Choices of Therapy for Metastatic Colorectal Cancer

Tanios Bekaii-Saab, MD, FACP:For most of the patients with colorectal cancer, recurrence does happen in the first 2 to 3 years. As you go beyond the 2 to 3 years—meaning when you look at the disease-free survival curves at 2 and 3 years—they do correlate somewhat with survival, although we continue to see a small cohort of patients showing evidence of progression after 3, 4, 5, 6, and 7 years. So, he’s a little bit unusual in terms of his later recurrence rather than his earlier recurrence. So, most patients actually do recur early.

Now what’s particular about this patient is although his tumor is on the right side, most right-sided tumors would carry essentially a mutation in theRASgene. This patient was aRASwild-type andBRAFwild-type, which is a bit unusual for the right-sided tumors. But still, the right side by itself, regardless of the mutational status, tends to confer a worse prognosis, and, therefore, a high risk of recurrence at some point.

For patients with metastatic colorectal cancer, when they present with a recurrence like this gentleman, you have to look at the history a little bit and understand what they were exposed to. So, this is a patient who had a resection, was exposed to FOLFOX, and had residual neuropathy grade 1. Now, usually what we look at is we take a cutoff point of 1 year. If the recurrence is before the year, we consider those as platinum-resistant, oxaliplatin-resistant patients, and we tend not to initiate oxaliplatin and move immediately to FOLFIRI plus bevacizumab.

For those who have been pre-exposed to oxaliplatin and recur after the year, then you have 2 options. The option of going to FOLFOX again with bevacizumab versus FOLFIRI with bevacizumab. And in aRASwild-type patient, you may consider EGFR inhibitors, except the confounding factor here is the patient’s tumor is on the right side where we know that tumors tend not to respond to EGFR inhibitors. And so, in this situation, an EGFR inhibitor would not be an option in this particular patient’s case. I think the options would be FOLFOX/bevacizumab or FOLFIRI/bevacizumab.

Now that said, why did we choose FOLFIRI/bevacizumab? Grade 1 neuropathy by itself is not prohibitive of reinitiating oxaliplatin. The patient had some unpleasant experiences with oxaliplatin. His neuropathy was a little bit more than a grade 2 to grade 3 and was limiting at some point. It improved with time. But the patient essentially did not wish to go back on oxaliplatin.

The other reason for that is it was seen consistently on 2 studies—Maverick and the little cohort of patients who went on CALGB 80405—that FOLFIRI/bevacizumab may have an edge over FOLFOX/bevacizumab, directly or indirectly compared. And therefore, it would be, in my clinic at least, the first choice in a metastatic patient.

In terms of survival and progression-free survival, when we look at those patients’ outcomes, on the right side, their survival is with bevacizumab and chemotherapy, so FOLFIRI or FOLFOX is close to the 29- to 30-month range, on average. PFS ranges between 9 and 12 months, depending on which regimen you tend to use for first-line therapy. So, without treatment, those patients’ survival is limited to less than 6 to 8 months. It’s a pretty significant improvement, historically mostly, but also from the data we have that that discussion with the patient, there are multiple options. Platinum is always an option in the second-line setting. EGFR inhibitors perhaps at some point, I’m not sure about that. And then there’s regorafenib and TAS102. So, there are a number of options for this patient. But I think the choice of FOLFIRI/bevacizumab would make the most sense for this patient in the first-line setting.

Transcript edited for clarity.

January 2017

A 62-year-old African-American man presented with recurrent CRC

• Diagnosed at age 55 with stage 3 CRC, treated with surgery and adjuvant FOLFOX
• He underwent colonoscopy with biopsy
  • 6-cm ulcerated non-obstructive mass noted in the right colon
  • Pathology confirmed poorly-differentiated adenocarcinoma
  • Staging; T3N1M0
• History
  • Former smoker, 1 pack a day; quit 20 years ago
  • Obese, BMI = 30.2 kg/m²
  • Mother had inflammatory bowel disease, died at age 70
  • Other medications: metoprolol for hypertension, omeprazole, regular NSAID use
• PET/CT scan showed recurrent disease with multiple metastases in liver
  • CEA, 28.4 ng/mL
  • Biopsy of liver lesions suggests poorly-differentiated with colon primary
  • Mutation analysis;KRASandNRAS,WT;BRAF-wild-type; microsatellite-stable
• He was started on FOLFIRI with bevacizumab and achieved partial response

January 2018

• The patient reports feeling short of breath.
• PET/CT showed progressive disease in the liver and multiple metastases in both lung fields
• Therapy options were discussed with the patient; he preferred an oral therapy
• He was started on regorafenib, 80 mg once daily
  • He experienced grade 2 dermatologic toxicity on his hands and feet (palmar-plantar erythrodysesthesia syndrome [PPES]), which was managed with dose escalation from 80 mg to 120 mg to 160 mg. With recovery, he resumed regorafenib at 120 mg/day
  • At present,he remains on regorafenib 120 mg/day with evidence of stable disease at 6-month follow-up