Venook on Treatment Recommendations in Colorectal Cancer Patients

Alan P. Venook, MD

Alan P. Venook, MD

Alan P. Venook, MD, recently discussed 2 cases of patients with colorectal cancer, and the treatment treatment considerations and decisions he would make when treating these patients. Venook, Shorenstein Associate Director for Program Development, Helen Diller Family Comprehensive Cancer Center, and professor, Department of Medicine, University of California San Francisco, discussed these cases during aTargeted Oncologylive case-based peer perspectives dinner.

Case 1

A 51-year-old Caucasian female presented with severe crampy right lower quadrant pain. She had a 4-month history of bloody stool and weight loss of 10 pounds in the past 8 months. Her past medical history included gastroesophageal reflux disease and an appendectomy at age 35. Laboratory findings showed her hemoglobin level was 8.7 g/dL. An abdominal CT scan with contrast showed an obstruction at the level of the right colon and widespread lesions in both lobes of the liver. Her carcinoembryonic antigen (CEA) was 4.5 ng/mL.

The patient was taken to surgery for right hemicolectomy. Pathologic findings from biopsy of the obstructed lesion revealed an invasive, poorly differentiated adenocarcinoma with ulcer. Ten of 15 lymph nodes sampled were positive for disease. Mutation testing showedKRAS,NRAS, andBRAFwild-type. He was microsatellite stable.

TARGETED ONCOLOGY:What therapy would you recommend for this patient? What role does mutation testing play in the therapy selection?

Venook:This is a patient with a right-sided colon cancer, so I would not have needed mutation testing to determine how I would treat the patient. The reason is that you're not going to use an EGFR antibody in someone with a right-sided primary tumor, no matter what, at least as first-line therapy.

In my view, mutation testing does not play much of a role because right-sided patients would either be treated with chemotherapy, which is bevacizumab (Avastin), if you use one. I don't think mutational testing is particularly important in this patient.

TARGETED ONCOLOGY:If she was diagnosed today, does the location of the tumor (left versus right) play a role in patient prognosis and therapy selection?

Venook:Yes. For right-sided tumors, you do not have to wait for mutation testing. Microsatellite status is not mutation testing because that is a germline as opposed to a tumor itself, but you would like to know microsatellite status. At least right now, you're not going to do that as first-line therapy.

Treatment was initiated with FOLFIRI (irinotecan, fluorouracil, and folinic acid) and bevacizumab. The patient continued to improve and reported feeling significantly better. Follow-up imaging showed a reduction in the size of the liver lesions.

December 2016

Follow-up CT showed progression in the liver with new lesions and new small masses in the abdomen and pelvis. The patient's ECOG performance status is 1.

TARGETED ONCOLOGY:What would you choose as a second-line therapy for this patient, and why?

Venook:The answer depends on what you did first line, and it depends how long the first therapy worked. Did the patient progress immediately, or did they have a great benefit? If they had a lot of shrinkage, maybe you do surgery now. Maybe you remove metastases. If the primary was in place, maybe you would remove the primary. There are all these variables. The point is that what you do second is a function of what you do first.

The most important thing is probably if you start with bevacizumab, as would have been likely in this patient, it is important to continue with bevacizumab, because there is evidence that if you stop bevacizumab, the disease sometimes progresses because it is sort of a resistance mechanism that develops around bevacizumab. That possibility is one of the factors you should consider.

For first-line treatment, we do know that EGFR antibodies in right-sided tumors are not affected. We don't know that necessarily in subsequent line treatment that is still the case. For that reason, I think by this time you would like to know the mutational status. If the patient is microsatellite instability-high, for example, and has progressed, you might jump in with a checkpoint inhibitor, like pembrolizumab (Keytruda) or nivolumab (Opdivo). At this point, this is where you would like to know the mutational status.

The patient began second-line treatment with FOLFOX (oxaliplatin, fluorouracil, and folinic acid) plus bevacizumab.

June 2017

The patient complained of severe fatigue and need for frequent rest during the day. A CT scan revealed progressive disease, no improvement in the size or number of the abdominal lesions, and 3 pulmonary nodules in the right lung.

TARGETED ONCOLOGY:What are the goals of therapy at this point in the patient's disease course? What are the options for this patient?

Venook:The options are TAS-102 (Lonsurf) and regorafenib (Stivarga) in this particular patient or, depending on what the patient's mutational status was, you could go back to an EGFR antibody at this point. It is not known if that is ever appropriate on right-sided patients, but it is possible.

TARGETED ONCOLOGY:Can you discuss the importance of proactive monitoring for adverse events and patient education?

Venook:With any drug, proactive monitoring is important. With regorafenib, it's particularly important because patients can get bad skin toxicity, such as a painful rash on the bottom of their feet. I believe, especially in oral medications, you need to be very proactive, because if you don't see patients regularly, they may just keep taking the pills. When you give intravenous chemotherapy, you see them regularly, because they can't self-administer the chemotherapy. I think it is incredibly important to be active. We have our nurses talking to our patients at least once, maybe twice per week, when they are on oral medications, because we need to dose-adjust promptly with these drugs. TAS-102 has more hematologic toxicity. With regorafenib, if patients get a skin rash, if they stay on the drug, they might get really sick. It is very important that you are very proactive in interacting with your patients to keep track of the toxicities.

Case 2

A 55-year-old Caucasian man was admitted to the hospital with severe lower quadrant pain. He had a 2-month history of constipation, general abdominal discomfort, and fatigue. His past medical history was remarkable for hyperlipidemia managed with diet and statin therapy. Laboratory findings were remarkable for hemoglobin level of 9.0 g/dL. A chest, abdominal, and pelvic CT scan showed a probable mass in the sigmoid colon and no metastases. His CEA was 6.7 ng/mL. A biopsy performed during colonoscopy showed poorly differentiated adenocarcinoma. He underwent a sigmoid colectomy, which showed the tumor infiltrated the full thickness of the bowel wall into subserosal adipose tissue; neither perineural nor lymphovascular invasion; R0 resection with clear margins, 0 of 13 lymph nodes were positive, and the patient was microsatellite stable.

TARGETED ONCOLOGY:What factors should be considered when determining the need for adjuvant therapy for this patient?

Venook:You need to look at the stage of the patient. This is a patient who has 0 of 13 positive lymph nodes. We usually think of 12 lymph nodes as the minimal collection. If the patient has 0 of the 12, or greater, then, on average, the survival of these patients is in the 80% range, depending on other factors. In this case, the patient has no perineural or lymphovascular invasion. Those would be high-risk features.

This is a patient where some people would say treat, and some people would say don't treat. The marginal benefit of chemotherapy on the average is somewhere around a 1% gain.

TARGETED ONCOLOGY:If the patient had perineural and lymphovascular invasion, would the approach change?

Venook:Some people think that may push you a little bit more toward higher risk, but it's very much a philosophical decision. The general value in a node-negative patient is going to be very small, and it's a matter of what risks patients [are willing to] take for the slight gain.

TARGETED ONCOLOGY:If the patient had 4 positive lymph nodes, which therapy would you recommend and for how long?

Venook:That is entirely different. That is a stage III patient, and a patient who should get chemotherapy, like FOLFOX.

TARGETED ONCOLOGY:What is the optimal duration for treatment?

Venook:That's the biggest topic that came out of the ASCO Annual Meeting this year. If the patient had 4 positive nodes, let's say you decide to treat with FOLFOX. Do you give 3 months or 6 months? That's a very complicated, nuanced discussion. In my view, 4 nodes or greater would reflect a high-risk patient. For that patient, I would lean more toward the standard of 6 months of therapy. For a patient with less than 4 nodes, I would lean toward 3 months of therapy. For every patient, I might offer chemotherapy with FOLFOX, as long as they don't develop neuropathy or side complications. At the earliest sign of complications, I would usually stop the chemotherapy. For the most part, this analysis called the IDEA pooled analysis generally showed that 6 is almost entirely as good as 12, maybe. This is such a nuanced discussion. I think the point is that people need to learn about this new study and figure out how they present the data, because it's an extremely close call.

Reference:

Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.J Clin Oncol.2017;35(suppl; abstr LBA1).