Sandy Srinivas

Abstract

Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3).Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001).The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

View details for DOI 10.1093/annonc/mdt492

View details for PubMedID 24356626

View details for Web of Science ID 000328639000005

Abstract

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

View details for PubMedID 24335682

Abstract

This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized.Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteriaThe median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P < .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P < .0001) and TTF (4.2 vs 7.8 months; P < .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P < .0001) and 1.54 (95% CI, 1.33-1.79; P < .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P < .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P < .0001).Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients. Cancer 2013;119:2999-3006. © 2013 American Cancer Society.

View details for DOI 10.1002/cncr.28151

View details for Web of Science ID 000322632400011

View details for PubMedID 23696129

Abstract

Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer.A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m(2)) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin.There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone.The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer.

View details for DOI 10.1007/s10637-013-9940-0

View details for Web of Science ID 000322333600026

View details for PubMedID 23435622

Abstract

Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade.In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS.The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity.In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.

View details for DOI 10.1016/j.clgc.2012.12.002

View details for PubMedID 23352238

Abstract

Tyrosine kinase inhibitors (TKI) have dramatically changed the management paradigm of advanced renal cell carcinoma (RCC) and are increasingly being used preoperatively to achieve cytoreduction.To review our case series of post-TKI surgical procedures to add to the current perioperative efficacy and complication profile.Between October 2006 and February 2010, 14 cytoreductive nephrectomies, radical nephrectomies, and metastectomies were performed after neoadjuvant sunitinib or sorafenib for advanced RCC. During the same time frame, a control group of 73 consecutive patients underwent radical nephrectomy, cytoreductive nephrectomy, or metastectomy in the absence of prior systemic therapy. We compared the incidence of perioperative complications and outcomes after surgical procedures between the two cohorts.Median preoperative renal mass size was 11 cm (6.7-24.2 cm). Primary tumor shrinkage was seen in 57%; median shrinkage was 18% (8%-25%). The median treatment period was 17 weeks, and the median time from TKI discontinuation was 2 weeks. Compared with a control group and after adjusting for confounding covariates, presurgical TKI use was not associated with a significant increase in perioperative complications (50% vs. 40%, P = 0.25) or perioperative bleeding (36% vs. 34%, P = 0.97) but was associated with increased incidence and grade of intraoperative adhesions (86% vs. 58%, P = 0.001; grade 3 vs. 1, P = 0.002).Compared with the published reports, we observed less hemorrhagic and wound healing issues but a significant increase in incidence and severity of intraoperative adhesions, which can present a formidable technical challenge. Potential reasons for our lower complication rate could be increased time from TKI discontinuation to surgery, longer time to postoperative TKI re-initiation, increased use of preoperative angioembolization, and the lack of preoperative bevacizumab administration. Presurgical TKI therapy can permit effective surgical cytoreduction with a safety and complication profile equivalent to that of non-TKI-nephrectomy; however safety data continue to evolve, and preoperative TKI use requires further prospective investigation.

View details for DOI 10.1016/j.urolonc.2011.01.005

View details for Web of Science ID 000317169500015

View details for PubMedID 21353796

Abstract

Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ? 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

View details for DOI 10.1200/JCO.2012.45.0494

View details for Web of Science ID 000314099800007

View details for PubMedID 23169517

Abstract

Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

View details for DOI 10.1200/JCO.2012.43.3383

View details for Web of Science ID 000313345100010

View details for PubMedID 23213094

Abstract

To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.

View details for DOI 10.1158/1078-0432.CCR-12-2605

View details for Web of Science ID 000313051100023

View details for PubMedID 23136195

Abstract

Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

View details for DOI 10.1371/journal.pone.0049144

View details for Web of Science ID 000311935800219

View details for PubMedID 23145101

Abstract

The aim of this study was to assess fluctuations in normal serum alpha-fetoprotein (AFP) levels in patients with germ cell cancer. Marked variations occur after serum AFP levels normalize, creating anxiety among patients and physicians during surveillance.We conducted a retrospective review of patients with germ cell tumors in clinical remission, who had normal AFP levels and were followed at our center from 1991 to 2009. 72 patients, with a median follow-up of 50 months, were identified.Of the 72 patients, 57 (79%) had a non-seminomatous germ cell histology, and 15 (21%) had seminomas. Seminomas were included as controls as serum AFP levels do not increase in this group. 68 patients underwent orchiectomy, and 50 patients received systemic chemotherapy. The majority of patients (93%) demonstrated fluctuations in serum AFP. There was no difference in the mean AFP values between patients with seminona (2.95 ng/ml) and those with non-seminomatous germ cell tumors (3.3 ng/ml) (standard deviation 1.01 ng/ml).Marked variations occur after serum AFP levels normalize in patients undergoing surveillance. Fluctuating AFP levels within normal limits did not result in relapse in our cohort of patients with extended follow-up.

View details for DOI 10.1159/000342695

View details for Web of Science ID 000309666500007

View details for PubMedID 23038230

Abstract

The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival--a measure that accounts for elapsed time since treatment initiation--for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies.We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival.In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0-34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41-47) at 0 months to 51% (46-55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8-15) at 0 months to 33% (18-48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41-47) to 68% (60-75) in the overall population and from 74% (68-79) to 90% (77-96) in the favourable group, 49% (45-53) to 57% (45-67) in the intermediate group, and 11% (8-15) to 73% (43-89) in the poor risk group.Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients.The Trust Family Fund for Kidney Cancer Research.

View details for DOI 10.1016/S1470-2045(12)70285-1

View details for Web of Science ID 000308425600020

View details for PubMedID 22877847

Abstract

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

View details for Web of Science ID 000308575200006

View details for PubMedID 22956807

Abstract

Enzastaurin is an oral serine/threonine kinase inhibitor of the beta isoform of protein kinase C that may have therapeutic activity in prostate cancer. We explored the efficacy of enzastaurin on two cohorts of patients with prostate cancer progression in the castrate state.A two-cohort phase II trial was conducted, with both groups participating simultaneously. Cohort 1 consisted of patients with non-metastatic castrate prostate-specific antigen progressive disease. Cohort 2 consisted of patients with castrate metastatic disease with progression following docetaxel-based chemotherapy. Patients in both cohorts received 500 mg/day enzastaurin.Therapy was well tolerated in both cohorts. One complete response was observed in Cohort 1, with limited activity in the majority of patients. In Cohort 2, no objective responses were seen and the median progression-free survival (11 weeks [90% confidence interval: 7.6, 11.7]) did not differ from the historical control.Enzastaurin as a single agent has limited activity in castrate progressive prostate cancer. Evaluation in combination with docetaxel is ongoing.

View details for DOI 10.1007/s10637-010-9428-0

View details for Web of Science ID 000294824200035

View details for PubMedID 20369375

Abstract

To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC).A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ?1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout.A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively.Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.

View details for DOI 10.1016/j.urology.2011.04.041

View details for Web of Science ID 000294483300049

View details for PubMedID 21762967

Abstract

The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management.

View details for PubMedID 21827392

View details for DOI 10.1200/JCO.2010.32.6165

View details for Web of Science ID 000288990100005

View details for PubMedID 21220606

Abstract

To assess whether high ribonucleotide reductase subunit M1 (RRM1) expression in patients with resected, muscle-invasive (T2-4NxM0) urothelial carcinoma (UC) correlated with longer overall survival (OS). RRM1 is the primary cellular target of gemcitabine and previous studies in resected early-stage lung cancer have shown a survival benefit for patients with high expression.In all, 84 radical cystectomy specimens with muscle-invasive UC were identified from existing tissue microarrays. The patients' medical records were retrospectively reviewed to confirm pathology and stage. Specimens were analysed for RRM1 expression using automated quantitative analysis. The median value of RRM1 was established a priori as the threshold for high and low expression.The median age of the patients was 69 years. Stages were nearly equally distributed: 30%, 38%, and 32% for stage II, III, and IV, respectively. Most were high grade (99%) with no nodal involvement (69%). The median (range) OS was 2.0?(0-13.1) years. Tumoral RRM1 levels did not correlate with OS for the entire cohort, but when adjusted for age, high tumoral RRM1 expression in younger patients (aged <70 years) correlated with increased survival. Younger patients with high RRM1 expression had a median OS of 10.6 years compared with 1.6 years in older patients (P= 0.001). There was no difference in OS among low RRM1 expressors: 2.3 vs 1.6 years in younger and older patients, respectively (P= 0.22).Our results suggest that high RRM1 expression may be prognostic for improved survival in patients with muscle-invasive UC aged <70 years.

View details for DOI 10.1111/j.1464-410X.2010.09327.x

View details for Web of Science ID 000284275200049

View details for PubMedID 20438561

Abstract

This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC).Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either

View details for DOI 10.1158/1078-0432.CCR-09-3026

View details for Web of Science ID 000278597600023

View details for PubMedID 20460477

View details for PubMedID 20141676

Abstract

Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma (RCC) in both the US and Europe. Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative.

View details for Web of Science ID 000286671700001

View details for PubMedID 21049084

Abstract

Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

View details for DOI 10.1200/JCO.2008.20.5476

View details for Web of Science ID 000269381100008

View details for PubMedID 19652072

Abstract

Androgen-deprivation therapy is commonly used in patients with progressive prostate cancer (PCa), but can be associated with unpleasant side-effects. The objective of the study was to determine whether treatment with calcitriol and naproxen is effective in safely delaying the growth and progression of PCa in men with early recurrent disease.Patients with biochemical relapse after local therapy for prostate cancer were treated with high dose calcitriol (DN101, Novacea) (45 microg once per week) and naproxen (375 mg twice daily) for one year and followed with serum PSA levels as well as imaging studies.Twenty-one patients were enrolled in the trial. Four patients met criteria for progression, with a PSA doubling time (PSADT) that decreased while on therapy. Fourteen patients had a prolongation of PSADT compared to baseline.Combination therapy with weekly calcitriol and daily naproxen is well tolerated by most patients and prolongation of PSADT was achieved in 75% of patients.

View details for Web of Science ID 000268846900016

View details for PubMedID 19667155

Abstract

A 57-year-old woman presented to the emergency department at a community hospital with a 2-month history of fatigue and right-sided flank and abdominal pain. Noncontrast CT of the abdomen and pelvis revealed a 9.1 cm right renal mass.Contrast CT of the chest, abdomen and pelvis, MRI of the abdomen and pelvis with gadolinium, radionuclide bone scan, lung nodule biopsy, complete blood count, comprehensive metabolic profile, and measurement of serum lactate dehydrogenase.Stage IV, T3bN0M1 clear cell renal cell carcinoma, with an associated tumor thrombus extending into the vena cava.The patient was treated with neoadjuvant sunitinib, which resulted in a marked response in the primary tumor and metastatic lesions as well as regression of the tumor thrombus well into the renal vein. Thus, laparoscopic radical nephrectomy was feasible and was achieved without hemorrhagic or wound healing complications. One month after surgery, she had evidence of disease progression in the lung and a periaortic lymph node. She was restarted on sunitinib with resultant disease stabilization, but discontinued the drug owing to toxicity. Eight months after cessation of sunitinib, she received a dendritic cell vaccine. She remains alive without evidence of disease progression 2 years after her diagnosis.

View details for DOI 10.1038/nrurol.2009.84

View details for Web of Science ID 000266773900012

View details for PubMedID 19498412

Abstract

Despite high response rates with front-line platinum-based therapies, 80% of patients with metastatic urothelial cancer progress. Multiple agents and couplets have been investigated, but no standard second-line regimen exists. We conducted a phase II study to evaluate the efficacy and safety of docetaxel and oxaliplatin in metastatic urothelial cancer patients who had received prior platinum therapy.Patients with metastatic urothelial cancer, who had disease progression after platinum therapy, were treated with docetaxel 75 mg/m(2) and oxaliplatin 85 mg/m(2) every 3 weeks until disease progression or intolerable toxicity.Between November 2004 and September 2005, 11 patients were enrolled. All patients had low or intermediate Bajorin risk. The median number of cycles administered was 2 (range 2-8). One patient achieved near complete response. Three patients experienced disease stabilization, resulting in a disease-control rate of 36%. Median overall survival was 7 months. The most common toxicities were fatigue and anemia (50%).Second-line docetaxel and oxaliplatin in metastatic urothelial cancer is safe and tolerable but did not achieve an appreciable response rate.

View details for DOI 10.1159/000230695

View details for Web of Science ID 000270361800004

View details for PubMedID 19641314

Abstract

We retrospectively analyzed whether increased hemoglobin is a surrogate biomarker of efficacy for vascular endothelial growth factor (VEGF) inhibitors in advanced renal cell carcinoma (RCC) patients. Twelve patients were identified who had received bevacizumab alone or as combination therapy. Eleven patients experienced a rise in hemoglobin. Median change was 1.6 g/dL (0-4.0). Degree of peak increase correlated with longer progression-free survival (PFS) in metastatic patients: increase of < 15% yielded a 3.1-month median PFS compared to 8.2 months with rises > 15%. This study identifies increased hemoglobin as a possible consequence of VEGF inhibitors. The correlation with longer PFS suggests that rise in hemoglobin may be a surrogate biomarker of efficacy.

View details for DOI 10.1080/07357900902744528

View details for Web of Science ID 000269542600007

View details for PubMedID 19603304

Abstract

Our research is aimed at obtaining a better understanding of the molecular mechanisms of the anti-proliferative and cancer preventive effects of calcitriol with the goal of developing strategies to improve the treatment of prostate cancer (PCa). In PCa cells calcitriol inhibits the synthesis and biological actions of prostaglandins (PGs) by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the upregulation of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, we hypothesize that the inhibition of the PG pathway contributes to the ability of calcitriol to prevent or inhibit PCa development and growth. We have shown that the combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of the growth of PCa cell cultures and this combination therapy offers a potential therapeutic strategy. These findings led us to embark on a clinical trial combining the non-selective NSAID naproxen with calcitriol in men with early recurrent PCa. The results indicate that the combination of high dose weekly calcitriol with naproxen slows the rate of rise (doubling time) of PSA in most patients indicating the slowing of disease progression. Further studies are warranted to determine the role of this combination therapy in the management of recurrent PCa.

View details for PubMedID 20046582

Abstract

Despite the introduction of newer treatment approaches in metastatic renal cell carcinoma (mRCC), overall survival remains disappointing and further exploration of current chemotherapeutic agents for second or third-line treatment is imperative. We conducted a phase II trial to determine the efficacy and safety of the combination of thalidomide and capecitabine in mRCC.We enrolled 13 eligible patients, who had progressive measurable metastatic disease, between May 2003 and January 2005. Treatment consisted of thalidomide 200 mg daily for 21 days per cycle, and capecitabine 1250 mg/m(2) twice daily for 14 days per cycle. The primary end point was response rate. Secondary endpoints included overall survival and toxicity assessment.Twelve patients were eligible for statistical analysis. The median age was 59 years, and most patients had an Eastern Cooperative Oncology Group performance status of 0-1 (92%). Nine patients had previous nephrectomy. The median number of administered cycles was 4 (range 2-10). Anemia was the only grade 3 toxicity. Grade 2 toxicities included fatigue, constipation, anemia, hand-foot syndrome, diarrhea, and peripheral neuropathy. Although no radiographic responses were observed, 5 patients (42%) achieved stable disease. Seven patients (58%) experienced disease progression. The median overall survival was 10.2 months.Despite being well tolerated with manageable side effects, the use of thalidomide and capecitabine in patients with mRCC did not significantly impact response or survival.

View details for DOI 10.1097/COC.0b013e318168ef47

View details for Web of Science ID 000260123000003

View details for PubMedID 18838876

Abstract

In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

View details for DOI 10.1093/annonc/mdn168

View details for Web of Science ID 000259505400015

View details for PubMedID 18436521

Abstract

Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.

View details for DOI 10.1002/cncr.23519

View details for Web of Science ID 000256914200010

View details for PubMedID 18484647

View details for DOI 10.1159/000144179

View details for Web of Science ID 000259273700004

View details for PubMedID 18787349

Abstract

The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.

View details for DOI 10.1586/14737140.7-12.1749

View details for Web of Science ID 000251891100016

View details for PubMedID 18062749

Abstract

Bevacizumab (Bev) has clinical activity in advanced renal cell carcinoma (RCC), and, when combined with erlotinib (Erl), has shown encouraging objective response rate (ORR) and progression-free survival (PFS). We performed a phase II, randomized, double-blind, multicenter, placebo-controlled trial to assess whether Erl provides additional clinical benefit with regard to PFS and ORR when combined with Bev in first-line treatment of metastatic RCC.One hundred four patients received intravenous Bev (10 mg/kg) every 2 weeks in combination with oral Erl (150 mg) or placebo daily. Patients were treated until progression or toxicity.A landmark analysis was performed 9 months after enrollment was completed (median follow-up, 9.8 months). Sixty-five patients had discontinued therapy; time to study discontinuation did not differ between the two treatment groups. The median PFS was 9.9 months (Bev + Erl [B+E]) versus 8.5 months (Bev; hazard ratio = 0.86; 95% CI, 0.5 to 1.49; P = .58). ORR (complete plus partial) was 14% (B+E) versus 13% (Bev). One complete response occurred in the B+E group. Median survival was 20 months for B+E but not reached for Bev. The most common grade 3/4 adverse events (> 5% of patients) were hypertension, rash, proteinuria, diarrhea, and hemorrhage. One treatment-related death occurred on study (GI perforation, B+E group).The addition of Erl to Bev was well tolerated, but did not provide additional clinical benefit compared with Bev alone. Bev has encouraging clinical activity for previously untreated metastatic RCC patients.

View details for DOI 10.1200/JCO.2007.11.5154

View details for Web of Science ID 000251073600008

View details for PubMedID 17876014

Abstract

Since its FDA approval in December 2005, sorafenib (Nexavar) has been in use for the treatment of metastatic renal cell carcinoma. With this increased use have come reports of adverse effects of sorafenib. To the best of the authors' knowledge, they are the first to describe an 80-year-old Asian male with a history of metastatic renal cell carcinoma who developed acute pancreatitis confirmed by computed tomography (CT) one month after taking sorafenib 400 mg orally twice a day. Sorafenib was eventually discontinued, and the pancreatitis resolved. The molecular biologic mechanism causing this side effect is discussed. Patients should be informed of this rare but potentially serious adverse effect before initiation of sorafenib therapy. Early recognition of this complication and complete discontinuation of sorafenib are recommended.

View details for Web of Science ID 000249669600014

View details for PubMedID 17902294

View details for PubMedID 17692170

View details for Web of Science ID 000248995500012

View details for PubMedID 17867384

Abstract

We provide recommendations for defining and treating bone related events in high risk prostate cancer.A focused literature review was done.Men with prostate cancer often have osteoporosis and osteopenia even before initiating androgen deprivation therapy. After starting androgen deprivation therapy they experience accelerated bone loss. Bone mineral density is the most common tool to assess the degree of bone loss, although the use of bone turnover markers for this purpose is being actively explored. Bisphosphonates are effective for increasing bone mineral density and treating osteoporosis. The benefits derived from bisphosphonates should be weighed against the adverse effects, including the risk of osteonecrosis of the jaw. Treatment is indicated in patients with prostate cancer with osteoporosis and it may be considered in patients with osteopenia and/or additional risk factors. The time of initiation of therapy and duration of treatment have not been conclusively established.Prolonged androgen deprivation therapy results in bone loss and it has a potential to impact quality of life. Additional research is needed to characterize patients who would benefit from therapy and optimize strategies to prevent osteoporosis.

View details for DOI 10.1016/j.juro.2006.06.076

View details for Web of Science ID 000242029200011

View details for PubMedID 17084167

Abstract

To examine grade reliability when biopsies contain very small amounts of prostate cancer. Prostate biopsy findings are known to undergrade prostate cancer compared with the pathologic specimens yet remain the only grade guiding disease management.The presence of a clinically significant grade change from biopsy cores to matched prostatectomy specimens was examined in 371 patients. The biopsies were characterized for primary and secondary Gleason grade, number of positive cores, and total linear length of cancer. The pathologic specimens were characterized for cancer volume and relative percentage by grade. The rates of upgrading or downgrading were tested against all clinical and biopsy information for any significant predictive value.The overall rate of upgrading was 40.7% and downgrading was 16.1%. Upgrading was constant and independent of any clinical or biopsy tumor volume indexes. Specifically, when cancer was present in only one biopsy core and measured 2 mm or less (n = 48), it was just as predictive of the pathologic grade as that from any greater number of positive cores and any greater extent of cancer length present. Downgrading was less frequent for biopsies with small amounts of cancer.Histologic grading from small amounts of cancer in prostate biopsies is reliable and not more prone to grading errors. A repeat biopsy for these patients may not be indicated.

View details for DOI 10.1016/j.urology.2005.12.031

View details for Web of Science ID 000238390900026

View details for PubMedID 16765184

Abstract

Carcinoma of the bladder is the second most prevalent genitourinary malignancy and the fifth most common solid malignancy in the USA. Combination chemotherapy is used in most patients with advanced disease. Traditionally, on the basis of favorable response rates and survival data, cisplatin-based regimens have been the preferred chemotherapy for patients with metastatic bladder cancer. However, the toxicity profile of cisplatin precludes its use in a significant subset of patients with advanced bladder cancer. Conversely, noncisplatin-containing regimens have been shown to have a more favorable toxicity profile and to have activity in advanced bladder cancer. Here, various nonplatinum chemotherapy regimens for advanced disease are reviewed.

View details for DOI 10.1586/14737140.6.6.887

View details for Web of Science ID 000240923100013

View details for PubMedID 16761932

Abstract

To assess the effect of triamcinolone administration on the serum prostate-specific antigen (PSA) response and the time to progression in patients with androgen-independent prostate cancer (AIPC).Patients with AIPC were prospectively treated with oral triamcinolone 4 mg twice daily, and their serum PSA and cortisol levels were measured monthly. Patients with greater than 25% increases in serum PSA from baseline were considered to have progressive disease and were removed from the study. Those patients who had a decrease in serum PSA levels or stable disease continued in the study until disease progression. Bone scans were obtained every 12 weeks and at progression.Twenty-four patients with AIPC were treated from November 2002 to June 2004. A partial response with a more than 50% decrease in serum PSA level was seen in 29%. Another 21% achieved stable disease. No statistically significant difference was found in the time to progression in the partial responders and patients with stable disease. The median time to progression in both groups was 7.5 months. Treatment was well tolerated without any grade 3 or 4 toxicity.Oral triamcinolone was well tolerated by patients with AIPC, with 50% of the patients exhibiting a good response to therapy in terms of serum PSA level and time to progression.

View details for DOI 10.1016/j.urology.2005.11.004

View details for Web of Science ID 000238390800026

View details for PubMedID 16698360

Abstract

This study was designed to determine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in the evaluation of metastatic transitional cell carcinoma (TCC).Fifty-eight FDG PET scans were performed on 46 consecutive patients with TCC. Results were correlated with radiologic, pathologic, and histologic findings in these patients and the sensitivity of PET for detecting malignancy in untreated TCC patients (n = 48) was compared to the sensitivity in patients who had undergone prior chemotherapy (n = 10).Of 48 scans in patients who had no prior systemic chemotherapy, 10 had increased uptake in proven metastatic TCC lesions and 3 PET studies failed to reveal metastatic TCC (sensitivity 76.9%). In patients free of metastatic disease, 33 revealed no abnormal uptake and 1 study revealed a suspicious area in a patient free of metastases (specificity = 97.1%). However, in 10 patients imaged after receiving chemotherapy, the sensitivity fell to 50% for the detection of histologically confirmed residual/recurrent tumor by PET.FDG PET detects increased metabolic activity. After chemotherapy, viable cancer cells may still be present but with a diminished metabolic rate. As a result, PET imaging is often useful in the evaluation of untreated metastatic TCC metastasis but should be interpreted with caution in patients who have received prior chemotherapy.

View details for DOI 10.1159/000092937

View details for Web of Science ID 000238913100014

View details for PubMedID 16825819

View details for PubMedID 16192608

Abstract

To conduct a dose-finding trial using a single low dose and dose escalation of a higher dose of thalidomide in patients with metastatic renal cell carcinoma (RCC), and to evaluate the antineoplastic effectiveness of thalidomide as an anti-angiogenic agent on RCC.The 14 patients enrolled in the study had progressive measurable metastatic RCC and consented to participate. Patients were randomized to either a fixed low dose of 200 mg of thalidomide or to a high dose of 800 mg that was increased to a maximum dose of 1200 mg daily. Patients were evaluated for response after 8 weeks of therapy.Stable disease was achieved in six patients and was seen in both the low-dose and high-dose thalidomide groups. The median overall survival was 9 months. The low-dose thalidomide regimen was better tolerated and patients survived longer than those on the high-dose regimen (16 vs 6 months, P = 0.04)The use of low-dose thalidomide in patients with metastatic RCC was well tolerated and they survived for longer than those on the high-dose regimen.

View details for DOI 10.1111/j.1464-410X.2005.05680.x

View details for Web of Science ID 000231387900017

View details for PubMedID 16104906

Abstract

Cisplatin-based chemotherapy is the most effective standard treatment available for patients with metastatic bladder cancer. For those patients who are unable to receive cisplatin, other effective combination treatments are needed. The objective of this research was to determine if a combination of paclitaxel and gemcitabine would be effective in patients who were unable to receive cisplatin or have failed cisplatin treatment.Patients with histologic-proven metastatic bladder cancer who had measurable disease were eligible. Patients received chemotherapy (in an outpatient clinic) with paclitaxel at 110 mg/m2 plus 1000 mg/m2 gemcitabine on days 1 and 15 of a 28-day cycle. Patients were evaluated after 2 cycles of therapy using computed tomography and bone scan imaging.An objective response rate was achieved in 61% of the patients (13 of 18 subjects). Fifty-five percent of the patients who were previously treated with chemotherapy had an objective response (11 of 18 subjects). The median duration of response was 5 months and the toxicity was mild. All patients with low-risk disease had a response (8 of 18 subjects), compared with a 30% response rate in the intermediate-/high-risk group (P = 0.001, 10 of 18 subjects).The combination of paclitaxel and gemcitabine given in an every 2-week regimen is very well tolerated and has significant activity in previously treated patients with metastatic transitional cell carcinoma. The combination of paclitaxel and gemcitabine appears to be effective for patients with good-risk disease who are unable to take cisplatin-based chemotherapy.

View details for DOI 10.1097/01.coc.0000143018.04650.f9

View details for Web of Science ID 000228240600002

View details for PubMedID 15803002

Abstract

Primary tumors known to metastasize to the testis, in order of decreasing frequency, are prostate, lung, gastrointestinal tract, melanoma, and kidney tumors. Metastasis from bladder cancer to the testis is extremely rare, occurs with advanced and metastatic disease, and is usually a finding at autopsy. We report a rare, and probably the first, case of solitary and synchronous metastatic transitional cell carcinoma of the bladder to the testis, discovered on the preoperative workup. An incidentally discovered testicular mass in a man with high-grade, invasive bladder cancer should be considered a metastatic lesion until proven otherwise.

View details for Web of Science ID 000224680300054

View details for PubMedID 15491734

Abstract

A prior comparison of 750 mg flutamide daily to 500 mg daily with an LHRH analog or orchiectomy showed no difference in effect on prostate specific antigen (PSA). However, any difference was likely masked by hypogonadism from concomitant LHRH analog or orchiectomy. We sought to evaluate different flutamide dosing schedules without this confounding factor. We recruited 50 men with advanced prostate cancer who elected to receive hormonal therapy to be randomized to 1 of 3 flutamide treatment groups: 1) 250 mg once daily, 2) 250 mg twice daily, or 3) 250 mg 3 times daily for 3 months, after which the therapy of their choice was instituted. Serum samples at the initiation of therapy and at the 1- and 3-month time point were assessed for PSA, testosterone, liver function tests, hematology, and renal function. Prostate volume, androgen deficiency symptoms, and a compliance diary were also recorded. Testosterone and PSA levels show a dose-dependent response to flutamide monotherapy. Loss of libido and erectile dysfunction occurred in all 3 treatment groups, with a trend toward worsening sexual function with higher flutamide dosing, but this trend did not reach statistical significance. Prostate volumes decreased by an average of 34.3% in the patients receiving 250 mg flutamide 3 times daily, 27.8% in patients receiving 250 mg flutamide twice daily, and 19.2% in those receiving a once daily dose of 250 mg flutamide. There was a significant difference between the once daily group and the 3 times daily group (P =.047). Flutamide at 500 mg did not result in significant changes in testosterone, PSA, prostate volume, or androgen deficiency symptoms compared to 750 mg daily after 3 months.

View details for Web of Science ID 000222455000022

View details for PubMedID 15223852

Abstract

To assess the value of positron emission tomography (PET) compared with computed tomography (CT) in the initial staging of esophageal cancer.Case series.Tertiary care veterans hospital.Patients with newly diagnosed esophageal cancers from January 1996 through May 2001 who underwent both CT and PET scanning within 4 weeks were included in the study (n = 24). Only patients who underwent pathological or radiographic follow-up were included.The sensitivity, specificity, and negative and positive predictive values of CT and PET were determined based on a criterion standard of pathological staging in 16 patients (67%) and follow-up imaging in 8 patients (33%).For staging regional lymph node involvement, CT and PET scans showed no statistically significant difference in sensitivity (57% and 71%, respectively) and specificity (71% and 86%, respectively). For detection of metastatic disease, CT and PET showed no significant difference in sensitivity (83% and 67%, respectively) and specificity (75% and 92%, respectively). There was no significant difference in clinical decision making when the results of both tests were discordant.There was no significant difference between the 2 imaging modalities in the initial staging of esophageal cancer. The CT scan was a sensitive indicator of distant metastases, whereas PET was more specific. It is unclear what additional role PET scanning should have in the initial screening of patients.

View details for Web of Science ID 000177920800004

View details for PubMedID 12215149

Abstract

Testicular cancer is a highly curable cancer. However, 30% of patients are refractory to standard therapy and will need additional therapy. This article focuses on the use of high-dose chemotherapy in germ-cell tumors. High-dose chemotherapy use is discussed both in the refractory setting and as either first-salvage or first-line therapy. Various criteria for risk assessment are also discussed.

View details for Web of Science ID 000090129800010

View details for PubMedID 11098508

Abstract

Pneumothorax occurring in the absence of obvious lung disease is defined as spontaneous pneumothorax. Spontaneous pneumothorax occurs in a variety of settings in patients with malignancies.We present a case report of spontaneous pneumothorax in malignancy and review the literature.No correlation was found between the occurrence of pneumothorax with age, sex or smoking history. Pneumothorax occurred with a variety of primary tumors. However it was always associated with lung metastases or lung involvement with tumor. In certain cases the metastases were detected after the occurrence of pneumothorax.The occurrence of pneumothorax in a patient with malignancy should prompt a search for lung metastases.

View details for Web of Science ID 000089244400026

View details for PubMedID 10997821

Abstract

Purpose: Positron Emission Tomography (PET) with F18-fluorodeoxyglucose has been proven useful for staging non-small cell lung cancer. Bone scans are frequently performed for suspected skeletal metastases. The purpose of this study was to evaluate if bone scans compared to PET scans provide additional information that changes the stage of disease.Procedures: Nineteen patients with non-small cell lung cancer had PET and bone scans done for staging of the malignancy. The results of both studies were compared.Results: Bone and PET scans agreed on the presence or absence of skeletal metastases in all nineteen patients. The addition of a bone scan to a PET scan did not change the stage of the disease or the management in any of the patients. Bone scans allowed for more precise localization of the lesions in some patients.Conclusions: Bone scans do not change the stage of disease when performed in addition to PET scans, but provide more precise localization of skeletal abnormalities.

View details for PubMedID 11008099

Abstract

Between 20-30% of patients with advanced germ cell tumors relapse or fail to achieve a complete response to conventional cisplatin based chemotherapy. Ifosphamide has been used very effectively in combination with cisplatin and etoposide (VIP) or in combination with cisplatin and vinblastine (VeIP). Actinomycin D with chlorambucil and methotrexate was widely used in the 1960s with complete responses in 20% of patients and long term survival of 6-10%. There exists no information on the use of actinomycin as a salvage in cisplatin refractory patients.One patient with metastatic germ cell tumor who failed chemotherapy with cisplatin and ifosphamide was successfully treated with an actinomycin D based regimen.Actinomycin D is an active agent in testicular cancer and maybe used in patients refractory to platinum.

View details for Web of Science ID 000080742700018

View details for PubMedID 10228505

Abstract

Methotrexate is readily absorbed from the intestinal tract. When given to patients with urinary diversion to the intestinal tract, methotrexate may be reabsorbed into the circulation, thus increasing its serum concentration and potentially increasing its toxicity.Forty-eight patients with transitional cell carcinoma of the urinary tract who had undergone cystectomy and either an ileal conduit or a continent diversion were evaluated for their tolerance of chemotherapy. Of the 42 evaluable patients, 23 had a continent diversion and 19 had an ileal conduit. None of the patients with the continent diversion had an indwelling Foley catheter during the course of chemotherapy.There were no statistically significant differences in incidence of fever or neutropenia, mucositis, dose modification, or delay in chemotherapy between the two groups. When compared with a group of patients with native bladders who received the same chemotherapy, patients with continent diversions did not have increased incidence or severe toxicity from chemotherapy.Patients with continent diversions tolerated chemotherapy as well as patients with ileal conduits.

View details for Web of Science ID 000072376400018

View details for PubMedID 9506360

Abstract

The goals of this study were to define the efficacy and toxicity of doxorubicin and dose-escalated cyclophosphamide (Cy) along with granulocyte colony-stimulating factor (G-CSF) in the treatment of hormone-refractory prostate cancer (HRPC), to determine the maximal-tolerated dose (MTD) of Cy in this regimen, and to evaluate the impact of prior pelvic irradiation (XRT) on MTD and toxicity.Thirty-five patients were treated every 21 days with fixed-dose doxorubicin (40 mg/m2) and Cy 800 to 2,000 mg/m2 (in a cohort dose-escalation schema) along with G-CSF.Five of 15 patients (33%) with measurable disease obtained an objective response. Sixteen of 35 patients (46%) had a greater than 50% decrease in prostate-specific antigen (PSA) level (95% confidence interval [CI], 28.8% to 63.4%). Ten of 35 patients (28.6%) had a greater than 75% decrease in PSA level. The median survival time was 11 months. The median survival duration of patients with a greater than 50% decrease in PSA level was 23 months, versus a median survival time of 7 months in patients without a PSA response (P = .02). Although 33% of cycles were associated with grade 4 neutropenia, febrile neutropenia occurred in only 7.8% of all cycles. Thrombocytopenia and anemia were rare. Nonhematologic toxicity was minimal. Patients who had received prior pelvic XRT had a lower Cy MTD, but their hematologic toxicity was not appreciably different.This is a well-tolerated, active regimen for the treatment of HRPC. Toxicity was not different in patients with prior pelvic XRT, although these patients had a lower MTD.

View details for Web of Science ID A1996UJ40300029

View details for PubMedID 8622080

Abstract

Flutamide withdrawal has been reported to be therapeutically efficacious for patients with hormone-refractory prostate cancer, with a reported prostate specific antigen (PSA) response rate of 29%.to evaluate the results of flutamide withdrawal in a large group of unselected patients, the medical records of 107 consecutive patients with metastatic prostate cancer who developed progressive disease while receiving flutamide therapy were reviewed retrospectively. Flutamide withdrawal was undertaken at the time of disease progression.Eighty-two patients were evaluable. Of these, three had a > 80% fall in PSA value, and another nine had a > 50% decrease, for a response proportion of 14.6% (95% confidence interval 7.8%-24.2%). The median response duration was 3.5 months (range, 1-12+ months). Eight of patients treated with combined androgen blockade at the time of diagnosis of metastatic disease had a response (14%), whereas 4/25 responses (16%) were noted in patients in whom flutamide was added later, at the time of first progression. When patients who responded were compared with patients who did not respond, there was not a significant difference in age, pretreatment PSA level, type of gonadal androgen deprivation, or the likelihood of prior combined androgen blockade versus late addition of flutamide. The duration of prior therapy with flutamide was longer in patients who responded (21.5 vs. 12.0 months).These findings confirm the flutamide withdrawal phenomenon in a large group of unselected patients, although its frequency is not as high as previously reported. In contrast to earlier reports, whether patients have had initial hormonal therapy with combined androgen blockade or monotherapy does not appear to be predictive of the likelihood of response to antiandrogen withdrawal.

View details for Web of Science ID A1995RY50600019

View details for PubMedID 8620419

Abstract

To determine whether an intravenous heparin dosing nomogram based on body weight achieves therapeutic anticoagulation more rapidly than a "standard care" nomogram.Randomized controlled trial.Two community teaching hospitals in Phoenix, Arizona, and Rochester, New York.One hundred fifteen patients requiring intravenous heparin treatment for venous or arterial thromboembolism or for unstable angina.Patients were randomized to the weight-based nomogram (starting dose, 80 units/kg body weight bolus, 18 units/kg per hour infusion) or the standard care nomogram (starting dose, 5000-unit bolus, 1000 units per hour infusion). Activated partial thromboplastin time (APTT) values were monitored every 6 hours, and heparin dose adjustments were determined by the nomograms.Activated partial thromboplastin times were measured using a widely generalizable laboratory method. The primary outcomes were the time to exceed the therapeutic threshold (APTT > 1.5 times the control) and the time to achieve therapeutic range (APTT, 1.5 to 2.3 times the control). Bleeding complications and recurrent thromboembolism were also compared.Kaplan-Meier curves for the primary outcomes favored the weight-based nomogram (P < 0.001 for both). In the weight-based heparin group, 60 of 62 patients (97%) exceeded the therapeutic threshold within 24 hours, compared with 37 of 48 (77%) in the standard care group (P < 0.002). Only one major bleeding complication occurred (in a standard care patient). Recurrent thromboembolism was more frequent in the standard care group; relative risk, 5.0 (95% CI, 1.1 to 21.9).The weight-based heparin nomogram is widely generalizable and has proved to be effective, safe, and superior to one based on standard practice.

View details for Web of Science ID A1993MD71100002

View details for PubMedID 8214998

Abstract

To characterize internists' dosing practices when administering and adjusting intravenous heparin regimens.A survey administered by physician-investigators.Two community teaching hospitals and one Veterans Affairs Medical Center.Sixty-one attending physicians in internal medicine.Physicians' choices of therapeutic activated partial thromboplastin time (APTT) range, initial heparin bolus, initial infusion dose, and dose/infusion adjustments when APTT levels are < 1.2 x control (< 35 seconds), 1.2-1.5 x control (35-45 seconds), 1.5-2.3 x control (46-70 seconds), 2.3-3.0 x control (71-90 seconds), and > 3.0 x control (> 90 seconds).Physicians' dosing decisions and therapeutic ranges during heparin treatment varied widely. Responses to nontherapeutic APTT levels had especially high coefficients of variation (0.67-0.81). Two groups of physicians, together comprising a majority of all respondents, use mutually exclusive therapeutic ranges (mean 44-56 seconds and 60-83 seconds). These two groups differ significantly in several types of dosing decisions.In the absence of generalizable standard guidelines for intravenous heparin therapy, internists' dosing practices vary widely. Because such practices may impede timely, effective anticoagulation, experimental studies comparing standardized dosing protocols are needed.

View details for Web of Science ID A1993MC43800003

View details for PubMedID 8271085