Factors to Consider in Colorectal Cancer

Tanios Bekaii-Saab, MD, FACP:Today, it’s a little different world than, let’s say, a year and a half ago where mutational status was the only important thing for us to decide on VEGF versus EGFR inhibitors. Today, in addition to molecular characterization—and I’ll quickly refer to what that means—we also have anatomic considerations. There are also, of course, other concentrations: performance status, age, and microsatellite status. So, we’re really now thinking about colon cancer in the patient who presents to us in terms of deciding on what therapy we should proceed forward with, with decisions that are linked to molecular/genetic characterization. So, it’s very important to have an expandedRAS—notKRAS—which includes expandedKRAS, expandedNRAS.

And also, I think it’s very important to getBRAF, becauseBRAFhelps us a lot to understand how aggressive the tumor is and even consider 3-drug versus 2-drug therapy plus bevacizumab. Microsatellite status is very important. Everyone should get microsatellite status checked. If the patient is MSI-high, then you can consider immune therapy or an immune therapy clinical trial.

And then, there are anatomical locations. So, this now goes into the equation, regardless of theRASstatus. Let’s say you have a patient like this one who’sRASwild-type,RAFwild-type,BRAFwild-type, and microsatellite stable, but the tumor is on the right side. Those patients do not seem to benefit from EGFR inhibitors. So, anatomic location matters—although conceptually, let’s say 2 years ago, we think ofRASwild-type and you have the 2 options. Well, today, if you’re on the left side of the colon, you have both options. We can talk a little bit more about this. But on the right side, clearly in the first-line setting, EGFR inhibitors do not seem to have any benefit. And so, those patients, regardless of theRASstatus—because of the anatomic location on the right—should receive bevacizumab plus chemotherapy, if eligible, first.

On the left side, it gets a little bit more complicated, in a good way, because then we have more options. All the studies that we have on hand—like CALGB/SWOG 80405—are, of course, relevant to our practices in the United States, but we also have hints from other studies. There’s the European study, FIRE3, which is primarily powered for response rate. CALGB was primarily powered for survival and reflects more the practice in the United States.

The 2 studies sticking together suggest that an EGFR inhibitor may have a little edge on the left side. But when you look at the overall picture, you continue to integrate into the equation potential toxicities, you have to think about your biologics. EGFR inhibitors can cause a rash and can enhance the risk of diarrhea with chemotherapy. When I give bevacizumab, I say it has more silent toxicities.

So, when you look at the NCCN guidelines today and the way they included the right versus left story, then it’s clear that for theRASwild-type tumors, EGFR inhibitors in the first-line setting are not recommended. On the other hand, for the left side, both EGFR and VEGF work. So, bevacizumab, cetuximab and panitumumab are indicated in theRASwild-type. Now, of course if you have aRASmutation tumor, then it’s a no-brainer; it’s bevacizumab as your only biologic whether you’re on the right or the left, and that’s in the first-line.

Now when we start thinking about going down the line of therapy—we’ll talk a little bit more about that later—things may get a little bit different in terms of our thinking, because we start running out of options as we go down the line of therapy. But your first-line of therapy is essentially the most important line of therapy because it sets the stage for everything you do in second-line, third-line, and beyond, and it’s also the line of therapy where patients spend most of their remaining lifetime on therapy. It’s very important to make the right decision in first-line in terms of what biologic, based on molecular characterization, genetic characterization, as well as anatomic characterization, and after that, of course, other clinical factors.

Transcript edited for clarity.

November 2015

• A 62-year-old Caucasian female presents with severe crampy right lower quadrant pain
  • 6-month history of occult bleeding and weight loss of 15 pounds in the last 8 months
• PMHx: tonsillectomy at age 23; hysterectomy at age 55
• FHx: Mother diagnosed with colon cancer at age 71
• Laboratory findings: remarkable for Hb, 7.6 g/dL; CEA 5.5 ng/mL
• Colonoscopy reveals a large mass in the ascending colon, measuring approximately 11 cm
• Biopsy results: Invasive, poorly differentiated adenocarcinoma
• Additional pathologic testing
  • KRAS,NRAS, andBRAFwild-type
  • Microsatellite stable
• CT scan revealed widespread lesions in the left lobe of the liver
• Performance status: 0
• Treatment was initiated with FOLFOX + bevacizumab
  • The patient experienced mild neuropathy, significant mucositis, grade 4 neutropenia, and severe diarrhea with the first cycle (suspected DPD deficiency)
  • She subsequently tolerated therapy well with 50% dose reduction of her regimen in addition to dropping the bolus 5-FU and leucovorin.
• Follow-up imaging showed reduction in the size of the liver lesions
• Patient is planned to start maintenance therapy with low-dose capecitabine plus bevacizumab after 8 cycles of FOLFOX

August 2016

• Follow-up CT showed progression in the liver with new lesions
• Performance status: 1
• She began therapy with mFOLFIRI + bevacizumab
• CEA levels stabilized

February 2017

• The patient complained of severe fatigue and additional weight loss. Her performance status remains at 1.
• CT scan revealed progressive disease with 2 new pulmonary nodules in the left lower lobe of the lung and mild progression in the liver.