Second-Line Therapy for Metastatic Colorectal Cancer

Edward Chu, MD:The issue of how long to continue bevacizumab has been an ongoing question for those of us who are treating patients with metastatic colorectal cancer. Axel Grothey, initially in the BRiTE observational trial, provided some very interesting data suggesting that bevacizumab beyond disease progression after the first line of treatment was associated with significantly improved median overall survival approaching 30 months. In contrast, for patients who did not continue on bevacizumab in the second-line setting, their overall survival was approaching 20 months based on the TML study, which was a large randomized study looking at this issue of bevacizumab beyond disease progression. The study was initially developed by the German AIO Cooperative Group and then expanded to other European sites. This study was led by Dirk Arnold and his colleagues. I think that study clearly showed that there was a benefit to continuing bevacizumab beyond disease progression and treating patients in the second-line setting.

There are 2 other interesting anti-VEGF agents. One is ziv-aflibercept, and the other one is ramucirumab. Both of these agents have also been approved in the second-line setting in combination with the FOLFIRI cytotoxic chemotherapy backbone. However, in contrast to bevacizumab, I think both agents are associated with increased toxicities, and also both of those agents are associated with increased cost. And then, when one looks at the benefit of continuing bevacizumab versus the benefit of adding those additional agents, the improvement in median progression-free survival approaches 1.5 months. So from my perspective, bevacizumab is very well handled, very well tolerated. We know the side effects well. We have data now to support continuing bevacizumab in the second-line setting.

Now that we’re in November of 2015, almost a year after the start of her therapy, this patient now presents with additional lesions in the liver, as well as retroperitoneal masses and lesions in the pelvis. So clearly, this patient now has disease progression. It’s clear that the patient now has to undergo a change in her therapy. It’s interesting—the patient has been treated with FOLFOX/bevacizumab for 11 months now. When one looks at the most recent data presented by Dr. Venook in the CALGB 80405 study, at the median progression-free survival in patients treated with FOLFOX/bevacizumab, that medium PFS is exactly 11 months. This patient is following exactly what we would expect for patients being treated with this regimen. The patient also is now symptomatic and presumably symptomatic from both the liver lesions and the lesions in the abdomen and pelvis.

With respect now to second-line therapy, the patient has progressed on oxaliplatin-based chemotherapy. The most appropriate treatment option now to consider in the second-line setting is an irinotecan-based chemotherapy. It appears that the patient’s overall performance status is still quite good. She’s experiencing tumor-related symptoms, so it’s quite appropriate to consider an irinotecan-based regimen in combination with either infusional 5-FU—that would be the FOLFIRI regimen—or combining irinotecan with the oral fluoropyrimidine, capecitabine, and that regimen is known as either XELIRI or CAPIRI. And as we talked about previously, it is quite appropriate to continue bevacizumab in the second-line setting with an irinotecan-based combination.

For patients whose performance status is poorer than what this patient has—so a patient’s performance status is perhaps 2 or they have more tumor-related symptoms—one might consider single-agent irinotecan in combination with bevacizumab. But, again, I think for this patient, who is still very young, whose overall performance status is still very good, and who has no other comorbid illnesses, I would tend to be still pretty aggressive and go with an irinotecan combination plus bevacizumab.

When one thinks about the various factors that need to go into the decision-making process, I think of, first and foremost, performance status, presence or absence of comorbid illnesses, previous therapies, and then also presence or absence of underlying liver and/or kidney dysfunction. The issue of underlying liver function is especially important in this case because as we’re now thinking about switching over from oxaliplatin-based chemotherapy to irinotecan-based chemotherapy, irinotecan is metabolized pretty heavily in the liver. So it’s critically important that the underlying liver function is normal.

I think we all now appreciate that the multidisciplinary care is critically important—and not only for patients with metastatic colorectal cancer. It really should hold for all patients with colon cancer—both patients with advanced disease as well as patients who have early-stage disease. This patient has, unfortunately, widespread liver disease, has involvement of both the retroperitoneum and the pelvis. Surgery is probably unlikely in this case. However, the goal even for patients who are deemed to be surgically unresectable upfront is to see whether or not, whatever treatment regimens we’re giving to a patient, we might be able to render that patient surgically resectable.

So even though it does appear that this patient has widespread metastatic disease that is surgically unresectable, we would certainly get our surgical GI oncologist to weigh in as to whether or not she is surgically resectable and at what point they would deem the patient to be surgically resectable. I think based on the Institute of Medicine report that came out a couple of years ago, it’s now critically important that we consider supportive care for all of our patients who come to our clinic, even at the very first visit. Supportive care and symptom management are critically important because this patient has tumor-related symptoms, so pain relief is going to be very, very important.

In patients with colorectal cancer and other GI cancers, nutrition is also a very important element. As a part of the multidisciplinary approach to this patient, we would have this patient and her caregivers see our dietitian/nutritionist to have them provide a nutrition plan. And then, for those patients who may be undergoing either psychological or emotional stress—resulting from the disease itself or from the treatments—our group here at the University of Pittsburgh Cancer Institute are fortunate to have a cycle oncology behavioral medicine program. And so, for any patient who has any kind of emotional issues, we will refer those patients to that group. Again, they’re part of our multidisciplinary approach to patients with colorectal cancer.

Transcript edited for clarity.

December 2014

• A 51-year old Caucasian female presented with severe crampy right lower quadrant pain
  • She had a 4-month history of occult bleeding, and significant weight loss of over 10 pounds in the last 8 months
  • She sought medical treatment after experiencing severe cramping in the abdomen and bloody diarrhea
• Past medical history included GERD, managed with a proton pump inhibitor and appendectomy at age 35
• Laboratory evaluation showed grade 2 anemia (hemoglobin 8.7 g/dL) and carcinoembryonic antigen (CEA) level of 4.5 ng/mL
• Colonoscopy revealed an obstructive lesion in the ascending colon, measuring approximately 15 cm
  • Pathological findings showed invasive and poorly differentiated adenocarcinoma with ulcer
  • 10 of 15 lymph nodes sampled were positive for tumor
  • CT scan revealed widespread lesions in both lobes of the liver, and she was diagnosed with stage IV disease
  • Mutation testing; KRAS-positive (G12D) and BRAF-negative
  • Her ECOG performance status was 0
• She was treated with six cycles of FOLFOX + bevacizumab, and appeared to be responding well to treatment; follow-up imaging showed reduction in the size of the liver lesions

November 2015

• Follow-up CT showed progression in the liver with new lesions and new small masses in the abdomen and pelvis
• Her ECOG performance status was 1
• She began therapy with FOLFIRI + bevacizumab

December 2015

• The patient complained of severe fatigue
• CT scan revealed progressive disease with no improvement in the size and number of the abdominal lesions and the presence of 3 pulmonary nodules in the right lung
• She was then switched to trifluridine/tipiracil (TAS-102)
• PET/CT at 3 months and 6 months showed stable disease
• Her ECOG performance status improved (PS 0)