What I Really Do: Mild or "Subclinical" Progression

Howard (Jack) West, MD, Founder and President

One of the topics that frequently occurs in the clinic, and that patients often ask about, is the situation in which there is some suggestion of slight progression. This can take the form of many different situations: a rising tumor marker (see prior post), a slight increase in the uptake on PET (see prior post), perhaps an increase in cough or pain between CT scans, or perhaps just a scant amount of disease progression on the CT that isn’t enough to lead to a definite transition to some alternative. This isn’t an area where there are any good studies, so we are left with our best judgment and no substantial information to inform us.

The definition of progression in the oncology world is based on CT scans rather than increasing symptoms, rising tumor markers, or increased uptake on PET scans. Specifically, the current system, called RECIST, is based on an increase in the size of the size of the sum of all measurable target lesions (which means that if there are 3 lesions that measure 2.4 cm, 1.5 cm and 1.1 cm in greatest diameter for each (4.0 cm total) , progression so that they total 4.8 cm is required to be called progressive disease, but 4.6 cm is called stable disease), or a new lesion, or “unequivocal progression of non-measurable disease in the opinion of the treating physician”, such as some bone metastases or a worsening pleural effusion, etc.

First, I’ll emphasize that I think of these situations as not exactly the same, but far more similar than different. Serum tumor markers aren’t elevated in all patients with lung cancer, and checking and following them isn’t a universally accepted standard (they aren’t ever mentioned as a reason to consider someone as having progressed). Some major centers even make a policy of never checking them. PET scans are really most established as a method of staging patients during their initial workup, but they aren’t routinely recommended as a method of following patients with advanced disease to assess response. And while patient symptoms increasing are correlated with scans worsening, and improvements with scans improving, that’s a very imperfect correlation (the well known placebo effect is an illustration of the potential disconnect between reported symptoms and objective outcomes).

The validated standard is still CT scans, and it’s very possible to see a slight rise in tumor markers, PET uptake, or worsening symptoms but little or no change in tumor measurements. Overall, I’d consider CT scans to be definitive and detailed enough that if they don’t show progression, there isn’t a convincing reason to make a change. Maybe there is the tiniest hint of progression, manifested by one of these factors, but if it’s not enough to register on the scans, I’d consider there to really be not enough progression to make a change. The setting of mild but not especially convincing progression (which I would also consider to include a tiny new lesion while everything else appears stable, though that’s technically progressive disease due to the new lesion) is more compelling than indirect hints and a stable scan, but it’s the same idea.

In such situations, I back up and consider that we’re trying to balance efficacy of the treatment against side effects. The other key factor I consider is the range of remaining options available, and how appealing they are.

I tell my patients that if we see a good response with meaningful tumor shrinkage after treatment, it makes sense to try to continue the treatment even if it’s challenging, perhaps by lowering the dose or making other changes to provide a better balance of efficacy vs. side effects. Obviously, if a treatment isn’t working and a patient’s cancer is significantly progressing, we don’t want to continue it, even if it has no side effects. In between, there’s the large fraction of patients who experience stable disease, where I suggest that whether we continue with the same treatment depends largely on how well it’s tolerated. If stable disease comes with minimal symptoms, I’m happy to recommend staying the course; if it’s an arduous challenge, I will usually recommend changing the plan.

The second major factor is the availability of good alternatives. If a never-smoker with an adenocarcinoma is receiving first line chemo, with or without avastin, and they demonstrate a slight amount of progression, I know that tarceva remains a good alternative just waiting in the wings. I’ll have a low threshold to recommend a transition to the tarceva. But in someone who is receiving fourth or fifth line chemo and they experience a hint of progression after a few months of stable disease, I know that the remaining options are very limited (really, primarily clinical trials or a test of “let’s just give it a shot”), and I’m far more inclined to accept minimal progression as good enough to keep going.

There's room for different styles here, but that's how I approach this common setting where there are no formal rules to guide us.

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