Richard Lehman’s journal reviews—3 April 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM 29 Mar 2018

Stage III colorectal cancer: 3 or 6 months of chemo?

“The IDEA collaboration was a prospectively conducted study involving 12,834 patients with stage III colon cancer who were enrolled in six individual trials and randomly assigned to receive either 3 months or 6 months of adjuvant therapy with oxaliplatin and a fluoropyrimidine. Robust data were generated regarding benefits and risks according to the duration of therapy in these patients. As expected, a shorter duration of adjuvant therapy was associated with a significantly lower incidence and severity of adverse events, especially neurotoxicity, but also symptomatic side effects such as the hand–foot syndrome, mucositis, nausea, fatigue, and diarrhea.” This summary perfectly encapsulates the message of the six trials bundled into this report, and as a patient I would have no hesitation in opting for the shorter course. But readers skimming through the abstract would take away quite a different message: “Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup.” Once again non-inferiority rears its stupid head, and it you look at the fine print you will see that it is accompanied by its even stupider twin, disease-free survival. I long for the day when valuable datasets like this are accompanied by interactive decision tools for patients and clinicians, rather than reduced to bogus binary statistical categories. 

Febuxostat: new, expensive and dangerous?

Next example of “noninferiority”: “In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol.” That’s the conclusion of the abstract.

Here is a tweet from Ken Covinsky which puts it a different way: “Allopurinol has been used for gout for decades (cost 20cents/tab). Febuxostat(uloric) is a new gout drug, heavy DTC advertising (cost $10/tab) RCT shows Febuxostat increases risk of death by 22% DO NOT USE Febuxostat.”  

MRI-guided biopsy for suspected prostate cancer

“MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer.” Here some seriously awesome investigators have to twist their minds in order to use the mandatory “non-inferiority” word. The UK-based PRECISION trial will change practice in the diagnosis of prostate cancer and mean that fewer men will receive unnecessary treatment. 

To say more about it would involve some really detailed explanation of the population enrolled, the diagnostic strategies which were compared, and the outcome measures used. It would involve knotty discussion of the predictive characteristics of PSA according to what lay further down the diagnostic and treatment pathway. All of which would be well worth attempting in a lengthy editorial. But since this isn’t one, suffice to say that when the lessons of this trial are adopted in practice, MRI will reduce transrectal biopsies and at the same time identify the high Gleason score cancers which really need treatment. Better diagnosis will reduce overdiagnosis and overtreatment.  

JAMA 27 Mar 2018

US infectious disease: diarrhoea deaths increase, rest decline

The years 1980-2014 saw one enormous infectious disease catastrophe in the USA which is hardly reflected in the data of this survey. AIDS came in the mid-1980s and became almost obsolete with HIV treatment by 2000. Other than that, there was a slow decline in mortality from infectious disease, mostly in the soft category of lower respiratory infections. There is an interesting section on “garbage code reallocation methods” but I think “chest infection” is always going to be a default garbage diagnosis for cause of death. The most interesting feature is the increase in deaths attributed to diarrhoeal illnesses, the second highest category for infectious death: from 0.41 per 100,000 in 1980 to 2.41 in 2014. Oddly the worst figures for fatal diarrhoea are from Ohio and the best from Hawaii.  

Oral ibuprofen best for PDA closure in prems

The debate about using drugs to close a patent ductus arteriosus in premature babies is mostly about whether to do it and when. Then there is the question of what drug to use. This systematic review and network meta-analysis gives a plain answer: high-dose oral ibuprofen. It has a much better success rate than IV ibuprofen or IV indometacin. In all groups including placebo there was no difference in mortality, necrotizing enterocolitis or intraventricular hemorrhage.

The Lancet 31 Mar 2018

Siponimod and secondary progressive MS

Siponimod is a new word that rhymes with God, though I doubt whether it will be used much by hymn-writers. And sadly I’m not sure it will be widely used by people with secondary progressive multiple sclerosis, though you might think otherwise reading the conclusion of the abstract: “Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding: Novartis Pharma AG.” 

The primary end-point was one I haven’t come across before: time to the occurrence of a prespecified number of confirmed disability progression (CDP) events. Adverse events were spectacularly common in both active and placebo groups, but lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. To save you further trouble, here is the key sentence from the accompanying editorial: “Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small. In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome are disappointing results and do not suggest that siponimod is an effective treatment for SPMS.”

War on malaria: latest drug combo

Artemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are potentially useful for diversification of ACTs in this region”. Forget the names unless you use these drugs. I just like to know that there are plenty of useful combinations still around to treat or re-treat uncomplicated malaria. In this context, I can even put up with non-inferiority: “Pyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified.

The BMJ 31 Mar 2018

Population attributable fraction

Public health “experts”—whether medically trained or not—seem very fond of preachy messages backed with statistics. When you look at how they were arrived at, they tend to be wild surmises that even stout Cortez would blush to make. This very useful summary of the Population Attributable Fraction shows why. Although it is a nice concept, trying to find the amount of disease that any given risk factor is responsible for is often a matter of assumption and extrapolation, sent round various loops of circularity. Beware PAF. It is often PIFF. Meaning adult-sized piffle.  

Plant of the Week: Hepatica nobilis

With their lobed leaves the colour of ox-liver, it’s easy to see how the hepaticas got their name. But how come this species got called nobilis? Humilis would seem more fitting for this shy woodlander with its little flowers of clear sky-blue. Maybe it is to do with their colour resemblance to lapis lazuli, the noble pigment which can still only be sourced from a remote mountain in Afghanistan, three days by donkey from the nearest highway. Five thousand years ago it was already turning up in places as far away as southern Mesopotamia and Egypt, set in gold jewellery; and in the depths of the Dark Ages it appears on illuminated manuscripts from Irish monasteries at the furthest limit of the known world.  

Hepaticas are treasures in their own right. But they are miffy, to use an invaluable word from Reginald Farrer. They have to be hidden in some damp patch among trees, or they will mank. One could not, however, call them mimpish*. Catching their flash of blue on the shaded ground is like glimpsing a kingfisher in a wood. Rare, and noble.

* for further explanation you will have to consult “Mimpish Squinnies: Reginald Farrer’s Guide to Worthless Plants“, of which 30 copies were issued in 2007.