Richard Lehman’s journal review—4 January 2016

richard_lehmanNEJM 24 & 31 Dec 2015 Vol 373
Second cancers after Hodgkin’s cure
2499 Hodgkin’s disease was one of the first cancers to move from invariably fatal to routinely curable. It happened about 50 years ago, and we have long known that the price for this was an increase in risk for later cancers, due to the treatment modalities used—extensive radiotherapy and highly toxic chemotherapy. But surely, with better targeted treatments over the decades, this risk has diminished? Alas, there is no evidence of this from a study of 3905 persons in the Netherlands who survived for at least 5 years after the initiation of treatment for Hodgkin’s lymphoma between 1965 and 2000. With a median follow-up of 19.1 years, the risk of a second cancer remained high across the board, with a cumulative incidence of a second cancer in the study cohort at 40 years of 48.5%. This paper expresses the risk as a standardized incidence ratio (SIR), which had me looking on Google. The SIR was 4.6 (95% confidence interval 4.3 to 4.9) in the study cohort as compared with the general population. And yes, unless I am mistaken, that means over 4 times higher than the population average.

Chlamydia and Boswell’s syndrome
2512 I am about to embark on reading a biography of James Boswell, best known as a late-life companion of Dr Samuel Johnson, and also famous as a sex addict who kept getting gonorrhea. He probably also got chlamydia too, but that wasn’t recognized as a cause of urethritis until the middle of the twentieth century. These two sexually transmitted bacteria stand at opposite extremes of adaptability to antibiotic challenges. This study shows that in young offenders’ institutions in the USA, Chlamydia trachomatis is 100% susceptible to doxycycline and 97% susceptible to azithromycin. By contrast, Neisseria gonorrheae, which is spread rapidly round the world by persons suffering from Boswell’s syndrome, has the genomic wherewithal to develop resistance to “all known antibiotics.” Allegedly. In fact I have heard this claimed repeatedly over the last 30 years. It is always about to happen. But never to me, I hasten to add.

Selexipag and the GRIPHON Investigation
2522 It sounds like the title of a science fiction story. Here is the science bit anyway. Selexipag got her unfortunate name through being an oral selective IP prostacyclin-receptor agonist. Why might you want to tickle up these receptors? After all, we’re more accustomed to reducing prostacyclin activity in people, by means of aspirin and non-steroidal anti-inflammatory drugs. And if you increase such activity you risk headache, diarrhoea, nausea, and jaw pain, all of which were experienced by some of those given selexipag in this trial. There were 1156 participants, all with pulmonary arterial hypertension, of whom 205 died in the course of the study. Selexipag made no difference to all-cause mortality and made a small difference in hospitalization and a considerable difference in the numbers who preserved their six minute walking distance during the three years of the trial. It is about to go on sale in the USA.

Elephants, cancer & dollars
2593 My eye was caught by the title of this commentary piece, “Value-Based Cancer Care.” It is the elephant in the room of medicine: “the average cost of some newer cancer drugs is now $10,000 to $30,000 per month, and combinations of checkpoint inhibitors cost as much as $100,000 per month. Virtually none of these treatments are curative, and some improve only disease-free survival, not overall survival.” The rest of the piece is a rather bland account of how various US cancer associations are trying to come up with formulae to assess the value of these treatments. I wish they had invited a commentary from Vinay Prasad instead. He has the necessary combination of knowledge and anger.

Homeric choices: salt v soap
2629 Here’s a trial which could have come straight out of Homer. The epic poet, I mean, not Father Simpson. Let’s imagine there is a version of the Iliad in which Achilles, meeting Hector on the windy plain of Troy, smashes his leg instead of killing him outright. Hector’s attendants rush to him with bowls of water to clean his compound fracture. Some are soapy and some are salty. Which should his surgeon use? Three thousand years on, you would have thought we might know, but this Canadian trial seems to be the first to settle the question. “The management of open fractures requires wound irrigation and débridement to remove contaminants, but the effectiveness of various pressures and solutions for irrigation remains controversial. We investigated the effects of castile soap versus normal saline irrigation delivered by means of high, low, or very low irrigation pressure.” Forget the pressures: they make no difference. But the reoperation rate was higher in the soap group than in the saline group.

Risky home birth
2642 Call it what you will—childbirth, midwifery, obstetrics—it is a risky business. Nature is indifferent to the suffering and fate of mother or child. They are dispensable, and many need to die for the process of parturition to become more efficient over evolutionary time. The Romans were typically brutal in their realism about this: they privileged a live male child over a dead mother. The name Caesar means “cut out” and one explanation of this unusual surname is that the family began with a male who was cut out of the womb, killing the mother in the process. In other words, caesarian section gave rise to the Caesars and not the other way round. The obstetric emergencies I have seen are so horrible that I judge the place-of-birth debate in very simplistic terms. Rule one: make sure that the mother and baby are safe by immediate access to intervention during labour if needed. Rules two and onwards can be whatever else you like. Here’s a survey of hospital versus out-of-hospital births in Oregon. “Planned out-of-hospital birth was associated with a higher rate of perinatal death than was planned in-hospital birth (3.9 vs. 1.8 deaths per 1000 deliveries, P=0.003; odds ratio after adjustment for maternal characteristics and medical conditions, 2.43.” Read on if you want. That’s “only” one extra dead baby per 500 births etc.

JAMA 22/29 Dec 2015 Vol 314
Carry On Egging
2654 JAMA ends the year on a rather dull note, though this British study of in-vitro fertilization provides a modicum of seasonal cheer. Perhaps it should be called Carry On Egging, in honour of Barbara Windsor’s new damehood. Although it is customary to stop IVF after 3-4 goes, UK data show that it can be successful all the way up to six, giving a cumulative live-birth rate of 65.3% after six cycles, with variations by age and treatment type.

JAMA Intern Med Dec 2015
Antibiotics: the Spanish strategy
OL Spain is a country where antibiotic prescribing is roughly similar to that in the UK. As I keep pointing out, antibiotic resistance is highly organism-specific, and for the most part respiratory pathogens are rather bad at developing it. Yet whenever the antibiotic doomsday scenario comes up, everyone from the Chief Medical Officer down to the bloke in the supermarket queue starts talking about how GPs hand out antibiotics for colds and flu as it they were Smarties. If this is true—which it actually isn’t—then it has made remarkably little difference over 60 years to the effectiveness of antibiotics for respiratory tract infections. The true problem lies elsewhere entirely. But let’s go back to Spain, where this nice primary care study was done to assess the effect of delayed prescription strategies for uncomplicated RTI. “Delayed strategies were associated with slightly greater but clinically similar symptom burden and duration and also with substantially reduced antibiotic use when compared with an immediate strategy.”

Snappy screening info splats
OL One of the authors commenting on that Spanish study is Paul Glasziou. I wish that they had used him instead to write about this trial of communication about screening. Paul once told me he had run a two-day “citizens’ jury” meeting about the use of PSA for prostate cancer screening. On day one, nobody really seemed to grasp the idea of overdiagnosis and its harms. If there was this test that picked up cancer early, that had to be a good idea. But gradually as day two wore on, most of the audience started getting it. They imagined having needles stuck up their bottoms and then having surgery that made them incontinent or impotent, while they would never know if any of it had been worthwhile. Even if you looked at the outcomes of the entire group, there would still be no difference. My gloomy take home message was that it takes two days of discussion and information to get people to understand the basic principles of screening. This study confirms that fear. It was conducted by Duke University and compared the effect of information formats on lay understanding of PSA screening, screening for colorectal cancer, and screening for osteoporosis. The four randomized groups were: 195 to words, 192 to numbers, 196 to narrative, and 192 to framed formats. These were equally ineffective.

Lancet 2 Jan 2016 Vol 387
BP lowering & the meaning of life
OL A meta-analysis of blood pressuring lowering for the prevention of cardiovascular disease and death appeared just before Christmas. It attracted a day’s worth of comment before we all went off to do seasonal things and then recover from them. I guess the debate will start to build up again now, and when the article appears in print. It is certainly worth a careful read: it’s a model for this type of systematic review and it is very clearly written, covering a vast range of trials using blood pressure lowering drugs both for high blood pressure and for other indications. It confirms that BP lowering, like the use of statins, should be governed by total risk and not by a specific level of systolic BP. Remember the Fifth Commandment: Thou shalt treat according to level of risk and not to level of risk factor. The study also identifies clear class differences for different drugs in relation to different outcomes, e.g. thiazide-like agents are better at reducing the incidence of heart failure, whereas the logic of using RAAS inhibiting drugs to prevent renal failure looks very shaky. The authors conclude: “Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease.”

I think this may mark a watershed moment in the use of BP lowering agents. But contrary to most commentators, I think it will lead to a large and welcome decline in their use. A clue comes in the sentence, “Rather than a decision based on an arbitrary threshold for a single risk factor, this approach needs individualised assessment of the balance of absolute risks and benefits when physicians decide on the blood pressure level at which to start blood pressure lowering and the target blood pressure.” So this is a decision for the physician, is it? Why isn’t it a decision for the person who is expected to take the drugs for the rest of their life? And it’s at this point that the whole stack of cards begins to fall apart. For a start, our cardiovascular risk prediction instruments fail to predict most of the absolute risk and have poor overlap with each other. There is no way that we can produce more than a vague ball-park guess about the likely contribution of various treatment possibilities—non-pharmacological as well as pharmacological—to the outcomes of particular individuals. And most of these outcomes are binary—you either have a stroke or you don’t. They cannot be expressed as days of life gained, but only in terms that are borrowed from gambling and so have no objective meaning for individuals. The trials lumped together here were on subsets of people for relatively short periods of time, so even if you make them into a smiley face chart, you will be giving out a false message about their predictive value. And when you do make them into such a chart, many sensible people will look at it and say, “You mean to say that I’d have to be one of 231 people to take these pills for ten years just so that one of us wouldn’t have a heart attack? Sod that.” Public health physicians will hold up their hands in horror. Oxford professors will rage at GPs (and The BMJ) for not imposing the supposed good of the herd on individuals. But why? It is for each of us to play the odds of our lives as we choose. Many will choose to take the pills—myself included. Many will not. The only right choice is informed patient choice.

Plant of the Week: Brassica oleracea var. “Flower sprout”

Botanists are great lumpers of the cabbage family, throwing together cabbage, kale and Brussels sprouts under a single name. Cultivars of B oleracea vary enormously in their habit, their colour, their size and their palatability. As a child, I quite liked Brussels sprouts, which my mother would boil for a while and then serve covered with breadcrumbs fried in butter, which she would call bułka. When I visited the houses of friends I was sometimes served the same vegetable cooked à l’anglaise, a pale brown sodden heap where the individual sprouts had coalesced. This is less good.

About five years ago, English farmers back-crossed Brussels sprouts with kale to produce purplish tufts like tiny cabbages with a deep nutty flavour. In a backwater town like ours they only arrived in Marks & Spencer last year, but I’m sure they’ve been in Chelsea Waitrose’s for ages and ages, darling. We grab them when we can, and being lazy, just cook them in boiling water for a couple of minutes. I’m sure there are many more creative things to be done with them. They are the most delicious of native green winter vegetables.