NICE celebrates 10th anniversary amid renal cancer drug controversy

Changes to guidance decision based on new appreciation of life expectancy


The National Institute for Health and Clinical Excellence (NICE) provides independent, national guidance on clinical practice, health technologies and public health to the UK's National Health System (NHS). Never shying away from tackling controversial topics, NICE is accustomed to a fair share of criticism, particularly when it comes to cost-effectiveness of treatments and interventions. Now, the agency is engaged in another debate (this time in the urology community) regarding the use of four drugs for the treatment of advanced renal cell carcinoma.

NICE was started 10 years ago when then–Prime Minister Tony Blair became aware of variations in medical practice across the UK, specifically as it affected patient access to new, expensive cancer drugs. Today, NICE has a staff of 280 and an annual budget of £33 million. At any given moment, more than 2000 people are actively involved in producing guidelines. Since its inception, NICE has provided the NHS with evidence-based guidelines of best practices for such diverse conditions as colon cancer, dementia, multiple sclerosis and osteoporosis. All of the guidelines have generated commentary from physician and patient groups.

“Physicians often think of best practice as being the most effective”, says Professor Peter Littlejohns, MBBS, clinical and public health director for NICE. “But, from a health care perspective, it is really seen as value for the money. We assess whether interventions are clinically and cost effective. That's what obviously generates the biggest debates”. In the past, NICE has said ‘yes’ to expensive interventions that were effective and ‘no’ to some less expensive ones that were not worth the money.

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‘We assess whether interventions are clinically and cost effective. That's what obviously generates the biggest debates’.

Professor Peter Littlejohns

NICE has issued a number of clinical guidelines, interventional procedures and technology appraisals to benefit the urology specialty (see ‘NICE Clinical Guidelines on Urology’). Currently, it is working on guidelines for male lower urinary tract symptoms (LUTS) and nocturnal enuresis in children (both due for release in 2010). But nothing NICE has done in the past has created such strong feelings among urologists as their current analysis of four drugs—sunitinib, bevacizumab, sorafenib and temsirolimus—used to treat kidney cancer.

Tensions ran high when Professor Tim Eisen, PhD, in the department of oncology at the Cambridge Cancer Center at the University of Cambridge, wrote a comment questioning NICE's cost-effectiveness analysis and methods of assessment for the drugs (BJUI. 2008;102:1491–1492). “No provision was made for the importance of gaining even a few months of extra life for patients, where these benefits are deemed to be extremely important by all patient groups”, Prof. Eisen pointed out. “Quite the opposite is the case, as NICE attributes a lower value to life on treatment due to the side effects of therapy.” Prof. Eisen and others expected NICE to approve the use of sunitinib, considered a first-line option by many physicians. NICE did not. In its consultation document, all four renal cancer drugs were not deemed cost effective despite being clinically effective.

Prof. Littlejohns concedes that the original metrics NICE used—particularly the quality-adjusted-life-year (QALY)—did not value a short period of life gain when life expectancy was short. “A few months in everyone's lifetime is very small, but if you've got a year to live, then 6 months is very important”, he admits. Given the public and professional outcry, NICE issued to its advisory committee in January what it calls ‘end-of-life’ advice. “Basically, this said that if there is definite evidence drugs will extend life, they should be more lenient about this threshold”, says Prof. Littlejohns. Following a committee meeting on January 14, NICE decided to split the appraisal in two, saying that sunitinib—but not the other three drugs—is recommended as first-line treatment. They also did not endorse the use of sorafenib and sunitinib as second-line treatment.

‘A few months in everyone's lifetime is very small, but if you've got a year to live, then six months is very important’.

The announcement was also sweetened by Pfizer, the maker of sunitinib, which agreed to a patient-access plan where the first treatment cycle of the drug is free to the NHS. “Basically, they are saying that if a drug works, then the NHS pays”, explains Prof. Littlejohns. “But, if it doesn't work, they get a rebate”.

Although the celebrations for the 10th anniversary of NICE have been reserved, this is probably not due to the guidelines controversy. Instead, NICE is busy preparing to launch its new evidence-based website. Called a ‘medical Google’, the site will allow anyone to access quality evidence on any disease or condition efficiently. In addition to NICE guidelines, the website will accredit other information providers—such as other organizations that write guidelines—to create a single point of access for reliable, evidence-based medical information from disparate sources. The site debuts this month and will include a link to the NICE main website (www.nice.org.uk). Over the next six months, NICE will move away from issuing guidance to setting standards for clinical practice. On the horizon is a series of national, evidence-based clinical standards for general practitioners.

NICE Clinical Guidelines on Urology

NICE has issued a number of clinical guidelines, interventional procedures and technology appraisals relevant to the urology community, on topics such as:

  • Chronic kidney disease;

  • Prostate cancer;

  • Type 2 diabetes and renal disease;

  • Urinary incontinence; and

  • Urinary tract infection in children.

Prof. Littlejohns believes even NICE's vocal critics want the organization involved in healthcare. “What they really challenge is our methodology and individual decisions”, he says. “At the end of the day, they still like having an organization that really looks at how to get the best care for the whole population”.

Clinical Trial: 1

SAFETY OF SGI-1776, A PIM KINASE INHIBITOR TO TREAT DOCETAXEL REFRACTORY PROSTATE CANCER

PROTOCOL ID NCT00848601

SUMMARY This phase I safety study will determine the maximum tolerated dose and the dose-limiting toxicity of SGI-1776 in patients with hormone- and docetaxel-refractory prostate cancer. Secondary outcome measures include prostate-specific antigen response and pharmacokinetics. A starting dose of 100 mg (total daily dose) will be given as 50 mg every 12 hours for 14 days of a 21-day cycle. There will be dose escalation in successive cohorts until progression or toxicity develops.

ELIGIBILITY Patients must have histologically-confirmed adenocarcinoma of the prostate that is now metastatic. There should also be evidence of progressive disease despite androgen deprivation (androgen ablation or surgical castration), anti-androgen withdrawal, and the progression of disease after docetaxel-based therapy. Additional inclusion criteria exist.

LOCATIONS AND CONTACTS Cancer Therapy Research Center, John Sarantopoulos, MD, 210-450-5882

University of California-Los Angeles, Sven de Vos, MD, 310-794-4376

Royal Marsden Hospital, Sutton England, UK, Johann De Bono, MD, 020-8-642-6011

Clinical Trial: 2

TENSION FREE VAGINAL TAPE (TVT) VERSUS THE MINIARC SLING

PROTOCOL ID NCT00843908

SUMMARY The randomized, prospective study aims to assess whether the Miniarc suburethral sling is equivalent to the TVT for treating women with urodynamic stress incontinence (USI). One group will have the TVT inserted; the other will have the MiniArc tape inserted—both under spinal anesthesia. Primary outcome measures will be the absence of stress incontinence at six weeks and six months as determined by direct questioning, the Kings Quality of Life questionnaire and urodynamics. Secondary outcome measures include intra-operative complications and post-operative voiding dysfunction.

ELIGIBILITY Patients must have subjective evidence of stress predominant symptoms and stress incontinence on urodynamics. Additional inclusion criteria exist.

LOCATIONS AND CONTACTS

Medway Maritime Hospital, Kent, UK, Jonathan Duckett, +1634-830000, ext. 5154, jonathan.duckett@medway.nhs.uk

DRUG AND TECHNOLOGY NEWS

OVERACTIVE BLADDER TREATMENTS APPROVED

The US Food and Drug Administration (FDA) approved two new therapies for overactive bladder (OAB), one an extended-release tablet and the other a topical gel.

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The first, fesoterodine fumarate (Toviaz, left), is a smooth-muscle relaxant. t is taken once daily at a starting dose of 4 mg, which can be increased to 8 mg if needed.

Approval was based on two 12-week, randomized, controlled studies of 1964 patients. There was an 88% median reduction in urge urinary incontinence with fesoterodine fumarate 8 mg compared with 50% on placebo. The 8-mg dose also reduced the number of urinations per day by up to 19% compared with 11% in the placebo group. Reductions in wetting accidents were observed as early as two weeks after treatment and maintained for 12 weeks. Already available in Europe, fesoterodine fumarate will be available in the US the first half of this year.

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The second, oxybutynin chloride (Gelnique Gel 10%, left) is the first topical drug to treat OAB. Because oxybutynin is delivered transdermally, it is not metabolized by the liver as are OAB medications delivered by the oral route. This results in lower levels of dry mouth and constipation, common with other OAB medications.

Patients apply a 1-gram dose (approximately 1 mL) of the gel to their thigh, abdomen, upper arm or shoulder once daily. It is quick drying, clear and colorless. Approval was based on a randomized, controlled clinical trial involving 789 patients with OAB. Over the 12-week trial, oxybutynin chloride was superior to placebo at relieving symptoms. Showering one hour after application did not significantly alter absorption. Applying sunscreen 30 minutes before or after the gel also did not interfere with efficacy. Oxybutynin chloride will be available in the US during the second quarter.

Should prostate cancer patients lose weight before surgery?

Ask Stephen J. Freedland, MD, associate professor of surgery at Duke Comprehensive Cancer Center in Durham, North Carolina, what he thinks about obesity and he will give you a quick, three-word answer. “Obesity is bad. There is a bad biology that goes along with it”, he explains. “Obesity makes prostate cancer detection and surgery more difficult. Once you detect it—and all things being equal—it is just harder to treat in obese men”.

His two recent papers support these observations. In the first (BJUI. 2008;102:964–968), obesity was associated with an increased risk of overall positive surgical margins (PSMs) at all anatomical locations. The second (BJUI. 2008;102:969–974) showed that a higher body mass index (BMI) was association with high-grade disease and biochemical progression.

Dr. Freedland speculates on whether or not a specific surgical approach would decrease the likelihood of PSMs. “The limitations are predominantly in patients having open surgery. We have no data to say laparoscopic robotic surgery would be better in obese men, but it might be”, he says. “Some advocate a peritoneal approach, but we found it increases PSMs as well. Preferring one technique over another in these men is highly controversial”.

Should the trouble surrounding prostate cancer in obese men be used as a motivator to get them to lose weight? Dr. Freedland thinks so. In fact, he regularly brings it up to his patients. “I absolutely use this as a motivator. I say to them, ‘look, I'm 50% more likely to leave cancer behind. You are twice as likely to have the cancer come back and 30% more likely to die from it,’” he says. “If that's not striking, then I don't know what else is”.

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Dr. Freedland believes tumors in obese men are pre-programmed to be more aggressive in an active, hormonal environment. Losing weight can help before surgery and even afterward. Some men might benefit from undergoing bariatric surgery to help them lose weight before prostate cancer surgery. According to Dr. Freedland, if a man with low-risk disease can lose just 30 pounds in three months, it can make a large difference for surgery. “I know surgeons who tell patients they need to lose 30 pounds or they won't do the surgery”, he says. “Losing weight makes the technical side of surgery better and easier”. Currently, he is studying the value of weight loss after prostate surgery.

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‘Losing weight makes the technical side of surgery better and easier’.

Stephen J. Freedland, MD

Obese men have lower prostate-specific antigen (PSA) levels. This may be the result of hemodilution from a larger plasma volume. “The PSA appears to be about 15% lower for these men”, Dr. Freedland points out. “Some papers in the literature say there is not a great correlation. But, when you look at studies involving 10 000 and 30 000 people, including ours, it is pretty convincing”.

Not everyone, however, agrees with adjusting the PSA cutoff point in obese men to reflect these findings. “Some have published their own data of 400 patients and didn't see it. So they don't believe the larger studies”, says Dr. Freedland. “They are some of the most vocal critics. In time, I hope more and more will accept the data supporting using cutoffs. I'm just not sure what more we can do to prove this”.

Dr. Freedland and his team are now actively looking at the mechanism behind the PSA phenomenon by prospectively measuring plasma volume in men and then correlating it with their PSA levels. “Rather than just taking their height and weight and calculating their blood volume, we are actually measuring it and then correlating the two values”, says Dr. Freedland.

The study will enroll 1000 men over the next two years.

In this issue …

Reconstructive and Paediatric Urology

KEYS TO SUCCESSFUL FISTULA REPAIR P1122

What determines a good outcome when repairing vesico-vaginal fistulae (VVF) and urethra-vaginal fistulae (UVF)? That is the question Ockrim et al. asked when they reviewed retrospectively 41 consecutive patients with VVF (32) and UVF (9). Fistulas were repaired successfully in 94% of women with VVF and in eight out of nine women with UVF.

The study did not find a significant difference in outcome when it came to the route of repair for VVF. All 11 patients with a VVF and eight out of nine with a UVF were treated successfully with a transvaginal approach. An abdominal approach was used for larger or more complex fistulae.

Two key factors were identified as determinants of success: fistula size and tissue interposition. A failed outcome was more likely for VVF fistulae measuring larger than 3 cm where omental interposition was not possible. The study found that all failed fistulae possessed extensive defects and limited tissue to interpose.

Factors not considered significant were the patient's age, menopausal status, body mass index, anesthesia grade and the length of time between fistula onset and repair. In future reports, the authors plan to publish data on quality of life, urinary function and sexual function after fistula repair.

Mini Reviews

LESS IS MORE IN RENAL SURGERY P1034

LESS, NOTES, SILS, OPUS. Urologists should become familiar with these acronyms, because they represent the future of urologic surgery. Just where is the urology community when it comes to the evolution of laparo-endoscopic, single-site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES)?

Kommu et al. review the preliminary advances of LESS in renal surgery and speculate on its future application to other more complex and technically demanding procedures (i.e., laparoscopic radical prostatectomy and partial nephrectomy). Also referred to as single port (access/incision) laparoscopic surgery (SILS), LESS uses articulating or bent instrumentation with specialized multi-lumen ports. It is performed through a small, solitary portal of entry into the abdomen. When a transumbilical port is used, the approach is called one-port umbilical surgery (OPUS).

In their review of preliminary studies in porcine models, the authors note the need for further advances in instrumentation while also testing survival, in order to expand the NOTES and LESS techniques. Reports from experienced groups in laparoscopic urological surgery point to the approach being feasible if optimal technique is effectively combined with optimal instrumentation.In the future, NOTES and LESS will be further enhanced by magnetic anchoring and guidance systems to control cameras and instruments.

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