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Dr West

Retrospective Data and Real World Evidence: The Poor Stepchild of Clinical Trials?

EvidenceMany physicians worship evidence-based medicine, which is generally a very good practice that ensures that medical practice isn’t dictated by our biases and assumptions but rather on interventions that we have proven show benefits that exceed their anticipated risks.  The optimal way to confirm value of an intervention is by a prospective randomized clinical trial, which is when we enroll a population of patients with the same general disease condition, ideally with no or few other significant medical issues that might cloud the interpretation of what the study intervention is doing, and then randomize them to either pursue what we’d consider the best current practice or an experimental approach that might be better but might also be no better, or even worse.  Other clinical trials may be smaller and may not randomize patients, but they all share a specific list of enrollment criteria, both things that are required in the potential participants (inclusion criteria) and other things that are specifically forbidden (exclusion criteria) to ensure that the study group is reasonably homogeneous.

Cancer treatments are essentially invariably approved on the basis of prospective clinical trials, most often randomized phase 3 trials (large studies of standard vs. investigational strategy), and this gives us confidence that these new approaches are effective.  Aside from the problem that this denies patients who are older and potentially sicker from the opportunity to participate in trials and receive new treatments that may be beneficial, this approach also leaves us wondering whether the treatments proven to help clinical trial candidates are as safe and beneficial for the teeming masses of other people who have complicating issues that would have disqualified them from the trials with such patients.  For example, the trial comparing the immunotherapy Keytruda (pembrolizumab) to standard combination chemotherapy as first line treatment for patients with high level expression of the protein PD-L1 on their tumor cells (a biomarker associated with a higher chance of benefit from immunotherapy) excluded patients who are unable to work or are in bed >50% of the time (performance status of 2 or higher — see here for more discussion), which is a significant minority of patients with advanced non-small cell lung cancer).  We might presume that more frail patients with high PD-L1 expression also do very well with Keytruda, but we can’t know that from the evidence we have.   Because sicker patients don’t have as strong an immune system as more fit patients, immunotherapy may not be as effective as we’d hope. In fact, my  limited experience of treating frail patients with Keytruda or other, similar immunotherapy agents has been quite disappointing, even when the patient has high PD-L1 expression that would lead us to be very hopeful of an excellent chance to respond well. 

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Dr West

How long should we continue immune checkpoint inhibitor therapy in patients who respond?

Over the past several years we have seen some great triumphs  in a subset of patients with advanced cancers who received an immune checkpoint inhibitor like Opdivo (nivolumab), Keytruda (pembrolizumab), or a growing list of other agents that act by removing a braking mechanism on the immune system and can stimulate it to recognize and attack the cancer.. In some patients, we can see the cancer shrink to the point of actually having no evidence of disease (NED) on post-treatment scans.  In many other patients. the cancer will shrink (sometimes immediately, sometimes after a delay of a few months), then remain visible but smaller for a long time.  In the original trials, most treatment protocols plan to have patients continue on ongoing IV therapy with these therapies meant to be given every 2 or 3 weeks, without any endpoint until their cancer shows significant progression or the patient develops significant side effects.  There are reasons to be tempted to discontinue treatment at some point: many of the leading experts with the most experience in immunotherapy have seen side effects that seem to be cumulative, raising the question of whether continued treatment with an immune checkpoint inhibitor for more than 6 or 12 months adds anything other than risk, inconvenience of coming in for infusions every few weeks, and major expense.  Many patients are also inclined to not be tethered to the clinic for regular visits and infusions every few weeks if they add no real value. And one of the basic tenets of immune response is that the immune system has a memory and may continue to respond to a recognized target or a very long time, even without ongoing active stimulation.

Moreover, many of these trials often allow patients to continue on immunotherapy after scans show evidence of tumor growth, based on the concept of pseudo-progression that I described in detail previously. I noted the potential harm of having patients continue on immunotherapy while their cancer was actually progressing, but how long should we continue a patient on immunotherapy when they’re doing well? Is there any end, or should we have them continue on immunotherapy indefinitely?  

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Dr West

Evidence, Judgment, and the “Art of Medicine”

I was recently discussing the debatable point about whether the various PD-1 and PD-L1 inhibitors becoming increasingly available in clinical practice show any clinically significant differences among them (I and many others in the field think they don’t), when in doing so I showed a slide comparing the efficacy and leading side effects of three of the most studied in advanced lung cancer thus far. A colleague with a strong academic background, who I respect and who shows thoughtful judgment, chastised me (somewhat in jest) “but those are cross-trial comparisons! Naughty”.  And it’s true that this approach of comparing results of agents tested in different trials, so called “cross-trial comparisons”, are something we’re taught by statisticians and academic purists is not valid. But the problem is that there is often a marked gulf between the ideal world that we live in at conferences as we debate these points as an intellectual exercise and the real world, where we actually need to make clinical decisions based on incomplete information. In the real world, that means using judgment, but ideally trying to couple that with the best evidence available. 

I must admit that I find that the term “the art of medicine” seems to be invoked all too often as a license to avoid any pretense of weighing evidence and just going with the biases of the physician.  Instead, practicing in the real world should involve using solid evidence when it’s available, allowing room for judgment (such as if a patient is against the evidence-based treatment), but it’s extremely common to need to assess the quality of the best evidence and do the best you can. What are we to do with a patient who has a remote history of an autoimmune disorder or has mild to moderate rheumatoid arthritis? Do we disqualify them from immunotherapy, as just about every immunotherapy trial has? With the promise of immunotherapy, you can make a fair argument that the risk might be worth it.  And pretty much every patient who comes in with compromised liver function or a history of hepatitis C or even, for that matter, a second inconvenient cancer of another type would preclude that patient from participating on the clinical trials that shape our current standards.  We’re left to judge whether we can expect similar results or whether the risks of complicating issues require a deviation. 

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Dr West

FAQ: How Much Does Attitude Matter When Fighting Cancer?

Most people feel a loss of control when faced with a new diagnosis of cancer. You can meet with doctors, develop a plan, perhaps do surgery, radiation, chemotherapy, targeted molecular therapy,  immunotherapy, or some combination of these.  But beyond showing up and taking recommended interventions, how much does a positive attitude help?

While it’s comforting to think that you can control much of your outcome and some argue that a positive attitude makes all of the difference, cancer experts are largely humbled by how little control we have over the outcome, even with the many potentially effective tools we have at our disposal. Patients need a positive attitude in order to pursue the treatments that can be very effective rather than just giving up, but the truth is that a positive attitude can’t overcome a very aggressive cancer biology.

It would be nice to live in a world where a positive attitude makes all of the difference in overcoming a nasty cancer, but to be honest, that’s a make-believe world of rainbows and unicorns. 

 Rainbows and unicorns

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Dr West

FAQ: What is “Performance Status” and Why Does it Matter so Much?

Along with a patient’s age, sex, and past and current medical issues, performance status (PS) is one of the most important factors that is categorized for patients. It essentially refers to a patient’s ability to manage his or her activities of daily living — things like bathing, dressing, feeding yourself, etc., as well as general activity level and ability to do whatever work they need to do. 

There are two leading scales for measuring PS. The most frequently used one, known as the Zubrod or ECOG scale,  simply goes from 0 to 4, with 0 representing no symptoms or limitations, and 4 representing being bedridden and completely unable to care for yourself.  

Zubrod PS


The alternative is called the Karnofsky PS scale, describing the range of activity from fully functional (100%) down to 10%, bedridden; obviously, this is essentially the same range, but with finer grading, as if you could assign half points on the Zubrod scale. Here’s the description of the levels on the Karnofky scale:

Karnofsky Performance Status PS Scale

Though this scale suggests that there is a clear number for everyone, it is more fair to acknowledge that PS is somewhat in the eye of the beholder.  Certainly, one person’s 70% Karnofsky PS may be 60% to someone else, and this may depend on how well a person happens to be doing on a given day at a given hour.  This may be part of why the Zubrod PS scale is more widely used: it doesn’t put too fine a point on a subjective measure.

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