Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events.

BACKGROUND: In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. PATIENTS AND METHODS: Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. RESULTS: Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. CONCLUSION: In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.

Body site matters: an evaluation and application of a novel histological methodology on the quantification of mucous cells in the skin of Atlantic salmon, Salmo salar L.

Mucous cell size and distribution were investigated in the skin of five salmon using a novel stereology-based methodology: one (48 cm) fish to test 15 tissue treatment combinations on measures of cell area and density on the dorsolateral region and, using the most suitable treatment, we mapped mucous cell differences between body regions on four (52 cm) salmon, comprising a male and a female on each of two diets. The section site, decalcification, embedding medium and plane of sectioning all impacted significantly on mucous cell size, whereas mucous cell density is more robust. There were highly significant differences in both mucosal density and mean mucous cell size depending on body site: the dorsolateral skin of the four salmon had significantly denser (about 8% of skin area) and larger (mean about 160 µm(2)) mucous cells, whereas the lowest mean density (about 4%) and smallest mean area (115 µm(2)) were found on the head. We found that 100 random measurements may be sufficient to distinguish differences >7 µm(2) in mean mucous cell areas. The results further suggest that salmon exhibit a dynamic repeatable pattern of mucous cell development influenced by sex, diet and possibly strain and season.

A phase I study to determine the safety, tolerability and maximum tolerated dose of green-lipped mussel (Perna canaliculus) lipid extract, in patients with advanced prostate and breast cancer.

BACKGROUND: This was a phase I trial to determine the maximum tolerated dose (MTD) of a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus), as an inhibitor of 5- and 12-lipo-oxygenase enzymes, in patients with advanced breast and prostate cancers. PATIENTS AND METHODS: This was an open-labelled, phase I, dose-escalation study. Proprietary form of green-lipped mussel lipid extract (GLMLE), 260-mg capsule, was administered on a twice-daily schedule, orally. Patients remained on study until disease progression or unacceptable toxicity. RESULTS: From December 1999 to May 2003, 17 patients were enrolled. Fifteen of them were male with advanced prostate cancer and two were female with advanced breast cancer. The median age of the patients was 74 years (range 56-85 years). Sixteen patients were assessable for adverse events and dose-limiting toxicity (DLT). Reason for withdrawal from the study included progressive disease (n = 12), death (n = 1) and DLT (n = 3). Two patients had evidence of grade 4 hepatic dysfunction. The MTD was not reached. There were no objective tumour responses noted. CONCLUSIONS: GLMLE appears to be a well-tolerated compound in this setting. There appears to be no objective benefit. However, grade 3/4 hepatic toxicity noted in two patients is of concern and should be considered while evaluating patients taking GLMLE or while designing studies with this agent.

The influence of first-feeding diet on the Atlantic cod Gadus morhua phenotype: survival, development and long-term consequences for growth.

Atlantic cod Gadus morhua larvae reached four-fold (at low larval density) to 11 fold higher body mass (high larval density) at 50 days post hatch (dph) when fed zooplankton rather than enriched rotifers. A short period (22-36 dph) of dietary change affected larval growth positively if changed from enriched rotifers to natural zooplankton and negatively if prey type changed vice versa. Overall survival did not differ between the two larval groups at low larval density, but at high density the rotifer group had a higher overall survival (10.8% v. 8.9%). Long-term growth was affected significantly by larval diet in favour of the zooplankton diet; juveniles reached a 23% higher mass in a 12 week growth period. No difference in growth performance was found between juveniles fed natural zooplankton during the larval period for 36, 22 or 14 days, but all these juveniles performed significantly better compared with the rotifer-fed group. These findings suggest that optimal diet during a short period in the larval period can result in improved growth in both the larval and juvenile period. Improved rotifer quality may, therefore, hold a large potential for growth improvement in this species.

Management and survival trends in advanced colorectal cancer.

AIMS: Significant improvements in the outcome for patients with advanced colorectal cancer (CRC) have been achieved. The median survival for advanced CRC reported in clinical trials now approaches 2 years, but there is often a question as to whether this partly represents patient selection. We aimed to explore whether the availability of new chemotherapy drugs (irinotecan and oxaliplatin) and surgical advances have affected survival in a normal clinical setting. MATERIALS AND METHODS: A review of the Queen Elizabeth and Lyell McEwin health service prospective CRC database from 1992 to 2004 was carried out to assess outcome differences between two time cohorts (1 January 1992-31 December 1997 and 1 January 1998-31 December 2004). RESULTS: For all patients (n = 744) overall survival was seen to improve over time and is maintained out to 5 years. There have been a number of trends over time (1992-1997 vs 1998-2004) that have probably contributed to this gain; increased overall chemotherapy use (33% vs 43%); use of combination chemotherapy (i.e. oxaliplatin and irinotecan regimens); increased hepatic resection rates (1.9% vs 10.8%) and increased clinical trial uptake (0.6% vs 14.5%). CONCLUSION: This current analysis confirms an improvement in survival over time for advanced CRC and this is seen in unselected patients including those over 70 years of age.

Hyperammonaemic encephalopathy associated with rituximab-containing chemotherapy.

Abstract Hyperammonaemic encephalopathy has been infrequently reported after both standard and high-dose chemotherapy for solid and haematological malignancies. It is important to consider this diagnosis for patients with unexplained behaviour changes or encephalopathy and this case report emphasizes this condition and the importance of early diagnosis and is the first reported in association with rituximab-containing chemotherapy.

A phase I and clinical pharmacology study of intravenously administered carminomycin in cancer patients in the United States.

Carminomycin (CMN) was administered i.v. to 44 patients with a variety of nonhematological cancers every 4 weeks at doses of 15, 20, 22.5, and 25 mg/sq m. Granulocytopenia was the dose-limiting toxicity. The median granulocyte count for previously untreated patients receiving 22.5 mg/sq m was 0.962 cells/microliters, and for previously treated patients receiving 20 mg/sq m it was 0.420 cell/microliters. Moderate to severe phlebitis was associated with drug administration in 50% of cases. Nausea, vomiting, and alopecia were mild. Three of nine patients who received a total CMN dose of greater than or equal to 100 mg/sq m (mean, 132 mg/sq m) developed unexplained decreases in radionuclide cardiac ejection fraction, with one patient developing decreased QRS amplitude and congestive heart failure at a total dose of 160 mg/sq m. CMN is rapidly metabolized to carminomycinol. The elimination half-lives of CMN and carminomycinol are 6 to 10 and 50 hr, respectively. CMN was found to be a more potent inhibitor of human granulocyte-macrophage colony-forming units than was carminomycinol. Objective partial responses were seen in two of seven previously untreated patients with non-small cell lung cancer and one of three patients with squamous cell carcinoma of the head and neck previously untreated with chemotherapy.

Treatment and survival from colorectal cancer: the experience of patients at South Australian teaching hospitals between 1980 and 2002.

AIMS: To evaluate trends in colorectal cancer survival and treatment at South Australian teaching hospitals and degree of adherence to treatment guidelines which recommend adjuvant chemotherapy for Dukes' C colon cancers and combined chemotherapy and radiotherapy for high-risk rectal cancers. MATERIALS AND METHODS: Trends in disease specific survival and primary treatment were analysed, and comparisons drawn between diagnostic epochs, using cancer registry data from South Australian teaching hospitals. Statistical methods included univariate and multivariable disease specific survival analyses. RESULTS: Five-year survival increased from 48% in 1980-1986 to 56% in 1995-2002. Largest gains were for stage C, where survivals were higher when chemotherapy was part of the primary treatment. By comparison, gains in 1-year survival were largest for stage D. Chemotherapy was provided for 4% of patients with colorectal cancers in 1980-1986, increasing to 32% in 1995-2002. Among stage C cases below 70 years at diagnosis, the proportion having chemotherapy increased to 83% in 1995-2002. The most common chemotherapy was fluorouracil (5FU) as a single agent in 1980-1986 and 5FU with leucovorin in 1995-2002. As expected, radiotherapy was used more frequently for rectal than colon cancers, and particularly for stage C. Among stage C rectal cases below 70 years, the proportion having radiotherapy increased from 10% in 1980-1986 to 57% in 1995-2002. Approximately 93% of colorectal cancers were treated surgically. Patients not treated surgically tended to be aged 80 years or more and to present with distant metastases. CONCLUSIONS: Trends in chemotherapy and radiotherapy accord with evidence-based recommendations. There have been reassuring gains in survivals after adjusting for stage, grade and other prognostic indicators. The data show survival gains and treatment patterns that individual hospitals can use as benchmarks when evaluating their own experience.

Multiple-dose phase I study of transnasal butorphanol.

The safety, tolerance, and pharmacokinetics of transnasal butorphanol were evaluated in a double-blind, multiple-dose phase I study. A total of 18 subjects received either placebo (n = 6) or a single transnasal dose of 2 mg butorphanol tartrate on the first day and 1, 2, and 4 mg doses of butorphanol tartrate every 6 hours on days 2 through 6, 7 through 11, and 12 through 16, respectively. Safety assessment was performed on days 7, 12, and 17. Serial blood samples were collected on days 1, 6, 11, and 16, and the plasma was analyzed for unchanged butorphanol by a validated and specific radioimmunoassay. Butorphanol was rapidly absorbed and peak levels in plasma were generally attained within 1 hour after the nasal administration. The values of maximum concentration, minimum concentration, and area under the concentration versus time curve from time zero to the dosing interval [AUC(0-tau)] increased as the administered dose increased in a dose-proportional manner. The values of AUC from time zero to infinity after a single dose of 2 mg butorphanol tartrate, 10.9 ng.hr/ml, were identical to the values of AUC(0-tau) after a multiple administration of 2 mg dose, 10.4 ng.hr/ml. Mean elimination half-life value was 5.45 hours. Steady state was reached in fewer than eight doses when given every 6 hours. Transnasal butorphanol was well tolerated by all subjects. After repeated administration of transnasal butorphanol, no significant changes were observed in the nasal examination, which included evaluation of color, wetness, and thickness of nostril membrane, air flow, airway patency, and general nasal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of anagrelide, an inhibitor of platelet aggregation.

A single dose of 14C-anagrelide (6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazoline-2(3H)-one monohydrochloride) equivalent to 1 mg free base and containing 100 muCi radioactivity, was taken by five healthy, fasting men. Blood, plasma, urine, and feces were analyzed for total radioactivity. Plasma and urine concentrations of anagrelide were determined, and the urinary metabolite profile was established by high-performance liquid chromatography (HPLC). The drug was rapidly absorbed with peak plasma levels of radioactivity equivalent to 50 ng anagrelide per milliliter at about 1 hr. These levels decreased to less than 10% of peak in 24 hr. Plasma levels of anagrelide peaked at 5 ng/ml at about 1 hr, decreased rapidly during the first 6 to 8 hr, and then declined more slowly, with an estimated terminal elimination half-life of about 3 days. No significant quantities of radioactivity were associated with the cellular elements of blood. Anagrelide was extensively metabolized before elimination in urine. Means of 68% and 72% of the dose were excreted in urine as metabolites in 24 and 144 hr, and 10% of the dose recovered in the feces. Several urinary metabolites were detected by HPLC.

Food-induced reduction in bioavailability of didanosine.

The effect of food on the pharmacokinetics of didanosine was evaluated in an open two-way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration-time curves (AUC0-infinity) were 3902 (1316) and 2083 (922) hr.ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact didanosine when didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0-infinity, and %UR were significantly lower for subjects who received didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half-life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0-infinity and %UR, was reduced significantly in the presence of food. It is recommended that didanosine be administered under fasting conditions.

Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex.

The pharmacokinetics of didanosine (2',3'-dideoxyinosine) after intravenous and oral administration were evaluated in an open, escalating-dose phase I study in patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex. Didanosine was administered twice a day for 2 weeks as an intravenous infusion of 60 minutes duration at doses ranging from 0.4 to 16.5 mg/kg, followed by 4 weeks of oral treatment at twice the intravenous dose. Serial blood and urine samples were obtained on the first and final day of intravenous administration and after the first oral dose, as well as at steady state. Didanosine demonstrated linear pharmacokinetic behavior over the dose ranges of 0.4 to 16.5 mg/kg intravenously and 0.8 to 10.2 mg/kg orally. There was no indication of significant changes in pharmacokinetic parameters with repeated administration. The apparent elimination half-life after oral administration was approximately 1.4 hour. Renal clearance values exceeded the glomerular filtration rate, indicating that active tubular secretion of didanosine occurs. Bioavailability of didanosine when administered as a solution with an antacid was approximately 43% for doses from 0.8 to 10.2 mg/kg in patients with AIDS and advanced AIDS-related complex. Bioavailability of didanosine from the citrate-phosphate-buffered solution, the formulation currently used in phase II and expanded access studies, was comparable to the formulation used in the phase I trials.

Pharmacokinetics of cefepime in subjects with renal insufficiency.

The pharmacokinetics of intravenously administered cefepime (1000 mg over 30 minutes) were studied in 5 healthy volunteers and 20 patients with various degrees of renal impairment. Cefepime concentrations in plasma, urine, and hemodialysate were assayed using reverse-phase HPLC with ultraviolet detection. Mean peak plasma concentrations of cefepime at the end of 30-minute infusion ranges from 63.5 to 73.9 micrograms/ml and were not affected by the degree of renal impairment. The half-life of cefepime was approximately 2.3 hours in subjects with normal kidney function; it increased proportionately as renal function decreased. Significant linear relationships between total body clearance and creatinine clearance, as well as renal clearance and creatinine clearance, were observed. The mean volume of distribution at steady state in healthy volunteers was 20.5 liters and was not significantly altered in subjects with renal insufficiency. The mean cumulative urinary recovery of cefepime in healthy volunteers was 82.9% of the administered dose and significantly decreased in subjects with creatinine clearance less than 30 ml/min. Hemodialysis significantly shortened the elimination half-life from 13.5 hours during the predialysis period to 2.3 hours during the dialysis period. Cefepime dosage should be reduced in proportion to the decline in creatinine clearance.

Bioequivalence evaluation of new megestrol acetate formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet. The tablets were administered to 24 male subjects in a three-way crossover study, balanced for sequence, with 1 week between administrations. The 40 mg tablets were administered qid at 8 AM, 12 PM, 6 PM, and 10 PM, while the 160 mg tablets were administered once at 8 AM. Plasma samples were collected at appropriate times up to 96 hours after administration and were analyzed for megestrol acetate with a validated high-performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h) the rate of absorption was the same for each of the tablets. Relative to the 40 mg qid dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97% and 118%, respectively.

The effects of estrogen on apomorphine-induced hypothermia and stereotypy in the rat.

The effects of various doses of estrogen on apomorphine (Apo)-induced hypothermia and stereotypy were investigated in ovariectomized rats. Daily administration of estradiol (5, 15 or 100 micrograms/kg) for 4 days or estradiol (100 micrograms/kg) for 3 days, followed by 4 and 72 hr withdrawal periods respectively, had no effect on apomorphine-induced hypothermia or stereotypy in a cold (4 degrees C) environment, although both effects were blocked by haloperidol. Large doses of estradiol (100 micrograms/kg) given for 3 days, followed by either 24 or 72 hr withdrawal, slightly attenuated apomorphine-induced stereotypy at 22 degrees C. Stereotypy observed at 22 degrees C was of greater magnitude than that seen at 4 degrees C. The results indicate that although high, non-physiological levels of estrogen may attenuate striatal-dependent stereotypies, this hormone has no detectable influence on dopaminergic mechanisms in the preoptic-anterior hypothalamic regions that are thought to mediate apomorphine-induced hypothermia.

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.

The effects of chronic lithium on behavioral and biochemical indices of dopamine receptor supersensitivity in the rat.

The effects of dietary lithium on several indices of dopamine receptor supersensitivity were examined in rats during withdrawal from chronic administration of haloperidol. Chronic haloperidol enhanced the locomotor stimulant action of d-amphetamine, and this effect was attenuated by lithium. In contrast, lithium did not affect the amphetamine response in animals that had not previously received haloperidol. Apomorphine-induced hypothermia was not influenced by the chronic haloperidol treatment. On the other hand, during withdrawal from chronic haloperidol, spontaneous locomotor activity (20 h) and apomorphine-induced stereotypy were increased, but neither of these effects was attenuated by lithium. In addition, lithium did not affect the chronic haloperidol-induced increase in 3H-spiperone binding sites in the striatum. Lithium alone had no effect on any of these measures except for causing a slight prolongation of the hypothermic effect of apomorphine. The results indicate that not all DA-receptor-mediated responses are enhanced by chronic administration of neuroleptics (e.g., apomorphine-induced hypothermia). In addition, while lithium reduces the effects of chronic haloperidol administration on d-amphetamine-induced locomotor activity, this is not because lithium prevents haloperidol-induced supersensitivity of postsynaptic DA receptors because more direct measures of this phenomenon (e.g., 3H-spiperone binding, apomorphine-induced stereotypy) are not affected by lithium.