'Oncology Done Right Is About Balance': Weighing Immunotherapy Side Effects

Mark G. Kris, MD


April 23, 2018

Hello. This is Mark Kris from Memorial Sloan Kettering. I am speaking to you today about three papers that appeared in JAMA Oncology on January 11, 2018, dealing with the adverse effects of immune checkpoint inhibitors.

There was a commentary[1] and two papers.[2,3] My issue with these presentations is the lack of discussion of benefits that these therapies have in context with the clear demonstration of their adverse effects. Balance is what we need in our reporting and our discussion of these issues. Anybody who practices oncology understands that every time we discuss cancer therapy with a patient, there is a need to clearly state potential benefits and potential risks. The physician and patient need to mutually agree that the degree of risk is acceptable and is likely to be outweighed by the potential benefit to that patient.

That is the missing piece of these three articles. They focus on side effects rather than talking about what could happen in terms of the good effects. These papers dealt to a great extent with lung cancers, and these folks have a disease for which there is no cure. The issue is the degree of benefit, the duration of benefit, and the degree of debility brought on by the therapy, counterbalanced against the sure debility brought on by the cancer should these therapies fail.

Dr Oshima and colleagues from Japan talked about the increased incidence of interstitial lung disease with epidermal growth factor receptor tyrosine kinase inhibitors and the immune checkpoint blockade drugs. It is well known that there is a higher incidence of interstitial lung disease that appears to be even higher when the two drugs are put together, particularly in Japanese populations. Missing from that article is what happened to these patients. Did they achieve benefit and could these side effects be managed?

Unlike side effects of many of our other cancer drugs, there are antidotes for adverse effects of immune checkpoint inhibitors. Usually doses of corticosteroids or anti-tumor necrosis factor drugs like infliximab can undo the adverse effects.

This issue of balance—benefit versus risk and whether risk can be mitigated or not—is the real question here. How do these drugs help the patients, what are the risks versus the benefits, and can the risks be mitigated? Please remember the alternatives for these patients. Cytotoxic chemotherapy has plenty of risk, up to and including death.

The other paper talked about an increased incidence of radionecrosis in patients getting checkpoint inhibitors with radiation for CNS disease. The incidence of this complication did appear to be higher. But it did not talk about what happened to these patients. Ultimately, what was the effect? Could it be mitigated by steroids, infliximab, or surgery? Indeed, if it is an immune reaction, it should be able to be mitigated by things like infliximab.

A cautionary note: Oncology done the right way is all about balance. We are constantly balancing effectiveness versus side effects—not just in a manuscript, but in a human being. We have to present this information clearly to our patients. We have to listen to them about what degree of side effects they find acceptable, particularly what degree of side effects is acceptable for exactly where they are in their disease. When cure is on the table, extraordinary side effects—up to and including death—could be acceptable to somebody. However, the noncurative setting is the usual situation we are dealing with in folks with advanced lung cancers.

Last, one thing we have seen with immune checkpoint inhibitors that we have not seen truly with chemotherapy or targeted therapies is the ability to deliver long-term remissions free of cancer. When we look at the residual tissue it actually does not contain cancer.

I urge you to do what you have always done. Present to your patients the risks and benefits, listen to them to determine what degree of risk and benefit they feel is acceptable, and then make a mutual decision. Be careful not to be swayed by the benefit side or the risk side. Balance is what is critical here.


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