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BACKGROUND EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC). METHODS Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy. RESULTS 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600 mg given once daily and 1800 mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of

Background Dysregulation of histone deacetylases (HDACs) is common in cancer and is critical to the development and progression of the majority of tumors. This first-in-human Phase Ia study assessed the safety, efficacy, and pharmacokinetics (PK) of OBP-801, a cyclic depsipeptide class I HDAC inhibitor. Methods Adult patients with advanced solid tumors were treated in 3 dose cohorts (1.0 mg/m2, 2.0 mg/m2 or 2.8 mg/m2) of OBP-801 that was administered via intravenous infusion weekly. Initially, an accelerated titration design was used that was followed by a 3 + 3 dose escalation strategy. Primary objective was assessment of safety. Secondary objectives included determination of PK and objective response rate. Results Seventeen patients were enrolled, of which 8 patients were evaluable for efficacy. Drug-related ≥ Grade 3 treatment-emergent adverse events included abdominal pain, anemia, fatigue, gamma glutamyl-transferase increase, hypertriglyceridemia and vomiting. No dose-limiting toxicity was observed in the 1.0 mg/m2 cohort. The PK data showed that OBP-801 and its active metabolite OBP-801-SH exposure increased proportionally and more than proportionally, respectively. No accumulation of either agent was noticed after repeat administration. Best response was stable disease (37.5%), with one patient each in the three cohorts. Conclusion Further investigations of the OBP-801 1.0 mg/m2 dose will be needed to better understand the efficacy of the agent, either alone or in combination. Trial registration: NCT02414516 (ClinicalTrials.gov) registered on April 10, 2015.

To assess the technical feasibility and outcomes of adrenal metastases cryoablation. This is an IRB approved retrospective review of adrenal metastases cryoablation between April 2003 and October 2018. Forty percutaneous cryoablation procedures were performed on 40 adrenal metastases in 34 patients. Histology, tumor size, ablation zone size, major vessel proximity, local recurrences, complications, and anesthesia-managed hypertension monitoring was collected. Complications were graded according to the Common Terminology of Complications and Adverse Events (CTCAE). Mean tumor and ablation size was 3.2 cm and 5.2 cm, respectively. Local recurrence rate was 10.0% (N = 4/40) for a mean follow-up time of 1.8 years. Recurrences for tumors > 3 cm (21.0%, N = 4/19) was greater than for tumors ≤ 3 cm (0.0%, N = 0/21) (p = 0.027). Proximity of major vasculature (i.e., IVC & aorta) did not statistically effect recurrence rates (p = 0.52), however, those that recurred near vasculature were > 4 cm. Major complication (≥ grade 3) rate was 5.0% (N = 2/40), with one major complication attributable to the procedure. Immediate escalation of blood pressure during the passive stick phase (between freeze cycles) or post procedure thaw phase was greater in patients with residual adrenal tissue (N = 21/38) versus masses replacing the entire adrenal gland (N = 17/38), (p = 0.0020). Lower blood pressure elevation was noted in patients with residual adrenal tissue who were pre-treated with alpha blockade (p = 0.015). CT-guided percutaneous cryoablation is a safe, effective and low morbidity alternative for patients with adrenal metastases. Transient hypertension is related only to residual viable adrenal tissue but can be safely managed and prophylactically treated.

Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. Methods We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Results Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. Conclusions This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. Clinical trials registration NCT01987362.

BackgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).MethodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16.ResultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).ConclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group.Trial registrationThis study was registered in the ClinicalTrials.gov website (NCT 02070549) on February 25, 2014. .

With the decrease in PSA screening based on the 2011 United States Preventive Services Task Force guidelines and the potential approval of highly sensitive imaging techniques over the next few years, we are likely to see an increasing trend of metastatic prostate cancer diagnosis. Traditional therapy for nonmetastatic prostate cancer (nmPC) has consisted of androgen deprivation therapy (ADT) followed by other hormonal therapy maneuvers, such as anti-androgen withdrawal, herbal preparations, low dose steroids, or ketoconazole. Androgen receptor-axis-targeted therapies (ARAT) were previously only approved for patients with metastatic castration resistant prostate cancer (mCRPC). This has recently changed after reporting of results from the SPARTAN and PROSPER trials, which were conducted in nonmetastatic CRPC (nmCRPC) patients. These studies demonstrated improved metastasis-free survival with apalutamide and enzalutamide, each compared to placebo in a double blind randomized setting. In 2017, the LATITUDE and STAMPEDE studies demonstrated marked survival benefit with early abiraterone and prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) in addition to ADT. Other second-generation AR antagonists are currently in phase 3 trials in mHSPC and nmCRPC. This article summarizes the key clinical trials that led to FDA approval of ARAT in the mHSPC and nmCRPC settings and highlights potential limitations, future directions, and treatment-algorithms when selecting patients for early therapy in mHSPC and NMPC.

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naive PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains-in particular, Ki67 and CyclinD1-when presented with such cases in their day to day clinical practice.

Due to the rapidly changing field of kidney cancer therapeutics, addressing the state of the art systemic therapy regimens, and sequencing with cytoreductive nephrectomy are the primary focus of this review. We will also discuss the role of biomarkers and novel therapeutic targets in the management of renal cell carcinoma. The management of metastatic renal cell cancer has undergone a paradigm shift with immune checkpoint inhibitors being used in the frontline setting. Over the last 4 years, programmed cell death-1 (PD-1) inhibitors as well as programmed cell death ligand-1 inhibitors have become available in various combinations with cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors and tyrosine kinase inhibitors (TKIs). These drugs have improved outcomes in patients with renal cell cancer and more work is being done to refine these targets as well as discover newer ones. Despite the availability of several new treatment options, some questions that still need to be addressed in the management of kidney cancer include the sequencing of treatment options, treatment of patients who progress on immune checkpoint inhibitors, and role of biomarkers to ascertain the best treatment options to minimize costs and improve outcomes.

PURPOSE: We conducted a pilot trial utilizing [(18)F]FMAU [1-(2′-deoxy-2′-[(18)F]fluoro-β-d-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [(18)F]FMAU-PET scans (about 1 week apart, range 2–12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0–1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09–2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.

INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In pre-clinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising pre-clinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

Background Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function. Methods Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56 mg/m2 doses. Results The majority of patients enrolled in this study had solid tumors (n = 44) vs. MM (n = 2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0–last, respectively (27 mg/m2 dose); increases at the 56 mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities. Conclusions In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20–50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure–response relationship of carfilzomib. Trial registrationhttp://clinicaltrials.gov NCT01949545; date of registration: September 6, 2013

Cabozantinib was approved by the FDA in April 2016 for the treatment of advanced renal cancer, pretreated with at least one prior antiangiogenic therapy. This is the first agent in the therapy of kidney cancer to show a statistically significant improvement in all three endpoints of clinical efficacy, response rate, progression free survival, and overall survival (OS), in a phase III randomized trial. The reporting of METEOR coincided with that of the Checkmate 025 study which randomized similarly eligible patients to receive nivolumab or everolimus 10 mg daily. As the drug development has occurred in parallel for cabozantinib and nivolumab, no evidence exists for decision making regarding optimal sequencing of these agents. A third option of lenvatinib and everolimus was also rapidly approved based on a phase II randomized trial demonstrating promising magnitude of improvement in response, progression-free survival (PFS), and OS. The differences in toxicity profiles, duration and toxicities of prior therapy, presence of brain metastases, concomitant immunosuppressive therapies, or autoimmune conditions are the factors that are taken into account when choosing therapy. The patients who have demonstrated response, prolonged clinical benefit and tolerability, and with anti-VEGF therapy are likely to benefit from continued antiangiogenic activity combined with MET and HGF inhibition with cabozantinib at progression. The patients who have intolerance or poor response to anti-VEGF TKI should be switched to nivolumab as the preferential therapy of choice. Clearly, better predictors are required to aid in guiding therapeutic decisions. The CABOSUN trial will likely shift the entire paradigm. The CABOSUN trial demonstrated superior PFS and response rates favoring cabozantinib as compared to sunitinib in untreated, intermediate, or poor-risk RCC and can be predicted to become the front-line therapy of choice. Immune-based regimens such as the combinations of nivolumab + ipilimumab and bevacizumab + atezolizumab have completed phase III trials, comparing to sunitinib, and results are awaited. In the future, a similar clinical dilemma will be shifted to the front-line therapy and the nuances of trial eligibility, and patient comorbidities will remain important factors. Optimal sequencing and predictive biomarkers are the questions that need to be incorporated in future clinical trials within RCC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (PCONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

There are many active drugs to treat metastatic renal cell carcinoma (mRCC) patients who progress through their first-line vascular endothelial growth factor (VEGF) inhibitor. Many clinicians choose a second-line VEGF inhibitor based on the type of response to first-line VEGF inhibitor, without data supporting this practice. This study was conducted to determine the association of response to second-line VEGF inhibitor with response to first-line VEGF inhibitor. All mRCC patients in participating centers of the International mRCC Database Consortium who were treated from January 2004 through June 2011 with a second-line VEGF inhibitor after failure of a different first-line VEGF inhibitor were retrospectively identified. The primary outcome is objective response rate (ORR) and the secondary outcome is progression-free survival (PFS) in each line of therapy. Of 1,602 total database patients, 464 patients received a first- and second-line VEGF inhibitor. The ORR to first-line therapy was 22 %, and the ORR to second-line therapy was 11 %. The ORR to second-line therapy was not different among patients achieving partial response versus stable disease versus progressive disease to first-line therapy (14 % vs. 10 % vs. 11 %, respectively; chi-squared trend test p = 0.17). The median PFS on first-line VEGF-targeted therapy was 7.5 months (95 % CI, 6.6-8.1), and the median PFS on second-line VEGF inhibitor was 3.9 months (95 % CI, 3.6-4.5). There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p = 0.59). The clinical response to a second-line VEGF inhibitor is not dependent on response to the first-line VEGF-inhibitor. Further studies are needed to define clinical parameters that predict response to second-line therapy to optimize the sequence of VEGF-targeted therapy in metastatic RCC patients.

The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected.

Advanced bladder/urothelial cancer remains an incurable terminal disease, and accounts for 3% of the cancer related mortality in the United States. Systemic chemotherapy achieves palliation, survival benefit, and occasional long-term remissions. The two regimens that have been widely adopted consist of either cisplatin and gemcitabine, or the MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen. Novel therapies are being evaluated in metastatic bladder cancer to improve survival outcomes. A randomized trial of larotaxel (a novel taxane) and cisplatin vs cisplatin and gemcitabine in frontline therapy of metastatic urothelial cancer is ongoing. The studies evaluating therapies targeted frontline involve cisplatin and gemcitabine with or without cetuximab (ongoing), and with or without bevacizumab (CALGB proposed trial). With the advent of adjuvant/neoadjuvant cisplatin-based therapy, and improvement in supportive care, more patients are being considered for second-line therapies in urothelial cancer thus making this a field of emerging importance. The only phase III trial in pretreated urothelial cancer compared vinflunine with best supportive care, and revealed no significant survival improvement. Clinical trials are ongoing with pazopanib, a VEGF inhibitor, and Zactima, a VEGF and EGFR inhibitor. The biggest hurdle to progress in advanced bladder cancer has been the slow accrual to studies in the United States. Making clinical trial participation a priority in bladder cancer is the dire need of the moment. At the same time, it is essential to take into account the changing needs of the population afflicted with bladder cancer, and tailor the therapeutic trials to fit a contemporary patient.

The cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to chemotherapy. A Phase-II study was undertaken to determine the activity of a dose attenuated schedule of irinotecan, capecitabine, and the COX-2 inhibitor celecoxib in patients with advanced colorectal cancer.The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum that was metastatic. Patients received a combination of irinotecan 70 mg/m2 over 30 min I.V. on days 1 and 8, capecitabine 1,000 mg/m2 twice per day orally on days 1-14, and celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days.Fifty-one patients were enrolled (median age 58 years; M : F 31 : 20). The objective response rate was 21/51 = 41% [95% confidence intervals (CI), 0.28-0.55]. The median time to progression was 7.7 months (95% CI, 6.2-8.6 months). Median survival time and probability of survival at 1 year were 21.2 months (95% CI, 13.8-n/a), and 75% (95% CI, 0.63-0.88), respectively. The major toxicity was Grade 3 or 4 diarrhea, seen in 24 and 10% of patients, respectively. There were no treatment related deaths.The lower dose intensity of irinotecan appeared to maintain activity and improve tolerability when combined with capecitabine. The addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of this doublet based on the RECIST criteria for objective response.

To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial.Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function.Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months.The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Summary Background .P ancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m 2 over 100 minutes, cisplatin 35 mg/m 2 I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results .T wenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9 ). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6‐7.6 months). The probability of survival at 6 months was 46% (90% CI, 27‐62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Purpose: Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods: Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status ≦2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m2 twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results: Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion: Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.

FMAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine) is a thymidine analog that can be phosphorylated by thymidine kinase and incorporated into DNA. This first-in-human study of [18F]FMAU was conducted as a pilot in patients to determine its biodistribution and suitability for imaging DNA synthesis in tumors using positron emission tomography (PET).Fourteen patients with diverse cancers (brain, prostate, colorectal, lung, and breast) were imaged with [18F]FMAU. We obtained dynamic PET images for 60 min and a whole-body image. Blood and urine samples were analyzed by high-performance liquid chromatography to measure metabolites and clearance.Active tumors in the breast, brain, lung and prostate were clearly visualized with standardized uptake values (SUVs) of 2.19, 1.28, 2.21, and 2.27-4.42, respectively. Unlike with other tracers of proliferation, low uptake of [18F]FMAU was seen in the normal bone marrow (SUV(mean) 0.7), allowing visualization of metastatic prostate cancer (SUV 3.07). Low background was also observed in the brain, pelvis, and thorax, aside from heart uptake (SUV 3.36-8.78). In the abdomen, increased physiological uptake was seen in the liver (SUV 10.07-20.88) and kidneys (SUV 7.18-15.66) due to metabolism and/or excretion, but the urinary bladder was barely visible (SUV(mean) 2.03). On average, 95% of the activity in the blood was cleared within 10 min post injection and an average of 70% of the activity in the urine was intact FMAU at 60 min post injection.Tumors in the brain, prostate, thorax, and bone can be clearly visualized with FMAU. In the upper abdomen, visualization is limited by the physiological uptake by the liver and kidneys.

Objective: The purpose of this study is to examine differences in survival after diagnosis with distant stage prostate cancer by decade of diagnosis. Methods: Subjects are 3337 Caucasian and 1947 African-American men with newly diagnosed primary distant stage prostate cancer between 1973 and 1997, with follow-up through 2001, from the Detroit SEER registry. The proportion of men within each category of each variable of interest is calculated. Relative survival is used to examine survival patterns over time. Kaplan–Meier and Cox proportional hazard models are also used to examine the relationship between decade of diagnosis and survival between short term (≤24 months) and long term (>24 months) survivors. Results: Relative survival has increased over the past three decades although this trend is not statistically significant. Relative survival is similar by race and decreases with increasing grade of tumor. Survival for men living ≤24 months after diagnosis is similar over time. However, for men living >24 months after diagnosis, there is a significant difference over time (p 24 months) that are the primary contributors to this difference in survival by decade of diagnosis.

Renal cancer is a malignancy that has been rising in incidence over the past 5 decades. The treatment of choice for localized cancer is radical nephrectomy, although nephron-sparing surgery can be considered in selected cases with small tumors. The risk of recurrence or metastatic disease ranges from 15 to 80%. Some of the factors predictive of prognosis are histology, stage, and grade of the cancer. Metastatic or stage IV disease is the major cause of mortality. The treatment of choice for metastatic disease is surgical resection of metastases, if feasible, as it can result in prolonged remissions in a small proportion of patients (10–20%). The results of randomized trials demonstrated a survival benefit with nephrectomy in metastatic disease. Consequently, this should be a consideration in patients with good functional status prior to immunotherapy. Adjuvant therapy has no proven role in renal cancer. The approved systemic immunotherapy is interleukin-2 (IL-2) with a reported overall response rate of 15% and durable remission rate of 7%. The wide application of IL-2 is limited by the severe toxicity profile. Thus, the use of IL-2 is restricted to patients with excellent performance status. Less toxic doses, schedules, and routes of administration of IL-2 have demonstrated responses in metastatic disease, but prolonged remission has not been clearly established. Cytotoxic chemotherapy has not shown promising results to date; however, novel cytotoxic agents and combinations are in the clinical evaluation phase. Biochemotherapy regimens, such as combinations of gemcitabine and capecitabine with IL-2 and interferon, have shown responses ranging from 15 to 40% with 10 to 15% complete remissions which, although favorable, have not resulted in major improvements in overall survival. In a preliminary study, allogeneic mini transplant produced responses in 10 of 19 patients with metastatic disease: three complete and seven partial remissions. However, the 10 to 20% treatment-related mortality associated with mini transplant, excellent performance status requirement, and low availability of matched donor, in this highly selected group of patients, indicates that this would be feasible in

In the field of advanced prostate cancer, a number of therapeutic agents are now available. The sequence of administration of medications with distinct mechanisms of action, toxicities and efficacies, will have a critical role in disease outcomes. The identification of biomarkers predicting response will help to determine the appropriate therapeutic sequence.