bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of gemcitabine and cisplatin followed by pemetrexed and gemcitabine in patients with metastatic transitional cell carcinoma of the urothelium: Preliminary results
Authors: Hutson T. E. , Vukelja S. , Nicol S. , Hood K. E. , Delgado A. , Ilegbodu D. , Berry W. R.
Published: March 2020

14550

Background: Pemetrexed has activity as a single agent and combined with gemcitabine (G) in platinum refractory metastatic urothelial cancer. The tolerability and activity of this new multi-targeted antifolate combined with standard platinum-based therapy is unknown. This Phase I multicenter trial was conducted in patients (pts) with metastatic TCC to determine the maximum tolerated dose (MTD) of G and cisplatin (C) followed by pemetrexed (P) and G. Methods: Cohorts of 3 to 6 pts were treated with escalating doses of G+C followed by P+G: Dose Level 0 -G+C (800+60 mg/m2) Day 1 and P+G (400+800 mg/m2) on Day 15; Dose Level I -G+C (800+70 mg/m2)/P+G (400+800 mg/m2); Dose Level II -G+C (1000+70 mg/m2)/P+G (400+1000 mg/m2); Dose Level III -G+C (1000+70 mg/m2)/P+G (500+1000 mg/m2) in a 28-day cycle. Pts received a maximum of 6 cycles of therapy; and all pts received folic acid and vitamin B12 supplements. The 3+3 standard Phase I escalation rule was used to establish the MTD. Results: A total of 10 pts have registered, 1 pt received only 1 dose and was replaced, and 9 have been treated: 3 at Dose Level 0 and 6 at Dose Level I. Of these 10 pts, 40% had Karnofsky PS of 100, and the median age was 68 years (range 58–82). One pt had a confirmed CR after 2 cycles, 1 pt at Dose Level I had a PR and received all 6 cycles, 6 pts did not finish treatment (4 pts due to toxicity and 2 pts due to PD), 1 pt at Dose Level I is continuing on therapy. Dose-limiting toxicity occurred in 2 pts at Dose Level I and included Grade 3–4 febrile neutropenia, pulmonary embolism, and diarrhea. The MTD of this triplet is Dose Level I, and the recommended Phase II dose (RP2D) is Dose Level 0. Patient accrual is continuing to further define toxicity at the RP2D. Conclusion: The addition of pemetrexed to standard gemcitabine and cisplatin as initial therapy for metastatic urothelial cancer is feasible. Toxicity of this triplet has been moderate. A Phase II trial is planned to determine the response rate, duration of response, TTP, time to treatment failure, and survival. Supported by Eli Lilly and Company, Indianapolis, IN

[Table: see text]
TGFBR3 is lost in prostate cancer, contributing to malignant transformation
Authors: Sharifi N. , Hurt E. , Farrar W. L.
Published: March 2020

14552

Background: Resistance to transforming growth factor-beta (TGF-beta) is common in solid tumors. Alterations of TGF-beta biology in prostate cancer are complex, with a downregulation of this cytokine reported in early disease and upregulation of TGF-beta in advanced disease. Mechanisms of TGF-beta resistance in early disease are not well understood. We have investigated the function of TGF-beta receptor 3 (TGFBR3) to determine its role in prostate cancer. Methods: We undertook an analysis of the data in seven published DNA microarray studies of nonneoplastic prostate tissue versus prostate cancer specimens using oncomine. Of the genes we identified as known to be directly involved in the TGF-beta pathway, loss of TGFBR3 was most significantly associated with prostate cancer. We determined TGFBR3 expression in prostate cancer cell lines and the immortalized prostate epithelial cell line RWPE-1. To assess the consequences of loss of TGFBR3 expression, we created an shRNA construct and stably infected RWPE-1 cells. We analyzed gene expression changes by DNA microarray analysis and confirmed changes by Western Blot. We then searched TGFBR3 regulated genes based on our knockdown studies in the data set from the seven previously published studies. Furthermore, we evaluated the phenotypic consequences of TGFBR3 knockdown. Results: TGFBR3 expression was significantly lost in 6 of 7 microarray studies. TGFBR3 was downregulated in 3 of 4 of prostate cancer cell lines, compared with RWPE-1. DNA microarray analysis of TGFBR3 knockdown in RWPE-1 cells showed that expression of DPYSL3, Vimentin, COCH, SERPINF1, PMP22, LTBP1 and BMP4 were decreased both with TGFBR3 knockdown and in the transition to prostate cancer. Of these genes, vimentin expression was most dramatically downregulated in TGFBR3 knockdown cells and we showed that vimentin protein expression was completely lost. The phenotypic consequence of TGFBR3 knockdown in RWPE-1 cells was formation of colonies that appear to reflect loss of contact inhibition. Conclusions: TGFBR3 is lost in prostate cancer. TGFBR3 knockdown leads to colony formation by immortalized prostate epithelial cells. Our data suggests that loss of TGFBR3 contributes to malignant transformation of the prostate.

No significant financial relationships to disclose.
A dose and schedule optimizing evaluation of MG98 given as either a 2 hour IV infusion twice weekly or as a 7 day continuous infusion in combination with interferon alpha (INF) in nephrectomized patients (pts) with advanced renal cell carcinoma (RCC)
Authors: Stephenson J. , Amato R. J. , Hotte S. , Nemunaitis J. , Berman B. , Bélanger K. , Patterson T. A. , Macleod A. R. , Reid G. K. , Martell R. E.
Published: March 2020

14557

Background: RCC is often associated with hypermethylated and silenced tumour suppressor genes. The enzyme DNMT1 is responsible for the majority of cellular DNA methylating capacity. MG98 is a second generation antisense inhibitor of DNMT1 which has been shown to reduce DNMT1 mRNA and protein. Methods: A trial of MG98 given as a 2 hour IV infusion twice weekly (Intermittent Schedule, IS) or as a 7 day continuous infusion (CI) in combination with INF has been conducted with nephrectomized pts with advanced RCC. Main endpoints: identification of the optimum regimen, safety, tolerability, pharmacokinetics (PK) and the degree of PBL DNMT1 mRNA suppression. Results: CI schedule: dose levels of 125mg of MG98 combined with 12 MIU of INF (125/12) and 125/9 have been evaluated (9 pts). The MTD has been reached; thrombocytopenia is dose limiting at 125/12. Pt demographics: M:F= 6:3, mean age of 63.2y (52–71). Most common Adverse Events (AEs): fever and chills (gr.1), fatigue (gr.1–2; 100% of pts), nausea and anorexia (gr.1–2), vomiting (gr.2; 66%). Best response: Stable Disease (SD) =3; Partial Response (PR) =1. Currently within the IS schedule, 3 dose levels (9 pts) have been evaluated: 160/12, 200/12 and 200/9, totaling 26 cycles. The MTD has been reached, with GI/constitutional symptoms being dose limiting at 200/12. Demographics: M:F= 7:2 median age 59.8y (40–76). Most common AEs in the first 3 pts are nausea and chills (100% of patients); fatigue (gr.1–2) and fever (66%; gr. 1–3). Best responses: 3 SD, 1 PR. PK evaluation on both schedules revealed no interaction between INF and MG98. DNMT1 inhibition data will be presented. Conclusions: Combination of INF and MG98 exhibits clinical activity and acceptable safety.

[Table: see text]
A phase II study of paclitaxel and vinorelbine (Pacl-Vin) in hormone-refractory metastatic prostate cancer (HRPC): Double tubulin targeting
Authors: Sewak S. , Kosmider S. , Ganju V. , Woollett A. , Le B. , Yeow E. , Henry M. , Bell R.
Published: March 2020

14559

Background: Phase 2 trials of Paclitaxel+corticosteroid or Vinorelbine+corticosteroid have shown 20–40% PSA responses. Preclinical models have shown synergy between Paclitaxel and Vinorelbine. A phase I trial showed this to be a tolerable combination. Methods: The aim of this study was to determine the efficacy and safety of Paclitaxel and Vinorelbine. 30 castrate pts with progressive, metastatic prostate cancer were enrolled. Previous radiotherapy, strontium therapy, 1 line of chemotherapy, and concurrent bisphosphonate therapy were allowed. Pts were treated with Paclitaxel 40 mg/m2 (1 hr), and Vinorelbine 20 mg/m2 iv on day-1 & day-8 of a 21-day cycle. All pts received standard premedication for Paclitaxel including dexamethasone. Results: Baseline pt characteristics were: median ECOG PS of 1 (range 0–2), median age 71, mean PSA 413ng/mL, mean Hb 11.9 g/dL. For 10 pts with measurable disease the partial response rate was 20%, with 70% of pts achieving stable disease (SD). Of 23 assessable pts, 9% had 50% decline in PSA, and 78% had SD, maintained for at least 4 weeks. Median overall survival was 7.3 months. Median progression free survival was 3.3 months. All pts completed quality of life (QOL) questionnaires. There was an improvement over baseline after 3 cycles of therapy in pts pain, appetite, constipation, voiding and overall wellbeing (p = non-significant). Grade 3/4 toxicities were: anemia 3%, neutropenia 8%, infection 2%, febrile neutropenia 4%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of sepsis and neutropenia. Conclusions: In this poor prognostic cohort of pts the combination of Paclitaxel and Vinorelbine is a tolerable regimen, which has demonstrated minor PSA response, with the majority of pts achieving PSA stability. There was some objective response to this regimen and importantly it stabilized disease in a majority of pts. Important QOL parameters such as pain were improved.This is a useful regimen to test in poor prognosis HRPC pts.

No significant financial relationships to disclose.
Thoracic surgery of residual masses after first-line chemotherapy in patients with testicular (T) or primary retroperitoneal (PR) non seminomatous germ cell tumors (NSGCT)
Authors: Flechon A. , Noel N. , Rivoire M. , Mithieux F. , Droz J.
Published: March 2020

14563

Background: Exeresis of all post-chemotherapy residual masses is the standard initial treatment of T and PR NSGCT patients. The aim of the study was to analyse the surgical procedure of thoracic exeresis of residual masses in patients receiving chemotherapy in a single cancer center. Methods: We reviewed the clinical, surgical and histological charts of 143 T or RP NSGCT patients operated on between 01/01/93 and 31/12/2003. All patients had initially at least one thoracic site (lung metastases and/or mediastinal lymph node involvement). We reviewed the indications for surgery according to the size, number of lung metastases and localization of mediastinal lymph nodes. Outcome criteria were relative risk (RR) of relapse and death. Median time of follow-up was 41 months (range 4–140). Results: After first-line chemotherapy, 43 patients (30%) obtained a thoracic complete response, and 100 had thoracic residual masses (70 PR markers -, 24 PR markers +, 2 SD, 4 PD).Thoracic surgery was performed in 32 patients (25 RP-, 4 RP+, 2 SD, 1 PD) by 14 different surgeons. Among these 32 patients, 26 had less than 10 pulmonary lesions, and 14 had only one. Wedge resections were performed in the majority of cases. The histological pattern was necrosis and/or fibrosis in 13 patients, teratoma in 11, growing teratoma in 4, active disease in 3 and nodular sarcoidosis in 1 patient. Six of the 32 operated patients relapsed (one of them in the thorax): 4 died of disease, 2 are alive with evolutive disease (AWD); all others are alive with no evidence of disease (NED). Sixteen of the 68 not operated patients died of disease and 2 of other cancers, 4 are AWD; all others (46) have NED. Five of the 43 patients with thoracic CR died of disease; all others (38) have NED. Patients not operated on for residual thoracic disease had respectively 1.6 and 2 RR of relapse and death when compared to patients with surgical exeresis of residual thoracic disease. Conclusions: Thoracic surgery is an important part of the management of patients with post-chemotherapy residual NSGCT masses in the thorax.

No significant financial relationships to disclose.
22 year phase 1/2 study of single agent carboplatin in metastatic seminoma: Potential for acceleration by a new surrogate end point, 72 hr PET scan response?
Authors: Oliver R. , Powles T. , Ell P. , Somasundram U. , Shamash J.
Published: March 2020

14565

Background: That metastatic seminoma may be more chemo-curable than non-seminoma was first suggested by Samuels (1980 Proc ASCO 21 abst 415) 4 of 5 patients durable CR to single agent cisplatin and by Oliver (1984 Proc ASCO 3. Abst 636) 9 of 10 durable responses. Carboplatin proved less effective and in randomised trials involving 361 patients relapse free survival was 72% with Carbo and 92% with cisplatin-based combination. Prompted by successful dose escalation of carboplatin in ovarian cancer, the initial phase 1 study that preceded the UK randomised trial was reopened and dosage escalated to AUC 8 and then 10. This abstract updates this study and provides more prolonged follow up of the previous reported cases. Methods: Initially patients received Carboplatin 450 mg/m2 (1983–7) and then AUC 7 (88–94), 8 (95–6) and 10 (97–06). The treatment was repeated q21 when possible and if delayed because of toxicity blood counts were repeated every 24 hours. Results: 60 metastatic seminoma patients have been treated between 1983 and 2006. 79%/95% of 19 receiving 450 mg/m2, 88%/94% of 17 receiving AUC 7 or 8 and 92%/100% of 24 receiving AUC 10 are progression free/alive. Overall 58 (97%) are alive and with 28 patients followed more than 10 years there have been no relapses after 26 months. Mild and rapidly recovering (med 14 d) transaminitis in 64% of AUC × 10 (med 93 range 51–541) suggests this may be the upper limit for safe use. As a pilot study 5 seminomas receiving AUC × 10 and 6 non-seminomas receiving BEP had PET scan before and at 72 hours after treatment. The only patient failing to respond substantially was a seminoma who showed increased PET activity on AUC × 10 but achieved complete remission of PET activity after one course of BEP. Conclusion: This data confirms the need for more studies of single agent platinum analogues in seminomas and reinforces the view that it may be preferable to radiotherapy for patients electing adjuvant treatment. With increasing attention being paid to late events, minimizing treatment toxicity and finding a fast track approach to proving safety is an increasing need. The data presented demonstrates the potential of early PET scan as a surrogate for response and could have accelerated the phase 1/2 study reported.

No significant financial relationships to disclose.
A phase II trial of epirubicin (E), estramustine phosphate (EP), and celecoxib (C) as second line treatment of patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: Zhong F. , Kasimis B. , Chang V. , Sambamoorthi N. , Srinivas S. , Cogswell J. , Morales E. , Gonzalez M. , Duque L. , Blumenfrucht M.
Published: March 2020

14567

Background: Celecoxib, epirubicin, and estramustine phosphate affect prostate cancer cells through different mechanisms. All three could be synergistic. We studied the effects of this combination on PSA, response, toxicity and survival in pts with HRPC. Methods: Pts after progression from first line taxane-based chemotherapy with rising PSA and radiographic progression were eligible. Treatment was E30 mg/m2 iv on day 1 and 8 of each 4 week cycle; EP 280 mg po bid daily × 3 days every wk × 2 followed by 2 wks rest; C 400 mg po bid daily for 28 days. All pts were assessed for response every 2 cycles. Dose modifications for hematologic and hepatorenal toxicity were made. RECIST criteria and PSA decline>50% were used to define response. Results: Sixteen pts enrolled, and 13 are evaluable for toxicity and response. Two withdrew before treatment and one for toxicity. The Median (M) age was 71.5 yrs (59–87), ECOG PS 1 (0–1), Gleason score 7 (4–9), LDH 172 (131–244), Hgb 11.1 (8.8–11.9), PSA 75 (6–814). Pts received M 4 cycles (2–10). Nine (69%) pts had soft tissue and 12 (92%) pts had bone metastases. For radiographic response, 11 pts were evaluable; 6 had stable disease and 2 had complete response by CT. Two pts had response by bone scan. Nine (69%) pts had PSA response. The M survival was 441 days (10–995). There were 5 SAE - DVT, diarrhea, bowel obstruction, cord compression and myocardial infarction. There was good renal and cardiac tolerance. Conclusions: This combination was safe and showed good and durable response as a second line regimen.

[Table: see text]
Risk of late relapse after surveillance for stage I mixed (M) or non seminomatous (NS) testicular germ cell tumors (TGCT)
Authors: Theodore C. , Droupy S. , Laplanche A. , Wibault P. , Fizazi K. , Terrier-Lacombe M.
Published: March 2020

14576

Background: Surveillance is an alternative to retroperitoneal lymph node dissection or adjuvant chemotherapy for stage I M or NS TGCT. It has been shown to be associated with a low mortality rate of about 1%, similar to that of the other therapeutic options. However, there are few reports of long-term results. The aim of this retrospective study was to investigate late relapses in this setting. Methods: Screening of the computerized database from 1984 to 2005 for patients (pts) treated for a relapse of a M or NS TGCT at 10 years or more after an orchidectomy. Results: From 1994 to 2006, the files of 5 pts were retrieved. Two pts were referred from other institutions whereas 3 pts had initially been included in the surveillance program of the Institution out of a total of 88 from 1984 to 1996. (3.4% CI 95% 0.7–9.6). Initial histology was available in 4pts: it was pure mature and immature teratoma in one pt and mixed GCT with seminoma in 3 pts. There was no vascular invasion in any of the tumors. Relapse occurred between 10 and 13 years after orchidectomy (median 11 years). The diagnosis of relapse was made based on a systematic 10-year follow-up CT scan in one pt. The 4 other pts who relapsed presented with symptoms: abdominal and back pain due to retroperitoneal involvement in 2 pts, walking disability due to a spinal cord compression in one pt and acute respiratory distress syndrome due to massive metastatic lung involvement in one pt respectively. All 4 pts had bulky retroperitoneal masses. According to the IGCCCG classification, the prognosis was poor in 2 pts and intermediate in 2pts. One pt died of disease despite cisplatin-based chemotherapy. Conclusion: These data demonstrate that there is a small but clinically significant risk of late relapse of stage I M or NS GCT after orchidectomy alone and support the need for long-term surveillance and patient information.

No significant financial relationships to disclose.
Targeted molecular imaging of prostate cancer using tumor endothelium homing Arg-Arg-Leu peptides
Authors: Henry D. O. , Chen S. C. , Wong M. K.
Published: March 2020

14582

Background: Tumor endothelial cells express a specific and unique cell surface signature. We have previously reported on the discovery of tumor endothelial cell (TDEC) binding peptides that possess the amino acid sequence Arg-Arg-Leu (RRL). We now show specific binding of this synthetic peptide to both surgically resected and experimental human prostate adenocarcinoma tumors thereby allowing for tumor imaging. Methods and Results: Cryosections from human lung, colon, renal, breast and prostate cancers were immunohistochemically processed to reveal the relationship of RRL-peptide staining in relation to Factor VIII labeled tumor vasculature. The RRL-peptide tightly co-localizes onto tumor endothelium within human prostate adenocarcinomas, and did not stain the tumor cells proper. Alexa 680, 800 are two near-infrared dyes that can be conjugated to RRL peptide and which emit at a wavelength unquenched by biologic tissue, thus permitting whole animal imaging. Intravenous administration of RRL-peptide-Alexa chimera to human PC3 prostate tumor bearing mice or TRAMP (transgenic prostate cancer) mice results in the fluorescent visualization of tumors within the intact animal through the prolonged intra-tumor retention of the RRL-dye complex as compared to controls. Direct time-lapse intravital microscopy of such tumors show real-time tumor vascular binding of the RRL peptide. Whole animal imaging revealed the tumor and did not show an appreciable image signal at any other site or organ. Conclusion: The RRL peptide homes to prostate vasculature and is useful for the specific detection of experimental prostate tumors in vivo. Further development of the RRL-peptide into a drug delivery and imaging agent is underway.

No significant financial relationships to disclose.
Miniautologous transplantation of lymphokine-activated killers (LAK) in cytokine-pretreated patients with metastatic renal cell carcinoma (RCC): A Slovak phase II study
Authors: Mardiak J. , Lakota J. , Sycova-Mila Z. , Obertova J. , Reckova M. , Mego M. , Ladicka M. , Salek T. , Brozmanova K. , Risnyovszka Z. , Koza I.
Published: March 2020

14593

Background: Prognosis of patients with metastatic renal carcinoma remains poor. We evaluated the efficacy and toxicity of miniautologous transplantation of LAK in cytokine pretreated patients (pts) with metastatic RCC. Methods: Between May 1998 and July 2005, 29 pts (23M/6F) with metastatic RCC were included. All patients were pretreated with cytokine-based therapy (9 pts with interferon alfa, 9 pts with interferon alfa+5FU+IL-2, 10 pts with interferon alfa+5-FU and 1 patient with IL-2). Median age was 58 years (range 49–71). Patients were assigned into three prognostic groups according to MSKCC prognostic criteria for 2nd line treatment (Motzer et al., 2004). Six, seventeen and six pts had 0, 1 and 2–3 risk factors, respectively. Median number of metastatic sites was 2 (range 1–6). 9 pts had liver, 12 bone and 2 patients had cerebral metastases. Median time from cytokine treatment to LAK therapy was 9 months (range 0–41). Periferal blood stem cells (PBSC) were isolated. Part of the PBSC was used to isolate mononuclear cells (MNC). The MNC were incubated in the presence of IL-1, IL-3, IL-6, GM-CSF and SCF. After the conditioning regimen with cyclophosphamide (2g/m2), the PBSC and MNC were pooled and reinfused. Results: Minor response was achieved in 2 pts (7%), 95% CI (0–16%). Overall survival was 8.0 months (5.0–9.8). Median survival 10.0, 8.0 and 9.7 months was achieved in patient’s group with 0, 1 and 2–3 MSKCC risk factors, respectively. Treatment was well tolerated. Four pts (14%) experienced febrile neutropenia after the conditioning regimen. There was no Grade 3–4 non-hematological toxicity and no treatment related death. Conclusions: Despite good tolerability and feasibile administration, the results of our trial do not warrant further study of herein presented experimental treatment. However, new treatment aproaches are needed.

No significant financial relationships to disclose.
Prostate brachytherapy post implant dosimetry: Timing matters
Authors: Minehan K. J. , Furutani K. , McNamara K. , Groshek D. , Mitchell E. , Price M. , Emme M. , Harms T.
Published: March 2020

14597

Background: Permanent seed implant (PSI) brachytherapy is a common treatment modality for low-risk prostate cancer. Post implant dosimetry (PID) is utilized to asses the quality of the implant. Significant prostate swelling occurs as a result of the implant procedure, and this swelling subsides over time. PID completed on Day 0 after the implant procedure captures the prostate swelling from the procedure. Conversely, PID completed one month later does not have this swelling. PID can therefore show great variation, depending on the timing of the analysis. It is hypothesized that PID completed on Day 0 demonstrates lower dosimetric parameters than PID completed one month later. Methods: Thirteen low risk prostate cancer patients, (Stage ≤ T2, PSA < 13.9, Gleason Score ≤7) were implanted with 125Iodine seeds, with a prescription dose of 145Gy to the prostate plus a 5mm margin. Computed Tomography (CT) PID was completed for each patient on day 0 and on average 33 days following the implant. The prostate was contoured on each axial CT image and the data was analyzed using commercially available PSI planning software. The dose which encompassed 90% of the prostate volume (D90) was calculated for day 0 and day 33 PID. Results: On average, the prostate volume contoured was larger on day 0 PID (Avg. 44.9 cc; range 19–97 cc) compared to day 33 PID (Avg. 38.9 cc; range 18–59 cc) (P = 0.068). The D90 values however, were significantly higher on day 33 PID (Avg.163.7 Gy; range 125–212 Gy) than on day 0 PID (Avg.149 Gy; range 112–166 Gy) (P = 0.003). This D90 relationship was even demonstrated paradoxically in two patients whose contoured prostate volume was larger on the day 33 PID as compared to the day 0 PID. Conclusions: Timing does matter in the analysis of post implant dosimetry for PSI brachytherapy. The D90 values were significantly greater on day 33 PID compared to Day 0 PID while the contoured prostate volumes were not. Future studies which use PID planning to evaluate implant quality should specify the timing of the PID, as this would facilitate cross study comparison.

No significant financial relationships to disclose.
Phase 1 study of atrasentan (ABT627), novel endothelin receptor-A antagonist, in Japanese patients with hormone refractory prostate cancer
Authors: Fujisaka Y. , Fujiwara Y. , Yamada K. , Shimizu T. , Horiike A. , Yamamoto N. , Yamada Y. , Matsuoka N. , Fujimoto H. , Tamura T.
Published: March 2020

14602

Background: Endothelin (ET)-1 and its primary receptor, the ETA receptor, contribute to tumor cell growth, survival, angiogenesis and invasion. Atrasentan is a highly potent, selective ETA receptor antagonist. This study assessed safety and pharmacokinetics (PK) in Japanese patients with hormone refractory prostate cancer. Methods: This open-label, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5, 10 or 20 mg) given daily on day 1 and day 4 through 27 (except day 2 and 3). Dose-limiting toxicity (DLT) was defined as Grade 3 or greater adverse events related to study drug. Results: Eighteen patients, aged 54–74 (median; 66) were treated in cohorts of 6 patients each. The compliance of all patients was 100%. The most common toxicities were rhinitis, peripheral edema, headache, hypotension and anemia, all of which were well tolerated. These events were consistent with the anticipated vasodilatory effects or with a hemodilution effect of the study drug. DLTs were not observed. Atrasentan was rapidly absorbed following oral administration of 2.5 to 20 mg, maximum plasma concentrations averaged from 0.4 to 0.8 hours. After peaking, plasma concentrations declined bi-exponentially with a terminal half-life of approximately 25 hours. In the 10 mg dosing group, the steady-state maximum plasma concentration (Cmax) and the area under the curve (AUC0–24h) averaged 135.5 ng/mL and 533 ng h/mL, respectively. The Cmax and AUC values generally increased linearly with increasing dose after single- and multiple-dose administration. Compared to baseline, PSA decreased 50% or more in 1 patient (20 mg) and increased 25% or more in 10 patients (2.5 mg;2, 10 mg;5, 20 mg;3). The PSA of the remaining 7 patients (2.5 mg;4, 10 mg;1, 20 mg;2) ranged from < 25% increase to < 50% decrease. Fourteen patients continued on study drug in an extension study. Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 20 mg in Japanese patients. The main adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing.

No significant financial relationships to disclose.
Phosphodiesterase (PDE) inhibitors reduce in vitro proliferation of prostate primary cells but do not interfere with growth of prostate carcinoma cell lines
Authors: Pernkopf D. G. , Untergasser G. , Berger P. , Plas E.
Published: March 2020

14604

Background: PDE 5 is highly expressed in cavernosal and prostatic tissue. The mechanism of PDE-5 inhibitors on cavernosal tissue is well established but the effects of PDE-5 inhibitors on prostatic cells are unknown. The aim of this study was to analyze in vitro effects of PDE-5 inhibitors on prostate primary cells, fibroblasts (PrSC), basal epithelial cells (PrEC) and prostate cancer cell lines. Methods: Cultivated PrEC and PrSC, immortalized BPH cells (BPH 1), androgen dependent (LNCaP) and androgen independent (PC3) prostate carcinoma cell lines were exposed to increasing concentrations of commercially available PDE 5 inhibitors Sildenafil (Sil), Tadalafil (Tad), Vardenafil (Var). After incubation for 3 days cell viability was determined by a WST-1 assay (Roche-Biochemicals). Cells were evaluated morphologically by invert-light microscopy. PDE-5 protein concentrations were determined by western blot analyses and tissue distribution of PDE-5 by immunohistochemistry (IHC) with a polyclonal antiserum. Results: None of the PDE-5 inhibitors induced cell proliferation. Significant decreases in proliferation and viability were observed at high concentrations (1 mg/ml) of all substances in PrSC and PrEC. In PrSC, proliferation rate decreased to 37.7% in Sil, to 16.9% in Tad and to 63.7% for Var as compared to controls. In PrEC, proliferation decreased to 72.7%, 21.6% and 84.4% for Sil, Tad and Var, respectively. At 0.1 mg/ml only Tad reduced proliferation significantly to 57.4%. Moreover, Tad induced neuroendocrine-like morphology in some PrEC. High protein concentrations of PDE 5 were observed in PrEC, low concentrations in PrSC but none in cancer cells. Conclusions: Sil, Tad and Var inhibit proliferation of prostate primary cells in vitro. Tad showed highest inhibition. Tumor cells were insensitive to PDE-5 inhibitors, due to the lack of PDE-5 protein. It seems unlikely that any of these substances increases proliferation of prostate carcinoma. Tad induced neuroendocrine-like morphology in some basal PrEC indicating effects on cellular differentiation.

No significant financial relationships to disclose.
Undetectable PSA level following prostate brachytherapy
Authors: Barrett W. L.
Published: March 2020

14609

Background: Following radical prostatectomy for adenocarcinoma of the prostate, a long term undetectable PSA level is associated with cure. Patients with persistent long term detectable but low PSA levels after prostate radiation are frequently thought to be cured with the assumption that residual benign prostate tissue may produce low levels of PSA in the absence of cancer. There is not an established PSA nadir following radiation therapy that is universally associated with cure. In our institutional experience PSA nadirs of less than or equal to (≤) 0.2 and ≤ .5 have been associated with disease control by the ASTRO consensus statement in 95% and 89% of patients respectively. None of our patients who have obtained an undetectable PSA following prostate brachytherapy have subsequently gone on to have a rising PSA. The purpose of this study is to determine the frequency of undetectable PSA following prostate brachytherapy. Methods: 209 consecutive patients were treated with radioactive Iodine 125 seed implantation alone as definitive treatment between 1/96 and 1/03. No patients received external radiation therapy or hormone therapy. Post treatment PSA levels were reviewed to ascertain the number of patients achieving undetectable PSA levels, PSA of ≤ 0.2, PSA ≤ 0.5, and PSA failure based on the ASTRO consensus statement definition. Results: At a median follow up of 80 months (range 36 to 120), 75 patients (36%) have achieved and maintained an undetectable PSA level. 27 patients (13%) have experienced biochemical failure by the ASTRO definition. 72% and 78% have achieved and maintained PSA nadirs of ≤ 0.2 and ≤ 0.5 respectively. Conclusions: There has been difficulty in comparing treatment results in patients treated with radical prostatectomy compared to radiation therapy for cancer of the prostate due to the different PSA patterns following the different treatments and the varying definitions of success or failure. Undetectable PSA level after prostate brachytherapy appears in our experience to be consistently associated with disease free status based on the most stringent definition of disease free status following prostatectomy.

No significant financial relationships to disclose.
Zoledronic acid in patients with adenocarcinoma of the prostate M1
Authors: Calais Da Silva F. M. , Calais Da Silva F. E.
Published: March 2020

14623

Background: There is presently clinical evidence that confirms the value of bisphosphonates in metastatic bone disease. Studies have demonstrated that bisphosphonates may reduce bone morbidity and pain, thus increasing the quality of life of patients with multiple mieloma and bone metastases in breast cancer. In metastatic prostate cancer several oral and i.v. bisphosphonates have demonstrated a symptomatic improvement. Zoledronic acid is a bisphosphonate that has proved to diminish the skeletal related events (SRE) in metastatic prostate cancer. Methods: We have initiated a study with two types of patients: patients with bone metastases, With and Without pain, with the primary objective of measuring the efficacy of zoledronic acid in these patients, assessing the time to reduce the pain score or decrease the analgesic score in symptomatic patients and SRE in those non symptomatic, evaluating the time to bone pain and SRE. We started zoledronic acid 4 mg i.v. monthly. Results: We evaluated 87 patients, 16 were not evaluable and 71 evaluable, with at least 3 administrations. From these 70 patients, 11 had no pain with a median follow-up of 9.7 months (3–22 months) out of which 6 (54%) remain pain free (3–18 months). No SRE were registered. The remaining 60 patients had pain at initiation: 24 (40%) were not responsive and 36 (60%) were responsive and registered pain palliation, within an average follow-up of 9.2 months (3–22 months). The average time to response was 3.2 months (1–8 months) and average response duration was 4 months (1–11 months). Only 2 patients required administration of Samarium i.v.; no other SRE. Conclusions: Zoledronic acid is and I.V. bisphosphonate effective in the palliation of pain in patients with bone metastases, which produces decrease of pain and analgesic score with a fast response - in average 3.2 months - and a therapeutic efficacy maintained in average for 4 months. In high-risck patients with bone M1 but without pain, it was also verified that 54% kept pain free at the end of 9.2 months and 45% only started to feel pain again at 6 months.

No significant financial relationships to disclose.
Interstitial high dose rate (HDR) brachytherapy alone for early stage prostate cancer
Authors: Mark R. J. , Anderson P. J. , Neumann T. , Nair M.
Published: March 2020

14633

Background: Transrectal Ultrasound (TRUS) guided interstitial implant for prostate cancer using Low Dose Rate (LDR) and High Dose Rate (HDR) technique has been reported with results comparing favorably to surgery and External Beam Radiation Therapy (EBRT). Often, HDR and LDR interstitial implant is combined with EBRT. There is little published data on HDR alone. We report our results with HDR alone. Methods: Between 1997 and 2006, 167 patients with T1 and T2 localized prostate underwent TRUS guided interstitial implant. There were no Gleason Score or PSA exclusions. No patient received EBRT or Hormonal Blockade. Median Gleason Score was 7 (range: 4 to 10). Median PSA was 9.3 (2.7 to 39.8). Treatment volumes ranged from 42 cm3 to 196 cm3. Treatment volume included the prostate and seminal vesicles in all cases. Our protocol for HDR alone, has called for two HDR Implants. The treatment volume received 2,250 cGy in 3 fractions prescribed to the 100% Isodose line, given over 24 hours. A 2nd implant was performed 4 weeks later, delivering a further 2,250 cGy in 3 fractions, bringing the final dose to the prostate to 4,500 cGy in 6 fractions. Urethral dose points (12–16) were followed, and limited to ≤ 105% of the prescription dose. Results: With a median follow-up of 64 months (range: 6 months to 112 months), PSA disease free survival was 89.8% (150/167). Urethral stricture requiring dilatation has developed in 4.2% (7/167) of patients. Urinary stress incontinence has occurred in 3.6% (6/167). RTOG late bladder toxicities were: 0% Grade 4, 0% Grade 3, and 3.6% (6/167) Grade 2. RTOG late rectal toxicities were: 0.6% (1/167) Grade 4, 0% Grade 3, 1.8% (3/167) Grade 2, and 2.4% (4/167) Grade 1. There have been no cases of rectal incontinence to date. Conclusions: Five year results with HDR implant alone compare favorably to EBRT, LDR ± EBRT, and HDR + EBRT, both with regard to PSA disease free survival, and complications. HDR offers other advantages over LDR, such as no radiation exposure to hospital personnel, no seed migration, greater dose flexibility and precision of radiation dose delivery. Larger volumes can be treated with HDR. By omitting EBRT, bladder and rectal complications appear to be significantly reduced.

No significant financial relationships to disclose.
The importance of age as a prognostic factor in corpus cancer
Authors: Husain A. , Karnik Lee N. , Cheung M. K. , Osann K. , Chen L. M. , Chan J. K.
Published: March 2020

15005

Background: To determine the prognostic factors that influence the survival of younger women diagnosed with uterine cancers. Methods: Patients with a diagnosis of uterine cancer were isolated from the Surveillance, Epidemiology, and End Results (SEER) cancer database from 1988–2001 and demographic and clinico-pathologic data were collected. Patients in the database were stratified by age at diagnosis into two age groups: ≤40and >40 years old. Disease specific survival was calculated using Kaplan-Meier estimates. Results: Of the 51,471 women diagnosed with uterine cancer in the study period, 2076 patients were ≤40 and 49,395 were >40 years old. The mean age in the younger group was 35.6 and that of the older group was 65.2. The overall distribution by stage was Stage I-76%, II-8%, III-7% and IV-9%. Younger patients were more likely to be non-white (30% vs 18%, p < 0.05), have earlier stage disease (79% vs 75%, p < 0.05), grade 1 lesions (48% vs 36%, p <0.05) and sarcomas (16% vs 8%) compared to their older counterparts. The overall disease specific 5-year survival demonstrated that younger patients (≤40 years old) had a significantly improved survival prognosis in comparison to older women (93% versus 86%; p < 0.0001). This survival difference remains significant after adjusting for stage, race, surgical treatment, and radiation treatment. Subgroup analysis revealed no statistical difference in outcome between the two age groups for patients with clear cell histology. There also was no statistical significance in survival for patients with grade 2 or 3 lesions and advanced stage disease. Conclusions: Our large population based study demonstrates that younger patients (≤40) have an overall survival advantage compared to women >40 years. This difference remains significant when adjusted for stage, race, surgical treatment, and radiation treatment. Women with clear cell cancers of the uterus appear to have a poor prognosis independent of age.

No significant financial relationships to disclose.
A phase II study of docetaxel and gemcitabine in the treatment of recurrent ovarian, peritoneal, and fallopian tube cancer
Authors: Shahin M. S. , Hanjani P. , Nolte S.
Published: March 2020

15006

Background: The aim of this trial was to investigate the efficacy and toxicity of weekly combination of docetaxel (D) and gemcitabine (G) in the management of recurrent ovarian, peritoneal, or fallopian tube cancer. Methods: D (30 mg/m2) was given as a one-hour IV infusion followed by G (650 mg/m2) as a 30 minute IV infusion on Day 1, 8 & 15 of a 28-day cycle. Results: Thirty pts were enrolled. Mean age was 67.4 (range 47–85). Twelve (40%) pts had Platinum sensitive disease, and 18 (60%) had Platinum resistant disease. One hundred eighteen cycles were evaluable for toxicity. The mean number of cycles was 4 (range 1–7). Twenty-six (22%) of the cycles were incomplete due to toxicity (day # 15 not given in 25 of the incomplete cycles). Dose delay was observed in 4 (13.3%) pts, and a one-dose level reduction was required in 11 (36.7%) pts. Hematologic toxicity included grade 3 neutropenia in 13 (11%) cycles, grade 3 thrombocytopenia in 11 (9.3%) cycles. No grade 4 neutropenia, thrombocytopenia or neutropenic fever was encountered. Bone marrow support with erythropoiten (36.6% pts), and filgrastim (13.3% pts) were utilized. Blood transfusions were given in 10 (8.5%) cycles. Elevated LFT grade 1/2 was seen in 7 (23.3%) pts and 3 (10%) pts, respectively. Nonhematologic grade 3 toxicites occurred in 4 pts (including one seizure). Mean follow-up interval was 19.6 months (mos) (range 1–36.6). To date, 14 (46.6%) pts are alive with disease, and 16 (53.4%) have died of disease. The overall response rate was 32% (1 CR and 8 PR in 28 evaluable pts). Ten pts (33.3%) had SD and 5 had ID. Median progression-free interval (PFI) was 3.8 mos (95% CI: 1.65–5.97). Overall survival was 19.6 mos (95% CI: 14.23–24.96), and no significant differences in PFI and survival between the Platinum-sensitive and resistant pts (P = 0.5, P = 0.08, respectively). Conclusions: Weekly docetaxel plus gemcitabine is an active and tolerable regimen with minimal toxicity in this older population of pts (9 ≥ 80 years of age). No significant difference in response between Platinum sensitive and resistant pts was observed. Overall response rate appears to be better than single agent regimens currently available. Elimination of the third week of treatment may not affect efficacy and will be more acceptable to pts with less toxicity.

No significant financial relationships to disclose.
Immunohistochemical staining for XRCC1, XRCC3 and Ku70/80 proteins and their correlation with clinical outcome in locally advanced cervical cancer
Authors: O’Hagan J. E. , Dodson A. , Foster C. S.
Published: March 2020

15011

Background: Locally advanced cervical cancer can be successfully treated with radiotherapy but the toxicity of this treatment is at the limit of tolerability (5–15% serious late complications). A test of the cancer’s likely response to radiotherapy would be invaluable to clinically individualize treatment. Protein XRCC1 is involved in DNA single strand break repair and sister chromatid exchanges. Protein XRCC3 is involved in homologous recombinational repair forming a heterodimer with RAD51L2. XRCC5 codes for the Ku70/80 heterodimer and is involved in double strand break repair and V(D)J recombination. The objective of this study was to correlate protein expression with the clinical response to treatment, disease free survival (DFS) and overall survival (OS). Methods: The archived paraffin embedded tissue blocks from 122 women with locally advanced cervical cancer previously treated with either radiotherapy or chemoradiotherapy were stained for XRCC1, XRCC3 and Ku70/80 proteins. The slides were reviewed and the intensity of the staining graded from 0 to 3 (none - strong). Clinical data from the patients’ case notes included baseline characteristics, response at the time of brachytherapy, response at 3months, dates of diagnosis, relapse, last clinic visit and death. The χ2 test, log rank test and Kaplan-Meier methods were used for statistical analysis. Results: The median follow up was 31 months (range 1–76 months). Clinical response at 3 months (RECIST criteria) was strongly correlated with both OS and DFS, patients who progressed had a mean OS of 9.5months (CI 4.2–14.7) compared to patients who had a partial response, mean OS 45.2months (32.6–57.8), and patients who had a complete response had 60% OS at 4years. However, no significant relationships were found between staining for XRCC1, XRCC3 or Ku70/80, OS, DFS or clinical response. Conclusions: This study did not find an association between expression of XRCC1, XRCC3 and Ku70/80 proteins and clinical response, OS or DFS in locally advanced cervical cancer.

No significant financial relationships to disclose.
Topotecan, paclitaxel, and carboplatin in advanced ovarian cancer: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Zubkus J. D. , Hainsworth J. D. , Spigel D. R. , Patton J. F. , Shipley D. L. , Baskette M. , Schnell F. , Greco F. A.
Published: March 2020

15015

Background: Topotecan (T) is standard therapy for patients (pts) with relapsed platinum refractory ovarian cancer (OC). The addition of T to paclitaxel/carboplatin (PC) may improve the first-line therapy for pts with stage III/IV OC. Methods: The primary endpoints were to assess the toxicity and response rate of TPC in previously untreated pts with advanced OC. Pts with previously untreated stage III/IV OC with performance (PS) 0 or 1, normal hematologic and organ function were eligible. Topotecan 1mg/m2 per day IV days 1, 2, and 3; paclitaxel 175mg/m2 IV on day 3 and carboplatin (AUC=5) IV on day 3 were administered at 21-day intervals for 6 cycles with standard dose modifications for toxicities. Responses were assessed clinically after 2 cycles and at completion of therapy. Second look laporatory (SLL) was required for pts without evaluable tumor. Results: 50 pts were enrolled: age range 27–79 (median 63); performance status 0=16, 1=34; suboptimal debulking surgery (tumor > 1 cm) 32; 70% high grade tumors. Intent to treat response rates: complete response (CR) 20 pts (40%); partial response (PR) 12 pts (24%); stable (S) 13 pts (26%); progression 2 pts (4%); not evaluable 3 pts (6%). 13 pts had SLL with 5 CR, 5 PR and 3 S. Toxicities included: grade 3/4 neutropenia/thrombocytopenia 84%/44%; grade 3/4 fatigue/infection 10%/10%; no treatment-related deaths. Median progression-free survival (PFS) for all pts was 13.6 months and 1-, 2-, 3-year PFS 60%, 42%, 36%. Median survival 33.9 months for all pts with 1-, 2-, 3-year survivals 90%, 65%, 49%. Conclusions: The combination of TPC is active and relatively well tolerated with PC given on day 3. The response rates, PFS, and survivals appear similar to standard regimens. Randomized prospective trials will be required to determine the value of T added to PC for first-line therapy of advanced OC.

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