Day: 03/08/2011

Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib

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Photodynamic therapy (PDT) effectiveness can be improved by employing combined modality approaches involving pharmaceuticals targeting the tumor microenvironment and/or tumor cell death pathways. In one approach, combining PDT with celecoxib improves long-term tumoricidal activity without increasing normal tissue photosensitization. However, side effects arising from the use of coxib based cyclooxygenase-2 (COX-2) inhibitors, including cardiovascular injury, decreases the clinical applications of this class of compounds. A growing number of studies demonstrate that the tumoricidal actions of coxibs such as celecoxib involve non-COX-2 mediated mechanisms. The celecoxib analog, 2,5-dimethyl celecoxib (DMC), lacks COX-2 inhibitory activity but exhibits cytotoxic properties comparable to the COX-2 inhibitor celecoxib. We compared the effectiveness of DMC and celecoxib in modulating PDT response at both the in vitro and in vivo level using a C3H/BA murine mammary carcinoma model. Both DMC and celecoxib blocked PDT induced expression of the pro-survival protein survivin, enhanced the endoplasmic reticulum stress (ERS) response of PDT, and increased both apoptosis and cytotoxicity in BA cells exposed to combination protocols. DMC enhanced the in vivo tumoricidal responsiveness of PDT without altering PGE2 levels. Our data demonstrates that DMC improved PDT by increasing apoptosis and tumoricidal activity without modulating COX-2 catalytic activity. Our results also suggest that celecoxib mediated enhancement of PDT may involve both COX-2 dependent and independent mechanisms.

source: cancer letter

Monthly Liver Tests No Longer Required for Ambrisentan

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The FDA is removing the warning from ambrisentan (Letairis), a pulmonary arterial hypertension drug, that had cautioned that the drug increases the risk for serious liver injury. The agency had mandated monthly liver enzyme tests.

The warning was first issued when the drug was approved in 2007 based on experience with other endothelin-receptor antagonists and a few cases of elevated liver enzymes. FDA analysis indicates that rates of liver problems in patients taking the drug are similar to rates in other patients with pulmonary arterial hypertension.

The boxed warning on the risk of serious birth defects will remain on the label, however.

source:FDA news release

 

Management of skin toxicity during radiation therapy: A review of the evidence

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Acute skin toxicity occurs in the majority of the patients undergoing radical radiotherapy. While a variety of topical agents and dressing are used to ameliorate side effects, there is minimal evidence to support their use. The aims of this study were to systematically review evidence on acute skin toxicity management and to assess the current practices in ANZ. A systematic review of the literature was conducted on studies published between 1980 and 2008. A meta-analysis was performed on articles on clinical trials reporting grade II or greater toxicity. Analyses were divided into breast (the most common site) and other sites. A survey of Radiation Oncology departments across ANZ was conducted to identify patterns of practices and compare these with the published evidence. Twenty-nine articles were reviewed. Only seven articles demonstrated statistically significant results for management of side-effects. These were for topical corticosteroids, hyaluronic acid, sucralfate, calendula, Cavilon cream (3M, St Paul, Minnesota, USA) and silver leaf dressing. Meta-analysis demonstrated statistical significance for the prophylactic use of topical agents in the management acute toxicity. The survey of departments had a low response rate but demonstrated variation in skin care practices across ANZ. A considerable number of these practices were based only on anecdotal evidence. Lack of evidence in the literature for the care of radiation skin reactions was associated with variation in practice. Only a limited number of studies have demonstrated a significant benefit of specific topical agents. There is a need for objective and prospective recording of skin toxicity to collect meaningful comparative data on which to base recommendations for practice.

source: journal of medical imaging and radiation oncology

Clinical care and technical recommendations for 90yttrium microsphere treatment of liver cancer

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Selective internal radiation therapy (SIRT) with 90yttrium microspheres is a relatively new clinical modality for treating non-resectable malignant liver tumours. This interventional radiology technique employs percutaneous microcatheterisation of the hepatic arterial vasculature to selectively deliver radioembolic microspheres into neoplastic tissue. SIRT results in measurable tumour responses or delayed disease progression in the majority of eligible patients with hepatocellular carcinoma or hepatic metastases arising from colorectal cancer. It has also been successfully used as palliative therapy for non-colorectal malignancies metastatic to the liver. Although most adverse events are mild and transient, SIRT also carries some risks for serious and – rarely – fatal outcomes. In particular, entry of microspheres into non-target vessels may result in radiation-induced tissue damage, such as severe gastric ulceration or radiation cholecystitis. Radiation-induced liver disease poses another significant risk. By careful case selection, considered dose calculation and meticulous angiographic technique, it is possible to minimise the incidence of such complications to less than 10% of all treatments. As the number of physicians employing SIRT expands, there is an increasing need to consolidate clinical experience and expertise to optimise patient outcomes. Authored by a panel of clinicians experienced in treating liver tumours via SIRT, this paper collates experience in vessel mapping, embolisation, dosimetry, microsphere delivery and minimisation of non-target delivery. In addition to these clinical recommendations, the authors propose institutional criteria for introducing SIRT at new centres and for incorporating the technique into multidisciplinary care plans for patients with hepatic neoplasms.

SOURCE: journal of medical imaging and radiation oncology

Offline adaptive radiotherapy for bladder cancer using cone beam computed tomography

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We investigated if an adaptive radiotherapy approach based on cone beam CT (CBCT) acquired during radical treatment was feasible and resulted in improved dosimetric outcomes for bladder cancer patients compared to conventional planning and treatment protocol. A secondary aim was to compare a conventional plan with a theoretical online process where positioning is based on soft tissue position on a daily basis and treatment plan choice is based on bladder size. A conventional treatment plan was derived from a planning CT scan in the radical radiotherapy of five patients with muscle invasive bladder cancer. In this offline adaptive protocol using CBCT, the patients had 10 CBCT: daily CBCT for the first five fractions and then CBCT scan on a weekly basis. The first five daily CBCT in each patient were used to create a single adaptive plan for treatment from fraction eight onwards. A different process using the planning CT and the first five daily CBCT was used to create small, average and large bladder volumes, giving rise to small, average and large adaptive bladder treatment plans, respectively. In a retrospective analysis using the CBCT scans, we compared the clinical target volume (CTV) coverage using three protocols: (i) conventional; (ii) offline adaptive; and (iii) online adaptive with choice of ‘plan of the day’. Daily CBCT prolonged treatment time by an average of 7 min. Two of the five patients demonstrated such variation in CTV that an offline adaptive plan was used for treatment after the first five CBCT. Comparing the offline adaptive plan with the conventional plan, the CTV coverage improved from a minimum of 60.1 to 94.7% in subsequent weekly CBCT. Using the CBCT data, modelling an online adaptive protocol showed that coverage of the CTV by the 95% prescribed dose line by small, medium and large adaptive plans were 34.9, 67.4 and 90.7% of occasions, respectively. More normal tissue was irradiated using a conventional CTV to planning target volume margin (1.5 cm) compared to an online adaptive process (0.5 cm). An offline adaptive strategy improves dose coverage in certain patients to the CTV and results in a higher conformity index compared to conventional planning. Further research in online adaptive radiation therapy for bladder cancer is indicated.

source: journal of medical imaging and radiation oncology

Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer

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Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. METHODS Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. Results Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. CONCLUSION Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.

source:JCO

Treatment for Lambert-Eaton myasthenic syndrome.

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Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Treatments attempt to overcome the harmful autoimmune process, or improve residual neuromuscular transmission
OBJECTIVES: The objective was to examine the efficacy of treatment in Lambert-Eaton myasthenic syndrome.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (12 October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (12 October 2010, Issue 4 2010 in the Cochrane Library), MEDLINE (January 1966 to September 2010) and EMBASE (January 1980 to September 2010).
SELECTION CRITERIA: All randomised or quasi-randomised trials of adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer, receiving any form of pharmacological or physical treatment.
DATA COLLECTION AND ANALYSIS: All authors independently assessed studies for inclusion and extracted data. Study authors were contacted for missing information when possible.
MAIN RESULTS: Four controlled trials of 3,4-diaminopyridine compared with placebo in a total of 54 participants with Lambert-Eaton myasthenic syndrome were eligible: three cross-over trials and one parallel group. Two were added at this update. One of these trials also assessed pyridostigmine in conjunction with 3,4-diaminopyridine. A further cross-over trial compared intravenous immunoglobulin (IVIg) to placebo in nine participants.Four trials of 3,4-diaminopyridine reported significant improvement in the primary outcome, muscle strength score, or myometric limb measurement for between hours and a week following treatment, and significant improvement in resting compound muscle action potential (CMAP) amplitude following 3,4-diaminopyridine, compared with placebo.A meta-analysis of the primary endpoint showed Quantitative Myasthenia Gravis (QMG) muscle score assessed between three and eight days was likely to improve by a mean of 2.44 points (95% confidence interval 3.6 to 1.22). Meta-analysis of the secondary endpoint CMAP amplitude also showed a mean improvement of 1.36 mV (95% confidence interval 0.99 to 1.72) over the same period. The risk of bias was determined to be low, and quality of evidence moderate to high.A single cross-over trial reported significant improvement in myometric limb strength and non-significant improvement in mean resting CMAP amplitude with IVIg compared to placebo. Clinical improvement lasted for up to eight weeks.
AUTHORS’ CONCLUSIONS: Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4-diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials.

source: cochrane database

Interventions for preventing neuropathy caused by cisplatin and related compounds.

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Cisplatin and several related antineoplastic agents used to treat many types of solid tumors are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.
OBJECTIVES: To examine the efficacy of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related agents.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (25 August 2010), the Cochrane Central Register of Controlled Trials (Issue 3, 2010 in The Cochrane Library), MEDLINE (January 1966 to August 2010), EMBASE (January 1980 to August 2010), LILACS (January 1982 to August 2010), CINAHL (January 1982 to August 2010) for randomized trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related agents among human patients.
SELECTION CRITERIA: Quasi-randomized or randomized controlled trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant (acetylcysteine, amifostine, ACTH, BNP7787, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, or vitamin E) and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary).
DATA COLLECTION AND ANALYSIS: We identified 16 randomized trials involving five possible chemoprotective agents in the initial 2006 review. Each study was reviewed by two authors who extracted the data and reached consensus. The 2010 update identified 11 additional randomized trials consisting of nine possible chemoprotective agents, including three treatments (acetylcysteine, calcium and magnesium, and oxcarbazepine) not among those described in the 2006 review. The included trials in the updated review involved eight unrelated treatments and included many disparate measures of neuropathy, resulting in insufficient data for any one measure to combine the results in most instances.
MAIN RESULTS: One of four eligible amifostine trials (541 total participants in all four trials) used quantitative sensory testing and demonstrated a favorable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Of the six eligible glutathione trials (354 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing reported disparate results; meta-analyses of three trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. The single eligible trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), calcium and magnesium (33 participants), and oxcarbazepine (32 participants) and the two eligible trials involving vitamin E (57 participants) did not perform quantitative sensory testing. In all, data from 1,537 participants were included.
AUTHORS’ CONCLUSIONS: At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxycarbazepine, or Vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients.

source: cochrane database

Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) enhancesthe immune system of cancer patients

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Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy.
OBJECTIVES: To evaluate the effectiveness of pTE and sTP for the management of cancer.
SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010).
SELECTION CRITERIA: Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta-analysis.
MAIN RESULTS: We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin alpha(1)). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10 for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin alpha(1) the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I(2) = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23, P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias.
AUTHORS’ CONCLUSIONS: Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin alpha(1), there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.

source: cochrane database

Single dose oral fenoprofen for acute postoperative pain in adults

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Fenoprofen is a non-steroidal anti-inflammatory drug (NSAID), available in several different countries, but not widely used.
OBJECTIVES: To assess the efficacy of single dose oral fenoprofen in acute postoperative pain, and associated adverse events.
SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010.
SELECTION CRITERIA: Single oral dose, randomised, double-blind, placebo-controlled trials of fenoprofen for relief of established moderate to severe postoperative pain in adults.
DATA COLLECTION AND ANALYSIS: Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected.
MAIN RESULTS: Five studies (696 participants) met the inclusion criteria; 24 participants were treated with fenoprofen 12.5 mg, 23 with fenoprofen 25 mg, 79 with fenoprofen 50 mg, 78 with fenoprofen 100 mg, 146 with fenoprofen 200 mg, 55 with fenoprofen 300 mg, 43 with zomepirac 100 mg, 30 with morphine 8 mg, 77 with codeine 60 mg, and 141 with placebo. Participants had pain following third molar extraction, laparoscopy, minor day surgery and episiotomy. The NNT for at least 50% pain relief over 4 to 6 hours with a single dose of fenoprofen 200 mg compared to placebo was 2.3 (1.9 to 3.0). There were insufficient data to analyse other doses or active comparators, time to use of rescue medication, or numbers of participants needing rescue medication. There was no difference in numbers of participants experiencing any adverse events between fenoprofen 200 mg and placebo. No serious adverse events or adverse event withdrawals were reported in these studies.
AUTHORS’ CONCLUSIONS: Oral fenoprofen 200 mg is effective at treating moderate to severe acute postoperative pain, based on limited data for at least 50% pain relief over 4 to 6 hours. Efficacy of other doses, other efficacy outcomes, and safety and tolerability could not be assessed.

source: cochrane database