Today I'm going to veer into the realm of style in cancer management rather than focusing on hard evidence. Sadly, it's not a rare event to have cancer progress early despite a perfectly good initial therapy. I just saw a patient in my clinic who illustrates what I consider to be a very reasonable treatment idea that doesn't find its way into the textbook approaches for managing somewhat resistant cancers, but it's worth discussing the concept of upping the ante with subsequent treatment. To back up, the textbook answer to what to do in the face of a cancer that is progressing through first line treatment is to move on to second line treatment, though we know that our second line treatments tend to be less effective than earlier ones, and that early progression through good first line therapy represents a high probability that this is a pretty resistant cancer.

The particular patient I saw had been referred by a very good community oncologist for a second opinion after she had just had a scan that demonstrated a mixed response to first line carboplatin/Taxol (paclitaxel) for advanced squamous cell NSCLC, with more progression than response. She's relatively young, with a very good performance status, and despite the findings of progression, is still looking and feeling very well.While the standard approach for second line treatment for her squamous NSCLC would be either Taxotere (docetaxel) or Tarceva (erlotinib), it's hard to be extremely optimistic about either of these for her. Taxotere, a cousin of Taxol, could be better than the carbo/Taxol doublet, but I think that's pretty unlikely. Tarceva certainly can prolong survival in squamous cell NSCLC, but it doesn't tend to be a blockbuster in this setting. What her primary oncologist recommended, and which I think was a very solid idea, was to escalate her treatment to a plan that would still be in the range of appropriate treatment for advanced NSCLC but steps up the aggressiveness enough that I think it would have a fighting chance of being more effective. Specifically, the regimen he's just started her on is cisplatin/Gemzar (gemcitabine), with Erbitux (cetuximab). Here's why I think it represents such a good plan: 1) Cisplatin is probably a little bit more effective than carboplatin in the setting of advanced NSCLC. Though the differences aren't great and carboplatin often provides a very comparable efficacy with fewer side effects for many patients who do very well with a carboplatin-based combination, I sometimes recommend cisplatin for the most fit patients, or if there's a need to pull out all the stops. Here's a situation where the substitution may provide a little extra edge. 2) While the taxanes have the same mechanism of action, gemcitabine is a different kind of chemo agent that has a different mechanism of action as a "nucleoside analogue" (details of this aren't really that important, but you can read more here if interested). It's certainly an active agent for NSCLC. Moreover, it has been reported as being a more effective chemo for squamous NSCLC (albeit compared with Alimta (pemetrexed), which we now know is especially ineffective for squamous NSCLC). 3) Erbitux is associated with a modest improvement in survival in advanced NSCLC when added to at least some chemotherapy, cisplatin/gemcitabine among them, and it appears comparably effective in squamous cell and adenocarcinoma histology. It isn't FDA approved in NSCLC, and it isn't widely used in the setting of a relatively modest benefit and a significant chance that insurers won't pay for this expensive medication, but it remains an option. 4) She's fit, inclined to accept that this is a harder treatment that isn't the standard for second line treatment, but if you're pretty sure that standard treatment is going to be disappointing, it's appropriate to ask what the harm is in trying something different. This isn't a proposal to do a bone marrow transplant, but rather an aggressive treatment in the range of ways we might treat a newly diagnosed patient with advanced NSCLC. If she progresses through this treatment as well, she and her doctors will know that it was because her cancer is terribly resistant and not because she didn't get the potential benefit of a treatment strategy that was a little more aggressive than the standard approach. 5) She had a mixed response, and not just wild, explosive progression. If her cancer had grown through good first line chemo at a ridiculous pace, I don't think a different chemo combination would be markedly superior. Here, we're trying to push beyond a mixed response into the range of all shrinkage and/or stable disease by dialing up a bit. 6) This strategy doesn't burn bridges in terms of the other off-protocol treatments we'd consider standard as subsequent therapies. I wouldn't take Tarceva off the table, even if it's not something I think will provide a dramatic benefit. We'd be happy to accept a modest benefit over nothing, but the question is whether we might hope for better with her treatment starting now. 7) There wasn't a very promising clinical trial available available for this situation. I think a clinical trial combining standard second line treatment with a novel therapy would also be a strong choice, but the trials I have available for squamous cell NSCLC at this time are limited to the first line setting, and the Tarceva +/- ARQ-197 trial that we're participating in is only for non-squamous NSCLC (since the phase II randomized trial suggested that the combination was better only in this subset). I'll close with the caveat that I can't point to the evidence that this will be effective, and this strategy is entirely in the range of style, rather than a well-described, formally recommended approach. Still, I do think it's appropriate to underscore that there's plenty of room to step outside of the rule book, particularly if we're not satisfied with what we might expect and the alternative isn't expected to be overly toxic.