Treatment Beyond Progression for mCRC

Paul Helft, MD:In my own practice, I nearly always continue bevacizumab beyond first-line progression. And the rationale for that is multifarious. There are several studies now that have demonstrated a proven clinical benefit. In fact, there is a small overall survival advantage in patients who continue bevacizumab beyond progression. We also have retrospective studies—in some cases of several thousand patients—which lead us to the same conclusion. In a patient—especially who has aRASmutation and who, therefore, is not a candidate for an anti-EGFR drug—their treatment options are more limited, and, indeed, don’t have a second antibody to turn to in a rational way. And because of their limitations of therapy, I believe in trying to get as much mileage out of every therapy as possible. And so, all of those things in my mind justify the continuation of bevacizumab beyond first-line progression.

So, there are several studies which lead us I believe the conclusion or the support for using bevacizumab beyond progression. There is, as I mentioned, a large retrospective study which suggests that that’s the case. It obviously has inherent biases in it. There are several randomized trials to which we can turn for some support as well. The first one would be the trial known as TML, or Treatment through Multiple Lines, which showed approximately a 2-month overall survival advantage in patients who continued bevacizumab beyond progression compared to those patients who have not.

Going back even farther, in ECOG e3200, which was a trial technically of second-line therapy, although the patients had not previously been exposed to bevacizumab, they did better when bevacizumab was included in that. And finally, the aflibercept registration trial, which was a phase III trial of the other anti-VEGF therapy known as aflibercept, also showed an approximately 2-month median survival time advantage for those patients who continued that, having received an anti-VEGF antibody in the first line.

One of the nice things about using bevacizumab for patients in the first line is that, as I like to tell them, in general, it has very few side effects but has a number of significant risks. Now luckily those risks are infrequent events that don’t happen to the majority of patients. In fact, the vast minority of patients experience a very significant side effect, or toxicity, with bevacizumab. Those things include both arterial and venous thrombotic events, and other important toxicities. However, the majority of patients who take bevacizumab in first and second line will not experience dose-limiting toxicity in any way. And, in fact, the contributions to their day-to-day subjective toxicities are relatively small.

So, I have come to be a very strong proponent of maintenance therapy, and I certainly use maintenance therapy extensively in my practice with patients with metastatic colorectal cancer. The rationale for this are several fold, but include the fact that being on combination chemotherapy for long periods of time is quite taxing with respect to toxicity in patients. We have learned, over the course of many years of treating patients, that long holidays from therapy lead to a shorter progression-free survival, and perhaps even to a shorter overall survival. And so, patients in my practice, in general, do not take long holidays from therapy. They, therefore, have to continue therapy for long periods of time, and so the idea of modulating the intensity of therapy with more intensive therapy, alternating with less intensive therapy, is a very appealing one.

Finally, at least in the case of small studies, such as the Optimox series of studies, patients can be reintroduced to drugs after they have gone off of them for a period of maintenance therapy, and get more mileage out of those therapies even when reusing them again. So, for example, a patient who is on oxaliplatin-based therapy in first-line—let’s say for the sake of argument that they’re on FOLFOX and bevacizumab—in my practice would only continue with oxaliplatin for the first, say, 4 to 5 months. Then, they would stop that in favor of either 5-FU/leucovorin and bevacizumab, or capecitabine and bevacizumab, during a period of maintenance therapy. That maintenance therapy would then continue on until they had evidence of clinical progression, at which time—unless they had progressed very rapidly, or unless they had significant neuropathic side effects—I would reintroduce oxaliplatin, since in some studies that has shown a disease restabilization rate as high as 30%. This gives them another opportunity to respond and have disease control out of that drug before we move on to the next line of therapy. Just another way, in a sense, of getting as much mileage out of each therapy as possible.

As I like to tell my patients, this is a marathon more than a sprint, or a chess game rather than a checkers’ game. What you do in the beginning of therapy is going to affect what happens in later lines of therapy. And especially if patients have significant wear-and-tear from chemotherapy over long periods of time, their ability to withstand that intensity of therapy becomes very difficult as their disease progresses and as they go on to second and third-line therapies.

So- I try to pay very careful attention to toxicity management throughout the course of illness. I dose reduce liberally- and often when patients seem to require it. And that helps, in my mind, to allow patients opportunities to take therapy further on.

February 2013

• A 62-year old man presented to his primary care physician complaining of weight loss and bloody stool.
• PMH includes type 2 diabetes, well controlled on metformin
• He was referred for a colonoscopy:
  • Biopsy of a 6 cm. mass proximal to the sigmoid colon showed moderately differentiated adenocarcinoma
  • Genetic testing was positive forKRASexon 3 mutation
• Imaging of the chest, abdomen, and pelvis showed metastases to inguinal nodes, diffuse hepatic lesions and a 4 cm. nodule in the left lung.
• Diagnosis: stage 4 colorectal adenocarcinoma, unresectable
• After discussion with the patient about his options for systemic therapy, he was started on FOLFIRI and bevacizumab. Moderate nausea and vomiting was managed with ondansetron.
• Follow-up imaging at 6 months showed marked regression in the primary tumor and lung lesion. Subsequent scans showed stable disease.

March 2014

• Thirteen months later, the patient reported weight loss and fatigue; he continued to do household chores but was too tired for exercise.
• CT scan showed increase in size of several of the hepatic lesions.
• Bevacizumab therapy was continued; the patient was also started on FOLFOX.
• Follow up CT showed significant shrinkage of hepatic metastases. The patient continued to tolerate therapy and appeared well.