Case Presentation in Advanced Colon Cancer Case: 1 - Episode 3
Michael A. Morse, MD:It’s important to point out that there are 2 oral agents that are available for patients who have refractory disease. There’s trifluridine/tipiracil, and there’s regorafenib. Whenever I’m considering which agent to use, I go back to the important considerations that the patient may have. Both drugs have slightly different side effect profiles. Also, there are important considerations about their comorbidities, their tolerance of prior therapy, and their blood counts, for exampleany lingering toxicities from previous drugs, such as diarrhea.
In this patient, trifluridine/tipiracil would be a very reasonable option for continuing use of the systemic chemotherapy. It’s important to point out that the clinical trial that led to the approval of trifluridine/tipiracil was a randomization against placebo plus best supportive care. In this trial, patients were treated until they had progressive disease or had intolerance to therapy. Therefore, I always tell my patients that we’re going to start on this therapy and we’re going to use it as long as it’s helping them. So, as long as the disease isn’t progressing and they’re tolerating the therapy well, we’ll continue it. In a randomized clinical trial, there was a better progression-free and overall survival for the use of trifluridine/tipiracil compared with placebo.
As part of the counseling for administration of trifluridine/tipiracil, we always warn patients about some of the side effects. The most important one is the development of neutropenia, and there were patients who developed neutropenic fever, as well, on the randomized clinical trial. Now there can certainly be other side effects, such as diarrhea, fatigue, and occasionally oral lesions. But the critical one that they need to let us know about is if they’re developing any fevers. We also do check white blood cell count during a cycle to inform whether a person is actually developing neutropenia. Furthermore, it’s critical that patients have a CBC performed prior to initiating a new cycle. If they have an ANC less than 1500, they should not be treated until the ANC rises above 1500. Similarly, if they have a platelet count less than 75,000, they should also be delayed until the platelet count exceeds that.
Because neutropenia is quite common in patients receiving trifluridine/tipiracil, we have found that it’s very important to consider whether to dose-delay or dose-reduce. Currently, we recommend that if a patient has an ANC less than 1500 on the day that they’re to start a new cycle, we delay another week and recheck their CBC. If their ANC is greater than 1500 at that point, we recommend continuing the same dose of the trifluridine/tipiracil as they received in the previous cycle. However, if the ANC continues to be less than 1500, or they’ve had other toxicities that cause a longer delay, then it is recommended to reduce the dose prior to starting that next cycle once the ANC is greater than 1500.
There are other interventions one could consider for patients who do develop neutropenia while on trifluridine/tipiracil. One of these is the use of G-CSF (granulocyte colony-stimulating factor). Now in the pivotal trial, only about 9% of patients did receive white blood cell growth factor support, but it certainly is acceptable to use it because there is a 14-day window from the time patients receive their last dose until they’re likely to start a new cycle.
There’s quite a bit of interest in administering trifluridine/tipiracil with other therapies. While this combination therapy is not the same as fluoropyrimidine, you can imagine in other areas where fluoropyrimidines have been administered that there’s considerable interest in using trifluridine/tipiracil. So, for example, there’s a clinical trial evaluating the use of maintenance therapy with trifluridine/tipiracil plus bevacizumab. Because there’s considerable interest in the use of immunotherapy in advanced colorectal cancer patients, there are also at least 2 clinical trials evaluating trifluridine/tipiracil with nivolumab. And furthermore, there are clinical trials administering trifluridine/tipiracil with other novel agents. For example, there’s an anti-NOTCH1 antibody in development that is being studied in combination with trifluridine/tipiracil. And, of course, there are at least 2 clinical trials that include an arm where oxaliplatin is being used with trifluridine/tipiracil as well.
The unfortunate reality for most people with metastatic colorectal cancer is that they will progress through all the lines of therapy. However, I found that in patients who have received oxaliplatin/irinotecan/fluorouracil/bevacizumab and, where appropriate, anti-EGFR targeted therapy, and still have a reasonable performance status, most patients do want to continue with some type of therapy to see if they can maximize survival. I’ve been very gratified to find that patients to whom I’ve administered trifluridine/tipiracil have tolerated it reasonably well.
We, of course, do have to consider the neutropenia. It is very common that we do need to dose-delay, but less frequently, we need to dose-reduce. We’ve been able to have patients maintain adequate quality of life throughout that therapy. And because it’s known to have, on average, a survival benefit, we believe that we’re giving those patients additional time for the things that are important to them. Also, I found that even at the point that they do progress, they generally maintained a reasonable performance status and quality of life, so they would be eligible yet for other therapies.
Transcript edited for clarity.