publication date: Apr. 3, 2020
Trials & Tribulations
COVID-19 and cancer: Ethical dilemmas in immune checkpoint blockade
Allison Betof Warner, MD, PhD
Assistant attending physician
Melanoma Service, Early Drug Development Service,
Memorial Sloan Kettering Cancer Center
This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.
As oncologists, we are all too familiar with making treatment recommendations and advising on end-of-life care in the absence of robust data. In ethical conundrums, we rely on guidance from our colleagues in the field, institutions, and national/international leadership bodies.
These decisions are even more urgent during the current COVID-19 pandemic. These are truly unprecedented times. While we certainly have faced outbreaks of life-threatening illness before, few have been as prevalent and as virulent as the novel coronavirus.
The closest parallel we can draw is to the 1918 influenza pandemic, which swept rapidly around the world, leaving an estimated 50 million people dead. Though devastating, medical management in this past era was reasonably straightforward. There were no vaccines, no antibiotics, and few supportive care interventions available to patients.
Personal hygiene, thorough cleaning, and isolation—so-called “social distancing” in the modern vernacular—became the best interventions against the virus. As they are today, individuals with comorbid conditions such as cancer were likely at high risk for contracting and dying from influenza.
A key difference, however, is that in 1918, the field of oncology was in its infancy. Surgery was employed for localized disease when possible, and radiation therapy with radium had recently been adopted. There were no options for systemic therapy. Thus, when the 1918 influenza pandemic struck, cancer patients and their doctors faced few management decisions surrounding how best to treat their cancer.
The remarkable therapeutic breakthroughs of the past century have yielded systemic treatment options for many patients with advanced cancer. Chemotherapy, targeted therapy, and now immunotherapy with immune checkpoint blockade, have all been incorporated into standard regimens for patients with cancer.
This relative abundance of therapeutic options has certainly improved outcomes for our patients. With each new therapeutic option comes new questions about the risk of toxicity versus the expected benefit and concerns about appropriate use of limited resources. These are challenging questions at the best of times.
The COVID-19 pandemic has magnified many of these ethical dilemmas and raised new and unexpected challenges. I will focus here on what I consider some of the key challenges during the COVID pandemic surrounding the use of immune checkpoint inhibitors, the fastest growing option for systemic therapy for a variety of malignancies.
When considering how to best care for our patients in these challenging times, we must come back to fundamental ethical principles. First, do no harm. While this is often a challenge for oncologists who need to consider toxicities from systemic therapy in the face of often a life-threatening cancer, this notion has taken on particular acuity during the COVID pandemic.
How should we view therapies that may treat the cancer but place the patient at higher risk of contracting, or having a more serious course with COVID-19, either as a result of immune suppression for treatment-related toxicities or, more directly, through higher baseline inflammation?
Do we delay therapy until we are past the peak of transmission, and therein take the risk of disease progression that we may or may not be able to control when treatment can be given more safely?
We know that immunotherapy comes with a risk of pneumonitis; could there be synergy between PD-1 inhibitor-induced pneumonitis and the inflammatory ARDS that can be lethal with COVID-19?
Taken further, might the proinflammatory state promoted by checkpoint inhibitors exacerbate COVID complications? Are these theoretical risks sufficient to withhold potentially life-sustaining immunotherapy? Alternatively, might the immune enhancing nature of checkpoint inhibitors help to prevent COVID infection?
No one can definitively answer any of these questions. We must rely on our colleagues to help guide decisions in the absence of robust data.
With this in mind, nonetheless, I humbly put forth a few of my own guiding principles for your consideration.
To minimize risk of immune-mediated adverse events and therefore the need for immunosuppressive treatment, I suggest considering a PD-1-targeting regimen alone, as opposed in combination (i.e. nivolumab + ipilimumab), in the absence of clear evidence of superiority of a combination regimen (e.g. melanoma brain metastases).
Incremental benefit of combination regimens must be weighed heavily against the likelihood of requiring steroids or other immunosuppressive agents, which may increase the likelihood of contracting COVID-19 or diminish the patient’s ability to clear the virus.
Similar considerations must be given to chemotherapy in combination with immunotherapy, as chemotherapy-induced immunosuppression could heighten risk of infection.
Fewer treatment sessions mean fewer opportunities for virus transmission from health care workers and other patients. This lowers risk for both patients and providers. Utilize available tools to extend time between treatment sessions.
For example, many oncologists continue to prescribe nivolumab 240 mg every 2 weeks, as opposed to the 480 mg every-4-week regimen, which has similar pharmacokinetic exposure over the 4 week period. Switching to the every-4-week regimen decreases the number of visits (and therefore, the risk of exposure at a health care facility) in half.
For patients with well-controlled disease (including low volume, stable stage IV), or those being treated with adjuvant immunotherapy, the risk of a health care visit may outweigh the benefit of a single dose.
For example, NCCN recently issued “Short-Term Recommendations for Cutaneous Melanoma Management During COVID-19 Pandemic” advocating for deferral of adjuvant therapy for patients with <50% estimated risk of disease relapse.
Given the risks, perhaps immunotherapy should be given only when the regimen has demonstrated some clinical activity. Truly novel agents or combinations should be discouraged. This is the most challenging of the proposed principles.
Often, patients with few treatment options wish to try cutting-edge therapies, either by compassionate use or on a clinical trial, despite little expected clinical benefit. I suggest that the known risks of immunotherapy and potential need for immunosuppression should drive our decisions during the time of the COVID pandemic.
Physicians must also balance the risk to themselves and other essential medical personnel needed to care for patients. I am not alone in this thinking, and many institutions have limited enrollment on clinical trials to those that have demonstrated clear therapeutic benefit.
While it is difficult to give up hope that an unlikely therapy may benefit the patient, we know that the risk of severe illness with COVID-19 is high, particularly in patients with advanced cancer. If a clinical trial is being considered, we should prioritize those with oral dosing (versus intravenous, radiation, or procedure-based) and less frequent visits to minimize risk of exposure to patients and medical staff.
Undoubtedly, these are challenging times. Perhaps the most difficult times some of us will face in our careers. Many of us are struggling with decisions we hoped we would never have to make and some that we never even imagined. Here, I suggest some of my personal guiding principles when faced with challenging decisions about immunotherapy.
They are by no means comprehensive, but my hope is that they will provide a framework around which to approach therapeutic decisions. But the strength of our community is just that—community.
We are in this together, and my hope is that these suggestions spark more conversation and collaboration. Though you may be the one writing (or not writing) the order, you are not alone in making these difficult decisions. Now, more than ever, is the time to lean on each other for help and support.