Assessment of celecoxib poly(lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats.

OBJECTIVE: Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP). MATERIALS AND METHODS: Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma and urine were assessed based on 100 g body weight. Using tissues collected 24 hrs post-treatment, gastrointestinal inflammation was estimated through duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) levels; while kidney tissue was examined for dilatation and necrosis. CEL concentration was assayed in renal tissue and plasma utilizing high-performance liquid chromatography. RESULTS: Although there were significant changes when comparing CEL and CEL-NP to VEH in plasma sodium concentration and potassium excretion rate, there was no significant variation between CEL and CEL-NP. There was a significant reduction of protective duodenal PGE2 in CEL compared to VEH (p = 0.0088) and CEL-NP (p = 0.02). In the CEL-NP formulation, t1/2, Cmax, AUC0-∞, and Vd/F increased significantly when compared to CEL. CONCLUSIONS: At the observed dosage and duration, CEL-NP may not affect CEL-associated electrolyte parameters in either plasma or urine; however, it does provide increased systemic exposure while potentially alleviating some gastrointestinal outcomes related to inflammation.

Assessment of a daily online implanted fiducial marker-guided prostate radiotherapy process.

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software-predicted set-up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set-up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in-plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in-plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5 mm (1 standard deviation) in all directions (range 0.2-3.9 mm). The random prostate errors ranged from 0.8 to 3.3 mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set-up error of more than 10 mm for one fraction. In 14 of 35 fractions, the postalignment prostate set-up error was greater than 5 mm in the anterior-posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2 degrees to 20 degrees for the patients. The differences between set-up shifts determined by the online software without in-plane rotations to align markers, and with rotations applied, was less than 1 mm (root mean square), with a maximum difference of 4.1 mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set-up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in-plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.

A quality assurance audit: phase III trial of maximal androgen deprivation in prostate cancer (TROG 96.01).

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme.

Acute toxicity and cost analysis of a phase III randomized trial of accelerated and conventional radiotherapy for squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group study.

The primary purpose of the present analysis was to assess the feasibility and acute toxicity of a pure accelerated fractionation regimen in a cooperative group setting. This analysis included the first 320 patients entered on to the Trans-Tasman Radiation Oncology Group (TROG) randomized controlled trial which compared accelerated radiotherapy (ART) with conventional radiotherapy (CRT) in stage III and IV squamous cell carcinoma (SCC) of the head and neck. Patients were randomized to either 59.4 Gy in 33 fractions over 24 days (ART) or to 70 Gy 35 fractions over 49 days (CRT) after being stratified for site and stage. Accrual began in 1991 and the trial was closed on 3 April 1998 with the targeted 350 patients. The 3-year survival for the whole group was 54%, and the 3-year disease-free survival was 41%. Toxicity data were available on 303 patients (148 ART; 155 CRT). Mucosal toxicity was worse in the accelerated arm, and it peaked approximately 3 weeks earlier than the conventional arm. Skin toxicity was equivalent but occurred approximately 7 days earlier in the accelerated arm. Acute effects in both arms healed completely. Hospitalization was more common in the ART arm (71 vs 52 patients; P = 0.01) but the total bed days in hospital was not greatly different (1707 bed days for ART and 1607 bed days for CRT). Patients were more likely to require nasogastric (NG) feeding in the ART arm (49 vs 33 patients; P = 0.02). There were 1157 NG feeding days for ART and 1154 NG feeding days for CRT. The average cost of radiation treatment per patient including hospitalization, NG feeding and accommodation was $11,750 in the ART arm and $11,587 in the CRT arm. The accelerated arm has been shown to be a tolerable, practical and cost-equivalent regimen. The assessment of the therapeutic ratio of this accelerated protocol (ART) will be determined when the analysis of late effects and loco-regional control is made when the data are more mature.

A pilot study of dermofilm in acute radiation-induced desquamative skin reactions.

Dermofilm (Innovatec, Australia Pty Ltd) is a topical preparation containing hydrophilic and lipophilic agents that enhance the barrier functions of damaged skin. It has been assessed in a pilot study of 50 patients with desquamative skin reactions to establish whether it is a suitable candidate to test against an existing, widely used alternative in a randomized controlled trial. Symptomatic improvement, compliance and healing time were the study endpoints. Symptomatic improvement occurred in 49 patients and compliance with the prescribing instructions was uniform. The range of healing times observed at all sites was large but a relationship with the size of the initial desquamated area was noted. It is concluded that a randomized trial comparing Dermofilm with a widely used and cheaper alternative would require a multicentre effort involving approximately 400 patients (200 per arm). Other trial design considerations are discussed.

How should we introduce high-dose chemotherapeutic strategies into the adjuvant management of high-risk breast cancer in Australasia?

BACKGROUND: Development of bone marrow support techniques has altered the standard chemotherapeutic management of haematological malignancies, and these techniques are now being increasingly utilized in solid tumours. In breast cancer, survival benefits have resulted from conventional dose adjuvant chemotherapy, but outcomes remain poor in many women with high-risk disease. Improved response rates with high-dose chemotherapy (HDC) in metastatic disease have led to the investigation of these techniques in adjuvant therapy of high-risk localized disease. In some high-risk patient subgroups survival is extremely poor, with 5-year rates below 30%. Improved adjuvant strategies for patients in these subgroups are therefore urgently required. In Australasia, oncology departments are currently considering accrual of women with high-risk disease into the International Breast Cancer Study Group (IBCSG) 15-95 Trial investigating HDC/stem cell transplantation. METHODS: The present paper reviews the available data on the efficacies and toxicities of currently available high-dose chemotherapeutic strategies; discussing methodological considerations relevant to their introduction and safe use in the adjuvant setting in Australia and New Zealand. RESULTS: Although response rates with HDC in metastatic disease are encouraging, the clinical effectiveness of current HDC regimens in adjuvant management has not been established and is limited by significant toxicity. CONCLUSIONS: The introduction of HDC strategies for high-risk breast cancer in Australia encounters difficulties both in trial design and potential clinical practice.

How do we bring an acceptable level of radiotherapy services to a dispersed population?

Radiotherapy referral data from four Australian States confirm that access difficulties contribute to low radiotherapy utilization rates. Access could be improved by the provision of further small treatment centres in moderately large rural or semi-rural population centres. Such a policy, however, could endanger existing standards of radiotherapeutic care unless the potential pitfalls of such an approach are addressed prospectively.