Upfront Therapy for Metastatic Colorectal Cancer

Tanios Bekaii-Saab, MD, FACP:So, in October 2015, the patient, a 64-year-old woman, presented with obstructing symptoms. She was found to have an obstructing mass at the rectosigmoid junction and then eventually underwent hemicolectomy. At the time when she was seen, labs were drawn, including CA level, which was elevated. After the left hemicolectomy, the pathology suggested a poorly differentiated adenocarcinoma that invaded through the muscularis mucosae up to the pericolic fat. Fourteen lymph nodes were taken out along with the tumor, and about 10 of them were actually positive for cancer.

Staging with CT scans and PET/CT showed multiple lung lesions; 3 of them actually measured up to 3 cm in size. The patient had a mutational analysis on her tumor, which was essentiallyRASwild-type. So, mutational testing was performed on the tumor. It revealed to be aRASwild-type tumor, so no mutations. There was alsoBRAFwild-type, so no mutations inBRAF. MSI testing revealed a microsatellite-stable tumor. Essentially, this was a metastatic stage 4 cancer because of the liver lesions.

When looking at the past medical history with this patient, she had a history of hypertension, which seems to be well controlled. The patient also had a prior history of coronary artery disease. She had an angioplasty for 4 years, but she continued to be asymptomatic. Her coronary artery disease was under control. She met with the oncologist, and the decision was made to proceed with FOLFIRI and cetuximab, which is an EGFR inhibitor. The patient tolerated the treatment well. She had grade 1 rash, which was manageable, and grade 2 thrombocytopenia, and this was manageable with dose adjustments to the FOLFIRI. Follow-up imagings at 2 months and at 4 months revealed significant response and shrinkage of these tumors in the lungs. The patient was doing well. So, the decision now was to move to maintenance therapy, and the oncologist decided to put the patient on maintenance cetuximab.

So, this patient is stage 4. Of course, her prognosis is guarded since the presence of multiple lesions in the lungs will make those unlikely to be ever resectable. Ultimately, she will succumb to her cancer. Right now, in patients with theRASwild-type tumors, the average survival is about 3+years, up from 6 months with no therapy. It’s much better from that standpoint, but unfortunately, her life is ultimately going to be limited by the cancer. For some patients, this may translate into many years. For other patients, it may translate to less. But nonetheless, the median is close to 3 years. So, her disease is ultimately going to take over her life.

In terms of what are the best frontline options for this patient, this patient has a left-sided tumor and this patient has no mutations,RASorBRAF. Now, her disease is microsatellite-stable so that only tells us that immune therapy may not be an option, other than onset in clinical trials, but it’s not an actual option in clinical practice. So, that’s death, and it also tells us that it’s unlikely to be related to Lynch syndrome. In term of RAS wild-type andBRAFwild-type tumors, we have 2 options proceeding with a biologic. The 2 biologic options are either a VEGF inhibitor or an EGFR inhibitor. A VEGF inhibitor would be bevacizumab. The EGFR inhibitor would be either panitumumab or cetuximab.

Because the tumor is on the left side, the data does suggest—both from CALGB 80405 and FIRE-3—that there may be a slight advantage for an EGFR inhibitor, specifically cetuximab over bevacizumab. And so, I think it’s very appropriate to start the patient on FOLFIRI/cetuximab. I think that’s a choice that’s acceptable with those tumors. My personal preference would still be to start those patients on bevacizumab, understanding that I can use those EGFR inhibitors at any point of therapy. It gets a bit complicated because those patients will have the longest exposure to their therapy in the first line. And EGFR inhibitors have a number of toxicities that can be quite significant, such as rash. It doesn’t get any worse with time, but it may be persistent for some patients and the rash would never improve significantly.

Hypomagnesemia, those patients almost universally will have issues with retaining magnesium. They shed magnesium out. Some will require infusions of magnesium more than others. Then, the other question would be, how do you maintain those patients and do we have data? We don’t really have strong maintenance data with the EGFR inhibitors. Unlike capecitabine and bevacizumab, we don’t have it with the EGFR inhibitors. So, that is relatively limiting. But if you look at the data overall, they look very similar between the EGFR and the VEGF inhibitors, maybe a slight edge for the EGFR inhibitors. After a discussion with the patient, typically I think you have to expose the patients to the benefits, the pros and cons of the 2 biologics, and have the patient be part of that decision with you.

In this particular patient, the decision was to proceed with FOLFIRI/cetuximab, which, as I said, is very appropriate. And obviously, the patient benefited from the treatment. Then, the question is, what type of maintenance therapy would we perceive? Given the absence of data, the question is, do we continue with the fluoropyrimidine or the EGFR inhibitor or with the 2? Again, we don’t have data. We know that ultimately, the toxicity of the EGFR inhibitors is amplified when you combine them with chemotherapy, and EGFR inhibitors, unlike VEGF inhibitors, have activity on their own. They can’t induce responses on their own without the assistance of chemotherapy.

So, logically just putting all these things together, I think it would make more sense to just proceed with the EGFR inhibitor on its own—cetuximab or panitumumab—as a maintenance strategy. The next question is, of course, how long do you continue with this? Given the cumulative toxicities and the issues you start having, I tend to limit this to a year or so if you have a persistent response. And then, the decision after that will depend on toxicities, patient preferences, etc. So, the key would be to have that discussion continuously with the patient to see if maintenance would make sense to continue.

Transcript edited for clarity.

October 2015

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
  • CEA were elevated, 23.3 ng/mL
  • Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic
  • Imaging with PET/CT showed several lung lesions, three measuring up to 3.0 cm in size
  • Mutational status was both RAS and BRAF wild-type
  • Microsatellite stable
  • Diagnosis; high grade colorectal adenocarcinoma, stage T4N2M1
• PMH includes arterial hypertension, well-controlled on an ACE inhibitor and coronary angioplasty with stent placement 4 years ago
• The patient received systemic therapy with FOLFIRI + cetuximab; grade 1 rash and grade 2 thrombocytopenia were managed with dose adjustment of FOLFIRI
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
• The patient was continued on maintenance therapy with cetuximab

August 2016

• The patient complains of weight loss, nausea and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions
• The patient was switched to CAPEOX with bevacizumab. Her blood pressure was closely monitored and remained stable
• Follow up imaging at 2 months and at 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms
• At 4 months, oxaliplatin was discontinued; maintenance therapy with capecitabine and bevacizumab was continued

January 2017

• At 5 months, the patient reports having reappearance of her symptoms, although she continues her normal physical activity
• CEA level is rising significantly
• Follow up CT showed further progressive disease in the lung and the appearance of several small boney lesions
• The patient is motivated to try another therapy and has opted for regorafenib