Richard Lehman’s journal review—17 November 2014

richard_lehmanNEJM 13 November 2014 Vol 371
1867 “Metastatic melanoma remains just over the border of curability. As we wait and hope for some breakthrough in an agonizingly incremental process, there will be more trials like this one,” I wrote last week about a paper in JAMA. They haven’t been long coming. The two in this week’s printed New England Journal represent the highest standards in the field, which I find less than encouraging. In this first one, funded by F. Hoffmann–La Roche/Genentech, the primary outcome measure was progression free survival, but oddly this was assessed first by the investigators themselves and only afterwards by an independent review panel. I could not find any reference to investigator blinding. Anyway, the conclusion of this trial, in which 495 patients were recruited at 135 sites around the world, is that “the addition of cobimetinib to vemurafenib was associated with a significant improvement in progression free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity.” There was no significant effect on mortality at nine months. Now at present, metastatic melanoma is a certain death sentence, and the median age of the patients was 55, ranging from 23-88. So these patients were mostly facing a severe curtailment of their lifespan, and they volunteered to receive a treatment that might significantly worsen the quality of the short life remaining to them. Our response to their courage and altruism should be to ensure that trials of this kind are interpreted from the viewpoint of the patient, rather than the pharmaceutical company trying to obtain a licence for a new drug. Individuals themselves should be able to judge how a “significant improvement” in disease progression might be weighed against “some increase in toxicity.” The best way to achieve this would be for F. Hoffmann–La Roche/Genentech to release their full datasets and meta-data to independent analysts, including an advisory group of patients with metastatic melanoma.

1877 GlaxoSmithKline have also gone through the immense labour of collecting over 400 patients with metastatic melanoma from 113 centres around the world. Once again I won’t try to explain the mechanistic rationale of their new drug trametinib, because it basically didn’t do anything, except give 51% of subjects a fever. But that’s not the way GSK are allowed to report it in their conclusion: “A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.” Never has there been a better illustration of the difference between statistical significance and patient centred significance. The median progression free survival was 9.3 months in the dabrafenib–trametinib group and 8.8 months in the dabrafenib-only group. That is two weeks in plain English. And this is not real survival: it is essentially just a surrogate outcome judged from scans. Again I must assert that these dying volunteers have a right to expect trials like these to be honestly reported from their perspective.

OL If you want more of the same, there are two more trials on the NEJM website. In a large GSK run trial, “Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.” The overall survival rate at 12 months was 72% (95% confidence interval 67 to 77) in the combination therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group. On the basis of this small difference, this open label trial was stopped. Do you think it should have been?

OL All the trials so far have been between “nibs”—BRAF inhibitors or MEK inhibitors. But there are mabs in the field too. These show promise in treating the kinds of advanced melanoma that do not have BRAF mutations. In 418 previously untreated patients with metastatic melanoma without a BRAF mutation, Bristol-Myers Squibb tests its new drug nivolumab against the older agent dacarbazine. Nivolumab is the clear winner: “At one year, the overall rate of survival was 72.9% (95% CI, 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group.” Now that, for a change, is useful knowledge.

1889 There is no medical intervention as good as a vaccine that works. And pneumococcal vaccination does work, when it is targeted at the right population, such as children in South Africa. And it works despite the fact that it targets only 7-13 of the 90+ serotypes of S pneumoniae. After the introduction of the 7-valent vaccine in 2009, rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100 000 person years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100 000 person years in disease caused by PCV7 serotypes. The 7-valent vaccine was replaced in 2012 with a 13-valent vaccine. Now the other pneumococcal serotypes are starting to replace the ones in the vaccine, but so far mankind remains far ahead in this game. As a result of protecting the children, invasive pneumococcal disease has also fallen in South African adults aged 25 to 44, from 3.7 to 1.6 cases per 100 000 person years.

JAMA 12 November 2014 Vol 312
1870 Exome sequencing is a technique for sequencing all the protein coding genes in a genome (known as the exome). I learnt that today from Wikipedia, and perhaps you have now learnt it from me. Keep reading these reviews, because you never know when you might learn something. But please do not count on learning anything more about exomes and genomes, because I really can’t engage with this stuff. When people tell me that it is bound to transform medicine one day, I don’t bother to disagree with them. They may even be right, but I will not live to see the day, and in the meantime there are far more urgent things to be getting on with. For people at high risk of genetic disorders, exome sequencing may already be a better form of detection than “traditional molecular diagnostic approaches in certain patients.” Notice how the individuals tested have already mutated into patients. Because exome sequencing throws up all sorts of incidental risk data, most of which can serve no purpose except to provoke anxiety. If you think the present world is full of overdiagnosis, you ain’t seen nothin yet.

1897 Pertussis is always with us, because immunisation provides only temporary protection, and a fifth of children and adults with persistent coughs are busy spreading it around all the time. Now and again it reaches epidemic proportions and kills some newborn babies. This happened a couple of years ago in England, and it was successfully addressed by immunising all pregnant women in the last trimester. The same was done in California in 2009, and careful follow-up of this cohort of women confirms that the vaccine is not associated with increased risk of hypertensive disorders of pregnancy or preterm or small for dates birth.

Lancet 15 November 2014 Vol 384
1749 Donald Gleason was a pathologist at the Minneapolis Veterans Affairs Hospital. Framingham is a town in Massachusetts whose sprawl is beginning to merge with that of Boston. Virginia Apgar was a professor of anaesthesia at Columbia University, and a keen violinist and flyer. Glasgow coma is what Glaswegians seek on Friday nights. What do they have in common? Scores, of course. These are four scores that people actually remember and use, whereas there are scores of scores we never bother with. The Apgar score was recorded for over one million births in Scotland between 1992 and 2010. “Low Apgar score at 5 min was strongly associated with the risk of neonatal and infant death. Our findings support its continued usefulness in contemporary practice.” Well done, Virginia. She never did get to fly under New York’s George Washington Bridge, but she did make her own violin and was able to play many fine scores.

1756 Unlike metastatic melanoma, hepatitis C genotype 1 is curable with the help of drug combinations. There is a similar scramble among drug companies to showcase their own drug. Janssen makes simeprevir. Gilead makes sofosbuvir. Put them together and 92% of patients will be clear of virus at 12 weeks. As I said last week, probably every millionaire in the world with hepatitis C genotype 1 can now be cured.

1766 You may be aware that there is something called hepatitis E as well. A new study finds that it is fairly widespread in southeast England. Just as well that it is hardly a pathogen at all, though it can become chronic in some immune suppressed patients. Testing 225 000 blood donations for hepatitis E, the investigators found that 79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. It is moot whether routine screening of donations is needed.

The BMJ 15 November 2014 Vol 349
A confession: these reviews are there to point you to the evidence, but do not constitute proof that I know much. For someone who never does percutaneous coronary interventions, there is simply no use in taking up brain space to try and remember which is the latest anticoagulant regimen to come up top in the meta-analysis stakes. Reporting the trials over the last 16+ years has been fun at times (this is a lie), but you can’t really expect me to remember my dabigatran from my enoxaparin. All it has done is give me a healthy scepticism about the possibility of a truly definitive and up to date meta-analysis. But here is the conclusion of the latest one: “In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding.” I’m a firm believer in shared decision making, but if I was about to undergo PCI, I think my eyes would just glaze over and I’d find myself saying “Just do whatever you think best, doctor.”

For most of the 31 years I was in my general practice partnership, we carried out patient satisfaction surveys, and we always came out very well. Latterly, these surveys have become more invasive and more personal, so that individual doctors are now rated on their perceived communication skills. This study shows that there is much more variability between doctors in generally low performing practices than in generally high performing practices. I guess this is to be expected.

When the Quality and Outcomes Framework was introduced into UK general practice in 2004, I welcomed it. Now I think it is poisonous and in urgent need of abolition. These contradictory stances can, with effort, be reconciled. First of all, I had no idea of how the QOF would mutate and become a bundle of ridiculous non-evidence based targets and gaming, all of which detracts from the real business of looking after patients under immense time pressure. Secondly, I welcomed a standardisation of practice where there was true evidence of benefit. But figures have repeatedly shown that once the QOF targets had been met, most care simply plateaued, and I suspect that this was often at the expense of overtreating the comparatively well at the expense of the “non-compliant.” The remarkable thing is that though the QOF had little effect on what it was measuring within primary care, its introduction coincided with a consistent fall in acute hospital admissions for the conditions for which structured care was incentivised. So it did some good initially. Let’s move on. It is now poisonous and in urgent need of replacement with care that is based on mutually agreed goal setting with patients.

Fungus of the Week: Lepista nuda (syn. Clitocybe nuda)

The wood blewit is a pretty safe mushroom to collect, because there is no fungus of similar colour and appearance that is likely to harm you. And, although I have had only one opportunity to go hunting this year, I suspect that it is a good one for blewits, which grow in wet heaps of rotting leaves, often around fallen boughs. Provided fallen leaves shore up in the same place year after year, blewits will keep appearing there year after year, which is always an advantage for the gatherer. This also allows them to be cultivated, but I am put off buying them by their expense, because in truth they are not all that much better than ordinary shop mushrooms.

A good fresh blewit has a smooth cap and is purplish blue throughout. It has about the same size range as the cultivated mushroom and is similarly gregarious. The caps of older and wetter specimens can be predominantly brown and will become bluer as they dry, but there is always plenty of purpliness about a blewit to make it distinctive.

Be sure to dry off any wet examples, and cook them immediately if they have any sign of larvae. If you squirm at the thought of eating the odd one of these nourishing little creatures, then there is little point collecting wild fungi at all: but you don’t want them to multiply and dominate your refrigerator, as they will if you try to store the fungi they live in. Your aim is to be more a fungivore than a larvivore.