RF FOR RENAL CANCER

Elderly patients with renal cancer and patients with comorbidities who are poor candidates for surgery do well after treatment with percutaneous radiofrequency ablation and have few complications and recurrences, according to a new study.

"Nearly half of all renal cancers are now diagnosed incidentally because of the increasing use of imaging. For these patients, a conservative surgery has been developed to preserve renal function," lead investigator Pierre Balageas, MD, from Saint-André Hospital in Bordeaux, France, told Medscape Medical News.

However, Dr. Balageas, who presented the results here at the European Congress of Radiology (ECR) 2013, pointed out that "there still are patients with small renal cancers who are poor candidates for surgery because of advanced age or comorbidities. For these patients, percutaneous radiofrequency ablation works well."

To evaluate the effectiveness of the approach, Dr. Balageas and his team retrospectively reviewed all T1a renal cancers treated with percutaneous radiofrequency ablation at a single centre from 2002 to 2009. A total of 93 patients (median age, 73.5 years) underwent the procedure.

The technique used depended on tumor size, morphology, and location. "Most patients were treated with computerized-tomography-guided ablation," but 2 were treated with ultrasound guidance, Dr. Balageas noted.

The survival analysis involved 62 patients (mean age, 69.5 years) with 71 tumors (mean size, 23.9 mm). Mean follow-up was 38.8 months.

After initial treatment of the tumors, the technical success rate was more than 95%. After the retreatment of recurrences, the secondary success rate was more than 98%.

There was no change in real function 2 and 6 months after the procedure. Rates of both tumor progression (~3%) and metastatic evolution (~10%) were relatively low, and median survival was 68 months, Dr. Balageas reported.

One year after radiofrequency ablation, more than 98% of patients were alive and free of disease; 3 years after, 92% were; and 5 years after, approximately 61% were.

"In our study, tumor site was the only independent factor predicting risk for residual tumor or in situ recurrence," Dr. Balageas said, "and all tumors less than 40 mm were completed ablated after 1 procedure."

Major complications occurred at a rate of 5.9% per session. Central location of the tumor was the only factor associated with an increased risk for complications.

"Our experience using radiofrequency for renal tumors is increasingly being helped, not only by our good results, but also by the treatment strategy established with members of our surgical team, who have become convinced of the benefits of this technique," Dr. Balageas observed.

Session chair Jurgen Fütterer, MD, from the Radboud University Nijmegen Medical Centre in the Netherlands, who was asked by Medscape Medical News to comment on this study, noted that both radiofrequency ablation and cryoablation can be used to treat small renal tumors with curative intent.

"Not every patient with renal cancer is a candidate for radiofrequency ablation, but patients with localized disease who have a high mortality risk with general anesthesia are," he said.

Dr. Fütterer noted that the literature suggests that radiofrequency ablation has a success rate of ~80%, so the success rate achieved by Dr. Balageas and colleagues is very good.

Factors Affecting Success

In another study presented during the same session, Vanessa Acosta-Ruiz, a medical student at Uppsala University in Sweden, reported that her team also found very high success rates in 44 patients treated with percutaneous radiofrequency ablation over a period of 4.5 years.

"After the first ablation, 75% of the tumors were completed ablated, 8 tumors were incompletely ablated, and 7 were retreated, so we ended up with a total success rate of 85%," Acosta-Ruiz said.

Correct positioning of the electrode over the tumor favorably affected results, as might be expected, she added.

However, a tumor smaller than 30 mm and a distance from the tumor to the collecting system of at least 10 cm were more likely to be associated with complete ablation, she added.

DIGOXIN USE IN AF INCREASE MORTALITY

SAN FRANCISCO, California — Patients with atrial fibrillation (AF) starting digoxin for the first time showed an independently significant jump in mortality over an average of one year compared with nondigoxin users in an observational study reported here today at the American College of Cardiology 2013 Scientific Sessions. Stratified analysis showed the effect to be consistent in men and women and by age.

Digoxin was given for rate control; patients with heart failure had been excluded from the study.

Although mortality doubled with digoxin use, hospitalizations appeared unaffected, suggesting that the people died at home, according to lead author Dr James V Freeman (Stanford University School of Medicine, CA). And though there were no data on cause of death, he toldheartwire that ventricular arrhythmias are a hazard from digoxin toxicity, "so our hypothesis is that maybe [digoxin users] had an increase in arrhythmic death and sudden cardiac death. But there's no way to know that for certain."

Digoxin in one form or another is one of the oldest still-used drugs in medicine and was never tested in substantial clinical trials for efficacy or safety in AF. Still, Freeman observed, the drug "is much more commonly used than people think, and it's not just that people who were using it 20 years ago are still using it."

The current findings support a recent propensity-adjusted secondary analysis of the AFFIRM trial,which found a 41% jump in all-cause mortality in AF patients taking vs not taking digoxin. As previously reported by heartwire , the increased hazard was seen in both men and women and in patients with and without underlying heart failure.

The group looked at 23 272 digoxin-naive patients newly diagnosed with AF from 2006 to 2009 within Kaiser Permanente Northern and Southern California. Of that group, 12.9% were started on digoxin for rate control.

The adjusted hazard ratio (HR) for all-cause mortality over a median of 0.8 years was 2.06 (95% CI 1.73–2.45) and for hospitalization was 1.05 (95% CI 0.98–1.13). The mortality finding remained significant in subgroup analysis by sex and three age groups.

Adjusted HR (95% CI), digoxin vs no digoxin use, for death from any cause in adults with incident AF (2006–2009)

Subgroup	HR (95% CI)*
Sex
Male	2.03 (1.58–2.60)
Female	2.13 (1.67–2.71)
Age (y)
21–74	2.31 (1.68–3.17)
75–84	1.66 (1.23–2.23)
>85	2.50 (1.85–3.38)

*Adjusted for age, race, income, laboratory parameters, prior CV disease and procedures, hypertension, dyslipidemia, cancer, lung disease, and cardiovascular medications

"This is about as strong an observational cohort study as you can get. I say that for a number of reasons," Freeman noted. It's large and from a "closed" healthcare system that is responsible for all patients' medications and lab results, and it would be known whether a patient might be noncompliant with meds, for example.

And there is potential from residual confounding due to differences in comorbidities and medications, which could--though they were adjusted for--suggest the study's results are conservative rather than overstated, he observed. Interestingly, nondigoxin users were sicker and showed a significantly greater baseline history of MI, stroke, and coronary revascularization, as well as more dyslipidemia and hypertension. Understandably, they were also on more CV medications.

The strong observational data for a hazard and thin evidence base supporting it, according to Freeman, is enough to recommend a reassessment of digoxin for AF rate control and maybe to give more consideration to certain patients--such as those who are highly symptomatic--for catheter ablation.

INCREASED STROMAL CELLS WORSENS SURVIVAL IN COLORECTAL CANCER

Medscapers ahoy. I am David Kerr, Professor of Cancer Medicine at University of Oxford and past President of the European Society for Medical Oncology. Today I want to talk about another prognostic index for colon cancer. This is related to a recent publication^[1] in Annals of Oncology by Dr. Huijbers and colleagues from the University of Leiden, The Netherlands, and the excellent medical center there, and also with colleagues, including me, from the University of Oxford.

These investigators looked at the contribution of stromal cells to prognosis in colon cancer. It was a nicely conducted, large study of 710 patients who had participated in one of our adjuvant colon cancer trials, hence our involvement. We [at University of Oxford] supplied the biological materials to our colleagues in Leiden, who did all of the analysis. They looked at the percentage of stromal cells and, using simple morphologic criteria that were validated with a reading by 2 pathologists, showed that patients who have a high fraction of stromal cells [have a worse prognosis]: If more than 50% of the cells are stromal compared with [the percentage of] epithelial cancer cells, [the patient will have] a bad prognosis, with a hazard ratio of 2.0 and a P value of .0001. For patients who have high stromal components in their cancers, the 5-year survival rate is around 69% compared with an 83% survival rate for those with a low stromal involvement.

This was a validation study of 710 patients, which followed from initial observations in a couple hundred patients. Therefore, in terms of looking at American Society of Clinical Oncology criteria and how we should report biomarker evidence, the numbers are good, the biostatistics are strong, and multivariate analysis was done. Because this was a validation study, it is a retrospective-prospective trial of a novel prognostic biomarker that is morphologically simple to characterize, pathologically straightforward, and reveals very interesting data.

It does not surprise me, in a way. I must admit that I am becoming much more interested in the interaction between epithelial cancer cells and stromal cells. The stroma, of course, is composed of fibroblasts, infiltrating microphages, lymphocytes, and so on, and the interaction among these in terms of production of cytokines and growth factors clearly can have an enormous impact on the biology of the epithelial cancer cells.

Although I have spent almost a lifetime working with colleagues like Ian Tomlinson, wanting to understand the somatic tumor mutations and changes that drive the behavior of colon cancer, we must not forget environment, context, and the stroma. Next time you see a patient with colon cancer, perhaps ask the pathologist to check whether the patient has high or low levels of stroma within the tumor, and then consider how those with a high stromal component may have a significantly worse prognosis.

SCREENING FOR LUNG CANCER

If all screening-eligible current and former smokers underwent low-dose computed tomography (LDCT) screening, 12,000 deaths from lung cancer could be averted each year in the United States, according to an analysis published onlineFebruary 25 in Cancer.

"Recently, the National Lung Screening Trial [NLST] demonstrated that, compared with chest x-ray, screening with LDCT reduced lung cancer mortality by 20% among current and former smokers, but the annual number of lung cancer deaths that could potentially be averted is unknown," senior author Ahmedin Jemal, DVM, PhD, from the American Cancer Society in Atlanta, Georgia, told Medscape Medical News.

"In this study, we sought to provide the first national estimate of the total number of lung cancer deaths that could be potentially averted with full implementation of lung cancer screening in current and former heavy smokers, aged 55 to 74 years, who smoked at least 1 pack per day for 30 years," Dr. Jemal said.

The investigators, led by colleague Jiemin Ma, PhD, MHS, also from the American Cancer Society, used a specially developed equation to estimate the number of lung cancer deaths that could be averted with screening.

The equation took into account the size of the American population (from 2010 Census data), the prevalence of screening eligibility (estimated from 2010 National Health Interview Survey [NHIS] data), and the lung cancer mortality rates in screening-eligible populations (estimated using 2000 to 2004 NHIS data and the Third National Health and Nutrition Examination Survey–linked mortality files).

In 2010, 8.6 million Americans (5.2 million men and 3.4 million women) were eligible for lung cancer screening.

According to the estimate, if the screening regimen used in the NLST was fully implemented in this population, 12,250 (95% confidence interval, 10,170 - 15,671) lung cancer deaths (8990 in men and 3260 in women) would be averted each year.

Start the Discussion With Your Patient

"Doctors with access to high-volume, high-quality lung cancer screening and treatment centers should initiate discussion with their eligible patients about the benefits, uncertainties, and harms of lung cancer screening," Dr. Jemal said.

"Our findings could provide additional data for setting or updating lung cancer screening guidelines," he explained. "They could also stimulate further studies on avertable lung cancer deaths and the cost effectiveness of LCDT screening under different scenarios of risk, various screening frequencies, and various uptake rates."

In an accompanying editorial, Larry Kessler, ScD, from the University of Washington School of Public Health in Seattle, writes that the most important influence on lung cancer mortality is the reduction in smoking.

He notes that antismoking campaigns in the United States have averted "hundreds and thousands of deaths," but that public health efforts are still needed to further reduce the prevalence of smoking.

Efforts to reduce smoking "should not minimize the potential importance of screening," he writes. "In many ways, these efforts must go hand in hand."

Dr. Kessler questions whether the 20% reduction in lung cancer mortality found in the NLST and the estimated 12,000 lives saved per year found in this study are sufficient justification to implement a national policy for screening.

"It is clear why a decision has not been yet taken in this direction," he writes. The high rate of false-positive tests, the related workup costs, and the cost of treatment that does not benefit patients complicate the issue.

The limits of screening emphasize the continued need for antismoking efforts, Dr. Kessler says. He issues a call to use "all of our technologies, primary prevention methods, screening methods, and treatment" to tackle this issue.

FLU VACCINE LINKED TO NARCOLEPSY

A study from England shows a significant 14-fold increased risk for narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix, GlaxoSmithKline) during the pandemic.

The study points to a "causal association" consistent with findings from Finland and Sweden, Elizabeth Miller, consultant epidemiologist, Health Protection Agency, Colindale, London, United Kingdom, and colleagues reported online February 26 in the British Medical Journal.

The researchers emphasize that the risk might be overestimated by more rapid referral of vaccinated children, and they call for long-term follow-up of children who received the vaccine to get a better handle on the exact level of risk.

Interpret Cautiously

Pandemrix was introduced in Europe in October 2009 during the second wave of infection, initially for people with high-risk clinical conditions and then in healthy children. By March 2010, around 1 in 4 (24%) healthy children younger than age 5 years and just over a third (37%) aged 2 to 15 years in a risk group had been vaccinated. v

Altogether, more than 30 million doses of the vaccine were administered in European countries during the H1N1 flu pandemic. It was not used in the United States.

In August 2010, concerns were raised in Finland and Sweden about a possible association between narcolepsy and this vaccine.

A 2012 study from Finland reported a 13-fold increased risk for narcolepsy in children and young people aged 4 to 19 years who got the vaccine. Most of those who developed narcolepsy had onset within 3 months of vaccination, and all did so within 6 months of vaccination.

However, in October 2012, a review of the evidence by the European Medicines Agency (EMA)'s Committee on Human Medicinal Products (CHMP) concluded the evidence was not sufficient to confirm a link between the vaccine and narcolepsy cases.

"After careful consideration, the CHMP concluded that the data presented by the Finnish researchers are preliminary and that the evidence presented so far is insufficient to allow conclusions to be drawn, and does not lead to any new concerns regarding Pandemrixor other vaccines, including other influenza vaccines," an EMA statement noted. "On the basis of the current evidence, the role of the Pandemrix antigen and its adjuvant on the association between Pandemrix and narcolepsy remains unknown."

To evaluate the risk for narcolepsy afterPandemrixvaccination in England, Miller and colleagues reviewed the medical records of 245 children and adolescents aged 4 to 18 years seen at sleep and child neurology centers across England.

From this group, they identified 75 children with narcolepsy (56 with cataplexy) with onset after January 1, 2008. Eleven had received the vaccine before their symptoms started, and 7 had received it within 6 months of vaccination.

In children with a narcolepsy diagnosis by July 2011, the odds ratios were 14.4 (95% confidence interval [CI], 4.3 - 48.5) for vaccination at any time before onset and 16.2 (95% CI, 3.1 - 84.5) for vaccination within 6 months before onset, the researchers say.

In a self-controlled case series analysis, the relative incidence in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (95% CI, 2.1 - 47.9).

In absolute terms, the researchers calculated that 1 in 52,000 to 57,500 doses of Pandemrixare associated with narcolepsy.

This study shows that the increased risk for onset of narcolepsy in children and young people after Pandemrixvaccination is not confined to Scandinavian populations, the researchers say.

"The magnitude of the increased risk found in English children and young people is similar to that reported from Finland," they write.

Although further use of this vaccine for prevention of seasonal flu "seems unlikely," they say their findings "have implications for the future licensure and use of AS03 adjuvanted pandemic vaccines containing different subtypes such as H5 or H9."

"Further studies to assess the risk, if any, associated with the other A/H1N1 2009 vaccines used in the pandemic, including those with and without adjuvants, are also needed to inform the use of such vaccines in the event of a future pandemic," the researchers conclude.