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DR LOVE: How would you approach a patient who presents with synchronous hepatic and lung metastases (Figure 21)?

DR GROTHEY: This presentation has a very poor prognosis. What is not an appropriate choice here is resection of liver metastases followed by systemic chemotherapy. This is probably one area where clinical investigators and community oncologists differ in opinion. I would approach this patient with neoadjuvant therapy followed by resection of the metastases.

DR LOVE: When you encounter a patient who has bilateral liver metastases, presenting with a nonobstructing lesion, would you resect the primary tumor (Figure 22)?

DR GROTHEY: I would not resect the primary tumor, particularly in young patients. I was a bit surprised in the shifting with age, because if I had an 85-year-old patient with a nonobstructing tumor and metastases, I would prefer to take care of the primary tumor and prevent any obstruction problem. For a 38-year-old patient, I would have clearly said, “No resection of the primary tumor.” In an 85-year-old, I would probably resect the primary tumor.

DR LOVE: What treatment strategy would you recommend for a patient who presents with metastatic disease and asymptomatic primary colon cancer?

DR O’CONNELL: We have a study that has been approved by the National Cancer Institute, which will evaluate the need for resection of an asymptomatic primary colon cancer in patients who present with metastatic disease. There’s been a lot of controversy about this in the literature. Approximately 25 percent of patients with metastatic colorectal cancer who have an unresected primary will develop a complication — primarily obstruction — if that tumor isn’t resected.

Now that we have more effective systemic chemotherapy, our goal is to determine whether we can avoid the need for resection in patients who don’t have any symptoms related to the primary tumor but who have distant, unresectable metastatic disease. We’ll treat them all with the modified FOLFOX6 regimen plus bevacizumab. Our endpoint of this Phase II trial is to determine the local complication rates.

DR LOVE: Can you talk about the NSABP trial investigating CAPOX with or without intra-arterial infusion in patients with hepatic metastases?

DR WOLMARK: NSABP-C-09 is for patients with liver-only metastases that have been removed or ablated. Patients will receive CAPOX with or without intra-arterial FUDR. The European data with CAPOX for patients with liver-only disease certainly influenced the decision of the hepatic surgeons to use CAPOX as the baseline therapy. The question being tested is the role of intra-arterial FUDR. I think the real challenge is to see if hepatic surgeons from different institutions with different concepts can work together to develop a clinical trial.

DR LOVE: What systemic therapy regimen do you generally recommend for a patient with metastatic colon cancer?

DR VENOOK: At UCSF, we lean toward FOLFOX rather than CAPOX because we have data for FOLFOX, and the current data are not adequate to say that CAPOX and FOLFOX are equivalent. In practice we have seen robust responses with CAPOX, FOLFOX, FOLFIRI and CAPIRI. Although we need more data, I do not anticipate that capecitabine will be a compromise for patients. The problem we have had with CAPOX has been dosing, because it can cause hand-foot syndrome. We are relatively conservative in our use of capecitabine and tend to favor it in elderly patients.

Whether research resources should be invested in investigating capecitabine in combination with either irinotecan or oxaliplatin is a good question. On one hand, with the new agents that need evaluation, it seems absurd to expend resources on proving the equivalence of combinations of capecitabine versus 5-FU. On the other hand, this has a huge impact on quality of life and patient satisfaction. In an ideal world, we would enroll more patients with colorectal cancer in clinical trials and be able to answer all of these questions.

DR PHILIP: At our institution, we evaluated the combination of capecitabine and oxaliplatin (CAPOX). At this time, our front-line nonprotocol treatment approach includes bevacizumab and CAPOX. Granted, no Phase III trial data are available comparing CAPOX to FOLFOX.

However, in the metastatic disease setting, taking into account the convenience for patients of receiving an oral agent instead of continuous infusion 5-FU, we feel that CAPOX would be better than FOLFOX. I probably would not make the same comment for adjuvant therapy. But in the metastatic disease setting, my approach would be bevacizumab plus CAPOX.

DR LOVE: What are your thoughts in general, as you evaluate the data in the survey, in terms of the amount of CAPOX being recommended?

DR GROTHEY: It is what I would have expected, although not necessarily what I would like. I think that the difference between FOLFOX and CAPOX — in the absence of Phase III data — is not so great that FOLFOX should dominate all of these answers. This is an interesting phenomenon, particularly when you look at what is happening across the Atlantic, where FOLFIRI is relatively more dominating compared to what we see here. The split in Europe is 60- 40 or 55-45 in favor of FOLFOX, but FOLFIRI has substantial market share. Here, FOLFIRI has a minor share.

I believe that CAPOX is a rational choice in the metastatic setting. For oxaliplatin in general, I think the standard of care is clearly a combination regimen. You would have to make a case for why you would not be able to use a combination regimen, particularly since we know that FOLFOX and CAPOX regimens are very well tolerated. In fact, rather than using the Mayo Clinic regimen, I would rather use FOLFOX, because it’s better tolerated.

DR LOVE: What about the tolerability of CAPOX versus FOLFOX?

DR GROTHEY: I think there is no difference in tolerability once you have determined the right dose of capecitabine. My personal preference is for FOLFOX over CAPOX. This is more or less what is reflected in this survey. You would have to make a case as to why you would utilize CAPOX rather than FOLFOX. The primary case to be made for selecting CAPOX over FOLFOX is convenience. There are patients that I have put on CAPOX because they want to travel. They want to be more independent.

I personally use a lot of capecitabine in combination with bevacizumab after a patient can no longer tolerate FOLFOX because of the oxaliplatin neurotoxicity. When you look at the patient who was treated one year ago for a Stage III lesion with FOLFOX, no one recommended FOLFOX re-treatment. I would have like to have seen at least one or two patients receiving FOLFOX. Interestingly, in the patient with a Stage III lesion who received six months of FOLFOX six months ago with no change in Grade II neurotoxicity, the same pattern emerges.

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DR LOVE: How do you generally approach the patient who has relapsed after adjuvant oxaliplatin-based therapy?

DR DANIEL HALLER: My approach to patients with a colorectal cancer recurrence after adjuvant therapy depends on when the relapse occurs. Obviously, this is now an issue because of the results from the MOSAIC adjuvant trial. In a patient who relapses less than six months after adjuvant FOLFOX and still has neuropathy, I would use FOLFIRI plus bevacizumab as first-line therapy. That type of patient would need all the help available, not sequential therapy.

A patient who relapses after adjuvant FOLFOX and doesn’t have neuropathy could be treated as a “virgin patient,” and whichever chemotherapy regimen is best for that patient should be selected, independent of their adjuvant therapy. In those situations, I base my chemotherapy decision on the Tournigand data. Then I select the most tolerable and efficacious biologic agent and marry it to the chemotherapeutic regimen that is best for the patient.

The best regimen is dependent upon both its efficacy and toxicity. For example, the first violinist in the Philadelphia Orchestra might be treated with FOLFIRI plus bevacizumab. In my clinic, patients will not be treated with IFL plus bevacizumab; they also won’t be treated with capecitabine plus bevacizumab outside of a trial. For the nonviolinist, most often FOLFOX plus bevacizumab would be selected.

In certain patients, bolus 5-FU/leucovorin — the Roswell Park regimen — plus bevacizumab, as used in the trial by Kabbinavar and one of the arms of the trial by Hurwitz, would be a reasonable option. Based on the data from the trial by Hurwitz, the efficacy of the Roswell Park regimen plus bevacizumab is somewhere in between the efficacy for IFL alone and IFL plus bevacizumab. I believe the Roswell Park regimen plus bevacizumab is probably less efficacious than FOLFOX plus bevacizumab.

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DR LOVE: What is your take on the treatment choices in the survey for the patient with colon cancer who progresses on FOLFOX/bevacizumab?

DR GROTHEY: I would not have expected 50 percent of the physicians to select cetuximab — whether or not it is with FOLFIRI. I would have anticipated something in the range of approximately 20 percent. This is not an approved regimen in this situation and it is clearly off label. It is interesting to see that 25 percent of the patients continue to receive bevacizumab.

The idea is that with bevacizumab, you enhance the activity of chemotherapy, regardless of the type of chemotherapy. You target genetically stable endothelial cells and increase the delivery of chemotherapy into the tumor, where you have the anti-angiogenic effect.

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Cetuximab has the same overall effect, but it is expensive and it is a last-line indication. So you can use it as a later option, particularly after second- line bevacizumab, which works in patients who have not previously received bevacizumab.

The continuation of bevacizumab in second line is really interesting. I believe that a continuation of bevacizumab is logical. However, FOLFOX/bevacizumab followed by FOLFIRI followed by irinotecan/cetuximab is perhaps the best-established sequence at present.

I personally continue bevacizumab because of the idea that it works on normal, genetically stable cells. My hypothesis is that the resistance we observe with FOLFOX/bevacizumab as firstline therapy is to FOLFOX, not to bevacizumab. Bevacizumab enhances the activity of chemotherapy; in colorectal cancer, it has been shown for 5-FU, irinotecan, cetuximab and oxaliplatin.

As we’re targeting genetically stable endothelial cells that provide neovascularization to the tumor, I think it definitely makes sense to use it this way. The role of bevacizumab following disease progression, however, is unclear. This is the main reason SWOG and NCCTG will be conducting a trial, the Intergroup Bevacizumab Continuation trial, in which patients who have progressed on FOLFOX/bevacizumab or FOLFOX followed by 5-FU/leucovorin/ bevacizumab will be randomly assigned to additional therapy with or without bevacizumab.

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DR LOVE: What is your general treatment algorithm for a patient with metastatic colon cancer?

DR HOWARD HOCHSTER: In a clinical setting, I’ve been comfortable using an oxaliplatin-based regimen in combination with bevacizumab as first-line therapy for patients with metastatic disease, based on the TREE study and our own personal experience. The best data for improved time to progression, response rate and survival are with bevacizumab as first-line therapy, and I am most comfortable using oxaliplatin in the firstline setting. Therefore, I tend to use FOLFOX with bevacizumab in patients not enrolled on a protocol. We have seen nice responses and patients staying on those regimens for a long time.

Irinotecan and cetuximab would be very reasonable second-line options, whether it’s with single-agent irinotecan and adding in cetuximab at the time of progression or, taking out the reimbursement issues, starting with both cetuximab and irinotecan together, which would make sense.

The third-line setting is wide open, and clinical trials would definitely have a value in identifying new agents.

DR PHILIP: For patients with disease that has progressed on an oxaliplatin-based treatment, we move to an irinotecanbased therapy. The question becomes, Do we use irinotecan as a single agent or in combination with a fluoropyrimidine (eg, capecitabine or 5-FU/leucovorin)? The third- or fourth-line options would be any of these agents with or without cetuximab.

DR LOVE: According to the physicians’ responses, a substantial number of doctors continue to order EGFR testing (Figure 30). Why do you think this is occurring?

DR GROTHEY: I believe that a number of physicians request EGFR testing to avoid the hassle of communicating with the insurance company. If the test results are positive, there is no need to worry about reimbursement issues. However, if the results are negative, the doctor has to struggle to make a case to utilize cetuximab. We need to translate to the community oncologists that this test is not really necessary.

Another interesting question is, Do you test in the primary tumor for EGFR in colon cancer? In breast cancer patients, we automatically determine the hormone receptor status of the primary tumor. For the colon cancer patient, testing the primary tumor for EGFR positivity is not needed. If you utilize cetuximab, it’s better to use it with irinotecan (Figure 31). Although it is logical to say, “If you have first-line oxaliplatin, you don’t necessarily need cetuximab” because it is not approved and it is expensive. Additionally, it is not as beneficial in a salvage therapy setting.

DR LOVE: Should the decision whether or not to administer cetuximab be based on EGFR testing/staining results?

DR SALTZ: We published an article in the Journal of Clinical Oncology that reports activity with cetuximab in colorectal cancer in tumors that do not express the EGFR by immunohistochemistry (IHC).

These are very compelling data. We all wanted to believe that EGFR would be an important prognostic indicator, but our technology for assessing EGFR expression is flawed.

We generally use the primary tumor as the basis for the EGFR status of the metastasis, but that appears to be inaccurate. Data show that EGFR degrades over time.

At this time, no clinical decision should be made on the basis of EGFR staining. Specifically, no patient should be excluded from a therapy — cetuximab or otherwise — simply because their IHC staining for EGFR is negative and, just as importantly, no patient should be treated with these agents simply because the tumor is strongly EGFR positive.

DR LOVE: The number of physicians who believe that capecitabine can be regarded as equivalent to 5-FU in the neoadjuvant, adjuvant and metastatic settings is pretty intriguing. It appears as though they are influenced by the results of the X-ACT trial. What is your interpretation of this?

DR GROTHEY: They may believe that capecitabine is a substitute for 5-FU in these settings; however, the dosing of capecitabine has not yet been well defined in the United States. A large trial in patients with colon cancer is being conducted, which utilizes a dose of 1,000 mg/m² twice a day in a one week on, one week off schedule.

Personally, in the adjuvant setting, I start with a dose of 2,500 mg/m² in two divided doses and then decrease as needed. In the metastatic setting, I prefer to start with 2,000 mg/m² in two divided doses. When dosing capecitabine with oxaliplatin, I utilize 850 mg/m² twice a day, based on the American experience.

DR ROBERT WOLFF: The maximum dose of capecitabine that I use as a single agent is 2,000 mg/m² in two divided doses. If I combine capecitabine with another agent, including irinotecan, oxaliplatin, or radiation, the dose is decreased to the 1,500 to 1,800 mg/m² range. If a patient experiences toxicity, the dose is reduced accordingly.

DR LOVE: What action do you instruct your patients to take if they experience capecitabine-related toxicity?

DR CASSIDY: We make an effort to educate patients about the potential for diarrhea because if patients develop diarrhea, they may become dehydrated and require hospitalization. Sometimes diarrhea is associated with neutropenia. Diarrhea and neutropenia together are dreaded side effects of the fluoro pyrimidines.

I tell my patients they should stop treatment and inform us if they are having diarrhea more than five times in a 24-hour period.

Hand-foot syndrome is a bit more subtle. Patients often develop a minor degree of hand-foot syndrome with the first cycle of capecitabine, and it may be worse with the second cycle. At that point, we reduce the capecitabine dose.

Because of that strategy, I don’t see many patients with severe hand-foot syndrome. We also tell patients to stop treatment if they develop redness of their hands or feet with pain that interrupts their level of functioning.

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