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Toxicities in Refractory Treatment
How I Manage Treatment-Related Toxicity in Refractory Metastatic Colorectal Cancer

Released: July 01, 2016

Expiration: June 30, 2017

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As newer therapies for metastatic colorectal cancer have prolonged survival, we can approach disease management more like a marathon and less like a sprint. And as patients are living through 2-4 years of treatment, there is obvious wear and tear on them in the form of cumulative toxicities as they progress from one line of therapy to the next. We are all quite familiar with oxaliplatin-associated nerve toxicity, and there has been an increased awareness of limiting exposure to this agent to prevent nerve toxicity. As well, irinotecan brings fatigue and bone marrow issues. Both oxaliplatin and irinotecan can cause severe liver toxicity, as we are seeing more patients with ascites, splenomegaly, and thrombocytopenia after 2 or 3 years of treatment. We also understand the hand–foot syndrome associated with 5-FU/capecitabine and how to manage it through dose modification. When we think about treatment beyond second progression of refractory metastatic disease, which currently entails a choice between regorafenib and trifluridine/tipiracil (TAS-102), we must consider these accumulated toxicities that patients have endured during the previous 1 or 2 years of therapy as well as the additional potential toxicities associated with the next line of therapy.

Regorafenib
Regorafenib has carried a relatively poor reputation for toxicity since its introduction. It is dosed at 160 mg/day for 3 weeks on, 1 week off, and we have come to recognize that this dose is difficult for many patients to tolerate, with the majority of patients developing hand–foot syndrome, as well as rash, diarrhea, fatigue, and hypertension. In response, we have had to refine the management approach for patients receiving regorafenib to involve more frequent follow-up appointments—ideally, weekly—to carefully monitor how patients are tolerating the drug. In addition, 2 different approaches have emerged for dose reduction of regorafenib to help manage the associated toxicities. The first approach initiates regorafenib at a reduced dose (80 mg to 120 mg) whereas the other initiates at the standard 160-mg dose with subsequent dose reductions. The ongoing randomized phase II reDOS trial will include a head-to-head comparison of initiating regorafenib at the standard dose vs the reduced dose in patients with refractory metastatic colorectal cancer and will hopefully provide evidence to inform which approach is more effective and minimizes treatment-related toxicities. In the meantime, regardless of which dose is administered, it is important for clinicians to closely follow patients receiving regorafenib to help manage these toxicities.

TAS-102
TAS-102 has a different set of toxicities that includes myelosuppression, most commonly characterized by a fairly profound nonfebrile neutropenia. The approved dosing schedule is 35 mg/m2 twice daily on Days 1-5 and 8-12 of each 28-day cycle. I suspect that over time, we will refine this dosing schedule. Complete blood count should be obtained on Day 15 of treatment to assess neutrophil counts. The current recommendation for patients with reduced neutrophil counts at Day 15 is to withhold TAS-102 until the absolute neutrophil count exceeds 500/mm3. Some may consider adding growth factors at that time. Personally, I prefer not to administer growth factors in this setting, as they add a significant cost burden to treatment and are more suited to relieving febrile neutropenia, which is not the prevalent form of neutropenia seen with TAS-102. The prescribing information also indicates that the dose of TAS-102 can be reduced. However, recent data from ASCO suggest that maintaining dose intensity leads to better outcomes. Moreover, early results suggest that the development of neutropenia within the first month of treatment is associated with improved PFS and OS. I look forward to more studies on this topic, but for now, my approach is to maintain the dose of TAS-102 when possible.

Selecting Therapy With Toxicity in Mind
With these toxicities in mind, the choice of sequence between regorafenib and TAS-102 in the refractory setting should be informed by the patient’s treatment history and cumulative toxicity. A patient who experienced significant hand–foot syndrome with previous 5-FU/capecitabine may not tolerate regorafenib very well. Likewise, patients who have struggled with myelosuppression probably should not receive TAS-102 first. Finally, when considering treatment and potential toxicity in the refractory setting, it is wise to pause and reset expectations for both our patients and ourselves and to carefully consider a patient’s goals of care and willingness to endure further adverse events.

Your Thoughts
How do you weigh treatment-related toxicities when planning therapy in the refractory setting? Answer the polling question and post your thoughts in the comments section below.