Treatment Options for KRAS-Mutant Unresectable mCRC

Paul Helft, MD:In the very recent past, we wouldn’t necessarily have tested a patient for the presence or absence of defective mismatch repair. In recent years, we have discovered that MSI status, or mismatch repair status as conferred by especially high frequency microsatellite instability, has become a very important biomarker for a small subgroup of patients who are now very important because other therapies are available to them. So, certainly, a patient such as this at the very beginning of their illness should have their MSI status determined.

Such a patient obviously has multiple options open to him for first-line therapy. One of the first ways that we sort patients when they walk into the office with such a situation is to determine whether or not they will ever become a candidate for curative intent therapies, such as surgery. Such a patient with widespread disease is exceedingly unlikely ever to go on to undergo intervention such as surgery with curative intent. So, in such patients, our goals of therapy are different. They are to improve overall survival and progression-free survival, and to maintain their quality of life for as long as possible through the course of their illness. In such a patient, we would always consider the question of surgery. In particular, the question of whether or not the primary tumor should undergo resection or not is an important question for the 25% of patients who show up with stage 4 de novo disease. This question was and has been a relatively complicated question, having to do with things like the patient’s performance status, their risks of surgery, the burden of their disease, the location and complexity of their primary tumor resection, whether the tumor is obstructing or not—or nearly obstructing—or whether there are other incidental complications such as bleeding.

Now in such a patient, some recent studies have suggested that patients through the course of their illness will never actually need to undergo such a surgery for their primary tumor. And in this patient who’s basically asymptomatic from the point of view of his primary tumor, I would not recommend that he go to surgery. As for other surgical techniques, such as metastasectomy—those surgeries which are aimed at resecting metastatic disease—he obviously has too widespread disease to undergo resection.

February 2013

• A 62-year old man presented to his primary care physician complaining of weight loss and bloody stool.
• PMH includes type 2 diabetes, well controlled on metformin
• He was referred for a colonoscopy:
  • Biopsy of a 6 cm. mass proximal to the sigmoid colon showed moderately differentiated adenocarcinoma
  • Genetic testing was positive forKRASexon 3 mutation
• Imaging of the chest, abdomen, and pelvis showed metastases to inguinal nodes, diffuse hepatic lesions and a 4 cm. nodule in the left lung.
• Diagnosis: stage 4 colorectal adenocarcinoma, unresectable
• After discussion with the patient about his options for systemic therapy, he was started on FOLFIRI and bevacizumab. Moderate nausea and vomiting was managed with ondansetron.
• Follow-up imaging at 6 months showed marked regression in the primary tumor and lung lesion. Subsequent scans showed stable disease.

March 2014

• Thirteen months later, the patient reported weight loss and fatigue; he continued to do household chores but was too tired for exercise.
• CT scan showed increase in size of several of the hepatic lesions.
• Bevacizumab therapy was continued; the patient was also started on FOLFOX.
• Follow up CT showed significant shrinkage of hepatic metastases. The patient continued to tolerate therapy and appeared well.