Among the many novel concepts in managing immunotherapy is the potential for “pseudo-progression”. This unusual phenomenon is when a patient’s scans of the areas of cancer actually appear worse on early imaging, potentially even with new lesions, after starting immunotherapy, but a patient’s scans later show shrinkage of the cancer.  These patients typically feel well, often with improvement in their cancer-related symptoms (fatigue, appetite, etc.) that don’t seem to be concordant with their worse-appearing scans.

Why might this happen? Some biopsies of lesions that have grown or appeared as new in such patients help explain that the growth is from infiltration of immune cells around tumor cells, preceding the time when those tumor cells are attacked and eradicated by the immune system.  In cases where new nodules appear that then resolve with later scans, it is felt that this situation represents immune cells infiltrating a “micro-nodule” of cancer that wasn’t visible until it was surrounded by immune cells that then enlarged it enough to become newly detectable on scans.

Pseudo-progression has been recognized as a situation worth knowing about, but it has created many problems and can lead to significant harm.  Initial efforts to educate physicians and patients about pseudo-progression highlighted it out of concern that patients who were actually benefiting from immunotherapy would be mistakenly taken off of it too early.  While this still occurs from time to time, the bigger worry now, at least among many immunotherapy experts focused in settings where pseudo-progression is rare, is that the wild excitement and optimism around pseudo-progression is leading to far too many patients with true disease progression to have it overly charitably called pseudo-progression.  And patients may well die earlier when we make this mistake.

As we gain experience with immunotherapy for various cancers, we are coming to appreciate that the incidence of pseudo-progression is very different depending on the cancer type.  In melanoma, it is common enough to consider it as a very likely possibility. In lung cancer, however, it is only really seen in perhaps 1-3% of patients.  But I and other colleagues often see patients being kept on immunotherapy far too long, as there is a mindset of “if the scan looks better, the patient is responding to immunotherapy, and we should keep going; if the scan looks worse, it’s pseudo-progression, and we should keep going.”

Some may feel that if a treatment is well tolerated and has a chance of helping for years, what’s the harm of continuing treatment until it is incontrovertible that the patient is progressing?  The answer is that if a leading alternative therapy, such as standard chemotherapy, would provide a significant survival benefit but needs to be given when a patient is strong enough, prolonging treatment with an ineffective treatment just because it is the sentimental favorite can easily mean that a patient will no longer be a candidate for this effective therapy later.  This “pseudo-pseudo-progression” can be motivated by the overly optimistic perspective of an oncologist, the patient, or may be the collusion of both of them. But either way, such wishful thinking has the very real potential to shorten the life of the patient.

While pseudo-progression can definitely occur with immunotherapy, it is important to be very judicious in deciding to continue immunotherapy in the face of worse scans. Experts favor carefully assessing how a patient is doing clinically. In someone with worse scans, it makes sense to continue the immunotherapy if they are experiencing clinical improvement in their cancer-related symptoms and perhaps in those who continue to feel stable compared with where they were before initiating immunotherapy. But for those who are losing weight, experiencing more pain, and/or have less energy after the first two months of immunotherapy, a worse scan is far more likely to simply represent progressing cancer.

Finally, it’s important to underscore that the risk of harm from making an inaccurate diagnosis of pseudo-progression on immunotherapy is far greater as immunotherapy moves into first line treatment of a cancer like advanced non-small cell lung cancer (NSCLC).  While the benefits of second line Taxotere (docetaxel)-based chemotherapy are typically modest, so that missing that opportunity is not an overwhelming loss, the potential benefits of first line chemotherapy are far greater.  Given that immunotherapy is still only clearly helpful for a minority of patients with advanced NSCLC (20-25% of all such patients, based on the best evidence we’ve seen), it is very easy to imagine that having too many of the other 75-80% continue for too long on immunotherapy that is ineffective for them may more than counterbalance the benefits of immunotherapy in the minority. We could see immunotherapy lead to overall harm if we aren’t careful in selecting not only which patients receive early immunotherapy but also in being realistic in deciding to cut our losses and switching to a different strategy in patients who have scans that look worse and who are experiencing any clinical decline.

While nobody wants to eliminate the hope provided by immunotherapy, it’s important not to let this optimism cloud good judgment. Pseudo-pseudo-progression is becoming a dangerous risk for patients receiving immunotherapy.