In cancer patients, the development of resistance to anti-angiogenic agents targeting the VEGF pathway is common. Increased pericyte coverage of the tumor vasculature undergoing VEGF targeted therapy has been suggested to play an important role in resistance. Therefore, reducing the pericytes coverage of the tumor vasculature has been suggested to be a therapeutic approach in breaking the resistance to and increasing the efficacy of anti-angiogenic therapies. To screen compound libraries, a simple in vitro assay of blood vessel maturation demonstrating endothelial cells and pericytes association while forming lumenized vascular structures is needed. Unfortunately, previously described 3-dimensional, matrix based assays are laborious and challenging from an image and data acquisition perspective. For these reasons they generally lack the scalability needed to perform in a high-throughput environment. With this work, we have developed a novel in vitro blood vessel maturation assay, in which lumenized, vascular structures form in one optical plane and mesenchymal progenitor cells (10T1/2) differentiate into pericyte-like cells, which associate with the endothelial vessels (HUVECs). The differentiation of the 10T1/2 cells into pericyte-like cells is visualized using a GFP reporter controlled by the alpha smooth muscle actin promoter (SMP-8). The organization of these vascular structures and their recruited mural cells in one optical plane allows for automated data capture and subsequent image analysis. The ability of this assay to screen for inhibitors of pericytes recruitment was validated. In summary, this novel assay of in vitro blood vessel maturation provides a valuable tool to screen for new agents with therapeutic potential.
Angiogenesis model; Pericyte; Imatinib; Sunitinib; Endoglin; Drug screening; Blood vessel maturation
Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible.
We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent prostate cancer after local therapy. Dose escalation occurred if a demethylating “response” [i.e. ≥10% decrease in peripheral blood mononuclear cell (PBMC) global 5meC content] was observed in <3 patients in cohort 1. Cohort 1 and 2 received disulfiram 250 mg and 500 mg daily respectively. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability.
Changes in global 5meC content were observed in 2 of 9 patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with 6 patients experiencing grade 3 AEs (3 per cohort). Three of the responders displayed pre-treatment instability in their 5meC content.
A minority of patients had transient global PBMC demethylation changes. Instability in 5meC may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.
Disulfiram; prostate cancer; epigenetics; demethylation; hypomethylation
Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5 years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents.
Metastatic castration-resistant prostate; cancer; Targeted therapies; Immune therapies; Molecular targets; Clinical trials; Drug development
Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non–clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.
Papillary renal cell carcinoma; mTOR; PTEN; AKT; S6; 4EBP1; HIF-1α
Although several new therapies have recently become available for the treatment of castrate-resistant prostate cancer (CRPC), the disease remains universally incurable and demands novel therapeutic approaches. To this end, great strides have been made in our understanding of the biologic and molecular mechanisms driving prostate cancer growth and progression in the past few years, resulting in widespread clinical investigation of numerous new targeted therapies. This review will highlight some of the key therapeutic agents that (in the opinion of the authors) may have the largest effect on the future management of CRPC, with a focus on both molecular targets and clinical trial design. These agents include angiogenesis inhibitors, mTOR pathway inhibitors, apoptosis-inducing drugs, IGF pathway inhibitors, Src family inhibitors, Hedgehog pathway antagonists, epigenetic therapies, PARP inhibitors, and prodrug approaches. The future of CRPC therapy appears brighter than ever before.
Clinical trials; CRPC; Drug development; Targeted therapy
High-dose interleukin-2 (HD IL-2) and interferon were the most commonly administered therapies before the recent introduction of targeted agents, including vascular endothelial growth factor and mammalian target of rapamycin pathway inhibitors. Although the new agents result in a progression-free survival benefit, high-dose IL-2 remains the only agent with proven efficacy in producing durable complete and partial responses in patients with metastatic renal cell carcinoma (RCC). Furthermore, although the use of single-agent interferon has decreased significantly since the introduction of targeted therapy, it remains in the frontline setting in combination with bevacizumab as a result of 2 large phase III trials. Lastly, improved understanding of immune regulation has led to the advancement of targeted immunotherapy using immune checkpoint inhibitors that have shown promising activity and are moving forward in clinical development. This article focuses on the current status of immunotherapy in the management of metastatic RCC.
Renal cell cancer; immunotherapy; interleukin; tumor immunity
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
While multiple therapies exist that prolong the lives of men with advanced prostate cancer, none are curative. This had led to a search to uncover novel targets for prostate cancer therapy, distinct from those of traditional hormonal approaches, chemotherapies, immunotherapies and bone-targeting approaches. The process of tumor angiogenesis is one target that is being exploited for therapeutic gain.
The most promising anti-angiogenic approaches for treatment of prostate cancer, focusing on clinical development of selected agents. These include VEGF-directed therapies, tyrosine kinase inhibitors, tumor-vascular disrupting agents, immunomodulatory drugs and miscellaneous anti-angiogenic agents. While none of these drugs have yet entered the market for the treatment of prostate cancer, several are now being tested in Phase III registrational trials.
The development of anti-angiogenic agents for prostate cancer has met with several challenges. This includes discordance between traditional prostate-specific antigen responses and clinical responses, which have clouded clinical trial design and interpretation, potential inadequate exposure to anti-angiogenic therapies with premature discontinuation of study drugs and the development of resistance to anti-angiogenic monotherapies. These barriers will hopefully be overcome with the advent of more potent agents, the use of dual angiogenesis inhibition and the design of more informative clinical trials.
angiogenesis; bevacizumab; cabozantinib; clinical trials; drug development; itraconazole; lenalidomide; prostate cancer; sunitinib; tasquinimod; vadimezan
The PatientViewpoint website collects patient-reported outcomes (PROs) and links them with the electronic health record to aid patient management. This pilot-test evaluated PatientViewpoint’s use, usefulness, and acceptability to patients and clinicians.
This was a single-arm prospective study that enrolled breast and prostate cancer patients undergoing treatment and the clinicians who managed them. Patients completed PROs every two weeks, and clinicians could access the results for patient visits. Scores that were poor relative to norms or substantially worse than the previous assessment were highlighted. After three on-study visits, we assessed patient and clinician perspectives on PatientViewpoint using close-ended and open-ended questions.
11/12 eligible clinicians (92%) and 52/76 eligible patients (68%) enrolled. Patients completed a median of 71% of assigned questionnaires; clinicians reported using the information for 79% of patients, most commonly as a source of additional information (51%). At the median, score reports identified 3 potential issues, of which 1 was discussed during the visit. Patients reported the system was easy to use (92%), useful (70%), aided recall of symptoms/side effects (72%), helped them feel more in control of their care (60%), improved discussions with their provider (49%), and improved care quality (39%). Patients and clinicians desired more information on score interpretation and minor adjustments to site navigation.
These results support the feasibility and value of PatientViewpoint. An ongoing study is using a continuous quality improvement approach to further refine PatientViewpoint. Future studies will evaluate its impact on patient care and outcomes.
KX2-391 is an oral non–ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC).
We treated 31 patients with oral KX2-391 (40mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50% success rate was predefined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption (urinary N-telopeptide [uNTx]; C-telopeptide [CTx]) and formation (bone alkaline phosphatase [BAP]; osteocalcin).
The trial closed early after accrual of 31 patients, due to a prespecified futility rule. PFS at 24 weeks was 8%, and median PFS was 18.6 weeks. The PSA response rate (≥30% decline) was 10%, and median PPFS was 5.0 weeks. Additionally, 18% of men with unfavorable (≥5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32% for uNTx, 21% for CTx, 10% for BAP, and 25% for osteocalcin. In pharmacokinetic studies, median Cmax was 61 (range 16–129) ng/mL, and median AUC was 156 (35–348) ng*hr/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea and constipation.
KX2-391 dosed at 40mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a Cmax of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.
KX2-391; prostate cancer; Src inhibitor; tubulin polymerization
This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC).
Patients with metastatic, pretreated CRC were treated at five dose levels.
Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8–36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs.
The recommended phase II dose (RP2D) is irinotecan 100mg/m2 i.v. days 1, 8; cetuximab 400mg/m2 i.v. days 1 and 250mg/m2 i.v. weekly; and sorafenib 400mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.
sorafenib; cetuximab; irinotecan; pharmacokinetics; colorectal cancer
Building on previous research documenting differences in preventive care quality between cancer survivors and noncancer controls, this study examines comorbid condition care.
Using data from the Surveillance, Epidemiology, and End Results (SEER) –Medicare database, we examined comorbid condition quality of care in patients with locoregional breast, prostate, or colorectal cancer diagnosed in 2004 who were age ≥ 66 years at diagnosis, who had survived ≥ 3 years, and who were enrolled in fee-for-service Medicare. Controls were frequency matched to cases on age, sex, race, and region. Quality of care was assessed from day 366 through day 1,095 postdiagnosis using published indicators of chronic (n = 10) and acute (n = 19) condition care. The proportion of eligible cancer survivors and controls who received recommended care was compared by using Fisher's exact tests. The chronic and acute indicators, respectively, were then combined into single logistic regression models for each cancer type to compare survivors' care receipt to that of controls, adjusting for clinical and sociodemographic variables and controlling for within-patient variation.
The sample matched 8,661 cancer survivors to 17,322 controls (mean age, 75 years; 65% male; 85% white). Colorectal cancer survivors were less likely than controls to receive appropriate care on both the chronic (odds ratio [OR], 0.88; 95% CI, 0.81 to 0.95) and acute (OR, 0.72; 95% CI, 0.61 to 0.85) indicators. Prostate cancer survivors were more likely to receive appropriate chronic care (OR, 1.28; 95% CI, 1.19 to 1.38) but less likely to receive quality acute care (OR, 0.75; 95% CI, 0.65 to 0.87). Breast cancer survivors received care equivalent to controls on both the chronic (OR, 1.06; 95% CI, 0.96 to 1.17) and acute (OR, 0.92; 95% CI, 0.76 to 1.13) indicators.
Because we found differences by cancer type, research exploring factors associated with these differences in care quality is needed.
Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.
Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT) <12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status.
49 patients were enrolled (14 ineligible), resulting in 35 pts for analysis. No PSA response was observed; best response was stable disease (n=28, 80.0%). Pre-treatment average slope was 0.19 log (PSA)/month (PSADT=3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT=5.44 months) using linear mixed effects models (p=0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (p=0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (p=0.09).
Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non-randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated.
Epidermal growth factor receptor; tyrosine kinase inhibitors; clinical trial
A noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole was conducted in men with metastatic prostate cancer.
The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer.
Patients and Methods.
We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses.
The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema.
High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression.
Itraconazole; Prostate cancer; Angiogenesis; Hedgehog pathway
Association between the pretreatment neutrophil-to-lymphocyte ratio and outcome of patients with metastatic castration-resistant prostate cancer treated with ketoconazole was assessed. The pretreatment neutrophil-to-lymphocyte ratio and prostate-specific antigen doubling time, and prior response to androgen-deprivation therapy, were associated with the progression-free survival interval in these patients.
The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole.
This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis.
Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups.
In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.
Ketoconazole treatment; Metastatic castration-resistant prostate cancer; Neutrophil-to-lymphocyte ratio; Outcome; Predictive nomogram
Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-Lcysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa.
Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time- activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1.
Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (µGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 µSv/MBq (mean ± SD).
Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.
prostate-specific membrane antigen; prostate cancer; 18F; urea; PET/CT
Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.
To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants).
PATIENTS AND METHODS
Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed.
All patients received docetaxel either as clinical trial participants (n = 142; 11 separate studies) or as non-participants (n = 105).
Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation.
There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage.
Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P = 0.027) among trial participants vs non-participants.
Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial.
Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers’ attitudes because of greater contact with medical services.
With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes.
prostate cancer; chemotherapy; clinical trial; metastatic castration-resistant prostate cancer; docetaxel; overall survival
Prostate cancer is the most common male cancer. Survival rates are high, making preventive care maintenance important. Factors associated with prostate-cancer cases’ preventive care in the short-term (Year 1) and long-term (Year 5), and how survivors’ care compares to non-cancer controls, require study.
This retrospective, controlled SEER-Medicare study included loco-regional prostate cancer cases age ≥66 in fee-for-service Medicare diagnosed in 2000 and surviving ≥12 months, and non-cancer controls matched to cases on socio-demographics and survival. Outcomes included influenza vaccination, cholesterol screening, and colorectal cancer screening. Independent variables were number of physician visits, physician specialties visited, initial prostate cancer treatment, socio-demographic characteristics, and case–control status.
There were 13,507 cases and 13,507 controls in Year 1, and 10,482 cases and 10,482 controls in Year 5. In Years 1 and 5, total number of visits (6/6 outcomes) and primary care provider (PCP) visits (5/6 outcomes) were most consistently associated with preventive care receipt. In Year 1, prostate cancer cases were more likely than controls to receive influenza vaccination (48% vs. 45%) but less likely to receive colorectal cancer screening (29% vs. 31%) (both p<0.0001). In Year 5, prostate cancer cases remained more likely than controls to receive influenza vaccination (46% vs. 44%; p<0.0001).
Differences in survivors’ short-term preventive care did not lead to worse long-term preventive care. The number of physician visits, particularly PCP visits, are important factors associated with appropriate care.
Implications for Cancer Survivors
PCP involvement in prostate cancer patients’ care is critical both during treatment and for long-term survivors.
Prostate cancer; Preventive care; Survivorship
There is increased interest in using patient-reported outcome (PRO) measures in routine clinical practice to improve patient management. The effectiveness of this intervention may be facilitated by providing suggestions to clinicians on how to address issues identified by the PROs. We sought to develop recommendations for clinicians on how to respond to issues covered by common cancer PRO questionnaires, including functional problems (eg, physical, social, emotional), symptoms (eg, diarrhea, pain), and needs (eg, patient care and support, information). The recommendations would be incorporated into a Web-based system for PRO assessment and reporting in use at our large, academic cancer center. To develop the recommendations, we conducted a multiphase, multidisciplinary, consensus process. We reviewed the literature and conducted one-on-one interviews with experts from various disciplines. Experts included medical oncologists, radiation oncologists, nurses, an internist, a palliative care specialist, an outcomes researcher, a chaplain, a social worker, and patient advocates. These interviews elicited the experts’ recommendations for addressing problems in common PRO domains. Finally, we held a panel meeting attended by all the experts to attain consensus on the recommendations. The final consensus suggestions recommend further assessment of the problem as a first step. Treatment suggestions range from medication adjustments to lifestyle modifications, to referrals to other disciplines. Further research will test whether clinicians find these suggestions useful for patient management.
patient-reported outcomes; clinical practice; guidelines; palliative care; symptom management
Ixabepilone is an epothilone B analogue with activity in a variety of solid malignancies, including prostate cancer. The main dose-limiting toxicity of ixabepilone is myelosuppression when administered by using an every 3-week schedule. Here we evaluate the activity of a weekly ixabepilone in men with metastatic castrate-resistant prostate cancer to minimize hematologic toxicity.
BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistant cancer cell lines. Here we report the activity and toxicity of ixabepilone, administered by using a weekly schedule, in men with metastatic castrate-resistant prostate cancer (CRPC).
Patients with metastatic CRPC received ixabepilone at 20 mg/m2 intravenous weekly × 3, in 4-week cycles. This noncomparative study stratified patients to either a chemotherapy naive (CN), prior taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The primary endpoint was prostate-specific antigen response by using PCWG (Prostate Cancer Working Group) 1 criteria. Secondary endpoints included radiographic response when using RECIST (Response Evaluation Criteria In Solid Tumors).
In total, 124 patients were enrolled, of whom, 109 were eligible (35 CN, 42 Tax, and 32 TCx) for the primary response determination in this study. Prostate-specific antigen responses were seen in 12 (34.3%) of 35, 12 (28.6%) of 42, and 7 (21.9%) of 32 patients with the partial objective response in 5 (22.7%) of 22, 2 (8.0%) of 25, and 0 (0.0%) of 24 patients for the CN, Tax, and TCx arms, respectively. Significant (grade 3/4) neutropenia was seen in 6 (15.4%), 7 (14.6%), and 9 (25.0%); and grade 3/4 sensory neuropathy was seen in 8 (20.5%), 12 (25.0%), and 12 (33.3%) for CN, Tax, and TCx, respectively. Grade 3/4 thrombocytopenia was infrequent and seen in only one patient on the CN and the TCx arm.
Ixabepilone was found to have an acceptable toxicity profile when administered by using a weekly schedule with less myelosuppression compared with prior studies when using the every 3-week schedule. Single-agent activity was observed and met prespecified activity levels for the Tax treated arm.
BMS-247550; Chemotherapy; Epothilone; Microtubule-inhibitor
A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m2 intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity.
In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005).
Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.
We retrospectively explored changes in immunological parameters in men with biochemically recurrent prostate cancer treated with either 5mg or 25mg of lenalidomide in a randomized phase 2 trial, and determined whether those changes correlated with disease progression.
Cytokine levels were compared for each patient at baseline and after 6 months of treatment with lenalidomide. Regression models for correlated data were used to assess associations of cytokine levels with lenalidomide treatment effect. Estimates were obtained using generalized estimating equations (GEE). Changes in circulating anti-prostate antibodies were evaluated using a high-throughput immunoblot technique.
Treatment with lenalidomide was associated with global changes in immune-reactivity to a number of prostate-associated antigens, as well as with changes in circulating levels of the TH2 cytokines IL-4, IL-5, IL-10 and IL-13. Disease progression in treated patients was associated with an increase in circulating IL-8 levels, while IL-8 levels decreased significantly in non-progressors.
Lenalidomide demonstrates immunomodulatory properties in patients with biochemically recurrent prostate cancer. The induction of novel anti-prostate antibodies is a potential mechanism for lenalidomide response. Changes in serum IL-8 levels may serve as a potential biomarker in treated patients. These hypotheses require formal testing in future prospective trials.
prostate cancer; antibody; cytokine; IL-8; lenalidomide
Several phase II trials in men with non-castrate PSA-recurrent prostate cancer have assessed the impact of novel non-hormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS).
We performed a retrospective post hoc analysis of 146 men treated in four phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n=39), imatinib (a tyrosine kinase inhibitor; n=25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n=22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n=60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation.
After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P=.05), baseline PSA slope (P=.01), on-study change in PSADT (P=.02), and on-study change in PSA slope (P=.03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% CI 34.6–not reached) and 28.9 months (95% CI 13.5–68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively.
This hypothesis-generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically-recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate endpoint for screening new agents in these patients.