were obtained from our prospective surgical database and subsequently analyzed. Results: The median pretreatment AFP level was 339 ng/ml (interquartile range [IQR]: 42, 1,006). Clinical stage at initial presentation was IIa in 1, IIb in 1, IIc in 9, and III in 4. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, 6 patients had good, 6 had intermediate, and 3 had poor risk for disease. The histology at PC-RPLND demonstrated teratoma in 6 patients (40%), fibrosis/necrosis in 6 patients (40%), and viable germ cell tumor in 3 patients (20%; 1 embryonal, 1 yolk sac, and 1 seminoma). Overall, 8 of 15 (53%) had persistent nonseminomatous retroperitoneal histology after chemotherapy. At a median follow-up of 4.2 years (IQR: 2.3, 7.1), 10 patients were alive without disease, 2 were alive with disease, and 3 died of disease. Cancer-specific survival rate was 83% at 5 years (95% confidence interval: 47, 96). Conclusion: Contrary to prior reports (Nazeer, Oncol Rep 1998;5:1425), patients with pure seminoma and an elevated AFP level should be managed as having nonseminomatous germ cell tumor (GCT), including post chemotherapy RPLND because more than half will harbor either teratoma or viable GCT. No significant financial relationships to disclose.
Interleukin-2, interferon alpha and 5-fluorouracil immunochemotherapy with and without 13-cis-retinoic acid in patients with metastatic renal cell carcinoma: Results of a prospective randomized trial
Authors: Bierer S. , Bode M. E. , Brinkmann O. A. , Hertle L. 
Published: March 2020

14571 Background: Combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma has shown objective response rates up to 30% and more. The therapeutic effect of adding 13-cis-retinoic acid still remains controversial. Methods: Between 05/2001 and 11/2003 we randomly assigned patients with metastatic renal cell carcinoma either to receive a combined immunochemotherapy of interleukin 2 (s.c.), interferon alpha (s.c.) and 5-fluorouracil (i.v.) = group A or the same regimen plus 3 × 20 mg 13-cis-retinoic acid daily (p.o.) = group B. 83 patients were eligible (41 in group A and 43 in group B). All patients had ECOG 0 or 1 and no prior systemic therapy. Objective response (OR = Complete response, CR + Partial response, PR + Stable disease, SD), time to progression (TTP) and median survival were determined. Results: Patient characteristics were well balanced between both groups. There was no significant difference in objective response between both groups (A/B: CR 2%/2%, PR 22%/5%, SD 46%/69%, p = 0.8). The responders in both groups showed no significant difference in TTP (A/B: 11.5/9.5 months, p = 0.4). Median survival was 23 months for all patients with no significant difference between the two groups (A/B: 26/22 months, p = 0.42). Slightly more therapeutic side effects (e.g. mucositis) were seen in group B. Conclusions: The addition of 13-cis-retinoic acid to a combined immunochemotherapy of interleukin 2, interferon alpha and 5-fluorouracil in patients with metastatic renal cell carcinoma does not seem to have a therapeutic benefit. No significant financial relationships to disclose.
Sequential administration of cisplatin (c), gemcitabine (g) and docetaxel (d), as first-line treatment in patients with advanced transitional cell carcinoma (TCC) of the urothelial tract: A multicenter phase II study
Authors: Androulakis N. , Boukovinas I. , Bozionelou V. , Kalykaki A. , Potamianou A. , Pallis A. , Vamvakas L. , Gkioulbasanis I. , Souglakos I. , Sfakiotaki G. 
Published: March 2020

14574 Background: The GC combination has become a standard of care for advanced TCC. D has demonstrated broad single agent activity in many solid tumors including bladder cancer. We evaluated the safety and the activity of their sequential administration in patients (pts) with locally advanced or metastatic TCC who have not received prior chemotherapy. Methods: Chemotherapy-naïve pts with histologically proven locally advanced or metastatic TCC were enrolled. G 1100 mg/m2 was administered over 30-minutes IV on days 1 and 15, C 80 mg/m2 on day 1 with the adequate hydration and D 80 mg/m2 over 1 h on day 15. Results: From 4/2004–12/2005, 26 pts (25 male, 1 female), median age 65.5 years (range, 48–75), (PS 0/1/2: 16/8/2) were enrolled onto the study. The majority (19pts, 73.1%) had metastatic disease. A median of 4 cycles (range 1–9) was given for a total of 113 cycles. There were 12 delayed cycles due to toxicity and 15 dose reductions. Three (16.7%) complete responses (CRs) and 6 (33.3%) partial responses (PRs) [2 of them were converted to CR with additional surgery] were observed in 18 evaluable pts [overall RR of 50%; 95% CI 26.9%-3.1%]. The median time to progression was 7.9, and the months while median survival has not yet reached. The 1-year survival is 68.86%. Gr III-IV hematologic toxicity included neutropenia (61.5%), febrile neutropenia (11.5%), anemia (7.7%) and thrombocytopenia (7.6%). Non hematologic toxicity was mild (grade III vomiting and diarrhea in 7.7% and 3.8% of the pts, respectively). There was no neutropenic sepsis or toxic death. Conclusions: The sequential administration of cisplatin, gemcitabine and docetaxel is an active treatment for pts with advanced TCC. Toxicity is not manageable and this regimen warrants further investigation. No significant financial relationships to disclose.