Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science.

BACKGROUND: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL). METHODS: This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010. RESULTS: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population. CONCLUSIONS: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

Interpretation of fluorescence correlation spectra of biopolymer solutions.

Fluorescence correlation spectroscopy (FCS) is regularly used to study diffusion in non-dilute "crowded" biopolymer solutions, including the interior of living cells. For fluorophores in dilute solution, the relationship between the FCS spectrum G(t) and the diffusion coefficient D is well-established. However, the dilute-solution relationship between G(t) and D has sometimes been used to interpret FCS spectra of fluorophores in non-dilute solutions. Unfortunately, the relationship used to interpret FCS spectra in dilute solutions relies on an assumption that is not always correct in non-dilute solutions. This paper obtains the correct form for interpreting FCS spectra of non-dilute solutions, writing G(t) in terms of the statistical properties of the fluorophore motions. Approaches for applying this form are discussed.

A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy.

BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination.

Interpretation of quasielastic scattering spectra of probe species in complex fluids.

The objective of this paper is to correct an error in analyses of quasielastic scattering spectra. The error invokes a valid calculation under conditions in which its primary assumptions are incorrect, which results in misleading interpretations of spectra. Quasielastic scattering from dilute probes yields the incoherent structure factor g((1s))(q, t) = , with q being the magnitude of the scattering vector q and Δx(t) being the probe displacement parallel to q during a time interval t. The error is a claim that g((1s))(q, t) ~ exp (-q(2)<(Δx(t))(2)>∕2) for probes in an arbitrary solution, leading to the incorrect belief that <(Δx(t))(2)> of probes in complex fluids can be inferred from quasielastic scattering. The actual theoretical result refers only to monodisperse probes in simple Newtonian liquids. In general, g((1s))(q, t) is determined by all even moments <(Δx(t))(2n)>, n = 1, 2, 3, ... of the displacement distribution function P(Δx, t). Correspondingly, <(Δx(t))(2)> cannot in general be inferred from g((1s)) (q, t). The theoretical model that ties g((1s))(q, t) to <(Δx(t))(2)> also quantitatively determines exactly how <(Δx(t))(2)>∕2) must behave, namely, <(Δx(t))(2)> must increase linearly with t. If the spectrum is not a single exponential in time, g((1s))(q, t) does not determine <(Δx(t))(2)>.

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery - the SAVE-HIP3 study.

There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

Probe dynamics constraints on theoretical models for polymer dynamics.

Measurements of diffusion and driven motion by probe particles in polymer solutions constrain theoretical models of polymer solution dynamics. In this paper, motions of large, intermediate (smaller than a polymer chain, larger than a solvent molecule), and small (solvent, ion) probes through polymer solutions and viscous small-molecule solvents are analyzed. The resulting constraints limit the physical models that can plausibly be used to describe polymer motion and separately limit the mathematical structures that might be used to obtain quantitative predictions from those models. A transition in small-molecule mobility through polymer solutions, at polymer concentrations near 400 g/l, is explained in terms of the size of a solvent molecule relative to the gaps between pairs of chain segments on adjacent polymer molecules.

Position-displacement correlations in QELSS spectra of non-dilute colloids.

This paper examines relationships between the quasielastic light scattering spectrum S(q, t) and the distribution functions for particle displacements over various times. For dilute probes in a complex, non-scattering fluid, S(q, t) is determined by the even moments of the one-particle displacement distribution function P(X, t). For concentrated scattering particles, S(q, t) is not determined by P(X, t). Instead, S(q, t) is determined in part by P(X, t) and in part by a spatial Fourier transform of the two particle displacement distribution function P(2)(X, t, R(12)). Here, X is the displacement of particle 1 during t, and R(12) is the component (at t = 0), parallel to the scattering vector q, of the vector from particle 1 to a second particle 2.

Capillary zone electrophoresis and polymer dynamics.

Capillary electrophoresis with a polymer solution support medium is a well-established powerful analytical tool. This paper discusses a possible alternative application of capillary electrophoresis, namely a path for studying the dynamics of polymer solutions. The key to the approach is an inversion of perspective. Instead of treating the migrating species as the object of experimental importance and the support medium as being of importance only because it facilitates separations, one treats the polymer solution as being of experimental importance, and the choice of migrating species as being of interest only because different species may probe different aspects of polymer dynamics.

Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial.

BACKGROUND: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate. RESULTS: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m(2) and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively. CONCLUSION: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC.

Polymer segmental cross correlations from dielectric relaxation spectra of block copolymers.

Dielectric relaxation spectra of solutions of block polymers containing sequential type-A dipoles are considered from a theoretical correlation-function standpoint. Spectra of a specific set of block copolymers can be combined to isolate the dynamic cross-correlation between the motions of two distinct parts of the same polymer chain. Unlike past treatments of this problem, no model is assumed for the underlying polymer dynamics.

Optimizing the use of docetaxel in men with castration-resistant metastatic prostate cancer.

In 2009, castration-resistant metastatic prostate cancer continues to account for more deaths in US men than any other cancer apart from lung cancer. Although novel targeted molecular, hormonal and immunologic agents are accelerating in their development in this disease, docetaxel and prednisone remain the standard palliative regimen for the majority of men who have progressed despite hormonal therapies. Thus, understanding the practical and often subtle issues of docetaxel initiation, duration of therapy, cessation of therapy and treatment holidays is critical for the informed use of this US Food and Drug Administration-approved regimen. In this review we address these topics in light of prognostic and predictive factors to help guide the rational use of docetaxel chemotherapy in men with this aggressive disease.

Systemic strategies for prostate cancer.

Systemic therapy beyond hormonal therapy for advanced prostate cancer includes chemotherapy, antiangiogenic therapy, signal transduction inhibitors, immunomodulatory therapy, and other experimental therapeutics. This review will discuss the state of systemic therapy for advanced prostate cancer in 2007, with an emphasis on therapy in the neoadjuvant, adjuvant, and metastatic setting. As chemotherapy gains greater acceptance in the urologic oncology community for use in men with hormone-refractory disease, evaluating the role of systemic therapy in earlier disease states is essential given the success in other solid tumors for advancing cure rates. Current randomized phase III trials worldwide are addressing these questions in each disease state, and are anticipated to change the landscape of prostate cancer management for years to come. In this discussion, we will emphasize those agents that are currently being evaluated in phase II and III trials, with an emphasis on those trials that are likely to impact the standard of care in the near future. The collection of tumor or surrogate tissue is emphasized to define biomarkers that may predict for sensitivity to these systemic therapies.

Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate.

To determine the timing and patterns of late recurrence after radical prostatectomy (RP) alone or RP plus adjuvant radiotherapy (RT). Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have positive surgical margins, extracapsular extension and/or seminal vesicle invasion. Of these, 46 received adjuvant RT and 113 did not. The RT group generally received 45-50 Gy to the whole pelvis, then a boost to the prostate bed (total dose of 55-65 Gy). In the RP group, 62% received neoadjuvant/adjuvant androgen deprivation vs 17% in the RT group. Patients were analyzed with respect to timing and patterns of failure. Only one patient was lost to follow-up. The median follow-up for surviving patients was nearly 20 years. The median time to failure in the surgery group was 7.5 vs 14.7 years in the RT group (P=0.1). Late recurrences were less common in the surgery group than the RT group (9 and 1% at 10 and 15 years, respectively vs 17 and 9%). In contrast to recurrences, nearly half of deaths from prostate cancer occurred more than 10 years after treatment. Deaths from prostate cancer represented 55% of all deaths in these patients. Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with locally advanced tumors, reflecting the need for more effective therapy.

Enhanced septahedral ordering in cold Lennard-Jones fluids.

We report molecular dynamics calculations on a two-component, cold, 15,625 particle, three-dimensional Lennard-Jones fluid. We calculated spherical harmonic components Q(LM) for the density of particles in the first coordination shell of each particle, as well as their spherical invariants , time-correlation functions, and wavelet density decompositions. The spherical invariants show that noncrystalline septahedral () ordering is important, especially at low temperature. While < Q210> could arise from icosahedral ordering, its behavior so closely tracks that of the nonicosahedral that alternative origins for need to be considered. Time correlation functions of spherical harmonic components are bimodal, with a faster temperature-independent mode and a slow, strongly temperature-dependent mode. Volume wavelet decompositions show that when T is reduced, the correlation length of increases, especially below T=0.7 , but that the correlation length of is independent of T .

Interpretation of light-scattering spectra in terms of particle displacements.

Quasielastic light-scattering spectroscopy is regularly used to examine the dynamics of dilute solutions of diffusing mesoscopic probe particles in fluids. For probes in a simple liquid, the light-scattering spectrum is a simple exponential; the field correlation function g(1)(q,tau) of the scattering particles is related to their mean-square displacements X2 identical with [(delta x(tau))2] during tau via g(1)(q,tau) = exp(-1/2 q2X2). However, demonstrations of this expression refer only to identical Brownian particles in simple liquids and show that if the form is correct then it is also true for all tau that g(1)(q,tau) = exp(-gamma tau), a pure exponential in tau. In general, g(1)(q,tau) is not a single exponential in time. A correct general form for g(1)(q,tau) in terms of the X(2n), replacing the incorrect exp(-1/2 q2X2), is obtained. A simple experimental diagnostic determining when the field correlation function gives the mean-square displacement is identified, namely, g(1)(q,tau) only reveals X2 if g(1)(q,tau) is a single exponential in tau. Contrariwise, if g(1)(q,tau) is not a single exponential, then g(1)(q,tau) depends not only on X2 but on all higher moments X(2n). Corrections to the crude approximation g(1)(q,tau) = exp(-1/2 q2X2) closely resemble the higher spectral cumulants from a cumulant expansion of g(1)(q,tau).

Extended-range order, diverging static length scales, and local structure formation in cold Lennard-Jones fluids.

We report molecular-dynamics simulations on a three-dimensional, two-component Lennard-Jones fluid. We used 125 000 particles (equal numbers of A and B) at density N/V=1.29 and 34 temperatures T covering 5 x 10(4) > or =T > or =0.56. The pair potential was 4epsilon[(sigma(ij)/r)(12)-(sigma(ij)/r)(6)] with sigma(AA)=1, sigma(AB)=11/12, and sigma(BB)=5/6. We computed specific and generic radial distribution functions g(ij)(r), and several density-momentum dynamic correlation functions whose static (t=0) parts vanish by symmetry. Evidence is presented that our systems were adequately annealed to eliminate remnant initial order and were adequately equilibrated at each temperature. Static spatial correlations in cold Lennard-Jones liquids have longer ranges than are often reported: g(r)-1 unequal to 0 is found out to r > or =7 at T=2 and out to r > or =10 at T=0.56. |g(r)-1| has an envelope function that simultaneously fits both crests and troughs of g(r). The envelope function implies a temperature-dependent static length scale l(1); over (0.56 < or =T< or =100), l(1) approximately T(-0.3), contrary to suggestions that g(r) is temperature independent as the glass is approached. The highest-melting-point crystal that we identified melts at T(m) approximately 1.08. In the fluid phase, we observe short-range noncrystalline local structure formation in g(r) as the glass is approached. Local structure is only found below a local structure melting temperature T(mc)=2.0. Local structure vanishes above T=2. Local structure becomes more pronounced as temperature is reduced. However, at all temperatures at which there is local structure in g(r), the local structure is confined to r < or =4. Within the region r < or =4, the amplitude of the local structure diminishes with distance r from the central atom approximately as exp(-r/l(2)), thereby defining a second distance scale in the fluid. l(2), while more difficult to measure, appears to scale with temperature as l(2) approximately T(-0.6); l(2) is not the same as l(1). The static and dynamic properties of the local structure match properties assigned by Kivelson's glass model [S. A. Kivelson et al., J. Chem. Phys. 101, 2391 (1994)] to that model's frustration-limited local clusters.

Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate.

BACKGROUND: Medical or surgical castration is effective in advanced prostate cancer but with profound side-effects, particularly on sexual function. Effective, less toxic therapies are needed. This study examined whether the addition of finasteride to high-dose bicalutamide enhanced disease control, as measured by additional decreases in serum prostate-specific antigen (PSA). PATIENTS AND METHODS: Forty-one patients with advanced prostate cancer received bicalutamide (150 mg/day). Finasteride (5 mg/day) was added at first PSA nadir. Serum PSA was measured every 2 weeks until disease progression. Questionnaires were administered to assess sexual function. RESULTS: Median follow-up is 3.9 years. At the first PSA nadir, median decrease in PSA from baseline was 96.5%. Thirty of 41 patients (73%) achieved a second PSA nadir and median decrease of 98.5% from baseline. Median time to each nadir was 3.7 and 5.8 weeks, respectively. Median time to treatment failure was 21.3 months. Toxicities were minor, including gynecomastia. Seventeen of 29 (59%) and 12 of 24 (50%) men had normal sex drive at baseline and at second PSA nadir, respectively. One-third of men had spontaneous erection at both time points. CONCLUSION: Finasteride provides additional intracellular androgen blockade when added to bicalutamide. Duration of control is comparable to castration, with preserved sexual function in some patients.

Neutral polymer slow mode may signify an incipient growth-frustrated domain-forming glass.

Kivelson, et al. [J. Chem. Phys. 101, 2391 (1994)] propose a model for glass-forming liquids based on the potential existence of frustration-limited structures. Frustration-limited structures are equilibrium supramolecular assemblages. The maximum size of an assemblage is limited by geometric constraints. Here I propose that the "slow mode" found in the quasielastic light scattering spectra of some but not all neutral polymer solutions corresponds to the presence of an incipient growth-frustrated domain-forming glass in these solutions. A physical picture is proposed for the origin of frustration in polymer solutions.

Viscosity of hard sphere suspensions.

A simple functional representation of the concentration dependence of the low-shear viscosity eta of hard sphere suspensions is proposed. The representation, which agrees with published literature at all volume fractions phi, has a hitherto-unremarked transition in its functional form at phi approximately 0.42 identical with phi(t). phi(t) is definitely less than the volume fraction 0.49 of the hard sphere melting transition.