At the beginning of March, Ryan had a CT scan as part of the phase 1 trial, which revealed that despite our best efforts, the cancer is still growing. The good news? We no longer have to commute over an hour to New Brunswick, NJ. The bad news? Well, I think that can be inferred.
And so our options become a little more limited. We are now on a different chemotherapy called Lonsurf (aka TAS-102). Lonsurf is a combination of trifluridine and tipiracil, which is indicated for patients with advanced metastatic colorectal cancers who have already run the gamut of other standard therapies, as Ryan has. With this, our goals are to stabilize the cancer rather than for regression.
For you biology nerds out there, trifluridine is a nucleoside analog which becomes incorporated into DNA during DNA synthesis and inhibits thymidylate synthase (an enzyme used to synthesize thymidine – one of the nucleosides used to make up DNA). This brings DNA synthesis to a screeching halt, effectively stopping tumor cell growth*. Tipiracil, on the other hand, inhibits another enzyme (thymidine phosphorylase) which would otherwise try to break down trifluridine. Interestingly enough, the principle investigator who initially ran the phase 2 trial comparing Lonsurf to placebo also noted higher levels of thymidine phosphorylase in aggressive disease. References are below for more information.
The cancer also seems to be the worst in the liver at this point, so we are looking to alleviate the tumor burden and hopefully decrease abdominal symptoms with more local liver-directed therapies (specifically, radioembolization with yttrium-90 – there’s an element to get your high school chemistry teacher excited!). For now we are taking a look at how well the liver is functioning, and taking things from there.
*If this sounds familiar to you, you’re right! At the very beginning of this journey, we initially started with a medication called Xeloda, which is the prodrug of 5-FU, another cytotoxic antimetabolite. He did also later get 5-FU itself through the handy chemoport in his body. How is trifluridine going to work any “better” than 5-FU when we failed that already, you ask? Well, one way it’s slightly different is that trifluridine is activated by another enzyme (thymidine kinase), and directly incorporated into the DNA, causing direct, hopefully long-lasting DNA damage. There’s also some thought that the other ingredient, tipiracil, has some antiangiogenic effects – basically, this may decrease blood supply to tumors, which tend to be quite bloodthirsty.