Upfront Systemic Therapy for mCRC

Paul Helft, MD:So, in terms of choosing the first-line chemotherapy backbone, we know from multiple studies and experiences that irinotecan- and oxaliplatin-based therapies are both appropriate therapies. However, there are important differences in their toxicities. In particular, the dose-limiting toxicity of oxaliplatin, which is peripheral sensory neuropathy, is a very important consideration and a very important toxicity in looking at how to choose that drug for all patients. Some patients, for example, who have preexisting diabetic neuropathy might better be served with an irinotecan-based regimen since it doesn’t involve the possibility of neuropathic toxicity along the way.

This patient who has preexisting well-controlled diabetes, and no mention of peripheral sensory neuropathy, I think is an appropriate patient for either therapy. There are some United States oncologists who prefer one drug over the other, partly because of their experience, partly because of the longer-term toxicities. Some people, for example, feel that irinotecan can be maintained in a patient for obviously longer periods of time than oxaliplatin, where you reach a ceiling fairly quickly within the first 4 to 5 months.

In general, the first-line therapy for any patient with metastatic colorectal cancer is, in many ways, the most important decision and the most important therapy that the patient will encounter through the entire trajectory of their illness. This is because they get the greatest, I like to say, “bang for the buck,” the most mileage out of that first-line treatment. The progression-free survival is likely to be the longest. The contribution to the overall survival of the patient is also likely to be the longest. And, therefore, they will be on those therapies for the longest period of time, and consideration of the toxicities that they will encounter, both acutely and over the long-term, are very, very important to decide.

So, my personal experience with FOLFIRI is that it has a manageable series of side effects for most patients, as long as one pays careful attention to side effect management along the way. The cumulative toxicities of irinotecan, which tend to be diarrhea, fatigue, and hair loss, some are obviously more manageable than others. The fatigue part of it and the hair loss part of it are not particularly manageable because we don’t have good treatments for those side effects. I think diarrhea management is very important with irinotecan. I frequently resort to testing patients at the very beginning of their treatment for the presence or absence of theUGT1A1promoter mutation to help guide dosing with respect to irinotecan in this first line, since they’re going to be on that for a long time.

The second point that I’d like to make is that patients who are on oxaliplatin-based therapy run out of runway, so to speak, within 4 to 6 months of beginning therapy because they begin to develop peripheral sensory neuropathy and have to have their oxaliplatin discontinued, even if they are responding. That’s a very important principle of managing patients who are on oxaliplatin, to stop it fairly early in the course of therapy, to switch patients then to a maintenance therapy, and allow them to recover from the neuropathic side effects. With irinotecan, we have fewer studies in a sense to guide us with respect to this question of maintenance therapy. And because it doesn’t have a cumulative toxicity analogous to oxaliplatin, the clinical guidance that we can offer in terms of maintenance therapies are a little more complicated. I personally tend to follow the same patterns that I do with oxaliplatin. In other words, to use irinotecan and a fluoropyrimidine at the beginning, to discontinue it within 4 to 6 months, and to leave the patient on the fluoropyrimidine and bevacizumab in this case for maintenance therapy.

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.