The Unsung Heroes of Healthcare: Part II

Medical Tribune August 2009 SFXII
David Brill

Born in 2004 from the legacy of SARS, the annual Healthcare Humanity Awards are given to those who go above and beyond the call of duty to improve the care and wellbeing of patients. David Brill spoke to two of this year’s recipients about their achievements, challenges and hopes for the future.

A picture of health: Putting patients at the center

Associate Professor Chia Sing Joo is designing a hospital. It’s his biggest project to date, yet he works on it alone. There are no meetings, no paperwork and no phone calls – he’s been doing it for years and no one even knows about it.

The blueprints, for now at least, are in Chia’s mind. He refines them constantly, hoping one day for the opportunity to put them to use. “I would like to build a hospital which is totally patient-focused,” he explains. “Patients don’t have to wait for a long time, and they don’t have to worry about unforeseen outcomes because the process is so transparent. The doctors all share the same values and are not for profit. Every patient would want to come here, and every doctor would want to train here.”

This vision may sound ambitious, but Chia is already striding toward it. As chairman of the division of surgery at Tan Tock Seng Hospital (TTSH), Singapore, he has worked hard to improve processes of care and ensure that the welfare of patients remains the primary focus. Day surgery is up; unnecessary inpatient stays are down. Increased collaboration with GPs has freed up hospital beds and reduced waiting times, and the establishment of a multidisciplinary surgical oncology group has improved quality of care and outcomes for cancer patients. The list goes on, and many more projects lurk in the pipeline.

Communication is a theme that surfaces repeatedly in conversation with Chia, and would form a central pillar in the ethos of his patient-centric hospital. As a member of TTSH’s mediator team he is often on the front line against complaints, and has come to believe that the majority could be avoided simply by spending more time talking to patients and their relatives. Misinformation can lead to misunderstandings, and anxiety and stress typically follow, he says. And nowhere is this need for openness greater than when advising patients on surgery.

“First I explain the options to the patient and the complications of each,” says Chia, who is also a senior consultant urologist. “Second, I tell them what I would choose if they were my uncle or auntie. Finally, I let them know that there is no guaranteed surgery in this world. Expectations are important – patients have to understand that we are only human and a lot of things are beyond our control. If you do these things, there are very few patients who will not trust you. If complications arise, 99 percent will understand that you have done your best and this was something unavoidable and unpredictable.”

Chia’s quest to improve patient-doctor communication, however, does not end in the clinic or the operating theatre. He speaks in public forums, has recently published a book entitled Male Urological Problems: The Essential Guide for Every Man & Couple, and is now working on another layman-orientated book about “how to spice up your sex life”. He also gives out his home and hand phone numbers to patients, and encourages them to call if they have any concerns or questions. And, it seems, they don’t hesitate: he estimates that his phone rings every 5 or 6 minutes on a typical working day.

Even by doctors’ standards, Chia is a busy man. In between the phone calls, books and surgery, he also spends one day a week as a visiting consultant at KK Women’s and Children’s Hospital, works on several research papers, oversees the development of a new training center at TTSH, raises three sons – none of whom want to be doctors – and still finds the time to run for an hour before dinner. Citing “every day” as his career highlight, however, it is clear that he wouldn’t change a thing. Except, of course, for the long-awaited chance to roll out those imaginary blueprints. “If I really had the opportunity to build my own hospital, that would be a great challenge for me,” he says.

Urine test could allow for lung cancer risk prediction

Medical Tribune August 2009 P12
David Brill

A simple urine test could one day reveal which smokers are at greatest risk of developing lung cancer, according to a team of Singaporean, Chinese and American scientists.

The group recently reported the first link between elevation of certain urinary metabolites – total NNAL* – and increased lung cancer risk in humans. Cigarette smokers with the highest total NNAL levels were over twice as likely to develop lung cancer.

A commercially available test remains at least 5 years off, but the identification of these urinary biomarkers raises “an exciting possibility,” say the researchers.

“Such a test would enable doctors to screen more frequently for lung cancer in smokers with high levels of biomarkers, and provide a strong incentive for these smokers to quit smoking,” said study authors Associate Professor Yuan Jian-Min of the University of Minnesota, US, and Associate Professor Koh Woon-Puay of the National University of Singapore, in a joint statement to Medical Tribune.

“With the identification of new biomarkers, we could ultimately develop an assay that simultaneously quantifies a panel of tobacco carcinogens or their metabolites to best predict the risk of lung cancer for an individual smoker,” they said.

The work goes some way towards explaining why some smokers develop lung cancer while others do not. With over 60 established carcinogens in cigarette smoke, it may be that individual differences in the uptake and metabolism of particular chemicals play an important role in the development of cancer, the authors say.

One such carcinogen, NNK**, has been strongly linked to lung cancer but an epidemiological link had only been shown in animal studies.

Yuan, Koh and colleagues instead investigated levels of NNAL – a metabolite of NNK – in a nested case-control study using data on 63,257 men and women from the Singapore Chinese Health Study, and 18,244 men from the Shanghai Cohort Study. They identified 246 cases of incident lung cancer, and 245 matched controls. [Cancer Res 2009;69:2990-5]

The odds ratio of developing lung cancer was 2.11 for smokers who were in the highest tertile of urinary total NNAL before cancer diagnosis, compared to those in the lowest tertile (95% CI 1.25 – 3.54; P for trend = 0.005).

Combination with cotinine, a nicotine metabolite, further increased the predictive value of NNAL: the odds ratio for developing cancer was 8.47 for smokers in the highest tertile for both markers, compared to those in the lowest tertile (95% CI 3.69 – 19.46; P for trend – 0.005).

“Biomarkers for prediction of cancer risk are useful as proxy measures of outcome in interventional studies. Nevertheless, for smokers, the best intervention for the reduction of lung cancer risk is still to quit smoking,” added Yuan and Koh.

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* NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Total NNAL is the sum of NNAL and its glucuronides.
**NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

New CV risk score could replace Framingham in UK

Medical Tribune August 2009 P13

David Brill

The long-established rules for cardiovascular risk assessment could be overhauled in the UK, following calls for the Framingham risk score to be abandoned in favor of a newer model.

An independent analysis found the QRISK score to be superior to Framingham on all measures – identifying a higher proportion of people who went on to develop cardiovascular disease.

The findings prompted a resounding endorsement of QRISK in a British Medical Journal editorial, recommending its routine adoption. Reports have since emerged that QRISK is under review at the UK National Institute for Health and Clinical Excellence (NICE), and is set to be integrated into software packages used by GPs.

University of Oxford statisticians validated QRISK using an independent cohort of 1.07 million patients from 274 UK general practices. There were 43,990 cardiovascular events over a median of 4.9 years’ follow-up. [BMJ 2009 Jul 7;339:b2584]

QRISK under-predicted cardiovascular risk by 12 percent (13 percent for men and 10 percent for women) but was considerably more accurate than the Anderson Framingham algorithm, which overestimated risk by 23 percent (32 percent for men and 10 percent for women).

“We believe this formula has the potential to save many thousands of lives, by helping clinicians to more accurately predict those at risk of developing cardiovascular disease – the nation’s biggest killer,” said Professor Julia Hippisley-Cox of the University of Nottingham, who led the team which developed the QRISK score.

“It will arm doctors with all the information they need to decide how best to target patients with preventative measures such as lifestyle advice and cholesterol-lowering treatments. We are delighted to receive another strong endorsement of the value of QRISK in assessing the risk of heart disease in the UK population,” she said.

QRISK includes most of the traditional risk factors seen in the Framingham equations but also includes family history, social deprivation, body mass index and use of antihypertensive treatments. It was first developed and validated in 2007, using data from 1.28 million patients from 318 UK general practices. [BMJ 2007 Jul 21;335(7611):136]

Further refinements to the model – QRISK2 – were published last year to include ethnicity and other conditions such as type 2 diabetes, hypertension, atrial fibrillation, renal disease and rheumatoid arthritis. The updated version, however, has yet to receive independent validation. [BMJ 2008 Jun 28;336(7659):1475-82]

The external validation of the original QRISK was commissioned by the UK Department of Health to compare the model against the Anderson Framingham algorithm, which is presently recommended by NICE as the basis for deciding on whether to prescribe statins.

The incidence rate of cardiovascular events was 30.5 per 1,000 person years among men who were classed as high risk by QRISK, compared to 23.7 per 1,000 person years among men classed as high risk by the Anderson Framingham score. In high-risk women, the incidence rates were 26.7 per 1,000 person years for those identified with QRISK, and 22.2 per 1,000 person years for those identified by Anderson Framingham.

Despite the improvements with QRISK, the data provide “a sobering message about the current state of cardiovascular risk prediction,” according to the authors of the accompanying editorial. Increased usage, improved data collection and further refinements to the system could however increase the accuracy of risk prediction in future, wrote Professor Rod Jackson of the University of Auckland, New Zealand, and colleagues. [BMJ 2009 Jul 7;339:b2673]

Fertility preservation guidelines overlooked by oncologists

Medical Tribune July 2009 P4
David Brill

The majority of US oncologists do not follow recommendations on discussing fertility preservation with cancer patients, a survey shows.

Although seventy nine percent of respondents reported broaching the subject with patients, less than 25 percent referred them to a specialist or provided educational materials.

Just 38 percent were even aware of the existence of the guidelines, issued by ASCO in 2006. [J Clin Oncol 2006 Jun 20;24(18):2917-31]

The findings could prompt the development of new training programs for physicians and nurses, said study author Dr. Gwendolyn Quinn of the H. Lee Moffitt Cancer Center and Research Institute, Miami, US.

“We send patients to get wigs before they lose their hair during chemotherapy. We give medications to prevent nausea. Discussing fertility preservation should be something else that we do early in a patient’s care, rather than waiting until infertility occurs,” she said.

The survey was mailed to 1,979 oncologists – 613 of whom completed it. Those working in gynecological oncology and hematological/medical oncology were the most comfortable with having fertility preservation conversations. Physicians’ views of fertility preservation were also a key factor: those with a favorable attitude towards preservation were nearly five times as likely to discuss the options.

The main reason given for avoiding the discussion was that patients were too ill to delay treatment. Of greater concern, however, was physicians who skipped it because they did not believe that the patient was going to survive their cancer, said Quinn.

“It’s the patient’s right. It’s their choice. They may never pursue it, and some of them can’t afford it, but just to be given that information is important, and it’s perhaps not the role of the physician to make decisions. The guidelines say all patients – they don’t specify the healthiest of patients or the ones most likely to survive,” she said.

Even those who do not survive may wish to review their options for “posthumous parenting,” she added, noting that many US couples cryopreserve embryos or sperm for this purpose before beginning treatment.

Quinn acknowledged, however, that there can be many barriers to discussing fertility preservation, including financial constraints for the patient, or a lack of physician resources in certain geographic areas.

“It’s important to bring it up very near to the time of diagnosis, but we understand that it’s an emotional time,” she said. Future training could move the emphasis towards nurses, who may be better placed to have an in-depth discussion with the patient, she added.

Statins could boost prostate health, studies show

Medical Tribune July 2009 P4

David Brill

Evidence is growing to suggest that statins could help to maintain a healthy prostate – protecting against both benign and malignant disease.

Recent studies have found that statins lowered the risk of developing prostate cancer, reduced the aggressiveness of cancers, and reduced the risk of cancer recurrence after surgery.

Other reports have suggested that the drugs can protect against lower urinary tract (LUT) symptoms, benign prostatic hyperplasia (BPH) and even erectile dysfunction.

Researchers, however, are urging caution, saying that further studies are needed before firm conclusions can be drawn.

Six key studies were presented recently at the annual meeting of the American Urological Association (AUA) in Chicago, US. Three come from a single cohort of 2,447 men aged 40 to 79, who have been followed since 1990 by researchers at the Mayo Clinic, Minnesota, US.

The first study found that men who were taking statins were three times less likely to develop prostate cancer than non-users. Just 6 percent of statin users developed cancer over a median of 14.1 years of follow-up – a considerable reduction compared to the US national average, which sees around 17 percent of all men diagnosed with prostate cancer in their lifetime.

The second study, which included only 1,480 of the men, found that statins reduced the risk of erectile dysfunction in those aged over 60. This apparent protective effect increased over time – men who had been taking statins for 9 years or more were 64 percent less likely to develop the condition than men not taking statins, whereas those taking statins for less than 3 years were equally as likely.

A third analysis of the Mayo Clinic cohort, meanwhile, reported that statin users had a 57 percent reduction in risk of developing BPH, and a 63 percent risk reduction for developing LUT problems.

"If you are taking a statin for a heart condition or to lower cholesterol, these studies suggest that statins could have other benefits," said one of the study authors Dr. Jennifer St. Sauver, an epidemiologist at the Mayo Clinic. "However, it's very clear we need more information before men are advised to start taking statins for their urological health."

The fourth study presented at the AUA meeting found that men taking statins at the time of radical prostatectomy for prostate cancer were 30 percent less likely to have a recurrence. They also had lower prostate-specific antigen levels than non-users, and were more likely to have T1-stage disease. The study included 1,325 men, of whom 237 were taking statins at the time of surgery.

“Our findings suggest that statins may slow prostate cancer progression after radical prostatectomy," said study author Dr. Robert Hamilton, of the University of Toronto, Canada.

“Although the results of these studies are exciting, they need to be confirmed,” he added. “At this point we cannot say with confidence that statins reduce the risk of prostate cancer recurrence after radical prostatectomy."

The fifth study, led by Johns Hopkins University, US, found that prostate cancer was less aggressive in statin users than non-users. Of 1,282 men who underwent radical prostatectomy over 5 years, the 418 who were taking statins had lower tumor volume, lower prevalence of positive surgical margins, and lower percentage of cancer in their prostatectomy specimens.

The final study, meanwhile, suggests that statins might exert their beneficial effects by reducing inflammation within prostate tumors. Researchers from Duke University Medical Center, US, examined specimens from 254 men who had undergone radical prostatectomy, and found that inflammation was reduced by 72 percent in statin users compared to non-users.

Despite the positive results presented at the AUA, not all studies have shown benefits of statins of prostate cancer outcomes. One paper published earlier this year found that statin usage had no effect on progression-free survival after radiotherapy for prostate cancer. [Urology 2009 Jan;73(1):158-62. Epub 2008 Aug 22]

Some researchers have even suggested that statins could actually increase prostate cancer, and have called for further attention to be given to the issue. [Cancer Epidemiol Biomarkers Prev 2008 Feb;17(2):459]

Gemcitabine improves safety for adjuvant pancreatic cancer therapy

Medical Tribune July 2009 P8
David Brill

Gemcitabine is a safer option than 5-fluorouracil/folinic acid (5-FU/FA) for the adjuvant treatment of pancreatic cancer, results of a phase III trial suggest.

Investigators from the European Study Group for Pancreatic Cancer (ESPAC) found that there was no difference in survival between the two therapies, but fewer side effects with gemcitabine.

The study included 1,088 patients who were randomized to one of the two therapies following resection of pancreatic ductal adenocarcinoma. It is the largest adjuvant trial ever carried out in this patient population and the first to directly compare gemcitabine against 5-FU/FA in the adjuvant setting, the researchers say.

“This study is important because it shows no difference between these treatments in prolonging survival,” said lead author Professor John Neoptolemos, head of surgery and oncology at the University of Liverpool, UK.

“On the basis of the safety profile, however, this trial shows that gemcitabine is likely to be the preferred adjuvant therapy. We are now also looking at combining the two treatments to see if we get a better response, because the drugs have different mechanisms of action,” he said.

After a median of 34 months follow up, overall survival times were 23.6 months for patients receiving gemcitabine and 23 months for those receiving 5-FU/FA.

Ten percent of 5-FU/FA patients experienced treatment-related hospitalization, compared to 3.5 percent of gemcitabine patients. Other adverse events which were more common in the 5-FU/FA group included stomatitis (10 percent versus 0 percent; P<0.001) and diarrhea (13 percent versus 2 percent; P<0.001). Some gemcitabine patients, conversely, experienced a drop in platelet count which was not seen in the 5-FU/FA group (1.5 percent versus 0 percent; P=0.0034).

Gemcitabine is typically used in the US for the adjuvant treatment of pancreatic cancer, whereas 5-FU/FA is the standard in some parts of Europe. It was previously unclear which treatment offered a better prognosis.

The trial, known as ESPAC-3, included patients from 16 countries, who were randomized between 11 July 2000 and 12 Jan 2007. Ages ranged from 31 to 85, with a median of 63.

The results will also help to reinforce the design of the upcoming ESPAC-4 trial, added Neoptolemos. The study is set to compare gemcitabine alone against gemcitabine plus capecitabine – a prodrug which is converted to 5-FU in tumors.

No change needed for anal cancer treatment

Medical Tribune July 2009 P8

David Brill

Radiotherapy combined with 5-fluorouacil (5-FU) and mitomycin-C should remain the standard of care for anal cancer, say UK investigators.

Pull quote: “We recommend that radiotherapy with 5-FU and mitomycin-C remains the standard of care for this condition.”Results of the largest-ever trial for anal cancer showed no benefit from switching mitomycin-C for cisplatin, or from adding maintenance chemotherapy to the regimen.

The Second UK Phase III Anal Cancer Trial (ACT II) included 940 patients (median age 58), followed up for a median of 3 years. Those who relapsed or failed to respond to therapy were treated with surgery.

The results of the trial provide good news, despite the lack of benefit shown by the alternative treatment regimens, said lead investigator Dr. Roger James, a consultant radiation oncologist at Maidstone Hospital, Kent, UK.

“Overall the outcome for patients in this study is excellent, with a 95 percent complete response rate at 6 months and an 85 percent survival at 3 years. These are very good results relative to the international trials published so far. We recommend that radiotherapy with 5-FU and mitomycin-C remains the standard of care for this condition,” he said.

Patients were recruited from 2001 to 2008. All were given radiotherapy and 5-FU, and were randomized to receive either additional mitomycin-C or cisplatin. They were then further randomized: half received an extra round of maintenance chemotherapy, comprising two cycles of cisplatin and 5-FU at weeks 11 and 14, and half did not.

Six-month response rates were 94.5 percent for mitomycin-C and 95.4 percent for cisplatin (P=0.53). Non-hematological toxicity was comparable between the groups, affecting 60.2 percent of mitomycin-C patients, compared to 64.6 percent of cisplatin patients (P=0.17). There was, however, more hematological toxicity in the mitomycin-C group (24.7 percent) compared to the cisplatin group (13.4 percent; P<0.001).>

Maintenance chemotherapy had no impact on 3-year recurrence-free survival rates, which were 75 percent for both groups. Overall survival at 3 years was also not significantly different between those who received maintenance therapy (85 percent) and those who didn’t (84 percent).

The ACT II trial results bring another blow to hopes that cisplatin would prove beneficial in anal cancer. Early data had shown anal tumors to be sensitive to a combination of cisplatin and fluorouacil, but a trial of 682 patients, published last year, found that it offered no survival benefits over mitomycin-based therapy. Moreover, cisplatin-treated patients were almost twice as likely to undergo colostomy as those treated with mitomycin (19 percent versus 10 percent; P=0.02), the US Gastrointestinal Intergroup trial Radiation Therapy Oncology Group reported. [JAMA. 2008;299(16):1914-1921]