Alex Nowbar’s research reviews—15 April 2019

Alex Nowbar reviews the latest research from the top medical journals

Mets meet their match
For many of us, being told a cancer has spread or metastasised is synonymous with being told that it is “incurable.” In this paper, the authors wanted to gather evidence on the oligometastatic paradigm, which is the idea that cancer with a limited number of metastases could be cured if all the lesions are eradicated. This international multicentre trial randomised 99 patients with between one and five metastases whose primary tumour had already been “controlled.”

They found impressive survival benefits (13 months longer) for those randomised to ablative radiotherapy compared with those randomised to standard care. This is good news for patients like those in the studied population, although 4.5% of patients in the radiotherapy group had treatment related death and toxicity was worse.

JAMA Internal Medicine
Function matters in middle age
Do you do your shopping, cooking, washing, and dressing? And what has that got to do with health? A lot apparently. Brown et al studied more than 5000 people initially aged 50 to 56, comparing those who developed functional impairment (difficulties in performing daily activities) prior to age 64 with those who did not develop functional impairment before age 64. Those who developed functional impairment were more likely to be hospitalised, admitted to a nursing home, or die despite adjustment for risk factors such as chronic illness. These observational data are an important signal that functional impairment is clinically significant, although we are left with the chicken versus egg question. Does functional impairment give way to disease or does an underlying disease process give way to functional impairment? Either way, functional impairment looks like a good target for healthcare intervention even if we don’t quite know the hows and whys.

Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is a rare but life threatening brain infection. It tends to occur in those who are immunosuppressed, but can get better if the immune system can be restored. This paper is a report on some patients with PML who consented to receive off-label pembrolizumab (an immune checkpoint inhibitor used in cancer treatment) but confusingly, not as part of a trial, but instead on what the authors describe as “a compassionate-use basis.” I didn’t realise that we could test drugs on people on “a compassionate-use basis” and avoid all that oh so tiresome regulatory oversight!

Trying to give the paper the benefit of the doubt though, I read on, to see if I could understand all the hullabaloo. In the supplementary appendices, for the eight included patients, I found 16 references to “improvement” and five references to “stabilisation”—always after the administration of the pembromlizumab treatment—and a vague mention of control patients not mentioned in the main paper (but only their immunopathology and immunohistochemistry, not their clinical status). In conclusion, this is an interesting case series of eight patients unjustifiably presented as a possible breakthrough treatment and inexplicably published in a major journal.

Dementia drug disappoints
Verubecestat is an oral drug developed to block amyloid-beta production to prevent progression of dementia due to Alzheimer’s disease. It had failed to show benefit in mild to moderate dementia, but the developers thought that perhaps this was too late in the disease process for the intervention. This time, Egan et al recruited people with memory impairment who did not meet the definition of dementia in a large double blind randomised placebo controlled trial of two doses of the drug. The trial was terminated after completed enrolment of more than 1400 patients but before follow-up completed due to lack of benefit on cognitive and daily function. In fact, the higher dose group had worse cognitive outcomes than the placebo group. Back to the drawing board then.

Head injuries in American football
This popular sport is dangerous for players as repeated head injury is linked to chronic traumatic encephalopathy. But the sport is so popular and the industry so massive that its downsides often get downplayed. This situation is not helped by difficulties in making the diagnosis until after death. Stern et al recruited 26 former National Football League players age 40 to 69 with cognitive, behavioural, and mood symptoms to compare their brains using PET MRI scans with 31 controls in the same age group who did not have symptoms or a history of traumatic brain injury. They specifically looked at regional tau deposition and amyloid-beta deposition. They found that tau deposition was a particular feature in the former players compared with the controls in a pattern that matched previously described post-mortem findings. However, amyloid-beta was not a particular feature, which suggests that the pathway to cognitive dysfunction in former players is different to the Alzheimer’s disease process.

Stress and cardiovascular disease
Anecdotally, we cling to the notion that stress is bad for the heart, but by stress we might mean any manner of things, ranging from diagnosed mental health conditions to work pressures, relationship breakdown, or bereavement. This Swedish population based study carefully reports on the association between stress related disorders and subsequent cardiovascular disease. Stress related disorders included post-traumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, and other stress reactions. Compared with siblings without a stress disorder, the hazard ratio for heart failure for those affected by a stress related disorder was 6.95 in the first year after diagnosis. For cardiovascular disease overall, there was a clear increase in risk with stress related disorders, but the hazard ratio was 1.64 (or 1.71 when compared with matched population controls rather than siblings). Of course, as with all observational data, this tells us little about causation but there is definitely a convincing link between stress related disorders and several types of cardiovascular disease.

Cut offs in screening for depression
This Canadian group used an individual patient data meta-analysis from 58 studies to assess the accuracy of the commonly used depression screening questionnaire, the Patient Health Questionnaire-9, compared with validated diagnostic interviews. The headline finding is that a score cut off of 10 or above maximised the sensitivity and specificity of the screening test. What is missing from this high quality study is what this means to patients. Questionnaires and their cut offs seem far removed from the patient experience. Where the questionnaires do have a lot of sway though, is in standardising recruitment to research studies for patients with depression.

Annals of Internal Medicine
Hepatitis C treatment in people who inject drugs
People who inject drugs have a key role in the prevalence of hepatitis C, but many are not offered the fantastic treatments that are now available. Apparently, this is due to fears about their adherence and medication resistance developing. This trial looks at adherence to hepatitis C therapy in people receiving opioid agonist therapy (i.e. people on a programme intended to help them stop injecting drugs). Participants were randomised to one of three groups: directly observed therapy, group treatment, or self-administered therapy. Adherence in all three groups was good at over 75%, with the directly observed therapy showing the highest adherence rate.

Comic for consent for elective coronary angiography
A German group performed a laudable randomised controlled trial of standard consent for elective angiography versus standard consent plus a comic with graphic explanations. The study included 121 patients. They found that standard consent plus the comic improved understanding of the procedure and reduced periprocedural anxiety.

The devil is in the detail though—the detail being the contents of the comic itself, which may have been satisfactory to the group of cardiologists who designed it (with an illustrator), but are unlikely to stand up to rigorous peer review. The comic comes across as biased towards having the procedure rather than offering up options tailored to the patient’s condition. It implies percutaneous coronary intervention is the only treatment and that not having it leads to a heart attack; this is usually not true for patients having elective angiography. There is almost no reference to medical therapy. Lastly, the complications are full of jargon and some could even say the risks are underplayed. However compared with current clinical practice, this is a positive step forward. There is much to celebrate about this study. It sets an excellent precedent for research that promotes patient education and involvement in decisions about their care (particularly in relation to procedural interventions). Yet there is also a missed opportunity to have involved a broader range of stakeholder views in the comic content—particularly patients.

Vitamin D for gastrointestinal cancers
A Japanese group randomised 417 patients with a digestive tract cancer (Stage I, II, or III) to oral vitamin D (2000 units per day) or placebo at their first postoperative clinic visit in a double blind trial. In both groups there were similar rates of overall survival, rates of relapse, and rates of the primary outcome: relapse-free survival. This trial appears to have been well conducted and is written with a very fair discussion that does not overstate any of their findings. It clearly explains that randomised controlled trial data have not corroborated the observational findings that vitamin D supplementation might be protective against cancer.

Alex Nowbar is a clinical research fellow at Imperial College London.

Competing interests: None declared.