mCRC: Combination Therapy and Testing

Tanios Bekaii-Saab, MD, FACP:In terms of the choice of the backbone, now we decided that for this patient an EGFR inhibitor doesn’t make sense because it’s on the right side, despite the fact, at least in the first-line, that it’s aRASwild-type tumor. So, that’s something very important to keep in mind. The question is, how do you choose your chemotherapy backbone? You have FOLFOX and FOLFIRI, and they’re both equally good. Study after study suggest that there’s probably interchangeability between the 2 backbones. Although some of the studies suggest that there’s a slight edge for FOLFIRI, it’s never really in the statistically significant piece, but it always trends a little bit better. So, FOLFOX and FOLFIRI are both reasonable. Most community physicians in the United States tend to use FOLFOX in the first-line and about 20% use FOLFIRI, and I include myself in that 20%.

Now, in terms of going to a 3-drug regimen—FOLFOX or FOLFIRI plus bevacizumab—that’s a tough regimen. It’s a 3-drug regimen that has more toxicities, so it induces more toxicities than the FOLFOX or the FOLFIRI. When do we integrate the 3-drug regimen? I think there are 2 areas in colorectal cancer where FOLFOX or FOLFIRI plus bevacizumab may make sense.

One is in theBRAF-mutated tumors. Those are very aggressive tumors. We have some hints from subgroup analyses from a couple of studies, including the TRIBE study, that suggest that for those patients, the 3-drug regimen may provide a much higher benefit than the 2-drug regimen. So, with those patients, theBRAF-mutated patients, I tend to go with FOLFOX or FOLFIRI plus bevacizumab in the first-line setting.

The other group are those patients with isolated liver metastases that are clearly resectable—so borderline resectable—that need a good response to move to surgery. Those patients, again if eligible, would go for the 3-drug regimen. So, these are the only instances where we’d use the 3-drug regimen.

In terms of routineDPDtesting andUGT1A1testing, I’d say for both, it’s a no. They’re not cost-effective and they don’t really provide us with a lot of guidance about what to do in the clinic. A number of studies over the years tried to look at their value. Ultimately, we have patients going through chemotherapy. The majority, more than 95% of those patients, will have no major issues. And for those very few patients who may have deficiencies inUGT1A1orDPD, interestingly at least half of those patients will not even have any issues in the presence of these alterations. So, you don’t know what to do really with a dosage of the chemotherapy. And the other half, they will manifest some clinical toxicities that would end up being resolved for 99% or more of them with those reductions—like this patient for example. And so, the cost of these, of universal screening forDPDand forUGT1A1, is really not justifiable given the bulk of data that we have available to us, and given our own clinical experience and understanding of where they fit in the clinic. So, I’d say no.

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.