Gefitinib reduces toxicity for advanced lung cancer patients

Medical Tribune January 2009 P11

David Brill

Gefitinib is a viable second-line alternative to chemotherapy for advanced non-small-cell lung cancer, offering similar survival rates with fewer side effects, a large-scale international study has shown.

The drug represents “an important shift in the treatment paradigm for this disease,” the authors of the INTEREST* trial reported in The Lancet. [2008 Nov 22;372(9652):1809-18]

Patients who took oral gefitinib also had improved quality of life compared to those who received intravenous infusions of docetaxel.

Asian patients, women, non-smokers and patients with adenocarcinoma all had longer survival with gefitinib – echoing the findings of previous trials which have shown the drug to be of particular benefit in these subgroups. Unexpectedly, however, INTEREST also found similar survival patterns with docetaxel, suggesting that these may be generally-applicable prognostic factors unrelated to the specific treatment.

Gefitinib is not currently approved for routine use by the US FDA. However in some Asian countires it is authorized for second-line use. For example in Singapore patients are typically given a choice between second-line treatment options in the event that initial chemotherapy is unsuccessful.

“Should the patient go on to further chemotherapy or should they go on to other drugs like gefitinib? This study confirmed that gefitinib is just as good as chemotherapy but may have fewer side effects,” said Dr. Toh Chee Keong, a consultant medical oncologist at the National Cancer Centre Singapore (NCCS).

Given the choice, most patients prefer an oral drug to chemotherapy but the higher cost of gefitinib can sometimes be a prohibitive factor, he said.

It remains unclear exactly who will benefit most from each treatment and why, he added, but noted that in his experience a non-smoking status is the most powerful predictor of a positive response to gefitinib.

In contrast to previous trials, neither epidermal growth factor receptor (EGFR) gene copy-number nor EGFR protein expression predicted survival with gefitinib in INTEREST.

The study is one of the few phase III clinical trials to directly compare the efficacy of docetaxel with an EGFR tyrosine kinase inhibitor. The analysis included 1,433 patients who had not responded to previous chemotherapy, recruited from 149 centers in 24 countries between March 1 2004 and February 17 2006.

The most frequent side effects of gefitinib were acne, rash and diarrhea. Just 4 percent of patients taking the drug experienced serious adverse events – a similar rate to that seen at NCCS, where Toh estimates that “less than 5 percent” of patients on gefitinib develop side effects to the point where they have to stop therapy.

For docetaxel the most common side effects in the trial were hematological toxic effects, hair loss and weakness. Serious adverse events occurred in 18 percent of patients in this group.

The non-inferiority of gefitinib was demonstrated by the median overall survival, which was 7.7 months in patients taking the drug compared to 8 months for those taking docetaxel. One-year survival rates were 32 and 34 percent in the respective groups.

Gefitinib patients were twice as likely to have a “sustained and clinically relevant improvement in quality of life,” as measured by the Functional Assessment of Cancer Therapy-Lung score (odds ratio 1.99; P<0.0001).>

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*Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere

Wealthy elderly more susceptible to air pollution

Medical Tribune January 2009 P12

David Brill

Abandoning your condo and moving to a poorer neighborhood might be good for your health if you live in a developing country, new research suggests.

The study of 7,358 elderly residents of Chinese cities found that those who lived in the wealthiest areas were more susceptible to the damaging effects of air pollution than those living in less prosperous parts of town.

An equivalent increase in pollution levels was linked to worse cognitive function, poorer self-reported health and greater difficulties with activities of daily living among residents of the highest GDP neighborhoods compared with the lowest.

The findings are at odds with research from Western populations which has found that the poorer the neighborhood, the greater the exposure to air pollution and the worse its effects on health. [Environ Health Perspect 2003 Dec;111(16):1861-70]

The new study shows that the relationship between air pollution and health in developing economies is more complex than previously thought, one of the researchers said.

“People tend to think in developing countries that when there’s more development there should be higher pollution but that is not what we’ve found. We showed that there is no clear correlation between the economic development level and the air pollution level,” said Rongjun Sun, an associate professor of sociology at Cleveland State University, US.

“The major message of our paper is that air pollution does have a dramatic impact on the health of the elderly but it’s not as simple as people imagine. I think when we look at this we will have to take a longer-term perspective.”

The researchers used data from the third wave of the Chinese Longitudinal Health Longevity Survey, conducted in 2002. Over-65s from 735 districts in 171 cities were included in the analysis. [Am J Epidemiol 2008 Dec 1;168(11):1311-8]

The reasons for the apparent discrepancy between East and West are not clear but may reflect differences in the usage of natural resources at the different stages of economic development, suggested Sun.

History suggests that as countries develop they move from industrial economies to more service-based economies, eventually becoming richer and reaching the position where they can begin to address the quality of the environment, he added.

Managing diabetic retinopathy in primary care

Medical Tribune January 2009 P14-15

Diabetic retinopathy is a leading cause of visual loss in Asia and one of the major chronic eye diseases handled by GPs. Left untreated, it can result in permanent blindness from neovascular glaucoma or tractional retinal detachment arising from proliferative diabetic retinopathy.

The condition is expected to become more common as the prevalence of diabetes continues to rise in Asia.

A recent study found that 38.1 percent of diabetics who were referred for retinal assessment as part of a nationwide screening program in Singapore had retinopathy. [Ann Acad Med Singapore 2008 Sep;37(9):753-9] The Singapore Malay Eye Study, meanwhile, demonstrated a retinopathy prevalence of 35 percent among diabetics of Malay ethnicity, of whom 9 percent had vision-threatening retinopathy. [Ophthalmology 2008 Nov:115(11):1869-1875]. This high rate of diabetics suffering from retinopathy is consistent worldwide. The proportion of type 2 diabetics having retinopathy has been reported to be 40.3 percent in the US, 35 percent in Taiwan and 10.5 – 26.2 percent in India.

Pathogenesis

Diabetic retinopathy is a highly specific microvascular complication of both type 1 and type 2 diabetes mellitus, resulting from progressive damage to the retinal blood vessels caused by hyperglycemia in the blood. The condition is caused by increased vascular permeability at onset, leading to fluid accumulation in the retina. With time, there is vascular shutdown, causing ischemia of the retina. This leads to retinal neovascularization at the disc or elsewhere, vitreous hemorrhages, fibro-proliferative changes and retinal detachment. Neovascular glaucoma can also develop. The prevalence is strongly related to the duration of diabetes mellitus, and most diabetic patients will develop retinopathy with time.

See the sidebar for a classification of the different disease stages.

Screening

As patients with sight-threatening retinopathy may not show any symptoms, fundal screening of diabetic patients is crucial in helping to identify those at risk of developing complications that will impact on their vision and quality of life. The importance of regular screening for diabetics, therefore, cannot be understated.

All diabetic patients should be screened for retinopathy on an annual basis at the very least, beginning from the point of diagnosis. Those who are at high risk for developing retinopathy need to be monitored more closely and should be screened at least twice yearly. The major risk factors to consider are hypertension, high cholesterol, smoking, patient’s age, duration of diabetes and a history of poor glycemic control. The Singapore Malay Eye Study also found that a history of stroke, cardiovascular disease or chronic kidney disease was associated with vision-threatening retinopathy.

Female diabetics who are planning to conceive should be screened prior to conception and again in the first trimester. The regularity of follow-up should then be determined based on the results of the first trimester examination.

For patients with established retinopathy, the timing of follow up examinations depends on their disease status.

Physicians who are involved in providing diabetic care have a pivotal role in ensuring that patients are screened. This can be performed via fundal photography, indirect fundoscopy or direct ophthalmoscopy through a dilated pupil.

While the need for regular screening is well accepted by the medical community, it is an unfortunate reality that patients are often not screened as frequently as they should be. Many patients do not understand the progressive nature of the disease process, mistakenly believing that if there is nothing wrong with their vision, then they do not need to see an eye doctor. Many appointments are missed as a result, and the early signs of diabetic retinopathy can often go undetected. Accessibility can also be a problem, particularly in rural areas, and can also contribute to the missing of screening appointments.

We must educate patients on the importance of these check-ups, and help them to understand that by the time they discover they have developed visual problems, it may already be too late to treat them. GPs can also help patients to attend their screening appointments by checking regularly whether they are compliant with their schedules, reminding them about upcoming
visits and making sure that they are referred to the most appropriate and convenient center.

Practice guidelines

The most widely-used guidelines on diabetic retinopathy come from the American Academy of
Ophthalmology. These have been incorporated into clinical practice guidelines on the management of diabetic retinopathy from Singapore’s Ministry of Health, published in January 2004, which help GPs plan their management and screening schedules for their patients. Diabetic retinopathy guidelines are also available from the Academy of Medicine of Malaysia.

Treatment

Laser treatment is the major therapy for diabetic retinopathy but can lead to long-term side effects such as a reduced field of vision.

There is now a considerable weight of data showing the benefits of good glycemic control on
retinopathy outcomes. The Diabetes Control and Complications Trial (DCCT) found that an intensive strategy reduced the risk of developing retinopathy by 76 percent and slowed disease progression by 54 percent. [N Engl J Med 1993 Sep 30;329(14):977-86] Recent data from the United Kingdom Prospective Diabetes Study (UKPDS) show that the benefits of intensive glucose control extended long beyond the trial intervention, with a 24 percent risk reduction for microvascular disease noted 10 years after the conclusion of the study. [N Engl J Med 2008 Oct 9;359(15):1577-89]

Tight blood pressure control is also important. The original UKPDS data demonstrated a 47 percent reduction in the risk of having decreased vision in both eyes, after 9 years of follow up. [BMJ 1998 Sep 12;317(7160):703-13] The 2008 data showed that the benefits disappeared once treatment was withdrawn, suggesting that blood pressure control needs to be maintained in order to continue to derive the maximum benefits. [N Engl J Med 2008 Oct 9;359(15):1565-76]

Medication adherence is often a major obstacle in achieving these targets. GPs should continue to ensure that patients are well-educated on the importance of taking their drugs, making them aware that failure to do so increases their risk of retinopathy. Regular HbA1c and blood pressure tests should be carried out to monitor progress, and medication adjusted accordingly.

Disease management tools

In October 2006, the Ministry of Health in Singapore launched the Chronic Disease Management Program, focusing initially on diabetes and then on hypertension, dyslipidemia
and stroke. The plan is to transform management of these diseases by forming an effective
partnership among GPs, medical specialists and patients through effective information flow within the partnership throughout the healthcare continuum. The program aims to equip GPs with a better understanding of patients’ medical histories through up-to-date electronic records and, in turn, reduce medical costs and enable the provision of quality healthcare services customized to individual requirements.

This integrated clinic management system provides GPs with a complete system to manage their patients and clinic operations. Critical clinical indicators are stored, enabling GPs to use this data to track the progress of their patients. Clinical decision support tools are also built into the system to help GPs plan effectively and communicate care plans to their patients. In this way, schedules for retinopathy screening can be built into the patients’ management plan, helping doctors keep to the intended schedules.

Conclusion

Regular screening is the cornerstone of detecting, monitoring and managing diabetic retinopathy and should be arranged from the very point of diagnosis. Patients should be educated about the importance of screening and followed up at all stages to ensure compliance to their schedules. Good glycemic and blood pressure control are also of vital importance in preventing the development and progression of this potentially sight-threatening condition. It is strongly recommended that the organization of retinopathy screening be primarily the responsibility of the GPs, who will then refer all patients with retinopathy or media opacity to an ophthalmologist for more specialized treatment.

Online Resources:

The American Academy of Ophthalmology guidelines:

www.guideline.gov/summary/summary.aspx?doc_id=4350

Office BP not prognostic for resistant hypertension

Medical Tribune January 2009 P16
David Brill

Office-based blood pressure (BP) measurements offer “no prognostic value” for patients with resistant hypertension, a recent study has concluded.


Ambulatory BPs – both systolic and diastolic – were predictors of future cardiovascular morbidity and mortality whereas neither measurement was a significant indicator when recorded in the office, the researchers found.

The study, which followed up 556 outpatients for a median of 4.8 years, also showed that nighttime ambulatory BP was superior to daytime as a prognostic indicator, suggesting that these time periods should be analyzed seperately to give the best assessment of a patient’s cardiovascular risk.

It is only the second prospective study to assess the different BP monitoring strategies in resistant hypertensive patients, according to the researchers, who are based at the Federal University of Rio de Janeiro, Brazil. They note that the superiority of ambulatory BP “is not generally accepted,” despite several studies showing that it offers better cardiovascular risk prediction than office BP in various other patient populations. [Arch Intern Med 2008 Nov 24;168(21):2340-6]

Dr. Chai Ping, a Singapore-based specialist, said that the study should encourage physicians to use ambulatory BP more often for patients with resistant hypertension.

“In the initial evaluation of a patient with elevated office BP despite three or more medications, ambulatory BP monitoring should be performed to confirm that the BP is truly elevated and not a ‘white-coat’ effect,” he said.

“This paper also tells us that suboptimal BP control, as has been known for more than 4 decades now, confers a worse prognosis for hypertensive patients, so every effort must be made to control BP to the targets as recommended by current clinical practice guidelines,” added Chai, who is clinical director of the noninvasive cardiac laboratory at the National University Heart Centre Singapore (NUHCS).

The patients included in the study met standard criteria for resistant hypertension. The mean hypertension duration at enrollment was 18 years. Some patients were followed up for as long as 9 years.

A total of 109 patients (19.6 percent) reached the study’s primary endpoint – a composite of fatal and non-fatal cardiovascular events.

Patients with a one standard deviation increase in nighttime systolic BP at baseline had a 38 percent increased risk of reaching this endpoint following multivariate adjustment (hazard ratio [HR] 1.38), while an equivalent increase in nighttime diastolic BP yielded a 36 percent increase in risk (adjusted HR 1.36; P<0.05 for both).

The only significant predictor of death was a so-called “true” diagnosis of resistant hypertension, based on ambulatory BP monitoring rather than office-based measurement. This diagnosis was associated with a twofold increase in the risk of all-cause mortality (adjusted HR 2.00; P<0.05).

Chai estimates that up to a quarter of patients being followed up at the NUHCS have resistant hypertension. He said that he presently uses both forms of BP measurement but noted that not all hypertensive patients require ambulatory BP monitoring.

The results of the study cannot be generalized to all patients with hypertension, he added.

The meteoric rise of HIV

Healthy Times December 2008
David Brill (aka David Wise)

December 1 is World Aids Day. To mark the event medical journalist David Wise looks at the humble origins of this global killer and its journey from an isolated outbreak to a worldwide pandemic.

Léopoldville may not be a familiar name to many, yet the city played host to one of the defining events of mankind’s recent history. The former Belgian colonial capital – now known as Kinshasa, Democratic Republic of the Congo – is thought to be the birthplace of HIV, the virus responsible for the AIDS pandemic which is currently affecting over 33 million people worldwide.

The precise origins of HIV remain a mystery but new research allows scientists to paint a more detailed picture than ever before. They now believe that the virus first reached humans in Léopoldville around 100 years ago, where it found a foothold among the booming population of the newly-founded city.

It is likely that HIV spread slowly at first, experts say, while the fact that symptoms differ widely between individuals may have prevented it from being recognized for many years. It was not until 1981 that French scientists Françoise Barré-Sinoussi and Luc Montagnier formally identified the virus – a discovery that was honored this year with the award of the Nobel Prize for medicine.

The true beginning of the story, however, begins not with humans but with our primate cousins. Today there are several different types of HIV, each of which may have its own tale to tell, but the particular strain responsible for the current pandemic seems to have evolved from a virus which naturally infects chimpanzees. In 2006 researchers announced that they had found this HIV forefather – the Simian Immunodeficiency Virus (SIV) – among wild chimps living in southeast Cameroon.

Most scientists accept that SIV became HIV, but how it first crossed the species barrier is largely a matter for speculation, according to Professor Robin Weiss, an HIV expert from University College London, UK.

“The most likely explanation is that it began with the butchering of apes,” he explains. “There was blood and splintered bones and goodness knows what lying around, and then the virus got transferred into small cuts or abrasions on the skin. If you wanted to be lurid you could raise a King Kong scenario of sex with a great ape but I think that’s a bit sensational myself.”

The first known case of HIV comes from a preserved tissue specimen dating back to 1959, which was found in the archives at the University of Kinshasa. In 2000, Betty Korber and her team at the Los Alamos National Laboratory, US, published an important research paper analyzing the genetic sequence of this virus. Their calculations, they said, suggested that the virus had likely been born around 1931 – back when Kinshasa was still known as Léopoldville.

But this information begged an important question which has only recently been answered: how did the slaughtering of chimps in southeastern Cameroon lead to the infection of humans in Léopoldville some 700km away?

The answer was provided in October of this year when Michael Worobey and his colleagues from the University of Arizona, writing in the journal Nature, announced that they had found another early HIV specimen lurking in the archives at Kinshasa. The tissue sample – a lymph node taken from an adult woman – had been fixed in preservative back in 1960.

This discovery enabled the team to compare the virus with Korber’s specimen from 1959. By looking at genetic differences between the two samples and tracing their family trees backwards, they established that the viruses must have shared a common ancestor between 1884 and 1924. Their best estimate puts the birth of HIV at 1908 – some 23 years earlier than previously thought.

Worobey’s team went one step further and placed their genetic studies alongside demographic data on the growth of cities in west-central Africa. They found that their estimate of 1908 coincided with a period of population boom in Léopoldville, suggesting that growth of the city provided the necessary kick-start for HIV to spread. Before 1900, there was not one settlement in the area with more than 10,000 people, but by 1910 Léopoldville had established itself as the region’s major city.

As the colonial outpost grew, so it continued to flourish as an administrative and trading center. With transportation at the time largely restricted to boats, Léopoldville found itself ideally situated on the Congo River – the final destination of many of the tributaries that run through the forests of Cameroon. The identity of the person that first contracted SIV may remain a mystery, but their arrival in the city now seems the likely trigger for the modern-day AIDS pandemic.

This newfound understanding of where HIV came from can provide important insights into the evolution of future pandemics, according to Weiss.

“These examples of particular viruses help to inform our general thinking about the origins of infections that come from animals. And for sure we’ve haven’t seen the last one – there’ll be some other disease like SARS or something that we haven’t even thought about today,” he says.
“And looking back at HIV in its very humble, small beginnings… who would have guessed that this would turn out to be the major killer at the end of the 20th century?”

JUPITER shows statin benefits for low-risk patients

Medical Tribune December 2008 P1 & 13

David Brill

Rosuvastatin can dramatically reduce the risk of death and major cardiovascular events among apparently healthy people, the highly-anticipated results of the JUPITER* study show.

The findings raise important questions about the indications of statins for primary prevention and should prompt a reassessment of current guidelines on risk assessment, one expert said.

JUPITER comprised 17,802 overtly healthy people with normal LDL cholesterol but elevated levels of high sensitivity C-reactive protein (hsCRP) – a group not currently indicated for statin treatment.

A 44 percent reduction in the incidence of the primary endpoint – comprising myocardial infarction (MI), stroke, cardiovascular death, arterial revascularization or unstable angina – was seen among those taking the drug compared to those on placebo (hazard ratio 0.56; P less than 0.00001).

Just 25 people would need to be treated with rosuvastatin to prevent one vascular event over a 5-year period, the researchers said.

The benefits of treatment were such that the trial was stopped a median of 1.9 years into the intended 4 year follow-up period.

"Despite evaluating a population with lipid levels widely considered to be optimal in almost all of our current guidelines, the relative benefit observed in JUPITER was greater than in almost all prior statin trials," said Professor Paul Ridker, the study’s principal investigator who presented the findings at a press conference during the recent annual Scientific Sessions of the American Heart Association.

"I think this is extremely reassuring for the statins as a class, and hopefully for the public at large who have been concerned about mortality benefits in this setting," he said.

Rosuvastatin reduced all-cause mortality risk by 20 percent and MI, stroke or cardiovascular death risk by 47 percent compared to placebo (hazard ratios 0.80 and 0.53; P=0.02 and P less than 0.00001, p=0.01).

The risk reductions were consistent across all subgroups regardless of gender, age, ethnicity, smoking status, BMI and Framingham risk score.

Statin therapy appears to have been safe, with no significant difference in serious adverse event rates between the groups. There was, however, an increase in the rate of physician-reported diabetes: 270 cases were recorded in the statin group and 216 in the placebo group (P=0.01).

Professor Andrew Tonkin, head of the cardiovascular research unit at Monash University, Melbourne, Australia, described the reduction in cardiovascular events in JUPITER as “extremely important.”

“I think that there will need to be a review of the guidelines for where CRP sits in risk assessment,” he said, adding that more information, such as the absolute risk reductions in subgroups and the cost effectiveness of treatment, is critically needed in order to establish the role of the marker as a screening tool for primary prevention.

Dr. Timothy Gardner, president of the American Heart Association, noted that the mechanisms for the risk reductions seen in JUPITER remain unclear.

“Statins lower both LDL cholesterol and hsCRP. Thus the findings presented today cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen in this paper,” he said.

JUPITER, which was concurrently published in The New England Journal of Medicine, included men aged 50 or older and women aged 60 or older who had LDL cholesterol levels below 130mg/dl and hsCRP levels of 2.0mg/l or higher. Participants were non-diabetics with no history of cardiovascular disease. [2008 Nov 9; Epub ahead of print]

Rosuvastatin treatment (20mg daily) reduced LDL cholesterol levels by 50 percent and hsCRP by 37 percent.

Ridker, of Harvard Medical School, Boston, US, acknowledged that the study was too short to fully assess long-term safety, but noted that there is a large amount of data on statins as a whole and that they have been found to be “remarkably safe.” Despite the early conclusion, over 1,000 people in JUPITER were followed up for more than 4 years, he added.

“These drugs as a class are extraordinary. We want to give out a message that we want to continue with diet, exercise and smoking cessation but now we have very overwhelming evidence that this class of drugs, this method of lowering these surrogates [LDL cholesterol and hsCRP], fixes hard endpoints,” he said.

The JUPITER trial was supported by AstraZeneca.

*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

ADA, EASD offer practical new guidance on diabetes treatment

Medical Tribune December 2008 P4
David Brill

An updated treatment algorithm has been released which promises to help guide primary care physicians through the ever-expanding field of treatments for type 2 diabetes.

The consensus statement, produced jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), places a strong emphasis on early treatment and the maintenance of HbA1c levels below 7 percent.

Metformin therapy plus lifestyle intervention is recommended from diagnosis for all patients, with further medications to be added promptly if targets are not achieved.

The statement also makes new differentiations within drug class
– advocating pioglitazone over rosiglitazone and dropping glybenclamide and chlorpropamide from the list of recommended sulfonylureas.

"We’ve seen absolutely that if you do not keep glucose levels within reasonable bounds you will reap a harvest of microvascular disease," said Professor Rury Holman, one of the authors of the algorithm.

"The tide is changing. The view that complications are inevitable is no longer true. They will occur even in the best controlled-people but the risk can be substantially reduced, and therefore I think we have a duty of care to minimize HbA1c to the extent that we can," he said.

Holman, head of the Diabetes Trials Unit at The Oxford Centre for Diabetes, Endocrinology and Metabolism, UK, said that the new algorithm is "not a prescription" to be followed in all cases but rather an evidence-based starting point for primary care doctors, who should still seek specialist advice where appropriate.

He also stressed the need to adopt a more cautious approach to HbA1c lowering in patients with a long-standing history of disease, noting that physicians should weigh up the relative risks and benefits before attempting to push HbA1c levels below 7 percent.

The latest version of the ADA/ EASD treatment algorithm, first issued in 2006, was published online recently in the journals Diabetes Care and Diabetologia. The document will continue to be updated as and when new data become available, Holman said.

For cases where the initial metformin approach is unsuccessful, the algorithm divides the subsequent intensification of therapy into two tiers according to how well validated the medications are considered to be. Tier 1 sees the addition of either sulfonylurea or basal insulin, progressing to initiation or intensification of insulin therapy. Tier 2 recommends pioglitazone or the glucagon-like peptide-1 agonist exenatide, before moving on to sulfonylurea or basal insulin.

Besides the algorithm, the consensus statement also contains a literature review on the relative merits of the different medications, and guidance on the titration of metformin and the initiation and adjustment of insulin regimens.

Dr. Kevin Tan, vice president of the Diabetic Society of Singapore, agreed that doctors now have a duty to initiate early, intensive glycemic control and said that incorporating the new algorithm would help them to focus on the older, better-established drugs and view the newer options as alternatives to be used where necessary.