Evidentia April/May 2011 by Peter Mas-Mollinedo

Volume 5 Issue 2 | April/May 2011 | ISSN 1753-464X

Scientists learn how to block pain at source Metabolic syndrome linked to memory loss NSAIDs linked to increased risk of erectile dysfunction Link between influenza vaccine and narcolepsy being investigated

The first and only orodispersible tablet for erectile dysfunction (ED)1,2

Ready when they are

Introducing Levitra® orodispersible tablet – the first and only treatment for ED to dissolve on the tongue within seconds;3 comes in a discreet, pocket-friendly pack to meet the needs of today’s man.

ED therapy wherever he needs it Levitra® film-coated tablets and Levitra® orodispersible tablets (vardenafil) Prescribing Information (Refer to full Summary of product Characteristics (SmPC) before prescribing) Presentation: Levitra® film-coated tablets: 5/10/20mg vardenafil (as hydrochloride trihydrate). Levitra® orodispersible tablets: 10mg vardenafil (as hydrochloride). Indication: Treatment of erectile dysfunction. To be effective, sexual stimulation is required. Posology and method of administration: Film-coated: 10mg approximately 25– 60 minutes before sexual activity. Based on efficacy and tolerability, dose may be increased to 20mg or decreased to 5mg. Maximum dose is 20mg/day. Can be taken with or without food. Onset of activity may be delayed if taken with a high-fat meal. Orodispersible: 10mg approximately 60 minutes before sexual activity. Maximum dose is 10mg/day. Can be taken with or without food, but not with liquid. Elderly men: no dosage adjustment required, though increase to a maximum 20mg film-coated tablets dose should be carefully considered depending on individual tolerability. Children and adolescents: Not indicated for individuals <18 years of age. Hepatic and renal impairment: Consider starting with 5mg film-coated tablets in patients with mild-moderate hepatic impairment or severe renal impairment. The maximum dose in patients with moderate hepatic impairment is 10mg film-coated tablets. Orodispersible tablets should not be used in patients with moderate to severe hepatic impairment or with end-stage renal failure. Use with other medicinal products: In combination with moderate CYP3A4 inhibitors, the dose should not exceed 5mg film-coated tablets. Contra-indications: Hypersensitivity to vardenafil or to any excipients; coadministration with nitrates/nitric oxide donors (such as amyl nitrite); loss of vision in one eye due to NAION; men for whom sexual activity is inadvisable; severe hepatic impairment; end-stage renal disease requiring dialysis; hypotension; recent stroke or myocardial infarction; unstable angina; known hereditary retinal degenerative disorders; concomitant use of potent CYP3A4 inhibitors ketoconazole and itraconazole (oral

form) in men older than 75 years; concomitant use of potent HIV protease inhibitors. Warnings and Precautions: Given cardiac risk associated with sexual activity, consider cardiovascular status. Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction can be sensitive to the actions of PDE-5 inhibitors. Use with caution in patients with anatomical deformation of the penis or conditions which predispose to priapism. Combination with other treatments for erectile dysfunction is not recommended. Patients on alpha-blocker therapy: concomitant use may lead to symptomatic hypotension, consider only if therapy is stable, initiate vardenafil at a starting dose of 5mg film-coated tablets and consider a time separation of dosing. Concomitant use with potent CYP3A4 inhibitors should be avoided. A dose of 5mg film-coated tablets must not be exceeded when given concomitantly with CYP3A4 inhibitors, e.g. erythromycin or clarithromycin. Avoid grapefruit or grapefruit juice. Prolongation of QTc interval: avoid use in patients with relevant risk factors. In case of sudden visual defect, treatment should be stopped. Administration to patients with bleeding disorders or active peptic ulceration should be considered carefully. Orodispersible tablets contain aspartame and sorbitol. Interactions: CYP3A4 inhibitors may reduce vardenafil clearance. Nicorandil may have a serious interaction with vardenafil due to the nitrate component. Prescribers should consult the SmPCs for full details on interactions. Pregnancy and lactation: Not indicated for use in women. Effects on ability to drive and use machines: Patients should be aware of how they react to Levitra® before driving or operating machinery. Undesirable Effects: Very common: flushing (film-coated tablets only) and headache. Common: flushing (orodispersible tablets only), nausea (film-coated tablets only), dizziness, nasal congestion, and dyspepsia. Serious side effects: cf. CI/Warnings and Precautions - in addition: tachycardia, palpitations, angina pectoris, myocardial infarction, seizure, priapism, NAION, visual defect, hypertension, somnolence, increased intraocular pressure, sudden deafness, syncope, amnesia & hypersensitivity & laryngeal oedema (film-coated tablets only), allergic reaction & angioedema (orodispersible tablets only). Serious

cardiovascular events, including cerebrovascular haemorrhage, sudden cardiac death, transient ischaemic attack, unstable angina and ventricular arrhythmia reported post marketing in temporal association with another medicinal product in the same class. In addition, paraesthesia/dysaesthesia, ventricular tachyarrhythmias and chest pain (orodispersible tablets only). Prescribers should consult the SmPC in relation to other side effects. Overdose: Doses of 40mg twice daily have been associated with severe back pain without any muscle or neurological toxicity. Standard supportive measures should be adopted & dialysis is not expected to accelerate clearance. Legal Category: POM. Package Quantities and Basic NHS Costs: Filmcoated: 4 x 5mg (£7.56), 8 x 5mg (£15.12), 4 x 10mg (£14.08), 8 x 10mg (£28.16), 4 x 20mg (£23.48), and 8 x 20mg (£46.96). Orodispersible: 4 x 10mg (£17.88). MA Number(s): EU/1/03/248/001-015. Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom, Telephone: 01635 563000. Date of revision: March 2011. Levitra® is a registered trademark of Bayer AG.

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk References: 1. Sperling H, Debruyne F, Boermans A, et al. J Sex Med 2010;7:1497–1507. 2. Levitra® ODT Summary of Product Characteristics. 3. Heinig R, Weimann B, Dietrich H, et al. Clin Drug Investig 2011;31(1):27–41. UK.PH.GM.LVT.2010.052h

Date of preparation: March 2011

Bringing clinical evidence to practice in primary and secondary care

Contents 4

COVER STORY

Guest Editorial by Dr. Sunil Upadhyay Is there an absolute truth in lung cancer?

Volume 5 Issue 2 | April/May 2011 | ISSN 1753-464X

5 11

American Heart Association & American Stroke Association revised guidelines Cardiology reports

Screening 'does not prevent prostate cancer deaths', 20-year study concludes

Scientists learn how to block pain at source

Prostate cancer reports

NSAIDs linked to increased risk of erectile dysfunction

Metabolic syndrome linked to memory loss

Link between influenza vaccine and narcolepsy being investigated

Screening and early detection

Scientists learn to block pain at source

Effect of sunlight and temperature on MS

Reports from EMC on Thoracic Oncology, Lugano

Scientists learn how to block pain at source

Pain study

Neurology study

Link established between ED and calcified coronary arteries Reporting from the American Urological Association meeting, San Francisco

EMA Highlights

The BIG FOUR

World Health Matters

FDA Highlights

View from The Waiting Room

Emerging uses of EMA approved drugs

Reporting from some of the latest journal articles

Medical news from around the world

Emerging uses of FDA-approved drugs

Rocking the boat

E V I D E N T I A • V O L U M E 5 • I S S U E 2 • A P R I L / M AY 2 0 1 1

Guest editorial by Dr. Sunil Upadhyay, Service Director and Consultant Clinical Oncologist, Queen’s Centre for Oncology and Haematology, Hull, HU16 5JQ

Is there an absolute truth in lung cancer?

ESPITE COMMENDABLE efforts in lung cancer awareness, preventative measures and research, a large proportion of lung cancer patients continue to present at advanced stages with poor outcomes. Systemic treatment with best supportive care and frequent use of other

The gold standard remains the use of single agent cytotoxic or molecular agents.

or later. These patients have a poor performance status, limited treatment options and dismal prognosis. To prevent further deterioration of performance status and achieve better QOL, an effective alternative to second-line chemotherapy is the use of molecular agents with better toxicity profiles. First generation, reversible Tyrosine Kinase Inhibitors remain an attractive alternative but many physicians assume that these agents will be ineffective in this difficult-to treat patient population, particularly with wild type EGFR mutation tumours. The gold standard remains the use of single agent cytotoxic or molecular agents. Based on historical data, NICE approved erlotinib as an alternative to Docetaxel, which it believes has a better toxicity profile compared to chemotherapy.

The TITAN study treatment modalities currently available remains the gold standard. Along with patient selection, tumour characteristic has become of great importance in treatment selection. Efficacy and tolerability are common concerns in patients with advanced disease. Choice of chemotherapy rests on an accurate understanding of histology and molecular sub-typing of the tumour. The primary goal of the clinician is to select a therapy with greatest benefit and minimal toxicity. Molecular profiling for treatment selection has become the main research field in the lung cancer arena. Unfortunately, despite recent breakthroughs in the understanding of lung tumour biology and treatment selection, nearly 40-50% of patients with advanced disease relapse sooner

Contributors: Adrain Catterall, Steve Devrell, Gary Finnegan, Peter Mas-Mollinedo, Bruce Sylvester, Samuel Peters, Dr. Sunil Upadhyay

The TITAN study is the first phase III head to head comparison of erlotinib vs docetaxel or pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer with poor prognosis. The study (n=424) was initiated to evaluate the relative efficacy and tolerability of the three agents in relapsed cases. The primary endpoints were overall survival and the secondary endpoints were PFS and OS by EGFR status, PFS in all patients, clinical benefit and safety. It is reassuring to see that the OS was similar in both arms in all subtypes including EGFR wild type and adenocarcinoma histology. As expected, the toxicity profile was more favourable for erlotinib with no new safety signals. TITAN data is important because it confirms that erlotinib has comparable efficacy to chemotherapy with better tolerability even in patients with poor prognosis regardless of their

Editorial / Advisory Board: Omar Ali Bsc MRPhamS, Y Callan MD MRCGP M Gray MRPharmS, M Gupta MD MRCP Tim Lewis MD FRCP, K O’Neill Bsc MRCGP Mr Ian Pearce, C Weston MD MRCP

ICR (UK) PUBLISHING

International Conference Reports

EGFR mutation status. Although treatment with first-generation TKI (gefitinib or erlotinib) in EGFR mutation positive cases is well established, there is no predictor for the duration of response to these agents. The duration of response with these agents remain heterogeneous hence these patients require regular follow-up and repeated scans both of which escalate cost and anxiety. Integrated digital gene expression technology detects expression levels of hundreds of genes in a single reaction with high levels of precision and sensitivity. A study on the use of this technology in EGFR mutation positive cases from Spain found that the

There is emerging evidence that EGFR mutation positive tumours with low levels of AEG-1 can achieve considerably prolonged remission with TKI.

patients with low levels of astrocyte elevated gene 1 (AEG) achieved up to 27 months of PFS compared to only 12 months with high levels. AEG-1 is a cancer-associated gene with multiple functions, which contributes to several hall marks of cancer including drug

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© ICR-UK Limited. The information contained in Evidentia is intended to be used with professional medical knowledge and in conjunction with other sources of clinical evidence and product literature. ICR-UK & sister company IMI, publish a number of medical jour nals and electronic jour nals. For more information visit www.icr-uk.com ICR-UK are affiliate members of the ABPI ISSN: 1753-464X Designed by JAM Design 01483 426017 P r i n t e d b y S t e p h e n s & G e o r g e 0 1 6 8 5 3 8 8 8 8 8 D i s t r i b u t e d b y P r e c i s i o n D i r e c t M a r k e t i n g 0 1 2 8 4 7 1 8 9 0 0

E V I D E N T I A • V O L U M E 5 • I S S U E 2 • A P R I L / M AY 2 0 1 1

Cardiology reports

American Heart Association & American Stroke Association revised guidelines

REATING METABOLIC syndrome and undergoing carotid angioplasty may prevent recurrent stroke or transient ischaemic attack (TIA), according to revised American Heart Association/American Stroke Association guidelines. Last updated in 2006, the evidence-based guidelines for doctors was published in Stroke: The Journal of the American Heart Association. "Patients who've had a stroke or TIA are at highest risk for having another event," said Karen Furie, M.D., M.P.H., writing committee chair and stroke neurologist. "Since the last update, we've had results from several studies testing different interventions. We need to reevaluate the science every few years to optimise prevention." Ischaemic stroke accounts for about 87% of all strokes, which are caused by a lack of blood to the brain, resulting in tissue death. TIA occurs when blockage of blood to the brain is only temporary and thus doesn't cause tissue death. The new guidelines feature several key updates for stroke or TIA survivors, including: The value of screening for metabolic syndrome after stroke is still not clear; however, if it's diagnosed, patients should receive counselling for lifestyle changes (including diet, exercise and weight loss) and treatments for metabolic syndrome

resistance. Its greatest role will be measuring levels in patients with the BRCA1 gene. There is emerging evidence that EGFR mutation positive tumours with low levels of AEG-1 can achieve considerably prolonged remission with TKI. Nearly 10% of the younger aged, never smokers with adenocarcinoma subset overexpress EML4-ALK translocation. These tumours are known to be more aggressive and resistant to TKI but benefit from ALK inhibitors like crizotinib. Similarly, preliminary data indicate that increased levels of ERCC1 predicts

components that are also stroke risk factors, especially high blood pressure and high cholesterol. If a stroke survivor has severe blockage of the carotid artery, angioplasty and stenting may be an alternative to surgery if he or she is at low risk for complications.

"Patients who've had a stroke or TIA are at highest risk for having another event.” Karen Furie

Excluding patients whose stroke or TIA was caused by a clot from the heart, among those taking an antiplatelet drug to prevent another stroke, either aspirin alone, aspirin combined with dipyridamole, or clopidogrel are reasonable options. Therefore, patients

resistance to platinum compounds and high levels of thymidylate synthetage to pemetrexed. Confirmation of these observations in phase III trials is desirable.

Emerging evidence Emerging evidence on the anti-angiogenic effect of bevacizumab (ECOG4599 & AVAiL), BIBF1120, vandetanib, cediranib and zoledronic acid underlines the importance of targeting VEGF and the potential role of bFGF in tumour growth and metastasis. Angiogenesis is a

and doctors must consider risk factors, cost, tolerance and other characteristics to tailor the appropriate therapy. Stroke or TIA survivors who are diabetic should follow existing guidelines for blood sugar control. All stroke or TIA patients who have carotid artery blockage should aim for optimal medical therapy through a multifaceted approach, including antiplatelet drugs, statin therapy and lifestyle risk factor changes such as blood pressure management. When patients with high stroke risk due to atrial fibrillation (an abnormal heart rhythm) need to temporarily stop taking the anticlotting drug warfarin, they should receive low molecular weight heparin as bridging therapy to reduce the risk of blood clots. High blood pressure is the most critical risk factor for recurrent stroke. Doctors should work with patients to find the best drug regimen to suit each individual's blood pressure control needs, said Furie, director of the Massachusetts General Hospital Stroke Service and an associate professor at Harvard Medical School. As well as being linked to stroke, Metabolic Syndrome has been linked with other conditions such as memory loss and Psoriasis.

complex process and efforts to identify predictive biomarkers for anti-angiogenic therapy remains elusive. The value of KRAS mutation in NSCLC remains questionable. In addition to known molecular markers, it is highly likely that we will have many unrecognised subtypes that will be rare but of great clinical importance. Progress will come from understanding each of these subtypes profiling each patient’s tumour and tailoring therapy for the individual molecular profile detected.

E V I D E N T I A • V O L U M E 5 • I S S U E 2 • A P R I L / M AY 2 0 1 1

The PLATO study met its primary endpoint of reduction in CV death, MI or stroke: ARR 1.9%, RRR 16%, p < 0.001.1 Brilique (ticagrelor), co-administered with aspirin for up to 12 months, is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS).

www.ACSunited.co.uk BRILIQUETM▼ 90MG FILM-COATED TABLETS (ticagrelor) PRESCRIBING INFORMATION. Consult Summary of Product Characteristics before prescribing. Use: Adults aged 18 years and older, co-administered with 75-150mg acetylsalicylic acid (ASA) daily: for the prevention of atherothrombotic events in patients with acute coronary syndromes (unstable angina, non-ST-segment elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Presentation: 90mg ticagrelor film-coated tablets. Dosage and administration: Treatment should be initiated with a single 180mg loading dose (two tablets of 90mg) and then continued at 90mg twice daily. Treatment is recommended for up to 12 months unless discontinuation is clinically indicated. Premature discontinuation of treatment or lapses in therapy should be avoided. Patients treated with clopidogrel can be directly switched to Brilique. For oral use. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of intracranial haemorrhage. Moderate-tosevere hepatic impairment. Co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole). Precautions: Due to the increased risk of non-fatal or non-life-threatening bleeding, use with caution in patients at an increased risk for bleeding (e.g. recent trauma or surgery, bleeding disorders or recent gastrointestinal bleeding) or those on concomitant medication that may increase bleeding risk (e.g. NSAIDs, anticoagulants) within 24 hours of taking Brilique. Brilique should be stopped 7 days prior to elective surgery if the antiplatelet effect is not desired. Use with caution in patients with an increased risk of bradycardic events (e.g. patients on digoxin), as asymptomatic ventricular pauses have been observed with Brilique, a history of asthma and/ or COPD, a history of hyperuricaemia or gouty arthritis. Creatinine levels may increase during treatment with Brilique. Renal function should be checked after one month and thereafter according to routine medical practice, paying special attention to patients

≥ 75 years, patients with moderate-to-severe renal impairment and those receiving concomitant treatment with an ARB. Co-administration of Brilique is not recommended with a high maintenance dose of ASA (> 300mg) or with doses of simvastatin > 40mg. Co-administration of ticagrelor with strong CYP3A4 inducers is discouraged, as this may lead to a decrease in exposure and efficacy of ticagrelor. Brilique is not recommended during pregnancy and breastfeeding. Undesirable events: Common side effects include dyspnoea, epistaxis, gastrointestinal haemorrhage, subcutaneous or dermal bleeding, bruising and procedural site haemorrhage. Other adverse events include intracranial bleeding, elevations of serum creatinine and uric acid levels. Consult SmPC for a full list of adverse events. Legal category: POM. Marketing authorisation number: EU/1/10/655/004. Basic NHS cost: Brilique 90mg film-coated tablets, 56: £54.60. Further information is available from: AstraZeneca UK Ltd., 600 Capability Green, Luton, LU1 3LU. BRILIQUE is a trademark of the AstraZeneca group of companies. 11/2010 CV 10 0118

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to AstraZeneca on 0800 783 0033 Date of preparation: January 2011 CZ005042-BRILIQ Reference: 1. Wallentin L, Becker RC, Budaj A, et al. N Engl J Med 2009;361:1045-57. * In the PLATO study, all-cause mortality was a secondary endpoint (nominal p < 0.001)1 CV = cardiovascular; MI = myocardial infarction; ARR = absolute risk reduction; RRR = relative risk reduction

Cardiology reports

Antiplatelet ticagrelor may boost CABG survival

HE NOVEL reversible antiplatelet agent ticagrelor was associated with lower mortality from coronary artery bypass graft surgery (CABG) compared with standard clopidogrel (Plavix), according to a subanalysis of the pivotal PLATO trial. Compared with clopidogrel, ticagrelor cut total mortality by a relative 51% (4.7% versus 9.7%, P<0.01) and cardiovascular mortality by 48% (4.1% versus 7.9%, P<0.01), according to Claes Held, M.D., Ph.D., of Uppsala University in Uppsala, Sweden, and colleagues. The mortality advantage came with no excess bleeding risk, the researchers reported online in the Journal of the American College of Cardiology. In this patient subgroup, ticagrelor also was associated with the same 16% reduction in the primary composite outcome of cardiovascular death, myocardial infarction, and stroke at 12 months seen in the analysis of the overall trial data. Although the primary endpoint didn't reach statistical significance in the subgroup analysis (10.6% versus 13.1%, P=0.29), the mortality benefit in CABG patients was roughly twice that in the parent trial. Following a subanalysis that confirmed benefit for ticagrelor in the PLATO patients who had stenting prior to randomisation, Held's group retrospectively examined the results in the acute coronary syndrome patients who went on to have CABG after randomisation to ticagrelor (180mg loading, 90mg twice daily maintenance) or clopidogrel (300mg loading, 75mg once daily maintenance). Of those 1,899 patients, 1,261 had the procedure within seven days of discontinuing their study drug. The protocol recommended withholding the blood thinners preoperatively for a period of 24 to 72 hours with ticagrelor and five days with clopidogrel. CABG typically occurred during initial hospitalisation and was followed by reinitiation of study drugs within seven days for 57% of patients and within 14 days for 84%, without a difference between treatment groups. The numerical reduction in the overall composite outcome with ticagrelor appeared to be driven by the reduction in cardiovascular

death. Noncardiovascular death was numerically, but not significantly, reduced by a relative 65% to 0.7% compared with clopidogrel's 2.0% rate (P=0.07). Gender alone appeared to play a role in treatment effect among the demographic subgroup analyses within the CABG population. Ticagrelor reduced total and cardiovascular mortality only in men; women showed no advantage from the drug compared with clopidogrel. Total and cardiovascular mortality were no different between ticagrelor and clopidogrel if surgery was done within a day or more than four days after stopping either drug. But the mortality effects weren't related to differences in bleeding risk. Major CABG-related bleeding, as stringently defined in PLATO, occurred in about 80% of patients in both groups without a difference between the two (P=0.84). Nor were there differences in life-threatening or fatal CABG-related bleeds (P=0.77) or bleeding by TIMI major or TIMI minor criteria (P=0.68 and P=0.82) or by GUSTO severe criteria (P=0.39). Transfusion of blood products and reoperation because of bleeding were similar between treatment groups as well. The extra mortality benefit in CABG patients may help explain why the drug works so well, David J. Schneider, MD, of the University of Vermont in Burlington, argued in an accompanying editorial. The key difference between ticagrelor and clopidogrel is ticagrelor's reversible binding, which allows redistribution of the drug to all platelets, he pointed out. "Thus, ticagrelor, unlike clopidogrel, has the capacity to bind to new platelets as they are released rather than after the next dose of medication," Schneider wrote in JACC. "The redistribution of ticagrelor may contribute to a reduction in cardiovascular mortality." CABG plays up this mechanism because bleeding induced by the surgery boosts release of new, young platelets,

which are more reactive and may contribute greater thrombotic complication risk, he noted. Another contributor may be off-target effects by increasing endogenous adenosine concentrations that improve myocardial flow, Schneider suggested. Limitations of the current study included the fact that it was a retrospective analysis of a nonrandomised subgroup of a larger randomised trial, and categorisation of vascular versus nonvascular causes of death was only performed for the parent study. Disclosure: PLATO was funded by AstraZeneca. Held reported having received institutional grants from ScheringPlough, GlaxoSmithKline, Bristol-Myers Squibb, and AstraZeneca; being on the advisory board for AstraZeneca and Pfizer; and having received a scholarship from Pfizer. One co-author reported equity ownership in AstraZeneca; two others reported being employees of the company and holding stock in it. Schneider reported receiving consulting fees and grants from Johnson & Johnson, Bayer Pharmaceuticals, The Medicines Company, sanofiaventis, and Bristol-Myers Squibb. Reference: Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: Results from the PLATO (platelet inhibition and patient outcomes) trial. J Am Coll Cardiol 2011; 57

E V I D E N T I A • V O L U M E 5 • I S S U E 2 • A P R I L / M AY 2 0 1 1

Cardiology reports

The five hospital factors that affect heart attack survival

NEW YALE University study has looked at why there is such a big difference in the mortality rates among patients treated for heart attacks in hospitals across the country. The study appears in a recent issue of the Annals of Internal Medicine. Until now, little has been known about the factors that may influence this variation in death rates. The Yale team reviewed 11 hospitals through interviews and site visits. Those selected were among the best and worst performers, as rated by the federal agency that administers Medicare and Medicaid. "Previous research looked at whether hospital characteristics like urban location, teaching status, geographical region, and socio-economic status of patients are related to acute myocardial infarction (AMI) mortality rates, but these factors don't explain much of the variation in mortality," said Leslie A. Curry, Ph.D., research scientist at the Yale Global Health Leadership Institute and lead author on

the paper. "We were particularly interested in the roles of social interactions and organisational culture, which are difficult to measure using common research approaches like surveys." Hospitals in the high- and low-performing groups differed substantially in five ways: organisational values and goals, senior management involvement, broad staff presence and expertise in AMI care, communication and coordination, and problem solving. "Our research shows that the key facets to safety and quality in hospitals may not be new gadgets," says Elizabeth Bradley, Ph.D., faculty director at the Yale Global Health Leadership Institute, professor of public health and senior author on the paper. "The essential ingredients are not expensive. If we could implement our findings in more hospitals, we could improve quality without adding to costs." Staff in the best hospitals reported strong communication and coordination across

disciplines and departments. In low-performing hospitals, sporadic involvement of senior management was common, in part due to frequent turnover, and management did not create an environment that encouraged taking responsibility for performance problems. Curry says that achieving high performance may

"Our research shows that the key facets to safety and quality in hospitals may not be new gadgets..." Elizabeth Bradley

require long-term investment and concerted efforts to create an organisational culture that supports full engagement in quality, strong communication and coordination among groups, and capacity for problem solving and learning across the organisation. "What we found was that the best hospitals were distinguished by a combination of factors that related to how they organised and managed the care and the performance of the teams," says Harlan Krumholz, M.D., professor of medicine and cardiology at Yale School of Medicine. "This study begins to address our need to know what it takes to be an outstanding performer." The study was funded by the Agency for Healthcare Research and Quality, the Commonwealth Fund, and the United Fund.

Staff in the best hospitals reported strong communication and coordination across disciplines and departments.

E V I D E N T I A â&#x20AC;˘ V O L U M E 5 â&#x20AC;˘ I S S U E 2 â&#x20AC;˘ A P R I L / M AY 2 0 1 1

The Global Health Leadership Institute supports health leaders to improve the performance of health systems through leadership development, quality improvement programmes, and health systems research. For more information on the AMI study or GHLI, contact: rosalind.deugenio@yale.edu.

Date of preparation: February 2011 DSC/11/0006/G

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Cardiology reports

Metabolic syndrome linked to memory loss in older people

LDER PEOPLE with larger waistlines, high blood pressure and other risk factors that make up metabolic syndrome may be at a higher risk for memory loss, according to a study published in the online issue of Neurology, the medical journal of the American Academy of Neurology. Metabolic syndrome was defined as having three or more of the following risk factors: high blood pressure, excess belly fat, higher than normal triglycerides, high blood sugar and low high-density lipoprotein (HDL) cholesterol, or "good" cholesterol. Metabolic syndrome has also been tied to increased risk of heart attack. For the study, 7,087 people age 65 and older from three French cities were tested for metabolic syndrome. A total of 16% of the participants had metabolic syndrome.

Participants were given a series of memory and cognitive function tests two and four years later. The tests included a memory test, a test of visual working memory and a test of word fluency. Researchers found that people who had metabolic syndrome were 20% more likely to have cognitive decline on the memory test than those who did not have metabolic syndrome. Those with metabolic syndrome also were 13% more likely to have cognitive decline on the visual working memory test compared to those who did not have the syndrome. Specifically, higher triglycerides and low HDL cholesterol were linked to poorer memory scores; diabetes, but not higher fasting blood sugar, was linked to poorer visual working memory and word fluency scores. "Our study sheds new light on how metabolic syndrome and the individual factors

of the disease may affect cognitive health," said study author Christelle Raffaitin, M.D., of the French National Institute of Health Research in Bordeaux, France. "Our results suggest that management of metabolic syndrome may help slow down age-related memory loss, or delay the onset of dementia." The study was conducted under a partnership agreement between the French National Institute of Health Research (INSERM), the University Victor Segalen Bordeaux 2 and Sanofi-Aventis. The 3C Study was supported by the National Fund for Health Insurance for Employees, Directorate General of Health, Mutual General Education, the Institute of Longevity and Aging, Regional Councils of Aquitaine and Bourgogne and the Foundation of France. The Lille Genopole was supported by an unconditional grant from Eisai.

Features of the metabolic syndrome common in people with psoriasis

NDIVIDUALS WITH psoriasis have a high prevalence of the metabolic syndrome, according to a report published in the Archives of Dermatology, one of the JAMA/Archives journals. According to background information in the article, individual features of the metabolic syndrome include obesity, high blood pressure, diabetes and high total cholesterol and triglycerides. Additional background information notes that while past studies have suggested a link between psoriasis and individual components of the metabolic syndrome, there is little data available regarding the association between psoriasis and the metabolic syndrome as a whole. Using data from the National Health and Nutrition Examination Survey, Thorvardur Jon Love, M.D., of Landspitali University Hospital, Reykjavik, Iceland, and colleagues, examined the association between psoriasis and the metabolic syndrome. The study included 6,549 individuals, and the mean (average) age of participants was 39, half

were men and the mean body mass index (BMI) was 28. Overall, 40% of individuals with psoriasis also had features of the metabolic syndrome, compared with 23% among controls. The most common feature of the metabolic

Overall, 40% of individuals with psoriasis also had features of the metabolic syndrome, compared with 23% among controls.

syndrome among individuals with psoriasis was abdominal obesity (63%), followed by high triglyceride levels (44%) and low levels

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of high-density lipoprotein (HDL) or "good" cholesterol (34%). High triglyceride levels are defined as at or above 150 milligrams per decilitre, and low HDL levels are defined as less than 40 milligrams per decilitre in men and less than 50 milligrams per decilitre in women. No elements of the metabolic syndrome were found in 28% of individuals without psoriasis compared with 13% of those with psoriasis. "In conclusion, these findings from a nationally representative sample of U.S. adults show a doubling in the prevalence of the metabolic syndrome among patients with psoriasis independent of age, sex, race/ethnicity and C-reactive protein levels," the authors write. "Given its associated serious complications, this comorbidity needs to be recognised and taken into account when treating individuals with psoriasis," they conclude. Reference: Arch Dermatol. Published online December 20, 2010. doi:10.1001/archdermatol.2010.370

Prostate cancer reports

Screening 'does not prevent prostate cancer deaths', 20-year study concludes

OPULATION-WIDE screening using the prostate-specific antigen (PSA) test would not help to reduce the number of deaths from prostate cancer, a Swedish study suggests. PSA is a protein made by the prostate that is sometimes elevated in men with prostate cancer. However, it is currently unreliable as a screening tool, as men with normal PSA levels can still have prostate cancer, while PSA may rise as a result of non-cancerous prostate conditions, sexual activity, infection or vigorous exercise in men who are cancer-free. The latest research from Sweden's Karolinska Institute, published in the British Medical Journal, provides further information to add to the ongoing debate. Researchers analysed data on 9,026 men, aged 50 to 69 years, who took part in a trial that started in Sweden in 1987. Of these, 1,494 were randomly chosen to have screening every third year between 1987 and 1996, while the remaining men did not undergo screening. Those who had screening underwent digital rectal examination on their first two visits, and this exam was combined with PSA testing from 1993 onwards. The researchers followed all men who were

diagnosed with cancer before the end of 1999 until December 2008. Their analysis revealed that 5.7% of men in the screening group were diagnosed with prostate cancer, compared with 3.9% in the control group.

Men with normal PSA levels can still have prostate cancer, while PSA may rise as a result of non-cancerous prostate conditions, sexual activity, infection or vigorous exercise in men who are cancer-free.

Tumours in men who were screened tended to be smaller and were less likely to have spread than those found in the control group. This suggests that screening helped to detect

prostate cancers at an earlier stage. Despite this, survival was not significantly longer or more likely for men in the screening group. Furthermore, the researchers pointed out that screening could increase the risk of overdiagnosis and over-treatment, which can cause harmful side-effects. This is because many of the small prostate tumours detected by screening are slowgrowing and unlikely to cause any problems during the patient's lifetime. At present, there is no way of telling the difference between harmless, slow-growing tumours and more aggressive ones that need treatment. To support their claim, the researchers cited a previous study suggesting that 1,410 men would need to be screened and 48 treated to prevent one death from prostate cancer. The study authors wrote: "After 20 years of follow-up, the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group." Professor Malcolm Mason, Cancer Research UK's prostate cancer expert, commented: "This trial found that screening did not reduce deaths from prostate cancer and there is no escaping from the fact that we need a better tool than PSA to help detect prostate cancers that actually need treating, as opposed to innocent ones that do not. "This study adds to the debate on prostate cancer screening. It re-emphasises that screening using PSA testing and digital rectal examination will detect a large number of prostate cancers that don't need treatment. But, once diagnosed, the cancer will be treated, sometimes leading to men suffering significant side-effects. "In the meantime, men should be fully informed about the pros and cons of having their PSA measured." Reference: Sandblom G, Varenhorst E, Rosell J, Löfman O, Carlsson P. Randomised prostate cancer screening trial: 20 year follow-up. BMJ 2011 Mar 31; 342: d1539 doi: 10.1136/bmj.d1539

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6 months between injections? I’m OK with that. Efficacy equivalent to the gold standard Decapeptyl® SR gives you the reassurance of predictable efficacy, equivalent to the gold standard of surgical castration,1-5 for the management of advanced prostate cancer

Extended choice Decapeptyl® SR is the only LHRH agonist in the UK that gives your patients the option of 1, 3 or 6 months between injections

Prescribing Information DECAPEPTYL® SR 3 mg, DECAPEPTYL® SR 11.25 mg and DECAPEPTYL® SR 22.5mg Presentation: Powder for suspension for injection. Vials for all preparations contain an overage to ensure the licensed dose is administered. Decapeptyl SR 3mg: Triptorelin acetate 4.2mg. Decapeptyl SR 11.25mg: Triptorelin acetate 15mg. Decapeptyl SR 22.5mg: Triptorelin pamoate 28mg. Triptorelin acetate and triptorelin pamoate are bioequivalent. Uses: Treatment of locally advanced, nonmetastatic prostate cancer, as an alternative to surgical castration, and treatment of metastatic prostate cancer. Dosage and Administration: Decapeptyl SR 3mg: One intramuscular (i.m.) injection every four weeks (28 days). Decapeptyl SR 11.25mg: One i.m. injection every 3 months. Decapeptyl SR 22.5mg: one i.m. injection every 6 months. Additional dosing information: No dosage adjustment necessary in the elderly. The injection site should be varied periodically. Inadvertent intravascular administration must be avoided. Contraindications: Hypersensitivity to LHRH, its analogues or any other component of the medicinal product. Precautions and Warnings: Long-term use of LHRH agonists is associated with an increased risk of bone loss and may lead to osteoporosis and increased risk of bone fracture. Particular caution in patients with risk factors for, or established osteoporosis is necessary. Rarely, LHRH agonist treatment may reveal the presence of a gonadotroph cell pituitary adenoma. Mood changes, including depression have been reported. Patients with known depression should be monitored closely during therapy. Initially, Decapeptyl SR, like other LHRH agonists, causes a transient increase in serum testosterone levels. As a consequence isolated cases of transient worsening of signs and symptoms of prostate cancer (tumour flare) and cancer related (metastatic) pain may occasionally develop during the first weeks of treatment and should be managed symptomatically. During the initial phase of treatment, consideration should be given to the additional administration of a suitable anti-androgen to counteract the initial rise in serum testosterone levels and the worsening of clinical symptoms. As with other LHRH agonists, isolated cases of spinal cord compression or urethral obstruction have been observed. Careful monitoring, is indicated during the first weeks of treatment, particularly in patients suffering from vertebral metastases, at risk of spinal cord compression, and in patients with urinary tract obstruction. After surgical castration, Decapeptyl SR does not induce any further decrease in testosterone levels. From epidemiological data it has been observed that patients may experience metabolic changes (e.g. glucose intolerance), or an increased risk of cardiovascular disease during androgen deprivation therapy (ADT). Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and their glucose, cholesterol and blood pressure adequately monitored during ADT at appropriate intervals not exceeding 3 months. Administration of triptorelin in therapeutic doses results in suppression of the pituitary gonadal system. Date of preparation: January 2011. DEC08376c

Normal function is usually restored after treatment is discontinued. Diagnostic tests of pituitary gonadal function conducted during and after discontinuation of therapy with LHRH agonists may therefore be misleading. Interactions: Drugs which raise prolactin levels should not be prescribed concomitantly as they reduce the level of LHRH receptors in the pituitary. When Decapeptyl SR is co-administered with drugs affecting pituitary secretion of gonadotropins, caution should be exercised and it is recommended that the patient’s hormonal status be supervised. Pregnancy and Lactation: Not applicable. Undesirable effects: Very common: Asthenia, hyperhidrosis, back pain, paraesthesia in lower limbs and hot flush. Common: Nausea, fatigue, injection site erythema, injection site inflammation, injection site pain, injection site reaction, oedema, musculoskeletal pain, pain in extremity, dizziness, headache, erectile dysfunction and loss of libido. Rarely, cases of anaphylaxis and hypersensitivity have been reported. Prescribers should consult the Summary of Product Characteristics in relation to other side effects. Overdosage: No human experience of overdosage. Pharmaceutical Precautions: Do not store above 25°C. Reconstitute only with the suspension vehicle provided. Decapeptyl SR is a suspension, therefore once reconstituted, it should be used immediately. Legal Category: POM. Basic NHS cost: Decapeptyl SR 3mg £69.00 per vial. Decapeptyl SR 11.25mg £207.00 per vial. Decapeptyl SR 22.5mg £414.00 per vial. Marketing Authorisation Numbers: Decapeptyl SR 3mg: PL 34926/0002. Decapeptyl SR 11.25mg: PL 34926/0003. Decapeptyl SR 22.5mg: PL 34926/0013. Marketing Authorisation Holder: Ipsen Ltd., 190 Bath Road, Slough, Berkshire, SL1 3XE, UK. Tel 01753 627777. Date of preparation of PI: Dec 2010. Ref: UK/DEC08401a. (PSUR work sharing update) Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to the Ipsen Medical Information department on 01753 627777 or medical.information.uk@ipsen.com References 1. Parmar H et al. Br J Urol Int 1987; 59(3): 248-254. 2. Botto H et al. 3rd International Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment. 1992. Paris. 107-110. 3. Heyns CF et al. Br J Urol Int 2003; 92: 226-231. 4. Heidenreich A. J Urol 2008; 179(4) Suppl: Abstract 513. 5. Data on file DEC/014/APR09.

Prostate cancer reports

Gene expression test for prostate cancer shows promise

HE EXPRESSION of specific genes in prostate stroma predicted the presence of nearby cancer with 97% overall accuracy, data from a large group of tissue samples showed. Stroma adjacent to or near prostate tumours exhibited gene expression that differed significantly from normal stroma. The correlation between stromal gene expression and cancer increased with proximity to cancer, as reported in the recent issue of Cancer Research. The 114-gene panel had 98% sensitivity and 88% specificity for predicting the presence of cancer. In contrast, a randomly selected 100-gene panel had no predictive value. "These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for categorising the presence of tumour in patients when a prostate sample is derived from near the tumour but does not contain any recognisable tumour," Dan

Mercola, M.D., Ph.D., of the University of California Irvine, and co-authors wrote in conclusion. If replicated in additional studies, the gene test has multiple therapeutic implications. "The information in nontumour tissue indicating 'presence of tumour' or not indicates who needs urgent rebiopsy and allows patients to consider alternative therapies to surgery or radiation, such as neoadjuvant therapy or prostate cancer prevention treatment," Mercola said in a statement. Numerous studies have identified a large number of changes in gene expression at the RNA level specific to the microenvironment of prostate cancer. Additionally, studies have shown that stromal tissue plays a major role in prostate cancer progression, the authors noted in their introduction. Whether changes in RNA gene expression could distinguish normal stroma from stroma near tumour remained unclear. Mercola and colleagues sought to determine whether stromal gene changes had diagnostic potential for prostate cancer. The investigators compared gene expression profiles in 13 prostate biopsy specimens containing stroma near tumour and in 15 biopsy specimens from men without prostate cancer. The analysis identified 3,800 significant changes in expression. After filtering for age-related genes and for genes known to be expressed at detectable levels in tumours, the authors developed a 114-gene stroma-specific classifier for nearby tumour. They tested the classifier in 364 prostate specimens, consisting of 243 tumour-bearing samples and 121 normal specimens. The 364 specimens included samples from normal prostate biopsies, normal prostate tissue obtained from autopsies, stroma remote to tumour, and stroma from within a few millimetres of tumour. The gene panel correctly identified all but two of the 243 tumour-containing specimens. Review of the two misclassifications suggested the tissue

might not have come from patients with prostate cancer. The investigators also compared expression patterns in stromal tissue near and remote from tumour. They found a gradient of classification frequency values of 98%, 75% and 36% for stromal samples adjacent to, close to, and remote (>15mm) from tumour. "Such observation bears on the likely mechanism for the production of differential

Numerous studies have identified a large number of changes in gene expression at the RNA level specific to the microenvironment of prostate cancer.

gene expression in tumour-adjacent stroma, which is generally believed to involve the influence of 'paracrine' factors emanating from tumour foci," the authors noted. Their findings compare favorably with the reported diagnostic accuracy of PSA-based classification techniques of about 70%, they added. The findings suggest several practical applications of the gene test, such as assessment of suspicious initial biopsies and possibly therapeutic targeting of stromal expression changes indicating the presence of tumour, leaving normal stroma relatively untouched. Mercola and co-authors Michael McClelland and Waldemar Lernhardt disclosed relationships with Proveri, a company involved in translational research related to the gene expression study. Reference: Jia Z, et al. Diagnosis of prostate cancer using differentially expressed genes in stroma. Cancer Res 2011; 71: 2476-2487

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European Multidisciplinary Conference on Thoracic Oncology Reports from the EMCTO, Lugano by Adrian Catterall

Screening and early detection

HERE ARE currently six randomised European lung cancer screening trials ongoing (32,000 people enrolled) in which low dose CT scanning is compared with no screening. Most have now been completed and the initial results of one trial (NLST) have been published by the National Cancer Institute (NCI).1 The main results show 20% fewer lung cancer deaths among those who were screened with low-dose spiral CT than with chest X-ray and an overall 6.9% all cause mortality reduction. However, the participants were of a younger age, better educated and less likely to be current smokers than with a similar U.S. population. The results of the European studies are anticipated between 2011 and 2015. The studies differ in their design and comparisons used, for example, the EUCT has non-screening as the control arm, others have 3D evaluation and different intervals between screening episodes. Additionally, there is no data on the costeffectiveness nor on the QALYs gained. As the full results will not be available for some time, investigators are using model predicted outcomes to obtain results with initial results showing an encouraging reduction in lung cancer death rates of 28% at five years.

Incidental lung nodules. What do you do?

The future of screening with molecular biology

A lung nodule is defined as a radiological round opacity up to 3cm, surrounded by lung parenchyma. The Bayesian approach is to estimate the probability of malignancy based on the clinical, radiological and metabolic characteristics (SUVmax [PET]) of the nodule.2 Dr. Sculier discussed several clinical scenarios to demonstrate the Bayesian approach and the higher the risk the more appropriate and speed of investigations can be performed.

The aim of developing biomarkers as a clinical application is to determine a marker for early diagnosis, progression and response to therapy. The different types of markers include DNA, RNA and proteins. The rate of studied markers (DNA methylation, microsatellite

Follow-up of the patient after curative treatment There is currently only one randomised study in NSCLC assessing follow-up of patients. Follow-up should focus on detecting asymptomatic recurrences and the results of treatment should be higher than for treatment only when symptomatic. Thus far no randomised study has proved a survival benefit to long-term survival following curative treatment. Several retrospective and prospective studies suggest that a survival advantage may occur in patients with asymptomatic recurrence and that a chest X-ray and or CT scan are the most appropriate investigations. Current recommendations advise history and physical examination, chest x-ray or CT scan with regular follow-up for 2 years then annually. The IFCT 03-02 is an ongoing randomised study from France that is comparing minimal follow-up with intensive investigation, including bronchoscopy. Thus far 1,337 patients have been enrolled.

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Follow-up should focus on detecting asymptomatic recurrences and the results of treatment should be higher than for treatment only when symptomatic.

changes, K-ras mutations, p53 mutations and RNA expression markers) generally have a low rate of expression in clinical lung cancer series. MicroRNA is a new class of biomarker, that has recently been shown to predict development and prognosis of CT detected lung cancer.3 The results from this trial indicate sensitivity and specificity in excess of 90%. Furthermore, specific microRNA lines were able to predict aggressive lung cancer and also lung cancer development before its clinical appearance. References: 1. National Cancer Institute. Lung cancer trial results show mortality benefit with low dose CT. 2011 [updated 2011; cited]; Available from:http://www.cancer.gov/newscenter/pressreleases/ NLSTresultsRelease 2. Cummings SR, Lillington GA, Richard RJ. Estimating the probability of malignancy in solitary pulmonary nodules. A Bayesian approach. Am Rev Respir Dis 1986 Sep; 134(3): 449-52 3. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci USA 2011 Mar 1; 108(9): 3713-8

Maintenance treatment - yes or no? What is maintenance? Terms and concepts

AINTENANCE TREATMENT is the prolongation of the treatment duration with administration of additional drugs at the end of a defined number of initial chemotherapy cycles, after achieving tumour control in an individual patient. A general consensus has not been reached on the terms: maintenance, consolidation, alternating, sequential, early second-line and switch maintenance. Sequential chemotherapy in NSCLC is the sequential administration of non-cross resistant chemotherapy for a defined number of cycles and does not require documented progression. Alternating chemotherapy is the alternating administration of non-cross resistant drug combinations for a defined number of cycles or until disease progression. For advanced NSCLC the options following first-line induction therapy include: Continue induction therapy for a fixed number of cycles (consolidation) or until progression (maintenance) Continuing third-generation (no platinum compound) used in induction regimen (continuation maintenance) Continuing only the target agent used in induction regimen (continuation maintenance) Initiating a different agent (early second-line or switch maintenance)

Maintenance by chemotherapy Overall, the evidence does not support continuation therapy in advanced NSCLC with no improvement in overall survival and continued regimens may increase the rate of toxicity.1 Switch maintenance trials have demonstrated an improvement in PFS (docetaxel and pemetrexed) and overall survival (pemetrexed). The immediate commencement of docetaxel following induction therapy improves PFS compared with delayed docetaxel (5.7 versus 2.7 months).2 Pemetrexed was recently shown to significantly improve both

PFS and overall survival.3 Continuation maintenance therapy consists of non-platinum agents used in combination, for example paclitaxel and gemcitabine. The data from several studies show an advantage to using continuation therapy with these two agents for PFS, but not for overall survival, however, the number of patients enrolled is small and insufficient to show a survival advantage. Furthermore, these studies generally have not shown a quality of life advantage. Significant toxicity associated with continuation maintenance is low. Studies with larger numbers of patients are in progress.

Advanced NSCLC: Maintenance with target therapies Targeted agents are currently used in the induction phase; both bevacizumab and cetuximab have been proven to improve PFS and overall survival. For maintenance treatment, the SATURN study (Phase III multicentre randomised placebo controlled) assessed erlotinib with a primary endpoint of PFS.4 The results showed that erlotinib significantly improved PFS compared with placebo, although the benefit occurred in both EGFR wild-type and mutated tumours, but more so in the mutated tumours. Dr. Gridelli also commented that the majority of patients treated in the placebo group additionally received a TK inhibitor. The overall survival in patients with EGFR wild type and with stable disease was significantly higher in those treated with erlotinib. Consequently the EMEA and FDA approved erlotinib only for patients with stable disease. Erlotinib was generally well tolerated with low numbers of withdrawals and the commonest adverse events were rash and diarrhoea. A Phase III study (ATLAS) showed patients with advanced

NSCLC who received erlotinib in combination with bevacizumab as first-line maintenance treatment had a 39% improvement in PFS, compared with those who received bevacizumab plus placebo (hazard ratio=0.72; p=0.0012). Adverse events were consistent with previous bevacizumab or erlotinib NSCLC studies, and trials evaluating the two medicines together. The current recommendation for maintenance therapy is erlotinib or pemetrexed, but the final decision to treat should be based on histological type, response to induction therapy, toxicity and patient symptoms and preference. Tumours that express EGFR mutation should receive TK inhibitors. References: 1. Smith IE, O'Brien ME, Talbot DC, Nicolson MC, Mansi JL, Hickish TF, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomised trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001 Mar 1; 19(5): 1336-43 2. Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-smallcell lung cancer. J Clin Oncol 2009 Feb 1; 27(4): 591-8 3. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009 Oct 24; 374(9699): 1432-40 4. Cappuzzo F. Erlotinib as maintenance treatment in advanced non small lung cancer: a multicentre randomised placebo controlled phase 3 study. 2010 [updated 2010; cited]; Available from: http://www.thelancet.com/journals/lanonc/article/PIIS147 0-2045(10)70112-1/abstract

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European Multidisciplinary Conference on Thoracic Oncology Reports from the EMCTO, Lugano by Adrian Catterall

Personalised treatment in NSCLC Personalised treatment according to age and performance status

ATIENTS WITH a poor performance status (PS) are often excluded from clinical trials. Sculier et al, demonstrated that PS was the most important prognostic indicator for overall survival and age was an important risk factor.1 In 2009, Azzoli et al, made recommendations for the treatment of fit patients (PS 0-1).2 These included

Patients with NSCLC present at a median age of around 65 and 1/3 are aged greater than 70.

platinum-based combinations over nonplatinum combinations, that a combination of two cytoxic drugs is optimal, cisplatin produces higher response rates than carboplatin and that triple therapy is more toxic with no survival advantage. A meta-analysis was performed to evaluate chemotherapy versus best supportive care for patients with PS2.3 Patients with PS2

and treated with cisplatin or carboplatin gained a survival benefit of 6% and a one-year survival rate of 8% - 14% compared with 8% and 26% - 34% respectively for PS0, demonstrating a marginal benefit for less fit patients. Other studies show a similar outcome for patients with PS2, except for one study where patients with PS2 significantly gained from double therapy compared with monotherapy (comparing gemcitabine with gemcitabine plus carboplatin).4 Gefitinib was shown to benefit patients with EGFR mutated disease and a poor PS.5 Patients with NSCLC present at a median age of around 65 and 1/3 are aged greater than 70. Again, this group are under represented in clinical trials. For elderly patients, the EORTCLung Cancer Group-SIOG recommend thirdgeneration agents and published data to support the use of vinorelbine, gemcitabine or docetaxel. The new paradigm of treatment is carboplatin plus weekly paclitaxel which has proved superior to single agent chemotherapy in the IFCT-0501 study of elderly patients.6

Treatment based on EGFR/ KRAS mutations and ALK Identification of tumour molecular abnormalities has led to the development of new chemotherapeutic agents with increased efficacy. KRAS mutations have shown to act as a negative prognostic indicator and correlates with a response to EGFRTKIs, but there is no correlation with progression free survival or overall survival.7 Also there is no clear correlation with the efficacy of EGFRantibodies.8 However, a recent study (Battle trial) has suggested a correlation of disease control with sorafenib for patients with the KRAS mutation, but the number of patients evaluated was small.9

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Mutations in the tyrosine kinase (TK) domain of the EGFR gene are strong predictors of a more favourable prognosis and also a response to TK inhibitors compared with wild type.10 However, the prevalence of TK mutations is only around 10% in Caucasians and there is

The oncogenic fusion genes of EML4 EW are present in about 5% of NSCLC cases and act as an oncogenic driver.

concern regarding resistance developing after treatment. Afatinib has been used with some success in such cases. The oncogenic fusion genes of EML4 EW are present in about 5% of NSCLC cases and act as an oncogenic driver. Crizotinib, a cMET and TK inhibitor has shown to be efficacious in this group of patients. Crizotinib has also shown to improve response rate of 57% in patients with ALK positive NSCLC.11 A study is in progress to compare the effect of crizotinib with pemetrexed or docetaxel in ALK positive patients. It is anticipated that in the future, patients with NSCLC will be investigated for KRAS mutation, EGFR, EML4-ALK in a stepwise fashion and possibly with others that might be developed.

Chemotherapy selection according to chemotherapy markers Dr. Rossell performed a customised chemotherapy trial based on ERCC1 after evidence suggested ERCC1 was a predictive marker in patients with NSCLC. However, a Phase III study failed to show any evidence of a correlation with chemotherapy response. Several reports have suggested that the BRCA1 gene is crucial to DNA repair response. Preliminary results of two ongoing randomised trials in Europe and China have demonstrated

that progression free survival significantly improved in patients treated with erlotinib at low risk of BRCA1 and AEG-1 expression. RAP80, a ubiquitin-binding protein, regulates the function of BRCA1. A study showed that survival was improved with low levels of RAP80 and low levels of BRCA1. An ongoing international European study aims to assess BRCA1 and RAP80 expression in patients

Several reports have suggested that the BRCA1 gene is crucial to DNA repair response.

with advanced NSCLC. Patients in the control group are treated with docetaxel/cisplatin and the remaining patients (1:1 ratio) are randomised to receive: Gemcitabine/cisplatin for T1 RAP80 (T1-T3 BRCA1) Docetaxel/cisplatin for T2-T3 RAP80 (T1-T2 BRCA1) Docetaxel for T2-T3 RAP80 (T3 BRCA1) Thus far, 210 patients have been recruited, but no analysis has yet been performed.

Beyond EGFR/KRAS/ALK Somatic mutations of the HER2 gene occur in about 3% of cases of NSCLC and have an exclusionary relationship with EGFR/KRAS. There have been case reports of patients with HER2 mutations responding to trastuzumab and paclitaxel and similarly, patients with adenocarcinoma of the lung with mutations of HER2neu was shown to respond to BIBW2992 therapy. Inappropriate activation of "invasive growth" has been linked with mediation by hepatocyte growth factor (HGF) and the c-MET receptor. c-Met mutations occur on 1% - 6% of lung adenocarcinoma cases. A recent randomised trial revealed that c-MET antibodies in combination with erlotinib improved the median progression free survival in patients with advanced NSCLC.12 ROS (ROS1) is a proto-oncogene which is expressed in normal lung tissue, but elevated in

20 - 30% of patients with NSCLC. siRNA inhibits ROS expression in cell lines, prompting clinical studies of this action as a possible therapeutic target. Elevated phospho-PDGFR-alpha was found in 1/41 cell lines and in 8/150 tumour samples and occurs in 4% and 9% of adenocarcinomas and squamous cell carcinomas respectively. In cell lines, PDGFRA-activation sensitizes lung cancer cells to sunitinib. Other candidate ocogenes under evaluation include MEK1 (MAP2K1), BRAF, PIK3CA and FGFR4. Dr. Mitsudomi recommended systematic screening for activated oncogenes relevant to cancer cells via functional screening or a genomic approach and anticipated that TK is probably the most relevant target for new chemotherapeutic agents. References: 1. Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumours and the proposals for the 7th Edition. J Thorac Oncol 2008 May; 3(5): 457-66 2. Azzoli CG, Baker S, Jr., Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009 Dec 20; 27(36): 6251-66 3. NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomised controlled trials. J Clin Oncol 2008 Oct 1; 26(28): 4617-25 4. Kosmidis PA, Dimopoulos MA, Syrigos K, Nicolaides C, Aravantinos G, Boukovinas I, et al. Gemcitabine

versus gemcitabine-carboplatin for patients with advanced non-small cell lung cancer and a performance status of 2: a prospective randomised Phase II study of the Hellenic Cooperative Oncology Group. J Thorac Oncol 2007 Feb; 2(2): 135-40 5. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harbouring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009 Mar 20; 27(9): 1394-400 6. Quoix E. Weekly paclitaxel combined with monthly carboplatin versus single agent therapy in patients age 70 to 89: IFCT-0501 randomised Phase III study in advanced non small cell lung cancer (NSCLC). 2010 [updated 2010; cited 10th March 2011]; Available from: http://www.asco.org/ascov2/Meetings/Abstracts?&vmvi ew=abst_detail_view&confID=74&abstractID=41167 7. Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated nonsmall-cell lung cancer: data from the randomised Phase III INTEREST trial. J Clin Oncol 2010 Feb 10; 28(5): 744-52 8. Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a Phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010 Feb 20; 28(6): 918-27 9. Herbst. Battle Trial. American Society of Clincal Oncology; 2010 10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009 Sep 3; 361(10): 947-57 11. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010 Oct 28; 363(18): 1693-703 12. Spigel. Randomised, Phase II study evaluating MetMAb, in combination with erlotinib, in patients with advanced NSCLC (OAM4558g). European Society for Medical Oncology; 2009.

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Pain study

Scientists learn to block pain at source Discovery of pain-causing compounds leads to development of new non-addictive painkillers

SUBSTANCE SIMILAR to capsaicin, which gives chilli peppers their heat, is generated at the site of pain in the human body. Scientists at The University of Texas Health Science Center at San Antonio have discovered how to block these capsaicin-like molecules and created a new class of non-addictive painkillers. The findings were published in the Journal of Clinical Investigation. The senior investigator was Kenneth Hargreaves, D.D.S., Ph.D., professor and chair of the Department of Endodontics in the Dental School at the UT Health Science Center. Amol M. Patwardhan, M.B.B.S., Ph.D., a graduate of the Health Science Center's Department of Pharmacology who worked under Dr. Hargreaves' supervision, is the lead author. "Nearly everyone will experience persistent pain at some point in their lifetime," Dr. Hargreaves said. "Our findings are truly exciting because they will offer physicians, dentists and patients more options in prescription pain medications. In addition, they may help circumvent the problem of addiction and dependency to pain medications, and will have the potential to benefit millions of people who suffer from chronic pain every day."

A 'complex epidemic' Pain has been called a "complex epidemic" in the United States. Nearly 50 million Americans live with chronic pain caused by disease or injury. Few physicians or dentists specialise in the field of pain medicine. With pain medication options largely limited to opioids (such as

morphine) and aspirin-like drugs, some patients become addicted or dependent upon these drugs, or suffer side effects such as kidney or liver damage.

"Our findings are truly exciting because they will offer physicians, dentists and patients more options in prescription pain medications.”

Researchers at the UT Health Science Center found a new family of fatty acids, produced by the body itself, that play an important role in the biology of pain. "Capsaicin is an ingredient in hot chilli peppers and causes pain by activating a receptor called transient potential vanilloid 1 (TRPV1). We started out seeking the answer to the question "Why is TRPV1 consistently activated in the body upon injury or painful heat? We wanted to know how skin cells talk to pain neurons," Dr. Hargreaves said. "What we found was much more surprising and exciting. We have discovered a family of endogenous capsaicin-like molecules that are naturally released during injury, and now we understand how to block these mechanisms with a new class of nonaddictive therapies."

The hot chilli pepper effect Researchers used flaps of skin from laboratory mice that were heated in a water bath at temperatures greater than 43 degrees Celsius. The degree of heat used was significant because the human body normally begins to feel discomfort and pain at 43 degrees Celsius and higher, Dr. Hargreaves noted. TRPV1 resides on the membranes of pain- and heat-sensing neurons. When a person eats a hot chili pepper, for example, they immediately feel a burning sensation because the capsaicin, the primary ingredient in the chilli pepper, has activated the TRPV1 protein in the pain neurons. In high concentrations, capsaicin can also cause a burning effect on other sensitive areas of the skin. The fluid from the heated skin was then applied to sensory neurons cultured from two sets of laboratory mice, including one set of animals in which a gene was deleted or "knocked out." Neurons from the wild type (non-altered) mice were sensitive to capsaicin. The neurons of the knockout mice, in which the TRPV1 gene was deleted, were not sensitive to capsaicin and were used as the control. "We found that in the skin flaps heated at greater than 43 degrees Celsius, the cells' pain neurons showed tremendous activity in the wild type, but not in neurons from mice that lacked TRPV1," Dr. Hargreaves said. He indicated that this novel phenomenon was taking place because the cells, in response to the heat, began to create their own natural endogenous capsaicins, which they later identified as a series of compounds or fatty acids called oxidized linoleic acid metabolites (OLAMs). Linoleic acid is one of the most abundant fatty acids in the human body. Under conditions such as inflammation, low blood pressure and some other illnesses, linoleic acid is rapidly oxidized to form biologically active metabolites. However, little else is understood about these substances. The metabolites that were CONTINUED ON PAGE 20 >

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INTRODUCING A NEW CLASS IN PAIN RELIEF1

Start to unlock severe chronic back pain with Palexia SR

Palexia SR (tapentadol prolonged release tablets) is indicated for the treatment of severe chronic pain in adults, which can be adequately managed only with opioid analgesics2 Tapentadol is a Controlled Drug, Schedule 2

Visit evi.palexia.co.uk for more information

PALEXIA® and PALEXIA SR® Prescribing Information Refer to the Summary of Product Characteristics (SmPCs) before prescribing. Presentation: Palexia: 50 mg (white) and 75 mg (pale yellow) film-coated tablets contain 50 mg and 75 mg of tapentadol (as hydrochloride) respectively. Palexia SR: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Indication: Palexia is indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Swallowed whole with sufficient liquid, with or without food. Palexia SR should not be divided or chewed. Palexia dosage: Initial dose 50 mg every 4 to 6 hours. On the first day of dosing, an additional dose may be taken 1 hour after the initial dose, if no pain control. The first day’s dose should not exceed 700 mg. Maximum maintenance daily dose of up to 600 mg. Palexia SR dosage: Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in severe patients. Caution and dose adjustments with moderate hepatic impairment.

Elderly: May need dose adjustments. Children below 18 years: Not recommended. Contraindications: Hypersensitivity to ingredients, suspected or having paralytic ileus, acute alcohol intoxication, hypnotics, centrally acting analgesics or psychotropics. Not for use when mu-opioid receptor agonists are contraindicated (e.g. significant respiratory depression, acute or severe bronchial asthma or hypercapnia). Special warnings and precautions: At risk patients may require monitoring due to misuse, abuse, addiction or diversion. At high doses or in mu-opioid receptor agonist sensitive patients, dose-related respiratory depression may occur. Caution and monitoring required with impaired respiratory function. Should not use in patients susceptible to intracranial effects of carbon dioxide retention (e.g. increased intracranial pressure, impaired consciousness or coma). Use with caution with head injury, brain tumors, history or at risk of seizures, moderate hepatic impairment, biliary tract disease or acute pancreatitis. Not recommended with severe renal or hepatic impairment. Avoid use in patients who have taken monoaminie oxidase inhibitors (MAOIs) within the last 14 days, due to cardiovascular events. Should not use with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: Use with benzodiazepines, barbiturates and opioid analgesics, antitussive drugs and substitutive treatments may enhance the risk of respiratory depression. Central nervous system (CNS) depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect and impair vigilance. Consider dose reduction with respiratory or CNS depressant agents. In isolated cases, serotonin syndrome has been reported with Palexia/Palexia SR in

combination with serotoninergic medicinal products (e.g. serotonin reuptake inhibitors). Care should be taken with mixed mu-opioid agonist/ antagonists or partial mu-opioid agonists due to risk of reducing the analgesic effect. Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia/Palexia SR. Risk of decreased efficacy or adverse events if used with strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort). Pregnancy and lactation: Do not use. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in treatment, in connection with alcohol or tranquilisers. Undesirable effects: Very common (≥1/10): dizziness, somnolence, headache, nausea. Palexia only: vomiting. Palexia SR only: constipation. Common (≥1/100, <1/10): decreased appetite, anxiety, sleep disorder, tremor, flushing, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change. Palexia only: confusional state, hallucinations, dry mouth, muscle spasms, constipation, abnormal dreams. Palexia SR only: depressed mood, nervousness, restlessness, disturbance in attention, involuntary muscle contractions, dyspnoea, vomiting, mucosal dryness, oedema. Other important undesirable effects: Palexia only: respiratory depression (uncommon ≥1/1000, <1/100), hypersensitivity (rare ≥1/10,000, <1/1000); Palexia SR only: drug hypersensitivity (uncommon ≥1/1000, <1/100), respiratory depression (rare ≥1/10,000, <1/1000). No evidence of increased risk of suicidal ideation or suicide with Palexia/Palexia SR. Consult the SmPCs for full details. Overdose: Seek specialist treatment (see SmPCs). Legal classification: POM, CD (Schedule

II). Marketing Authorisation numbers, pack sizes and basic NHS cost: Palexia: 50 mg: PL 21727/0032, 28 (£12.46) and 56 pack (£24.91); 75 mg: PL 21727/0033, 28 (£18.68) and 56 pack (£37.37). Palexia SR: 50 mg: PL 21727/0041, 28 pack (£12.46) and 56 pack (£24.91); 100 mg: PL 21727/0042, 56 pack (£49.82); 150 mg: PL 21727/0043, 56 pack (£74.73); 200 mg: PL 21727/0044, 56 pack (£99.64) and 250 mg: PL 21727/0045, 56 pack (£124.55). Marketing Authorisation Holder: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, UK. Date of preparation: March 2011. P10 0057b

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Grünenthal Ltd (telephone 0870 351 8960). References 1. Kress HG. Eur J Pain. 2010; 14(8):781–783 2. Palexia SR, Summary of Product Characteristics. 06 August 2010 P11 0078e Date of preparation: February 2011.

Pain study

Experts call for greater pain assessment in hospitals as 65% of patients report problems 42% of those rated their pain as more than seven out of ten, where ten was the worst pain imaginable

EARLY TWO-THIRDS of the hospital in-patients who took part in a survey had experienced pain in the last 24 hours and 42% of those rated their pain as more than seven out of ten, where ten was the worst pain imaginable, according to a recent issue of the Journal of Clinical Nursing. Although eight out of ten patients had been asked about their pain levels by staff, less than half of those had been asked to rate their pain on a simple numeric scale. Researchers from Uppsala University, Sweden, studied 759 patients aged from six weeks to 95, with parents completing the surveys for the younger children. The average age of the patients was 59 and 52% were female. Just over two-thirds (68%) of the 1,112 patients in the hospital on the day of the survey were able or willing to take part. "Pain is a natural part of many medical conditions, but it can have a negative affect on quality of life, how successful treatment is and the patient's prognosis," says lead author Dr. Barbro Wadensten, associate professor in the Department of Public Health and Caring Sciences at the University. "Managing a patient's pain is very important and our survey sought to quantify how

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consistently seen in increased amounts in the mouse skin biopsies exposed to heat temperatures greater than 43 degrees Celsius are called 9- and 13-HODE (hydroxyoctadecadienoic acid).

'Major breakthrough' "This is a major breakthrough in understanding the mechanisms of pain and how to more effectively treat it," Dr. Hargreaves

department, where the levels ranged from 9% to 44%. 30% of patients were completely satisfied with their involvement in their pain management, but 12% were not at all satisfied. Satisfaction rates were highest in the Surgery Division and lowest in the Psychiatry Division.

common pain was, how it was being managed by hospital staff and whether patients were satisfied with the opportunities they were offered to get involved in their own pain management." Key findings of the study included: 65% of patients had experienced pain in the last 24 hours, ranging from 52% to 82% in the seven hospital departments included. Pain levels were highest in Diagnostic, Anaesthesia and Technology (82%), the Surgery Division (76%) and Women's Health and Paediatrics (73%). 81% rated their pain as three out of ten or more on a simple numeric scale, where zero was no pain at all and ten was the worst pain imaginable. 42% rated their pain as seven out of ten or more. Patients from the Surgery Department were most likely to report pain as exceeding seven at the time of the survey and in the preceding 24 hours. 82% had been asked about their pain levels by staff, but less than 39% had been asked to rate their pain using a numeric scale. Patients in the Surgery Division were much more likely to be asked to rate their pain using a scale (62%) than in any other

Reference: Why is pain still not being assessed adequately? Results of a pain prevalence study in a university hospital in Sweden. Wadensten et al. Journal of Clinical Nursing. 20, pp624-634. (March 2011). DOI: 10.1111/j.13652702.2010.03482.x

said. "These data demonstrate, for the first time, that OLAMs constitute a new family of naturally occurring capsaicin-like agents, and may explain the role of these substances in many pain conditions. This hypothesis suggests that agents blocking either the production or action of these substances could lead to new therapies and pharmacological interventions for various inflammatory diseases and pain disorders such as arthritis, fibromyalgia and others, including pain associated with cancer."

The research has led Dr. Hargreaves' team to develop two new classes of analgesics using drugs that either block the synthesis of OLAMs or antibodies that inactivate them. These drugs could eventually come in the form of a topical agent, or a pill or liquid that could be ingested, or in the form of an injection. Both approaches have the potential to block pain at its source, unlike opioid narcotics that travel to the brain and affect the central nervous system.

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"Our survey showed that too many patients are still suffering from pain and our findings echo the results of pain prevalence studies from other countries," concludes Dr. Wadensten. "We also found that the simple Numeric Rating Scale is not being used as often as it should be." "It is important that healthcare professionals work together on wards to improve pain management, especially on wards where pain levels may not be so obvious. "Using a pain assessment tool such as the Numeric Rating Scale helps patients to express their pain, makes them feel involved in their care and improves communication between patients and healthcare staff."

Pain study by Bruce Sylvester

Brain imaging shows that meditation reduces pain and pain-related brain activity

RAIN IMAGING shows that meditation induces painrelieving effects in the brain, researchers report in the recent edition of the Journal of Neuroscience. "This is the first study to show that only a little over an hour of meditation training can dramatically reduce both the experience of pain and pain-related brain activation," said Fadel Zeidan, Ph.D., lead author of the study and post-doctoral research fellow at Wake Forest Baptist Medical Center, in WinstonSalem, North Carolina.

“This study shows that meditation produces real effects in the brain and can provide an effective way for people to substantially reduce their pain without medications."

of mindfulness meditation, in which a person attends to the breath and lets go of distracting thoughts and emotions. The investigators evaluated subjects’ brain activity before and after meditation training, using arterial spine labeling magnetic resonance imaging (ASL MRI), which captures longer duration brain processes better than a standard MRI brain function scan. During scanning, the researchers put a paininducing heat device on the right leg of each subject. The device heated a small area of to 120° Fahrenheit, painful for most people, for five minutes. Scans produced following meditation training showed that every participant's pain ratings dropped, with decreases ranging from 11 to 93%. Also, the scans showed that meditation significantly reduced brain activity in the primary somatosensory cortex, an area involved in creating pain sensations. Scans

taken before meditation training showed high activity in this area. However, when participants meditated during scanning, brain activity in the primary somatosensory cortex was undetectable. The investigators also reported meditationrelated increased brain activity in the anterior cingulated cortex, anterior insula and the orbito-frontal cortex. "These areas all shape how the brain builds an experience of pain from nerve signals that are coming in from the body," said Robert C. Coghill, Ph.D., senior author of the study and associate professor of neurobiology and anatomy at Wake Forest Baptist Medical Center. "Consistent with this function, the more that these areas were activated by meditation the more that pain was reduced. One of the reasons that meditation may have been so effective in blocking pain was that it did not work at just one place in the brain, but instead reduced pain at multiple levels of processing," he added.

"We found a big effect – about a 40% reduction in pain intensity and a 57% reduction in pain unpleasantness. Meditation produced a greater reduction in pain than even morphine or other pain-relieving drugs, which typically reduce pain ratings by about 25%. This study shows that meditation produces real effects in the brain and can provide an effective way for people to substantially reduce their pain without medications," Zeidan added. The investigators enrolled 15 healthy volunteers who had not previously meditated. They attended four, 20-minute classes, learning a meditation technique known as focused attention. Focused attention is a form E V I D E N T I A • V O L U M E 5 • I S S U E 2 • A P R I L / M AY 2 0 1 1

Neurology study

Effect of sunlight and temperature on MS Two studies have shown that the incidence and severity of MS may be affected by exposure to sunlight and vitamin D levels and also by variation in temperatures

Memory deteriorates in warm weather in MS patients

HEN IT'S warm outside, memory, processing speed, and other aspects of cognition slow down for patients with multiple sclerosis, researchers found. Cognitive scores were 70% lower among MS patients tested on days when the temperature averaged 66° F than in those tested on days averaging 33° F (P=0.006) according to Victoria M. Leavitt, Ph.D., of the nonprofit Kessler Foundation in West Orange, N.J., and colleagues. This significant impact on cognitive function wasn't mirrored in healthy

controls (P>0.9), Leavitt's group reported in a paper that will be presented at the American Academy of Neurology meeting. Although this was the first study to document a link between temperature and cognition, the finding didn't surprise Lily Jung Henson, M.D., director of neurology at Swedish Medical Center in Seattle. Patients often comment anecdotally that it's harder to think when it's hot outside, noted co-author James F. Sumowski, Ph.D. Acknowledging that the group's small study could draw only preliminary conclusions, Sumowski pointed to another recent study that corroborated the temperature effect, finding that lesions flared up more on brain imaging on hotter days. Possible explanations could be that neurons fire more slowly when overheated or that heat amps up the inflammation associated with MS, he speculated. The magnitude of the cognitive effect seen in the study suggested a clinically meaningful impact, according to Sumowski, although what difference it would make in daily functioning isn't yet clear. And the study results indicate that air-conditioning alone may not solve the problem. The 40 MS patients and 40 matched controls were enrolled throughout the year but took the neuropsychological tests for processing speed, learning, and memory in a temperaturecontrolled clinic environment.

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"These are all questions we still have need to get better answers for, so, as of right now, we can't make clinical recommendations like people should move to colder climates or wait to take their final exams on days that are cooler

Cognitive scores were 70% lower among MS patients tested on days when the temperature averaged 66° F than in those tested on days averaging 33° F .

or such," he added. The study does hold broader implications for the understanding of clinical symptoms of MS, though, Sumowski noted. "Lesion activity may be occurring in the brain even when persons with MS don't show motor weakness or visual problems," he noted. Roughly 65% of MS patients have some form of cognitive impairment, typically slower processing speed, or problems with memory, he pointed out. Disclosure: Sumowski reported having no conflicts of interest to disclose. The study was funded, in part, by the National Multiple Sclerosis Society. Part of the data collection was supported by a grant from the National Institutes of Health. Reference: Leavitt VM, et al . Warmer daily temperature is associated with worse cognitive functioning in multiple sclerosis. AAN 2011

Gene analysis illuminates MS therapy side effect

EUKAEMIA THAT was observed in a small number of mitoxantrone treated multiple sclerosis patients may be the result of patients' genetic makeup, Italian researchers said. Variations in genes involved with DNA repair processes and in the gene encoding the CYP3A4 drug-metabolising enzyme were significantly associated with secondary acute promyelocytic leukaemia (sAPL) in a case-control study, according to Francesco Lo-Coco, M.D., of Tor Vergata University in Rome, and colleagues online in Neurology. Specific single nucleotide polymorphisms (SNPs) in the BRCA1 and BRCA2 genes and in the gene for CYP3A4 were more common in mitoxantrone-treated patients who developed sAPL and also predicted faster onset of the condition, the researchers found. Variants in another DNA-repair gene known as XRCC5 also were associated with sAPL in the study. The findings may help to explain why some MS patients develop sAPL after taking mitoxantrone while others do not. "Combinations of allelic variants in different pathways may have even greater impact on secondary leukaemia risk than single gene alterations," Lo-Coco and colleagues wrote. "In keeping with this view, we found that carriers of both variant alleles of XRCC5 and BRCA2 had a 50-fold increased risk of sAPL, suggesting that this synergistic effect of variation results in significantly hampered DNA repair capacity. The study was prompted by observations that sAPL appeared to be very common among MS patients receiving mitoxantrone. One 2009 report linking MS and leukaemia put the rate at 7.4 per 1,000 patients treated. Primarily a DNA-damaging cancer drug, mitoxantrone was approved ten years ago for MS treatment, but many neurologists have regarded it as a treatment of last resort because of the sAPL risk. The new study raises the possibility of identifying patients at lower risk for sAPL, which could lead to a revival of interest in mitoxantrone. Lo-Coco and colleagues performed genotype analyses in 18 MS patients who developed sAPL after taking mitoxantrone,

two MS patients diagnosed with sAPL after taking other drugs, 41 mitoxantrone-treated MS patients who did not develop sAPL, 253 MS patients who neither took mitoxantrone nor developed sAPL, and 310 healthy blood donors. From five to nine years of follow-up was available for most patients. Among the 18 patients with sAPL after mitoxantrone treatment, the median duration of treatment when sAPL was diagnosed was 26.5 months. The genotyping scanned for 210 SNPs in 22 DNA-repair and drug-metabolising enzyme genes. One SNP each in the BRCA1, BRCA2, XRCC5, and CYP3A4 genes appeared to drive much of the risk for sAPL. All mitoxantronetreated patients who were homozygous for the risk alleles of BRCA2 and XRCC5 developed sAPL within three years (P<0.05), and all such patients with two copies of the risk-associated BRCA1 SNP had been diagnosed with sAPL within about six years (P=0.015). In contrast, not even half of patients with other genotypes had developed sAPL by the end of follow-up. Associations involving CYP3A4 variants were different. Patients homozygous for an adenine

base at the target location were less likely to develop sAPL, whereas the riskiest genotype was heterozygosity for adenine and guanine (P=0.01) with about 20% of patients with the genotype remaining free of the leukaemia at final data analysis. "Our data, although obtained in a limited number of sAPL series arising after MS and of [mitoxantrone]-treated patients with MS who did not develop sAPL, point to increased sAPL susceptibility for patients harbouring certain genetic variants of DNA repair and drugmetabolising enzymes. Confirmation of our findings in larger series and functional in vitro studies are warranted to confirm that these genetic variants are linked to leukaemogenesis in patients with MS." Lo-Coco and colleagues said. Disclosure: Study authors reported consulting fees, honoraria, travel reimbursements, and/or research grants from Celgene, Roche, Teva, Merck Serono, Novartis, sanofi-aventis, Bayer Schering, and Biogen-Dompe. Reference: Hasan S, et al "Risk of acute promyelocytic leukaemia in multiple sclerosis: coding variants of DNA repair genes" Neurology 2011; DOI: 10.1212/WNL

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Neurology study

Managing post-stroke depression improves physical functioning

NDIANAPOLIS – STROKE patients who are not successfully treated for depression are at higher risk of losing some of their capability to function normally, according to a study in the recent issue of the journal Neurology. Although as many as a third of those who experience a stroke develop depression, a new study by researchers from the Regenstrief Institute, the Schools of Health and Rehabilitation Sciences and of Medicine at Indiana University-Purdue University Indianapolis and the Richard L. Roudebush VA Medical Center is the first to look whether managing post-stroke depression improves physical functioning. They researchers report that individuals who remain depressed three months after a stroke are more likely to have decreased functional capabilities than those whose depression was successfully treated. Functional capabilities include getting dressed, feeding oneself, and accomplishing other tasks. These capabilities increased significantly in those individuals who were treated for depression. Post-stroke depression appears to be linked to chemical changes in the brain, clinical evidence indicates. "The relationship between post-stroke depression and recovery of function after a stroke has not been well understood. Previous researchers have looked at both depression and function after stroke but they did not investigate whether identifying and managing depression improved ability to accomplish tasks of daily living and other function related issues," said study first author Arlene A. Schmid, Ph.D., a Regenstrief Institute investigator, an assistant professor of occupational therapy at the IU School of Health and Rehabilitation Sciences and a VA Center of Excellence on Implementing Evidence Based Practice investigator. The researchers in the new study report that successful depression management led to

better functionality that might enable the individual to return to work or more thoroughly enjoy leisure functions while decreasing the caregiver burden. "Restoring lost function after stroke is the number one reason individuals visit occupational therapists," said Dr. Schmid. "Since treating depression helps improve function, occupational therapists should screen for post-stroke depression and, in conjunction

"Since treating depression helps improve function, occupational therapists should screen for post-stroke depression and, in conjunction with other members of the patient's healthcare team, help manage depression."

with other members of the patient's healthcare team, help manage depression." In the Neurology study, whether an individual was depressed or not was determined through use of the Health Questionnaire-9 (PHQ-9), a widely used and easy to administer depression screening tool. The PHQ-9 was originally developed by Kurt Kroenke, M.D., a Regenstrief Institute investigator and IU School of Medicine professor of medicine. Dr. Kroenke, who is a co-author of the new study, has described the PhQ-9 as "a sort of a blood pressure cuff for depression." According to Dr. Schmid, since

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occupational therapists are trained in mental health issues and see patients frequently, occupational therapists could use the PHQ-9 to screen for depression after stroke and alert a post-stroke patient's physician to the individual's mental status. In addition to improving functionality, management of depression would lower health care costs associated with functional impairment and other post-stroke treatment issues. "Post-stroke depression often impacts quality of life after stroke more than even functional impairments. Since it is treatable with common medications, cognitive behavioural therapy and exercise, it is important to recognise it so patients can be treated. This study is one of the first to show not just the link between depression and worse function post-stroke, but that successfully treating depression symptoms actually improves post-stroke outcomes," said Linda S. Williams, M.D., a Regenstrief Institute investigator, associate professor of neurology at the IU School of Medicine, and a VA Center of Excellence on Implementing Evidence Based Practice investigator. Dr. Schmid and Dr. Williams participate in the VA's Stroke Quality Enhancement Research Initiative. Dr. Schmid is VA Career Development Award recipient. Co-authors of "Post-stroke Depression and Treatment Effects on Functional Outcomes" in addition to Dr. Schmid, Dr. Kroenke and Dr. Williams are Hugh. C. Hendrie, MB, ChB, D.Sc., of the Regenstrief Institute, IU School of Medicine and the IU Center for Aging Research; Tamilyn Bakas, D.N.S., R.N., of the IU School of Nursing and the IU Center for Aging Research; and statistician Jason M. Sutherland, Ph.D., of the University of British Columbia. The study was funded by the National Institute of Neurological Disorders and Stroke. For further information contact: Cindy Fox Aisen caisen@iupui.edu

American Urological Association Reporting from the AUA meeting, San Francisco

Link established between ED and calcified coronary arteries

N THE largest study to date evaluating erectile dysfunction (ED) and coronary artery calcification, researchers at Mount Sinai School of Medicine have determined that men with ED are at a significantly increased risk of high coronary artery calcification scores (CACS), a known predictor of future cardiovascular events. The research was presented at the American Urological Association (AUA) meeting in San Francisco. The study, titled "Erectile Dysfunction is an Independent Risk Factor for the Presence of High Risk Coronary Artery Calcification," evaluated 1,119 men enrolled in the World Trade Center Medical Monitoring and Treatment Programme, 327 of which had ED. The researchers learned that after adjusting for comorbidities men with ED had a 54% greater likelihood of having a

high-risk CACS than men without ED. The increased risk was similar to that of patients with a history of hypertension and smoking. "Our data further solidify the concept that ED is a harbinger-indicator of current and future cardiovascular disease," said Natan Bar-Chama, M.D., Director of Male Reproductive Medicine and Surgery and associate professor of urology at Mount Sinai School of Medicine. "These data show an indisputable connection between ED and atherosclerosis." The mean age of the men in the study was 50.5 years. All patients were evaluated with a cardiac CT scan to determine CACS. Erectile dysfunction was assessed using a validated questionnaire and defined as a Sexual Health Inventory for Men (SHIM) score of less than 22. After adjusting for risk factors like diabetes, smoking, and body-mass

index, Dr. Bar-Chama's team determined that ED was independently associated with a 54% increased risk of CACS. "The finding certainly raises the question as to what diagnostic tests we should perform in the newly diagnosed ED patient in order to assess cardiovascular risk," he added. "For example, should we be recommending that CACS scores be obtained in all these patients? Also, should we routinely be measuring serum inflammatory markers, conducting assessment of endothelial function or cardiac stress testing? Guidelines are urgently needed to stratify cardiovascular risk in the newly diagnosed ED patient in light of the significant and clear association between ED and cardiovascular disease.” For further information Contact: Mount Sinai Press Office newsnow@mountsinai.org

NSAIDs linked to increased risk of erectile dysfunction

EN WHO take non-steroidal anti-inflammatory drugs three times a day for more than three months are 2.4 times more likely to have erectile dysfunction compared to men who do not take those drugs regularly, according to a Kaiser Permanente study published online in The Journal of Urology. While previous research showed a trend toward this same finding, this observational study used electronic health records, an automated pharmacy database and self-reported questionnaire data to examine NSAID use and ED in an ethnically diverse population of 80,966 men aged 45 to 69 years throughout California. After controlling for age, race, ethnicity, smoking status, diabetes, hypertension, heart disease, high cholesterol and body mass index, the researchers found that ED was 1.4 times more likely - a modest risk - among regular NSAID users compared to men who did not

take the drugs regularly. This association was consistent across all age groups. "This study is a great example of how we work to understand the safety and effectiveness of what we recommend for our patients. We went into this study thinking we would find the opposite effect: that NSAIDs would have a protective effect because they protect against heart disease, which is also linked to ED," said study senior author Steven J. Jacobsen, M.D., Ph.D., an epidemiologist and director of research for Kaiser Permanente Southern California. "The next step is to dive a bit deeper to understand the underlying physiology of what might be happening with these drugs." Erectile dysfunction is a common problem in many middle-aged and elderly men. According to the National Institutes of Health, approximately 5% of 40-year-old men and between 15 and 25% of 65-year-old men

experience ED on a long-term basis. However, the researchers caution that men should not stop taking NSAIDs based on this study. "There are many proven benefits of non steroidals in preventing heart disease and for other conditions. People shouldn't stop taking them based on this observational study. However, if a man is taking this class of drugs and has ED, it's worth a discussion with his doctor," Jacobsen said. Study authors included: Joseph M. Gleason, MD, and Howard Jung, MD, from the Kaiser Permanente Los Angeles Medical Center; Jeffrey M. Slezak, MS; Kristi Reynolds, PhD, MPH, Reina Haque, PhD, MPH, Virginia P. Quinn, PhD, MPH, and Steven J. Jacobsen, MD, PhD, with the Kaiser Permanente Southern California Department of Research & Evaluation; Ronald K. Loo, MD, Kaiser Permanente Downey Medical Center; and Stephen K. Van Den Eeden, PhD with the Kaiser Permanente Northern California Division of Research. For more information contact: Emily Schwartz eschwartz@golinharris.com

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European Medicines Agency

highlights

by Gary Finnegan

EMA revamps insomnia guidelines

HE EUROPEAN Medicines Agency (EMA) is set to overhaul its 20-yearold guidance on insomnia treatments as part of ongoing efforts to reflect advances in the scientific understanding of sleep disorders. The current guidelines were first adopted by the European Commission in 1991, before the foundation of the EMA, and are now out of date. The new document, which comes into force in September 2011, informs companies how best to carry out studies on anti-insomnia medicines in order to increase their chances of gaining marketing authorisation. Details of how to design research studies, what types of patients to include in clinical trials and the use of randomised placebo-controlled investigations are included in the revised document. The inclusion of children and the elderly in studies of anti-insomnia drugs is also covered in the new guidelines. The EMA will also provide advice on how to assess the safety of anti-insomnia medicines, including ways of reducing the risk of tolerance or dependence. The updated guidance was adopted by the Committee for Medicinal Products for Human Use (CHMP) in February and follows a public consultation process which began in October 2009. The existing guidelines remain in force until September 2011 when they will be superseded by the revamped version. Meanwhile, the EMA has launched a public consultation on the use of HIV medicines for preventative purposes. As part of the process, the Agency has published a “concept paper” outlining the rationale behind the review, focussing on pre-exposure prophylaxis of HIV through sexual transmission. The move follows encouraging results from two studies using anti-HIV medicines to reduce the likelihood of catching the virus, one in women with a vaginal gel containing tenofovir and another in men with Truvada (tenofovir and emtricitabine) tablets. The concept paper is open for comments until 30 April 2011.

Fee hike for new applications The price of getting medicines onto market just got higher. Companies applying for marketing approval will face higher costs from April, as the EMA increases its fees in line with inflation. The Agency is expected to impose a 2.1% hike in fees, although the final adjustment will not officially be announced by the European Commission until the end of March. Revised fee reductions for orphan medicines will also come into effect on April 1, thanks to €4.9 million in EU funds devoted to reducing the barriers to bringing orphan drugs to market. Small and medium-sized companies will also continue to enjoy lower fees as part of an EUwide drive to reduce the cost of doing business for smaller firms.

Jury out on flu jab The EMA has reviewed data from Finland suggesting a link between an influenza vaccine and narcolepsy in young people but says there is not enough evidence to support a causal relationship. Pandemerix, which protects against the H1N1 strain of influenza that sparked the 2009 global flu pandemic, has been at the centre of case reports in Finland and Sweden where a number of children have reported sleep disorders. The EMA said the latest evidence “added to the concern” but added that the data remains “insufficient” to prove any link between the jab and narcolepsy. A detailed study is now under way with results expected later this year.

Green light for new medicines The CHMP has recommended the granting of marketing authorisations for the following new medicines: Hizentra (human normal immunoglobulin), from CSL Behring GmbH, intended for replacement therapy in adults and children in primary immunodeficiency syndromes, and in myeloma or chronic lymphatic leukaemia patients with severe secondary hypogammaglobulinaemia and recurrent infections. Methylthioninium chloride Proveblue (methylthioninium chloride), from Provepharm

S.A.S., intended for acute symptomatic treatment of methaemoglobinaemia induced by medicinal and chemical products. Rasilamlo (aliskiren/amlodipine), from Novartis Europharm Ltd, intended for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled with aliskiren or amlodipine used alone. Sprimeo HCT (aliskiren/hydrochlorothiazide), from Novartis Europharm Ltd, intended for the treatment of adult patients with essential hypertension. This application was an informed consent application referring to the dossier of the authorised medicine Rasilez HCT. Ibandronic Acid Sandoz (ibandronic acid), from Sandoz Pharmaceuticals GmbH, and for Ibandronic Acid HEXAL (ibandronic acid), from Hexal AG, intended for the prevention of skeletal events in patients with breast cancer and bone metastases. Ibandronic Acid Sandoz and Ibandronic Acid HEXAL are generics of Bondronat. The Committee also agreed to the extension of the therapeutic indications for Humira (adalimumab) from Abbott Laboratories Ltd, adding a new treatment option for the successful rheumatoid arthritis drug. The medicine can now also be used for the treatment of juvenile idiopathic arthritis in patients aged four to 12 years.

Supply shortage of Simponi Patients using Simponi (golimumab) pre-filled pens, from Janssen Biologics B.V, may have to find alternative treatments, according to the EMA. The Agency has been informed of a manufacturing problem which will lead to a temporary shortage of this presentation of the medicine in some EU countries. Simponi is a medicine for the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. To deal with the shortage, the CHMP is recommending that affected patients should be switched to the other presentation of Simponi, the pre-filled syringe, or to alternative treatments as advised by their doctors.

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Journal reviews by Bruce Sylvester

relief from bloating, abdominal pain and loose or watery stools. And relief was sustained for weeks after they stopped taking the antibiotic. Rifaximin is currently approved by the U.S. Food and Drug Administration to treat travelers' diarrhoea and hepatic encephalopathy.

Reporting from some of the latest articles in

www.jama.ama-assn.org

Nitrates appear to increase bone strength

R www.nejm.org

Antibiotic rifaximin effective for irritable bowel syndrome (IBS)

IFAXIMIN THERAPY appears to have a long-lasting effect on symptoms of IBS, even after treatment ends, researchers reported in the recent issue of the New England Journal of Medicine. Subjects in the newly reported study reported ongoing relief of bloating, less abdominal pain and improved stool consistency for up to 10 weeks after ending rifaximin teatment. “IBS often does not respond well to treatments currently available, such as dietary changes and fibre supplements alone,” said Mark Pimentel, M.D., GI Motility Programme director and principal investigator of the clinical trials at Cedars-Sinai Medical Center in Los Angeles, California. “With this antibiotic treatment, the patients feel better, and they continue to feel better after stopping the drug. This means that we did something to strike at the cause of the disease." The investigators noted that the response to an antibiotic therapy confirms that bacteria in the gut, ‘gut flora,’ triggers the symptoms of IBS. In two, 600-plus patient double-blind trials, IBS patients with mild to moderate diarrhoea and bloating were randomised to a 550mg dose of rifaximin or placebo three times daily for two weeks. Researchers tracked the subjects for ten weeks more. The investigators reported that about 40% of patients using rifaximin reported significant

ESEARCHERS REPORTED in a recent issue of JAMA that two-year treatment with nitroglycerin ointment of postmenopausal women correlated to a modest increase in bone mineral density and decrease in bone resorption/loss. "The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment may help limit this increase," the authors said. "Nitroglycerin stimulates bone formation and inhibits bone resorption, is inexpensive, and is

"The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment may help limit this increase."

They randomised subjects to nitroglycerin ointment (15mg/day; n = 126) or placebo (n = 117), applied for two years at bedtime to the upper arm. They reported that subjects randomised to the nitroglycerin group achieved significant increases in areal BMD at the lumbar spine (6.7%), total hip (6.2%), and femoral neck (7.0%) at 24 months. The actively treated women also showed increases in BMD and bone strength of the radius and tibia. Notably, when compared to placebo treatment with nitroglycerin was also significantly associated with an increase in bone-specific alkaline phosphatase, a marker of bone formation, and a decrease in urine N-telopeptide, a marker of bone resorption. Incidences of adverse events were similar in both groups. The authors wrote, "In conclusion, daily administration of nitroglycerin ointment increases bone formation and decreases bone resorption; thereby, substantially improving BMD, bone structure, and indices of bone strength at least as much as existing treatments. Together, these findings suggest that daily nitroglycerin may reduce the risk of vertebral and non-vertebral fractures. Furthermore, nitrates have a potential advantage of easy administration as an ointment, patch, or pill and wide availability of generic preparations. The efficacy of nitrates for reducing risk of fracture should be tested in a larger randomised controlled trial."

www.thelancet.com

Rituximab maintenance therapy improves progression-free survival in follicuar lymphoma widely available. Its effects on bone density, bone structure, and bone strength are unknown." Sophie A. Jamal, M.D., Ph.D., of the Women's College Research Institute and University of Toronto, Canada and colleagues evaluated once-daily nitroglycerin ointment to increase bone mineral density (BMD) at the lumbar spine, femoral neck and hip. They enrolled 243 postmenopausal women in a placebo-controlled randomised trial conducted from November 2005 to March 2010.

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OLLICULAR LYMPHOMA patients receiving two years of rituximabmaintenance therapy after immunochemotherapy, have achieved significantly better progression-free survival (PFS) and higher response rates, researchers reported in an Online First article published recently by The Lancet. As background, the authors noted that rituximab-plus-chemotherapy induction regimens have already become standard firstline treatment for follicular lymphoma. But the

benefit of continuing rituximab treatment after completion of chemotherapy was not previously known. Researchers designed the PRIMA study to evaluate the efficacy of two years of rituximabmaintenance therapy on the outcome of patients with follicular lymphoma. They enrolled 1,217 patients with previously untreated follicular lymphoma, from 223 centres in 25 countries. The subjects received an induction regimen of rituximab plus chemotherapy. After induction, 1,019 eligible patients (who had achieved a complete or partial response) were randomised to two years of rituximab maintenance (505 patients) or no treatment (513). The investigators established complete response and PFS by clinical examination and CT scans. Patients also completed quality-oflife questionnaires. After two years, 71.5% of patients in the rituximab group achieved complete or unconfirmed complete response compared with 52.2% in the observation group. After 3 years, maintenance with rituximab was associated with significantly better PFS (74.9% vs 57.6%) across all subgroups of patients with different demographics, disease characteristics, and prognostic factors. Time to next anti-lymphoma treatment and next chemotherapy was also longer in the maintenance group. The authors noted that two quality of life measurements showed no differences between the groups, which suggests that rituximab treatment had no detrimental effect on quality of life, in spite of ongoing infusions over the two years. Rituximab maintenance therapy was generally well tolerated. But grade three or four adverse events were significantly more common in rituximab-maintenance patients (24% vs 17%). The most common sideeffects were mild to moderate infections which occurred in 39% of patients taking rituximab compared with 24% in the no treatment group. The authors concluded, “The data from this study suggest that rituximab maintenance in patients with high tumour burden follicular lymphoma, who respond to rituximab plus chemotherapy induction, improves PFS and should now be considered as first-line treatment for these patients.”

BMJ www.bmj.org

Smoking raises breast cancer risk in postmenopausal women

ESEARCHERS REPORT that postmenopausal women who smoke or formerly smoked have up to a 16% higher risk of developing breast cancer than women who have never smoked. The findings were published online recently at bmj.com by the British Medical Journal. The investigators also found that women

Questions on passive smoking determined whether subjects lived in smoking households as children and/or as adults, and whether they had worked in smoking environments.

with extensive exposure to passive smoking, either in childhood or adulthood, also appear to have an excess risk of developing breast cancer. They noted that even though previous studies have suggested that smoking increases the risk of breast cancer, the theory that passive smoking is also a risk factor remains controversial. The researchers, led by Dr. Juhua Luo from West Virginia University and Dr. Karen Margolis from the HealthPartners Research Foundation in Minneapolis, evaluated data from the 1993-98 Women's Health Initiative Observational study

to determine correlations between smoking, passive smoking and breast cancer. They evaluated data from almost 80,000 women, between 50 and 79 years old, from 40 clinical centres in the United States. They identified 3,250 cases of invasive breast cancer during ten years of follow-up. Subjects were questioned about their smoking, whether they had ever smoked or were former or current smokers. Former or current smokers were asked about the age at which they started and the number of cigarettes smoked a day. Former smokers were also asked the age at which they quit. Questions on passive smoking determined whether subjects lived in smoking households as children and/or as adults, and whether they had worked in smoking environments. The researchers found current smokers to have a 16% increased risk of developing breast cancer after the menopause. The increased risk for former smokers is 9%. The highest rate of breast cancer was among women who had smoked for over 50 years or more compared with lifetime non-smokers. The investigators noted that subjects who started smoking as teenagers were at a particularly high risk. They also found an increased risk of breast cancer for up to 20 years after smoking cessation. They researchers reported that among nonsmoking women, those who had been exposed to extensive passive smoking (over 10 years in childhood, over 20 years as an adult at home and over 10 years as an adult at work) had a 32% increased risk of breast cancer. The authors emphasised that their analysis of the link between breast cancer and second-hand smoke was restricted to the most extensive passive smoking category, and more research is needed to confirm the findings. "Our findings highlight the need for interventions to prevent initiation of smoking, especially at an early age, and to encourage smoking cessation at all ages," Dr. Margolis said. In an accompanying editorial, Professor Paolo Boffetta from the Mount Sinai School of Medicine in New York, says Margolis' study "supports the hypothesis that smoking increases the risk of breast cancer, in particular when the habit starts early in life." Sources: Cedars-Sinai Medical Center, JAMA, The Lancet, BMJ

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Medical news from around the world by Gary Finnegan

World Health Matters NEW ZEALAND Childhood self-control predicts adult health and wealth CHILDREN WHO score lower on measures of self-control at the age of three were more likely to suffer health problems, substance dependence, experience financial troubles and to have a criminal record by the age of 32, according to a new long-term study. Self-control in the more than 1,000 New Zealand children who participated in the study was assessed by teachers, parents, observers and the children themselves. It included measures like “low frustration tolerance, lacks persistence in reaching goals, difficulty sticking with a task, over-active, acts before thinking, has difficulty waiting turn, restless, not conscientious”. Fast-forward to adulthood, and the children scoring lowest on those measures scored highest for things like breathing problems, gum disease, sexually transmitted disease, inflammation, overweight, and high cholesterol and blood pressure, according to the international research team behind the study. The impulsivity and relative inability to think about the long-term of the lower self-control individuals gave them more difficulty with finances, like savings, home ownership and credit card debt. They also were more likely to be single parents, have a criminal conviction record, and be dependent on alcohol, tobacco, cannabis and harder drugs. Terrie Moffit, a psychologist at Duke University in the U.S. who participated in the research said earlier behaviours help to predict later actions. “These adult outcomes were predictable across the entire spectrum of selfcontrol scores, from low to high,” Moffitt said. However, not all infants are condemned to a life of strife by their low level of restraint. Participants who found a way to improve selfcontrol as they aged fared much better in adulthood than their childhood scores would have predicted. Self-control is something that can be taught, the researchers say, and doing so could save governments a great deal of money on healthcare, criminal justice and substance

abuse problems down the road. The group ran the same analysis on 500 pairs of fraternal twins and found that the sibling with lower self-control at the age of five was more likely than their sibling to smoke, perform poorly in school and engage in anti-social behaviour at the age of 12. “This shows that self-control is important by itself, apart from all other factors that siblings share, such as their parents and home life,” said Avshalom Caspi, a member of the group.

SPAIN Genetic research holds key to Fanconi anaemia AN INTERNATIONAL consortium of researchers led by the Universitat Autònoma de Barcelona (UAB) has genetically characterised almost all Spanish patients with Fanconi anaemia in an effort to deepen understanding of the clinical impact of mutations.

Fanconi anaemia is a rare disease affecting one in every 500,000 people and is characterised by severe anaemia in children, congenital malformations and a high predisposition to cancer.

The new study, published in the journal Blood, describes over 130 pathogenic mutations. It also tracks the origins and global distribution of some of the most frequent mutations. Fanconi anaemia is a rare disease affecting one in every 500,000 people and is characterised by severe anaemia in children, congenital malformations and a high predisposition to cancer.

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One hundred people in Spain suffer from the condition and 80% of these have mutations in the FANCA gene. 90% of these patients were included in the study, along with people from Brazil, Mexico, Argentina, Peru, the United States, United Kingdom, Portugal, Germany, Pakistan and Nigeria. Tracing the history of changes in this gene, the researchers concluded that the predominant mutation is of Indo European origin which spread throughout Europe thousands of years ago before crossing the Atlantic. Almost half of all patients in Brazil share the same gene mutation, while prevalence of the disease was also found on the Canary Island of La Palma, indicating that the mutation spread widely in these areas. Finally, researchers analysed the effects of the genetic mutations and their clinical impacts. Results indicate that these mutations cause the absence or dysfunction of the FANCA protein, which prevent it from reaching the cell nucleus and activating a DNA repair pathway necessary for genomic stability. This in turn brings about cell death producing anaemia and abnormal tissue functions - or causes them to develop into tumours. For this reason the study of genes involved in Fanconi anaemia is essential to understand the factors which protect the general population from cancer. Dr. Jordi Surrallés, who led the study, said it would have significant applications in the diagnosis, prognosis and evolution of this rare disease.

AUSTRALIA Midwives need more guidance on alternative medicines COMPLEMENTARY AND alternative medicine (CAM) is increasingly popular in maternity care, but healthcare professionals need formal evidence-based education and guidance

about its use, according to an Australian-led review in a recent issue of the Journal of Advanced Nursing. University-based members of the Network of Researchers in the Public Health of Complementary and Alternative Medicine (NORPHCAM) reviewed 19 studies covering the views of more than 3,000 maternity professionals from Australia, Canada, the USA, UK, Germany, New Zealand and Israel. The studies, which were all based on interviews or surveys, were published between 1999 and 2009, 13 in the last five years. “There is no doubt that the popularity of CAM – including acupuncture, chiropractic, naturopathy, herbal medicine and yoga - has grown in recent years,” says lead author Dr. Jon Adams, Associate Professor at the University of Queensland, Australia, and Executive Director of NORPHCAM. “The use of CAM during pregnancy has been debated by practitioners and policy makers around the world and it is clear that there is a real need to develop an integrated approach to maternity care. However this has been hampered by a lack of understanding of the attitudes and practice of mainstream maternity care professionals towards CAM,” he said. In Canada and New Zealand, 72% of midwives recommend or offer CAM. The most common referrals were to homeopaths (51%), acupuncturists (50%), naturopaths (48%), chiropractors (36%), massage therapists (31%) and osteopaths (20%). All but one of the 381 obstetric departments who took part in a German survey said they offered at least one CAM therapy, with acupuncture (97%), homeopathy (93%) and aromatherapy (77%) heading the list. The authors raise concerns that most medical professionals have no CAM training and little understanding of the pharmacological nature of alternative therapies and their possible risks to pregnant women. “We hope that our research review will provide a first step in developing an evidence base on this important topic and provide vital insights for those managing, practising and receiving maternity care,” Dr. Adams said. However, the subject remains a bone of contention within the medical establishment.

Critics argue that where “alternative” therapies are shown to have a sound evidence base they are embraced by mainstream medicine, whereas treatments such as homeopathy have no scientific backing.

CHINA Level of tumour protein indicates chances cancer will spread RESEARCHERS AT the University of Hong Kong have discovered that high levels of a particular protein in cancer cells are a reliable indicator that a cancer will spread. The finding could become a new tool for estimating cancer patients’ outcomes. By measuring the protein's genetic material in tumours that had been surgically removed from patients, along with measuring the genetic material from surrounding tissue, the researchers could predict at least 90% of the time whether a cancer would spread within two years. The findings, which appear in the Journal of Clinical Investigation, raise the long-term possibilities of new tests to gauge the likelihood that a cancer will spread and, ultimately, of a treatment that could prevent cancer from progressing. The protein, known as CPE-delta N, is a form of carboxypeptidase E (CPE). Ordinarily, CPE is involved in processing insulin and other hormones. CPE-delta N, a variant of CPE, was present in high amounts in tumours that had spread and, to a much lesser degree, in surrounding tissues. In an analysis of tissue from 99 patients with liver cancer, the researchers compared

the amount of CPE-delta N RNA from the patients' tumours with the RNA levels in surrounding tissue. It was found that when the level of CPE delta-N RNA in tumours was more than twice that in the surrounding tissue, the cancer was highly likely to return or to metastasize within two years. At or below this threshold level, the cancer was much less likely to recur. Using this threshold measure, the researchers accurately predicted metastasis or recurrence in more than 90% of cases. Conversely, their predictions that tumours would not return in the two-year period were accurate 76% of the time. “Testing for CPE-delta N, if combined with existing diagnostic methods, offers the possibility of more accurately estimating the chances that a cancer will spread,” said Dr. Alan E. Guttmacher, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which supported the study. “Conceivably, a patient's CPE-delta N levels could be a key guide in individualising their cancer care to improve outcome.”

“Conceivably, a patient's CPE-delta N levels could be a key guide in individualising their cancer care to improve outcome.”

The study’s senior authors, Y. Peng Loh of NICHD's Section on Cellular Neurobiology, and Ronnie Poon from the University of Hong Kong, explained that the method used in the study might some day be used to treat cancers in human beings but improved methods are needed for delivering antisense RNA to tumour cells. Similarly, further research might lead to the development of drugs or other measures to block CPE-delta N and so prevent cancer from spreading.

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FDA highlights by Bruce Sylvester

Emerging Uses of FDA-Approved Drugs Bevacizumab offers significant advance in treating leading cause of childhood blindness

EVACIZUMAB HAS significant efficacy in treating premature infants with difficult-to-treat cases of retinopathy of prematurity, researchers reported in the recent issue of The New England Journal of Medicine. Lead investigator Helen Mintz-Hittner, MD, Department of Ophthalmology and Visual Science, University of Texas Health Science Center at Houston and colleagues compared treatment with intravitreal bevacizumab to conventional laser treatment. The study investigators treated infants with acute retinopathy of prematurity affecting zone I and posterior zone II, retinal zones with the highest rate of treatment failure. Outcomes from 143 infant subjects enrolled in the study showed that, among infants with zone I disease, the recurrence rate was 6% with intravitreal bevacizumab and 42% with conventional laser therapy. The drug therapy resulted in mild anatomical retinal abnormality in just one eye of 31 infants, whereas conventional laser treatment resulted in a mild structural abnormality in 16 eyes and severe abnormality in two eyes of 33 infants. “When I started working with babies almost 40 years ago, there was nothing we could do for those with retinopathy of prematurity,” said

Dr. Mintz-Hittner, the study’s principal investigator. “We’ve gone from nothing to a real solution. If you are careful and administer this therapy appropriately in stage 3+, you can get wonderful outcomes.” Dr. Mintz-Hittner noted that timing of bevacizumab treatment is critical. If administered too early, in stages one and two of the disease, it can cause retinal dystrophy. If administered too late, in stages four or five of the disease, the treatment can accelerate retinal detachment. “In that window, as the abnormal vessels begin to proliferate but before the retina begins to detach, that’s when you want to treat,” Dr. Mintz-Hittner said. Beyond reducing the recurrence rate for patients with retinopathy of prematurity in zone I, Dr. Mintz-Hittner emphasised that, compared with conventional laser therapy, bevacizumab therapy does a better job in preserving vision. Notably, with the drug treatment there is no need to intubate the infant and recovery is faster. “Our first available treatment for babies with retinopathy of prematurity was cryotherapy,” Dr. Mintz-Hittner said. “It was very painful and it wiped out all posterior ocular layers. The visual field was decreased and myopia or nearsightedness occurred. It was a long procedure - two to three hours - requiring intubation. With laser treatment, you still had

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to intubate, which could cause major setbacks for the baby, and field loss and myopia still occurred, but it was less painful and only destroyed the inner retinal layers.” “With this drug therapy, we use a few drops of anaesthetic to numb the eye. We take a

Timing of bevacizumab treatment is critical. If administered too early, in stages one and two of the disease, it can cause retinal dystrophy. If administered too late, in stages four or five of the disease, the treatment can accelerate retinal detachment.

syringe with a tiny needle and administer a small amount of the drug directly into the eye. The whole process takes two to three minutes, and you begin to see results within 24 hours,” she said. “The abnormal vessels virtually disappear and then normal vessels begin to grow out again. The field of vision is preserved and myopia is less.” Dr. Mintz-Hittner cautioned that the drug therapy does require longer follow-up, “You must follow the child for at least 16 weeks following the injection to make sure there isn’t a recurrence. Approximately 4% of patients [one in every 25 patients] may require a second injection. I explain to parents that it’s like a cancer. It can come back and if it isn’t treated in time, it can lead to blindness - so follow-up is very important.” Ongoing research will evaluate safety, refine the dosage and timing of follow-up, and also study long-term visual function.

FDA warns against terbutaline treatment of preterm labour

HE US FOOD and Drug Administration (FDA) said recently that, due to the potential for serious maternal heart problems and death, injectable terbutaline should not be used in pregnant women for prevention or prolonged treatment (beyond 48-72 hours) of preterm labour in either the hospital or outpatient setting. The FDA also said that oral terbutaline should not be used for prevention or any treatment of preterm labor, since it does not have proven efficacy and such use has provoked safety concerns. Officials noted that death and serious adverse reactions, including increased heart rate, transient hyperglycaemia, hypokalaemia, cardiac arrhythmias, pulmonary oedema, and myocardial ischaemia have been reported after prolonged use of oral or injectable terbutaline by pregnant women. Terbutaline is FDA-approved to prevent and treat bronchospasm associated with asthma, bronchitis, and emphysema. The drug is sometimes used off-label for obstetric purposes, such as those noted in the warning. The decision to require the addition of a Boxed Warning and Contraindication is based on new safety information reviewed by the FDA, specifically postmarketing safety reports of terbutaline used for obstetrical indications, as well as data from the medical literature. The FDA is requiring the addition of a new Boxed Warning and Contraindication to the terbutaline drug labels. The label changes are consistent with the position taken on the subject by the American College of Obstetricians and Gynecologists (ACOG).

Escitalopram appears to reduce menopausal hot flushes

OMEN IN transition to menopause or who are postmenopausal show a drop in the frequency and severity of menopausal hot flushes with the use of antidepressant escitalopram, when compared with women who received placebo, researchers reported according to a study published in the recent issue of JAMA (Journal of the American Medical Association). “Hormonal agents have been the predominant therapy for menopausal hot

flushes, but their use decreased substantially following the shifts in risk-benefit ratios that were identified in the Women’s Health Initiative Estrogen plus Progestin randomised controlled trial,” the authors wrote. “However, no other treatments have US Food and Drug Administration approval for menopausal hot flushes, and the efficacy of alternative pharmacologic and non-pharmacologic agents is inconclusive.” Ellen W. Freeman, Ph.D., research professor in the Department of Obstetrics/Gynecology and the Department of Psychiatry at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, and colleagues evaluated the efficacy of escitalopram versus placebo to reduce the frequency and severity of hot flushes in healthy women. They also evaluated whether race, menopausal status, depressed mood, and anxiety modified of any observed treatment effect.

“The three-week postintervention follow-up demonstrated that hot flushes increased after cessation of escitalopram but not after cessation of placebo, providing further evidence of escitalopram’s effects.”

In the eight-week, randomised trial, investigators enrolled 205 women (95 African American; 102 white; eight other) between July 2009 and June 2010. The subjects received 10 to 20mg/day of escitalopram or a matching placebo for eight weeks. The primary outcomes included frequency and severity of hot flushes assessed by prospective daily diaries at weeks four and eight. The researchers reported that the average frequency of hot flushes at the beginning of the study was 9.8 per day. Escitalopram treatment was associated with a significant reduction in the frequency of hot flushes relative to placebo, adjusted for race, site, and baseline hot flush frequency. Average

hot flush frequency at week eight decreased to 5.26 hot flushes per day (47% decrease or an average of 4.6 fewer hot flushes per day than at the beginning of the study) among escitalopram subjects . Among placebo subjects, frequency decreased to 6.43 hot flushes per day (33% decrease or an average of 3.2 fewer hot flushes per day). Notably, improvement at week eight (decrease of 50% or more from baseline in hot flush frequency) was significantly greater in the escitalopram group than in the placebo group (55% vs 36%). And escitalopram treatment significantly reduced hot flush severity compared with placebo, adjusted for race, site, and baseline severity. Overall discontinuation for adverse events was 4% (seven in the active group, two in the placebo group). “The three-week post-intervention follow-up demonstrated that hot flushes increased after cessation of escitalopram but not after cessation of placebo, providing further evidence of escitalopram’s effects,” the authors wrote. The researchers noted that even though decreases in hot flush frequency and severity appeared to be modest, the subjects experienced the improvements as meaningful, indicated by reported satisfaction with the treatment and their desire to continue the treatment. “Our findings suggest that among healthy women, 10 to 20mg/d of escitalopram provides a nonhormonal, off-label option that is effective and well-tolerated in the management of menopausal hot flushes,” the authors concluded. “Further studies are needed to directly compare the relative efficacy of SSRIs and SNRIs with hormone therapy in the treatment of menopause-related hot flushes.”

Sources: University of Texas Health Science Center at Houston, FDA, JAMA.

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View from the waiting room by Steve Devrell

Rocking the boat “C HEERS EVERYONE!” When you read this article, I will be on board the P&O Arcadia swaying gently, I hope, in some benign sea. It is my wife’s and my late mid-life treat to each other as we circumnavigate the globe on a world cruise. Three months, 26 countries and 32 ports, 42 formal meals almost 30,000 miles and half a million calories. Sounds fun, well I hope so. I will tell you when I get back. First I have to avoid sunstroke in the Caribbean, drug cartels in Mexico, cannibals in Tahiti, (I believe that is purely historical). I will need to tread carefully in Australia, avoid tsunamis in Thailand, rabies in India and the threat of malaria in Vietnam. Not to mention avoiding the Somali pirates off the Horn of Africa. I said don’t mention the pirates! Assuming I survive, or hopefully avoid these unpleasant eventualities, I still have to encounter the biggest threat to my well-being and that is the cruise ship itself! I am a comparative stranger to cruising, I did a short one about twenty years ago, but apart from that, like Manuel from Fawlty Towers, ‘I know nothing!’ But what I do know is that I will not be alone. Fourteen million passengers worldwide took cruises last year; it is by far the fastest growing section of the tourist industry. Senior citizens (over 65s) account for 39% of the market. On my particular world cruise, 85% of the passengers will be over 55 years old. We are sadly two of them. This fact alone will have considerable bearing on the disquieting health problems that are associated with taking a cruise. Fortunately, most large ships have their own modern medical facilities including its own infirmary and a team of doctors and nurses on call 24 hours a day. During a cruise, an average of 3% of passengers visit the infirmary, well over half of these will be people over 65 years old. Of the passengers needing a visit, 15% are as a result of onboard injuries like falling down stairs or losing their balance in rough seas. Twelve per cent are what can be called self inflicted excesses, from the sun or alcohol for example and the rest are as a result of medical conditions. There are of course many challenges for cruise ship travel with regards to maintaining a healthy environment. Densely populated, semi-enclosed cruise ship environments may

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permit repeated and prolonged exposure to communicable diseases. The Arcadia will have more than 2,000 passengers and 1,100 crew members sharing its 13 decks for its 2011 world cruise. Differences in sanitation standards and disease prevalence between ports may also lead to communicable disease exposure and spread. There is also the problem of having a multi-racial crew on board. About 50 nationalities are represented among crew members, most of who come from the developing world where susceptibility and resistance to disease differs markedly from that of the more developed countries. Of the majority of medical conditions that require treatment in the infirmary, almost 30%, are for respiratory tract infections, with influenza being the most common cruise ship illness. This illness can cause disease in all age

During a cruise, an average of 3% of passengers visit the infirmary, well over half of these will be people over 65 years old. Of the passengers needing a visit, 15% are as a result of on board injuries like falling down stairs or losing their balance in rough seas.

groups, but infection rates are highest among infants, children and adolescents. In Europe, influenza generally occurs in winter months, but there is no seasonal variation on cruises. Passengers on board can be exposed to influenza at any time as there will always be travellers from areas of the world where the influenza viruses are circulating. Legionnaires’ disease has led to pneumonia outbreaks on cruise ships. Contamination of ships’ whirlpools, spas and portable water supply systems has most commonly been implicated as the source of this cruise ship illness. This ‘modern’ disease has been a major headache for cruise

companies partly because pinpointing the source of the outbreak has proved difficult. Diagnoses in returning travellers may be delayed and clinical specimens may be unavailable for culture at the time of diagnosis. Fortunately there have been improvements in ship design and standardisation of spa and water supply disinfection. These meticulous improvements have greatly reduced the risk of Legionnaires’ disease on board the modern cruise liner.

Although unpleasant, a norovirus often goes unreported on ships as recovery is usually complete within three days, with symptoms tailing off after the first 24 hours, thus it is often referred to as the ’24-hour stomach bug’.

Perhaps the most common illness on board and certainly the one that causes most media attention are noroviruses. We have all seen pictures of pale faced hapless ‘cruisers’ clinging to the side of their ship as it comes into port. Dramatic headlines reach the press on a regular basis, angry passengers queue up to recount their ‘hell on earth’. But are such dramatics a true reflection of the perils of cruising? Well it appears not! According to the U.S. Center for Disease Control (CDC,) you are more likely to pick up a Norovirus from restaurants, nursing homes, hospitals or daycare centres. In spite of this, the virus is often unfairly dubbed the ‘cruise ship virus’. The Norwalk virus from which we get the term noroviruses comes from the town of Norwalk in Ohio where the virus was first recognised after an outbreak in the 1970s. In spite of the press coverage, your chances of suffering from a norovirus on a standard seven day cruise is less than 1% and it involves less than 10% of all

reported visits to the ship’s infirmary. Although unpleasant, a norovirus often goes unreported on ships as recovery is usually complete within three days, with symptoms tailing off after the first 24 hours, thus it is often referred to as the ’24-hour stomach bug’. Personally, I will be following my usual routines for foreign travel - no cold food, properly sealed bottled water, plenty of hand washing, gallons of alcohol based hand gel, Imodium and a little prayer! Perhaps the most obvious reason for visiting the ship’s infirmary is good old seasickness. Green-faced passengers huddled under a blanket gasping for fresh air whilst grasping a ship’s biscuit is a rather outdated image of sea travel. Indeed if you have never suffered seasickness before, you are unlikely to be a victim on the large fully stabilised ships of today. Unlike poor old Lord Nelson, who suffered from the condition for his entire naval career, only 1% of all passengers will suffer from seasickness during their cruise. But seasickness still accounts for 8.9% of all visits to the ship’s infirmary Ironically, the cheaper inside cabins on the lower decks are the cabins that experience less movement. The passengers on the higher decks at the front or the rear of the boat with a better ambiance and superior views experience the most movement giving rise to the much used expression in ‘cruise circles’ the more you pay, the more you sway! Well, I have just about frightened myself to death writing this article, but by the time you read it, I should be well and truly in ‘cruise control’. A great host of experiences await me I am sure, but with any luck, I will be back for the start of the cricket season! So with Pina Colada in hand and amazing sunset in view, I once again raise my glass. “Cheers!”

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* Individual needs may vary. That’s why there’s Rebif – with tailored treatment, device and support options, and more than 800,000 patient–years’ experience of use worldwide1 ®

Different patients. Different needs. Reference: 1. UKDOFREB110001 Merck Serono Data on File 2011.

Date of Preparation: March 2011

REB11-0054

PRESCRIBING INFORMATION – UK AND ROI

higher dose). RebiDose pre-filled pen is for single use and should only be used following adequate training of the patient and/or carer. Follow the instructions provided in the package leaflet. Rebif solution for injection in cartridge is for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer. Follow the instructions provided with the RebiSmart device. Limited published data suggest that the safety profile in adolescents aged 12–16 years receiving Rebif 22µg TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection and for 24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluate patients at least every second year of the treatment period. Contraindications History of hypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatment initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform patients of most common adverse reactions. Use with caution in patients with previous or current depressive disorders and those with antecedents of suicidal ideation. Advise patients to report immediately any symptoms of depression and/or suicidal ideation. Closely monitor patients exhibiting depression and treat appropriately. Consider cessation of therapy. Administer with caution in patients with a history of seizures and those receiving anti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening of their condition during initiation of therapy. Patients should use an aseptic injection technique and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients should consult their doctor before continuing injections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patients with history of significant liver disease, active liver disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver dysfunction appear. Treatment has potential to cause severe liver injury including acute hepatic failure. Full haematological monitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoring should be more frequent when initiating Rebif 44µg. New or worsening thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12 months. Use with caution in, and closely monitor patients with, severe renal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may develop and are associated with reduced efficacy. If a patient responds poorly and has neutralising antibodies, reassess treatment. Use with caution in patients receiving medicines with a narrow therapeutic index cleared by cytochrome P450. Women of childbearing potential should use effective

contraception. Limited data suggest a possible increased risk of spontaneous abortion. During lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider temporarily lowering or interrupting dose. Very common: flu-like symptoms, injection site inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue, rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea, depression, insomnia, severe elevations of transaminase. Serious side effects include: injection site necrosis, hepatic failure, hepatitis with or without icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiforme-like skin reactions, seizures, thromboembolic events, thrombotic thrombocytopenic purpura/haemolytic uremic syndrome, suicide attempt, Stevens–Johnson syndrome, dyspnoea, retinal vascular disorders. Consult the Summary of Product Characteristics for more information relating to side effects. Legal category POM. Price Rebif 8.8µg and 22µg: 6 (0.2ml) + 6 (0.5ml) syringes – £552.19. Rebif 22µg: 12 syringes (0.5ml) – £624.77. Rebif 44µg: 12 syringes (0.5ml) – £813.21. Rebif 8.8µg and 22µg: 6 (0.2ml) + 6 (0.5ml) pens – £552.19. Rebif 22µg: 12 pens (0.5ml) – £624.77. Rebif 44µg: 12 pens (0.5ml) – £813.21. Rebif 8.8µg/0.1ml and 22µg/0.25ml: 2 cartridges – £406.61. Rebif 22µg/0.5ml: 4 cartridges – £624.77. Rebif 44µg/0.5ml: 4 cartridges – £813.21. For prices in Ireland, consult distributors Allphar Services Ltd. Marketing Authorisation Holder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003; 006; 017; 013; 016; 010; 008; 009. For further information contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: 01 4687590. Date of Preparation July 2010.

REBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE REBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PEN REBIF ® 8.8 MICROGRAMS/0.1ML AND REBIF ® 22 MICROGRAMS/0.25ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE REBIF ® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE Interferon beta-1a Presentation Rebif 8.8µg and 22µg: Pre-filled glass syringe containing 8.8µg or 22µg of Interferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22µg or 44µg: Pre-filled glass syringe containing 22µg or 44µg Interferon beta-1a in 0.5ml. Rebif 8.8µg and 22µg: Disposable pre-filled pen injector (RebiDose) containing 8.8µg or 22µg of Interferon beta1a in respectively 0.2 or 0.5ml. Rebif 22µg or 44µg: Disposable pre-filled pen injector (RebiDose) containing 22µg or 44µg Interferon beta-1a in 0.5ml. Rebif 8.8µg/0.1ml and Rebif 22µg/0.25ml: Pre-filled glass cartridge containing 132µg of Interferon beta-1a in 1.5ml. Rebif 22µg/0.5ml or Rebif 44µg/0.5ml: Pre-filled glass cartridge containing 66µg or 132µg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity. Dosage and administration Initiate under supervision of a physician experienced in the treatment of multiple sclerosis. Administer by subcutaneous injection. Recommended dose: Weeks 1 and 2: 8.8µg three times per week (TIW); weeks 3 and 4: 22µg TIW; week 5 onwards: 44µg TIW (22µg TIW if patients cannot tolerate

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. In the Republic of Ireland information can be found at www.imb.ie. Adverse events should also be reported to Merck Serono Limited – Tel: +44(0)20 8818 7373 or email: medinfo.uk@merckserono.net.

Merck Serono is a division of Merck