Toxicity Management for Third-line Therapy for mCRC


Tanios Bekaii-Saab, MD, FACP:The 2 drugs, because of their nature—one is a multi-kinase inhibitor, one is a cytotoxic—have different toxicity profiles. TAS102’s toxicities are primarily bone marrow toxicities—neutropenia and thrombocytopenia. Neutropenia is pretty pronounced. In fact, 4% of the patients will have febrile neutropenia, which is pretty significant. We think about an oral drug as easy, but you do have some toxicities and they happen actually earlier on. There are also some GI toxicities and fatigue that can happen in patients who have been exposed to it in the longer term. Regorafenib, on the other hand, has toxicities like hand-foot syndrome, diarrhea, hypertension, some VEGF toxicities, and the kinase inhibitor toxicities that also happened earlier on.

Now, in terms of this patient, the patient was placed on regorafenib after discussion with her oncologist, which I think makes a lot of sense. This would be the natural positioning for regorafenib—patient has good performance status, failed 2 prior lines of therapy, and now gets to this level.

My personal experience with regorafenib has been pretty much placing it at the third- or fourth-line of therapy. When I look at my own experience and patients I’ve treated over the last couple of years, we’ve had a few patients who had CA responses, stable disease, and we’ve had many patients who did not respond to treatment. So, it’s what you would expect at this line of therapy. Most patients actually do not respond or respond well to treatment. For those patients who actually had a response—and when I say response, we almost never see significant shrinkage—you do see some shrinkage that wouldn’t qualify a patient for what you call a partial response. You do see what we call minimal responses. And we see, in some patients, steep drops in the CA. In fact, I have patients who went for 6 months. My longest patient has gone for close to a year, or a little bit more continuously, on regorafenib.

One of the things about regorafenib is its toxicity. Its toxicity has been a deterrent for some. And I think the concern is real because patients are pretty beat up when they get to this point. They have had a lot of therapies, they’re tired, and these toxicities can get amplified. But regorafenib’s toxicities happen very early, in the first 2 to 3 weeks. And in fact, the worst toxicities, so not just the toxicity itself, happened in the first 2 to 4 weeks of the treatment. So, I think it is essential to educate the patients really well about the toxicities, like when to call. But also in our practice, we bring the patients every week to the clinic. They don’t have to see the physician, they can see the nurse practitioners. Occasionally, they can have a quick check by the nurse. But the first 4 weeks are very critical and the patient has to be seen once a week for their follow-up. And that is one way to actually cut down on the risk of significant toxicities.

In the second month of treatment, every 2 weeks after the second month of treatment, patients will be seen on a monthly basis because most of these toxicities would have been figured out with dose adjustments. And the next question is, what dose do we start with? The dose at this point of time, that was defined by the CORRECT Study, is 160 mg orally every day for 3 weeks in a row, then 1 week off. Most physicians and most oncologists in the United States use a different dosage. Some start with escalation 160 mg, others start at 120 mg and stick to 120 mg. Others, like myself, right now in the absence of data, start with 160 mg knowing that 20% of the patients need that dose and will never actually require a dose reduction. We have a short amount of time for most patients with a PFS to 2 months. I don’t want to play around with the dose without data and then deescalate.

I don’t think there’s a right or wrong strategy, and we are addressing this question. There’s a study called ReDOS, which is a large phase II randomized study that’s looking at the question of starting with the standard dose versus a dose-escalation strategy. The good news is this study is about complete. We’re hoping to present the data at ASCO GI 2018 and help with the understanding of, can we safely and effectively start patients at the lowest dose and escalate rather than start at the highest dose when we know 80% of the patients will have to settle down at a lower dose?

Transcript edited for clarity.

October 2015

  • A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
    • CEA were elevated, 23.3 ng/mL
    • Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic
    • Imaging with PET/CT showed several lung lesions, three measuring up to 3.0 cm in size
    • Mutational status was both RAS and BRAF wild-type
    • Microsatellite stable
    • Diagnosis; high grade colorectal adenocarcinoma, stage T4N2M1
  • PMH includes arterial hypertension, well-controlled on an ACE inhibitor and coronary angioplasty with stent placement 4 years ago
  • The patient received systemic therapy with FOLFIRI + cetuximab; grade 1 rash and grade 2 thrombocytopenia were managed with dose adjustment of FOLFIRI
  • Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
  • The patient was continued on maintenance therapy with cetuximab

August 2016

  • The patient complains of weight loss, nausea and fatigue
  • CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions
  • The patient was switched to CAPEOX with bevacizumab. Her blood pressure was closely monitored and remained stable
  • Follow up imaging at 2 months and at 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms
  • At 4 months, oxaliplatin was discontinued; maintenance therapy with capecitabine and bevacizumab was continued

January 2017

  • At 5 months, the patient reports having reappearance of her symptoms, although she continues her normal physical activity
  • CEA level is rising significantly
  • Follow up CT showed further progressive disease in the lung and the appearance of several small boney lesions
  • The patient is motivated to try another therapy and has opted for regorafenib
Related Videos
Rohit Gosain, MD; Rahul Gosain, MD; and Pamela L. Kunz, MD, presenting slides
Rohit Gosain, MD; Rahul Gosain, MD; and Pamela L. Kunz, MD, presenting slides
Related Content