Multidisciplinary Management of Metastatic Colorectal Cancer

Edward Chu, MD:In this particular patient, I think the most important genetic testing that needs to be done is to determine whether or not their mutations are eitherKRASorNRAS. So, it’s important to do extendedRAStesting and also to determine whether or not mutations are present in theBRAFgene. Why this is critically important is if in fact there are no mutations inRASorBRAF, this patient would certainly be a very appropriate candidate to be treated with the anti-EGFR antibody, either cetuximab or panitumumab, in combination with cytotoxic chemotherapy. And, again, the goal would be to try to render this patient surgically resectable, have our GI surgical oncologist perform surgery for the liver lesions, and hopefully render this patient potentially curable.

My own view is that in anyone who presents with metastatic disease, or for the first time presents with progressive disease, it is important to document that one of the metastatic sites is in fact metastases from the primary colorectal cancer tumor.

The overall prognosis for this patient is still somewhat poor. Although with the improvements in chemotherapy and the improvements in biologic therapy, and now our better understanding of the importance of sidedness of the primary tumor, the median overall survival is now approaching 3 years, which is really quite remarkable. Because when I first got into this business of treating patients with metastatic colorectal cancer, which was probably nearly 30 years ago, the median overall survival for patients with stage 4 metastatic colorectal cancer was on the order of 8 to 10 months.

We had only 1 drug, and that drug was the golden oldie: 5-fluorouracil. But now we have a number of cytotoxic chemotherapy agents, and we have a number of biologic agents. And we now know this whole concept of the continuum of care, to be able to have our patients be treated with a full spectrum of the various treatment agents that are available to us, has taken median overall survival from 8 to 10 months closer to 33 to 36 months.

In terms of the treatment goals for this patient, ideally what we would like to do is be able to convert this patient from initially surgically unresectable to potentially surgically resectable—to get a nice cytoreduction with chemotherapy plus a biologic agent to have the patient undergo an R0 surgical resection and to then be followed by what would be called adjuvant chemotherapy, to be treated for an additional 3 to 4 months. Obviously, the critical element would be to see if the patient were able to undergo a nice response to the upfront systemic therapy and to be able to undergo surgical resection.

In terms of how to best approach all patients with colorectal cancer—whether it be early-stage disease or advanced metastatic colorectal cancer, as in this case—a multimodality, multidisciplinary approach is critically important, especially so in this case because this patient has liver-limited metastatic colorectal cancer. And, again, the initial concept would be to treat with aggressive up-front systemic therapy—chemotherapy in combination with a biologic agent—to treat for 2 months, and reassess. If there has been a nice response, we’ll probably continue for another 2 months and then have a very close ongoing dialogue with our GI surgical oncology colleagues to tell us when they think it might be the most appropriate time for that patient to undergo surgical resection.

We need to work very closely with our surgical oncology colleagues. We need to work closely with radiology, with pathology, and we also need to work very closely with the palliative supportive care team to help us work with the patient as it relates to symptom management—either the underlying disease or symptoms that may be the result of the systemic treatments that they’re receiving. Again, I think nutrition is going to be a very important element to keep this patient going, and so we typically would refer this patient to our nutritionists and dietitians.

This patient has HNPCC and Lynch syndrome II, which clearly increases the risk for this patient’s children to also have Lynch syndrome, or HNPCC. While somewhat controversial, I think what we would recommend, certainly in Pittsburgh, is to have the patient’s children be seen by our genetic counselors and undergo genetic testing. What that right age is, that’s probably the main controversy. I think in speaking with our high-risk genetic counselors, the recommendation would be to undergo genetic testing starting at age 18. For sure, this patient’s children are at increased risk for developing stomach cancer as well as colorectal cancer.

For colon cancer screening, the recommendation would be to undergo colonoscopy screening—probably starting at the age of 20—and then to have either annual or biannual colonoscopies from that point on because we do know that in patients who have HNPCC, the colon cancer usually starts somewhere in the early 20s and is a much more aggressive form of colon cancer. There’s also an increased risk for these kids to develop stomach cancer, so upper-endoscopy screening is going to be critically important. Again, the right age for when this starts is up for debate, but I think our genetic counselors and our high-risk physicians would recommend upper-endoscopy screening to start at age 18.

And then, finally, given the strong family history, this patient’s mother had endometrial cancer, and there are certain mismatch repair mutations that are particularly associated with an increased risk for developing ovarian cancer and/or endometrial cancer. So, certainly for females, endometrial biopsy sampling should occur, and the right age is not entirely clear. Probably somewhere in the mid- to late 20s. Whether or not a total hysterectomy and removal of the ovaries is necessary, to completely prevent a possibility for that patient to experience either endometrial or ovarian cancer, should be discussed very carefully with females.

I have a 40-plus-year-old patient who has Lynch syndrome II. There is a strong family history of colon cancer, endometrial cancer, and ovarian cancer. What was quite unfortunate was this patient and her husband were very hopeful to have children. But when the issue of her increased risk for developing either ovarian cancer or endometrial cancer came up, she made the immediate decision to undergo TAH-BSO. Now they’re in the process of adopting a child from overseas.

Transcript edited for clarity.

• A 47-year-old male presented to the doctor with abdominal pain and anemia
• He has a family history of cancer:
  • His brother was diagnosed with colon cancer at age 44
  • His sister was diagnosed with gastric cancer at age 24, and mother was diagnosed with endometrial cancer at age 50
  • He has 2 children, a 15-year old boy and a 10-year old girl
• Initial lab evaluations showed anemia (Hb 8.0 g/dL) and elevated carcinoembryonic antigen (980 ng/ml)
• CT-scan showed a large mass in the ascending colon and diffuse liver nodules
• Biopsy results showed a moderately differentiated adenocarcinoma
  • Microsatellite instability (MSI) testing revealed MSI-high (MSI-H) tumor and IHC confirmed the absence of expression of the MLH1 protein
  • He was referred for genetic testing
• The patient was diagnosed with hereditary nonpolyposis colorectal cancer syndrome