Considerations in Progressive, Advanced CRC

Marwan G. Fakih, MD:This patient now has progressed on FOLFIRI and bevacizumab. The patient has a KRAS-mutated tumor. Therefore, in this particular patient, there is absolutely no benefit from anti-EGFR therapy. The patient is refractory to fluoropyrimidines and is also refractory to irinotecan. We also consider this patient resistant to oxaliplatin since he has evidence of progressive disease about 6 months after adjuvant therapy. In addition, the patient has grade 2 neuropathy. In this particular setting, one has to consider TAS-102 as an option for treatment for progressive metastatic colorectal cancer despite standard of care therapy. Another option would be regorafenib, as well.

On a personal level, it’s very important for me to discuss potential side effects associated with treatment in a patient with metastatic colorectal cancer. Our focus is not only improving longevity, but also to maintain quality of life. Therefore, I have to have a very detailed discussion with the patient regarding the side effects of each compound or each drug that I use in metastatic colorectal cancer. So, what I would be discussing with the patient in this particular setting is the potential benefit of a treatment. In the setting of TAS-102, what we know is that there is a 32% relative improvement in survival, and, therefore, what I tell my patients is that receiving TAS-102 will likely improve the chances that they would be alive down the road. If we look at 1-year survival with TAS-102 versus placebo, there is a 10% absolute improvement in 1-year survival with TAS-102. But, also, if we look at the likelihood of survival, there’s a 32% improvement in longevity.

Now, it is important to note that this does not come at the expense of worsening in performance status. What is important about the RECOURSE clinical trial, that has evaluated TAS-102 versus best supportive care, is that it has shown that the time to deterioration in the performance status was delayed with TAS-102 versus placebo. And, therefore, it is fair to tell the patient that this treatment not only will improve the longevity, but likely will prolong the time when he is fit or where he is fit.

The other side effects that I do discuss is the possibility of infection with TAS-102. Now, we know that 38% of patients who received TAS-102 will have grade 3 neutropenia. However, it is important to note that only about 4% of those patients who receive TAS-102 will have an infection. So, we counsel our patients to monitor for signs of infection or for fever and to report to us if they have any fever during therapy. I do explain to the patient that with TAS-102, there is a slight fatigue that we can see with treatment. However, severe fatigue that limits activities of daily living is very, very rare. These are the most important discussions that I have with patients. Now, note that we monitor the blood counts on a routine basis in our patients who receive TAS-102. We check a CBC on an every-2-week basis.

The other option of treatment in this particular patient is regorafenib. Regorafenib was improved based on the CORRECT clinical trial, a phase III clinical trial that evaluated regorafenib versus best supportive care in patients who have progressed following standard chemotherapeutic agents, as well as anti-EGFR therapy in the setting of RAS wild-type or KRAS wild-type tumor. What I counsel my patients about in this particular setting is that regorafenib is also associated with an improvement in overall survival. In this particular setting, there is a 23% improvement in likelihood of longevity with regorafenib versus best supportive care.

I also discuss with the patient that this also comes at the expense of some side effects. In particular, we see that there is a higher incidence of hand and foot syndrome seen with regorafenib, as well as skin rashes. In my practice, this appears to be the most limiting factor for our patients. Approximately, 17% of patients will have grade 3 hand and foot syndrome and a significantly higher number of patients will have grade 2 hand and foot syndrome. In this particular setting, we ask the patients to come on a weekly basis for evaluation to assess for side effects.

Case Scenario 2:

• A 57-year old man presented for routine colonoscopy and was found to have a descending colon moderately differentiated adenocarcinoma. CEA pre-operatively was 6.
• Laparoscopic colectomy with colo-colonic anastomosis was performed. Final pathology showed a T3N2a (stage IIIb) lesion with 5/20 LNs positive. There was lymphovascular but no perineural invasion.
• Mutation testing revealed a KRAS mutation. The tumor was MSS.
• His ECOG performance status was 0.
• Following surgery, he was given adjuvant therapy with FOLFOX for 12 cycles with oxaliplatin help during the last two cycles because of grade 2 neuropathy.
• Six months later, follow-up imaging revealed recurrence and multiple metastatic hepatic lesions.
• The patient was started on FOLFIRI plus bevacizumab.