From Mark Levine, the Doc with Pink Tights
We are being bombarded with information about the COVID-19 pandemic. Areas that you may be wondering about are treatments for patients with severe COVID-19 infections, and vaccines to prevent the COVID-19 virus. My editor asked me to comment on research methods to help you better understand what you are hearing and reading about.
Patients with cancer are considered at increased risk for COVID-19. This makes biologic sense, as patients on chemotherapy or immunotherapy, or patients with advanced cancer, can have weakened immune systems. This is one of the reasons to screen for symptoms of COVID when asymptomatic cancer patients come to the Juravinski Cancer Centre. The goal is to detect COVID positive cases and prevent spread.
It is also believed that if cancer patients contract the infection, their cancer outcomes, e.g. survival are worse. Sometimes, this has resulted in COVID positive cancer patients not being offered potentially curative chemotherapy because of the concern that chemotherapy will further suppress the immune system. Is this the right thing to do?
What do I look for when reading a research paper reporting on the outcome of patients, for example, the survival of COVID positive cancer compared to COVID negative cancer patients?
I would want to see a large number (in the many hundreds) of cancer patients followed forward over time, with about half having COVID-19. Then, after 12 months, I would compare the survival of the COVID positive group versus the negative group. It is important to ensure that all patients at the beginning were followed until the end. We call this lost to follow-up. If greater than 20 per cent of patients are lost, the results should be questioned.
What you may not know is that the observation that cancer patients with COVID do worse in terms of their cancer is based on a very poor-quality study of only 18 cancer patients from Wuhan China. Although it makes sense to be extra careful when deciding on treatment for cancer patients with COVID, I hope that higher quality research studies will emerge soon to inform clinical care.
Patients with severe infection can have a severe inflammatory process in the lungs which results in very low oxygen levels and the need to be put on a ventilator. This has happened in large numbers of patients in Italy and New York City and it’s frightening. You have read a lot about chloroquine, a drug which can suppress inflammation and is used to treat lupus, rheumatoid arthritis and malaria. (I took it 40 years ago when I travelled in South East Asia). Chloroquine also has an anti-viral effect in laboratory experiments.
What do I look for when reading a research paper reporting on whether a treatment works or not?
I would want to see a large trial where some patients received chloroquine and some did not. The best design is called a randomized controlled trial (RCT). In this type of study patients are allocated by random chance to chloroquine or not (ideally a placebo). The outcomes, both efficacy and safety, are compared between the two groups. The RCT design minimizes bias in evaluating the comparison of two treatments.
A small study of 36 patients in France led to the immense interest in chloroquine. This study was not randomized. The sample of patients was mixed, with some of the patients on ventilators and others not. There were 20 patients who received chloroquine and 16 who did not. Patients who received the drug had a quicker decrease in their viral load than patients who did not take the drug.
This study was flawed. It was not randomized. Why some patients received the chloroquine and others not, is unclear. It could be that certain patients were selected to receive the drug. This introduces bias and is not a fair comparison. The outcome of decrease in viral load can be considered a surrogate or substitute for whether the patient’s condition improved.
Does clearing of the virus from the body equate to coming off a ventilator and leaving hospital recovered?
Perhaps. It really is impossible to draw any firm conclusions from this study. Nonetheless, U.S. President Donald Trump decided this drug works and advocated for it. Many patients are being administered this drug.
Is this a problem? In my view it is because chloroquine can cause heart problems such as arrhythmias, which are electrical disturbances. Recently, one study of chloroquine in Brazil was stopped because of cardiac toxicity and a second study in the United States reported that chloroquine did not reduce the risk of going on a ventilator in patients with COVID-19 and was associated with increased mortality. These studies were not RCTs. Whether chloroquine is beneficial in patients with COVID-19 will only be addressed by a large, well-done RCT, such as the one recently started by investigators at Hamilton Health Sciences.
In next month’s edition, I will continue this discussion and talk about vaccines for COVID-19.