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Refractory mCRC
How I Manage Patients With Chemotherapy-Refractory Metastatic CRC

Released: September 11, 2017

Expiration: September 10, 2018

John Strickler
John Strickler, MD
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With the proliferation of targeted therapies, treatment for patients with metastatic colorectal cancer has become increasingly complex. This complexity is particularly profound in the treatment of chemotherapy-refractory metastatic colorectal cancer (third line and beyond).

Ask the Right Questions
To determine the optimal approach in the chemotherapy-refractory setting, I ask a number of clinical questions:

First, how is my patient doing, both physically and emotionally? Chemotherapy is demanding, and many patients suffer from cumulative adverse events—neuropathy, myelosuppression, and fatigue are common in this patient population. Ultimately, selection of optimal treatment requires an understanding of the patient’s goals and expectations, performance status, burden of disease, and physical reserve.

Second, what molecular profiling data are available for the tumor? Current consensus guidelines recommend that all patients with metastatic colorectal cancer have tumor tissue genotyped for KRAS, NRAS, and BRAF V600E mutations. In addition, mismatch repair or microsatellite instability (MSI) testing is recommended in all patients. Increasingly, patients are receiving comprehensive tumor molecular profiling. These molecular profiling panels provide additional information that may predict response to immunotherapies or qualify the patient for a clinical trial. In cases where tissue genotyping has not been performed and tissue is not readily available (and obtaining a fresh biopsy is either unsafe or impractical), blood-based “liquid biopsies” are an option that is being increasingly used. The tumor’s molecular profile and genotype can have a profound impact on therapeutic selection.

Third, what therapy has the patient received prior to this point? How long did the patient receive each therapy? Did the patient experience disease progression, or was treatment discontinued due to toxicity? Is the patient a candidate for treatment rechallenge, or should a new therapeutic class be tried? Taking a detailed oncologic history is critical to designing a personalized treatment plan.

Consider the Available Options
Once these questions are answered, I review available FDA-approved treatment options. Panitumumab and cetuximab are anti-EGFR antibodies that are approved for use in patients with RAS wild-type metastatic colorectal cancer. These 2 antibodies are equivalent regarding efficacy and offer a response rate of approximately 20%. Regorafenib is an inhibitor of multiple tyrosine kinases, including VEGF, and offers modest survival benefit. Trifluridine/tipiracil (TAS-102) is an oral cytotoxic chemotherapy that also offers a modest survival benefit, albeit with a safety profile that is different from regorafenib. Regorafenib is associated with predominately hand–foot skin reaction, fatigue, and diarrhea whereas patients receiving TAS-102 typically experience myelosuppressive toxicities. In addition, some patients may be candidates for FOLFOX or FOLFIRI rechallenge, particularly if treatment was discontinued for reasons other than disease progression.

A Case From My Clinic
To illustrate how I manage patients in the third-line treatment setting and beyond, I would like to share with you a case from my clinic. My patient was a 33-year-old male who initially presented with resectable, stage III rectal cancer. He was treated with neoadjuvant chemoradiation, followed by surgery and adjuvant FOLFOX. Unfortunately, he developed recurrent metastatic disease shortly after completing adjuvant chemotherapy. His tumor had a KRAS mutation, and NRAS and BRAF were wild type (nonmutated). He was treated with FOLFIRI and bevacizumab but tolerated this treatment poorly and experienced disease progression. Fortunately, his tumor was MSI-high, which is a strong predictor of benefit from FDA-approved anti–PD-1 immune checkpoint inhibitors (pembrolizumab and nivolumab). With anti–PD-1 immunotherapy, he has achieved disease control for over 2 years with manageable adverse events.

Final Thoughts and Future Directions
With the proliferation of potentially actionable molecular targets, molecular profiling will be increasingly used to guide therapeutic decision making in the chemotherapy-refractory setting of metastatic colorectal cancer. Several other therapies have shown promise in clinical trials, and I expect this disease setting to be a rapidly evolving area of my practice.

For expert guidance in selecting the optimal systemic therapy for patients with metastatic colorectal cancer across multiple lines of therapy, look for CCO’s new Interactive Decision Support Tool, “Focus on Metastatic Colorectal Cancer: An Interactive Decision Support Tool” on this Web site in the coming weeks. The tool will provide evidence-based treatment selections from 5 experts based on multiple patient and tumor characteristics, such as mutation status, and previous treatment history.

How do you select therapy for your patients with chemotherapy-refractory metastatic colorectal cancer? What type of molecular profiling do you obtain?

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In the case example described in this commentary, which therapy would you choose if the patient’s tumor had NOT been MSI-high?
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