mCRC: Factors to Consider for First-Line Therapy

Wells Messersmith, MD:This is a very common scenario for advanced colorectal cancer on several counts. So, first of all, the patient is in his late 60s, and that’s really the most common age of colorectal cancer. We know that colorectal cancer is going up in younger patients, but really, for the older population, it has been going down but still represents a very common scenario. And we have about 150,000 cases in the United States every year.

The second thing that’s fairly usual for someone like this is that it is unresectable. So, when patients present with advanced disease, there’s only about one-quarter of them where we can try to cure with resection. Unfortunately, the majority are unresectable—we can’t do surgery. And also, about two-thirds are on the left side. So, the sigmoid colon, the descending colon—this is the left side of the colon—is the more common site. And this patient’s presentation of constipation, bloating, unexplained weight loss—all of that is fairly common symptoms.

One could have decided not to remove the primary tumor here, presumably due to the constipation. There was some concern about obstruction. And so, if the primary site seems to be bleeding or obstructing or otherwise causing a symptom, we’ll go ahead and have that removed. But if it’s not symptomatic—for instance, if this was picked up on a routine screening colonoscopy with no symptoms—then you could leave the primary in place and simply start palliative chemotherapy. So, I guess I would sum up by saying that on multiple levels, the age, the sidedness, and the type of presentation are fairly consistent with your average advanced colorectal cancer patient.

The prognosis of this patient, unfortunately being an incurable patient, is approximately 30 months. And the things that we consider when looking into prognosis are things like the spread or not—and, if it’s spread, whether or not it’s resectable. Again, this patient is unresectable, and so the goal of therapy is palliative—meaning to help the patient feel better and to extend life, but in general, we’re not able to cure. So, I think it’s very important to be clear with the patient as to what the goals of therapy are.

And we also know that prognosis is very much affected by sidedness. So, if you had told me this was a cecal tumor or an ascending colon tumor, which are right sided, those tend to have a poorer prognosis. We’re not sure exactly why that is. One reason may be that those tend to present not with bleeding but, rather, with other symptoms. And so, patients don’t pick it up if they’re testing for blood in the stool, for instance. And they tend to be diagnosed a little bit later.

But there might also be something intrinsic to right-sided colon cancers for several reasons. No. 1, the microbiome is different on the right side. No. 2, it’s from a different embryologic origin. The left side of the colon comes from the hind gut, whereas the midgut gives rise to the right-sided colon. So, there probably are biological reasons, as well. And finally, this tumor has aKRASmutation.KRAShas a weak but real, we think, prognostic effect in the sense that patients don’t live quite as long if they haveKRASmutations. But it’s a fairly small effect, so it’s not something I make a big deal of.

There are a number of options for first-line chemotherapy for a patient like this. One of the first things to consider is sidedness, and the reason for that is that right-sided tumors do not seem to benefit in the first-line setting fromEGFR-targeting monoclonal antibodies, such as panitumumab or cetuximab. So, that’s 1 thing—sidedness. The second thing is mutational status. Similar to having a right-sided tumor, if you have anNRASor aKRASmutation, you don’t seem to benefit from thoseEGFR-targeting monoclonal antibodies. So, another thing to consider would be theRASmutational status.

Third would be things like comorbidities. So, each of these drugs has specific side effects, and some of them also have drug interactions. For the backbone of chemotherapy that we start with, it’s usually oxaliplatin-based or irinotecan-based. Oxaliplatin tends to cause neuropathy. So, if we have a patient who, for instance, is diabetic and has diabetic neuropathy or some other history of neuropathy, then you’re going to think about starting with an irinotecan-based regimen so you’re not getting that neuropathy—or, if the patient has an occupation, for instance, or something that’s important to them that requires fine motor movement. So, if they tell you “I’m a pilot” or “I’m a musician” or “I’m an artist,” if they get numbing of the fingertips or toes, that’s going to really affect their profession and quality of life. That’s something important, as well.

Other patients have different feelings about their appearance. Irinotecan, for instance, tends to cause more hair loss. So, I’ve had patients who were counselors or psychologists or what have you where they have a lot of face-to-face interaction, and they don’t like to have that hair loss as part of their side effect profile. Irinotecan also tends to cause more diarrhea, so that can be another consideration. As you’re thinking through those things and discussing with the patient, those are some of the considerations.

And finally, irinotecan tends to have more in the way of drug interactions, and so it’s important to run through herbal medicines, such as St. John’s wort, and other medications that can have drug interactions with irinotecan. Additionally, these are metabolized and excreted by different routes. So, irinotecan is quite dependent on liver function, whereas oxaliplatin is quite dependent on kidney function. If you have dysfunction in either one of those organs, you might decide to go one route or the other.

It turns out that in the United States, roughly two-thirds or so use an oxaliplatin-based regimen, but there are people who believe strongly in one or the other, and I think whatever people are comfortable with after that conversation with a patient would be reasonable.

Transcript edited for clarity.

Progression of Left-Sided mCRC

February 2016

• A 66-year-old man reported with constipation, bloating, abdominal pain and weight loss of 12 pounds in 2 months
• PMH: mild hypertension, well-controlled on CCB
• Lab evaluation: Grade 2 anemia (Hb 9.2 g/dL)
• Colonoscopy revealed a7-cm mass in sigmoid colon
• CEA, 80 ng/mL
• The patient underwent sigmoid colectomy
• Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue;
  • Biopsy: 7of 12 resected nodes positive
  • Molecular testing:KRASmutation in codon 12 of exon 2; microsatellite stable
• CT scan showed several lesions in both lobes of the liver, measuring up to 17 mm in diameter, and 3 small lesions (<6 mm) in the left lower pulmonary lobe
• Diagnosis: Stage 4 colorectal cancer
• The patient received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• The patient was continued on bevacizumab maintenance

February 2017

• One year after starting therapy, the patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed progression in three of the liver lesions and one lesion in the right pulmonary lobe
• The patient was started on FOLFIRI and continued bevacizumab

January 2018

• Eleven months later, CEA level rose significantly
• Follow-up CT showed progressive disease in the lung and liver
• The patient is interested in knowing his options at this stage