An educational tool to assist in the management of hepatic metastases in patients with colorectal cancer

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Biologic Therapy

Bevacizumab versus cetuximab



We chose to use cetuximab over bevacizumab because the patient had some bleeding from his primary tumor, and we were concerned that by using bevacizumab, the risk for a life-threatening episode of gastrointestinal bleeding would be increased.


Biologic therapy with bevacizumab prior to surgery

Commentator: MICHAEL CHOTI, MD


The concern is that bevacizumab — a VEGF receptor inhibitor — may have some impact on surgical complications, specifically related to either bleeding or wound-healing problems. Indeed, some data for patients undergoing colon surgery show that it can cause wound complications. The other factor is that the half-life of bevacizumab is approximately 21 days. Liver surgery is often elective, so if you wait six to eight weeks after the last dose of bevacizumab, the complication risk is negligible. Theoretically, treatment with bevacizumab can be reinitiated six to eight weeks after surgery. We typically hold the last dose of bevacizumab, and then operate four to six weeks after the last chemotherapy and six to eight weeks after the last dose of bevacizumab.


Indications for adding biologics to chemotherapy

Commentator: RENÉ ADAM, MD


I believe that the delivery of chemotherapy including biologics can be broadly classified according to three categories of disease: resectable, unresectable and potentially resectable. The first category includes the use of conventional neoadjuvant chemotherapy for patients with resectable disease. The other extreme category includes those patients whose disease is definitely nonresectable due to bone metastasis, multiple metastatic sites, et cetera. These patients will probably not benefit from the use of biologics, at least during first-stage chemotherapy. An intermediate category includes patients those with marginally nonresectable metastasis that may be resectable if downsized. Within this category of patients, I feel that we should use potent chemotherapy along with biologics to induce resectability as soon as possible to potentially prolong survival.


Biologic therapy: Data on capecitabine with cetuximab



Few data exist on the use of capecitabine with cetuximab. The approach is mainly stop-and-go and simply continuing either cetuximab or bevacizumab into the maintenance setting, but we don’t have a lot of prospective data in the literature on the combined use of capecitabine and cetuximab.


Cost considerations for bevacizumab or cetuximab as adjuvant treatment in the United Kingdom

Commentator: JOHN PRIMROSE, MD


Neither cetuximab nor bevacizumab are reimbursed by the UK National Health Service, so the patient would have had to pay for the bevacizumab, if she had wanted it. I believe it’s expensive, and unless a patient is privately insured, it’s going to be difficult for her to afford it. The alternative to being in the clinical trial would be FOLFOX alone, which is currently the standard treatment. There is continuing activity in order to obtain reimbursement for cetuximab for patients who have K-ras wild-type tumors and bevacizumab for all patients, but that is still in progress. I’m fairly confident that bevacizumab will not become reimbursable here because of the cost effectiveness ratios.


Time between bevacizumab and surgery

Commentator: STEVEN CURLEY, MD


We wait at least six weeks before surgery after treatment with bevacizumab, whether we are resecting the primary or the metastatic disease. If we’re able to operate, we will essentially administer FOLFOX without the bevacizumab for one dose. Prior to surgery, patients will have been without bevacizumab for six weeks and other chemotherapy for four weeks.


Biologic agents combined with chemotherapy in the curative and palliative settings

Commentator: AXEL GROTHEY, MD


Today, if I see a patient with colon cancer and potentially curable hepatic metastases, I would test the K-ras status of the tumor. If it is the wild type, I would use cetuximab rather than bevacizumab for a couple of reasons. First of all, the response-inducing capacity of cetuximab in K-ras wild-type tumors is stronger than bevacizumab, particularly in combination with FOLFOX. The OPUS trial data showed a 24-percent increase in the response rate when cetuximab was combined with FOLFOX and that’s stronger than anything we’ve seen with bevacizumab.

Secondly, cetuximab is not associated with wound-healing problems, so it makes sense to use it in the perioperative setting. We now routinely test tumors for K-ras and B-ras mutations. These mutations are mutually exclusive — approximately 40 percent of cases will be K-ras mutant and another 10 percent will be B-ras mutant, so these tests will identify the 50 percent of patients who should not receive cetuximab.

However, in the palliative setting, bevacizumab is superior to cetuximab, even in patients with K-ras wild type tumors, based on cross-trial comparisons. In the CRYSTAL trial — comparing first-line FOLFIRI with or without cetuximab for patients with wild-type K-ras tumors — the median progression-free survival was only increased by 1.2 months. On the other hand, in the study of IFL with or without bevacizumab, the interplay between irinotecan/5-FU and bevacizumab was quite remarkable. Still, it’s a cross-trial comparison and the only comparison that will help us prospectively is CALGB-C80405 — the Phase III trial of first-line FOLFOX or FOLFIRI with bevacizumab or cetuximab or the combination of both biologic agents for patients with metastatic colorectal cancer.


Combining biologic agents with chemoradiation therapy

Commentator: DANIEL HALLER, MD


Not a lot of clinical data exist for concurrent radiation therapy and bevacizumab, which is problematic. Lee Ellis has some data from MD Anderson, and he told me it appears that this approach shows more toxicity. I’m concerned about combining an anti-angiogenic drug and a treatment that may have vascular toxicity as a late effect, so I don’t administer it off protocol.

We are gaining more information about the wild-type K-ras tumor and first-line chemotherapy with the biologic agent cetuximab. Especially in patients who need a response in the liver — considering the response data from the CRYSTAL and other trials that are now evolving, which is 69 versus 40 percent — it’s likely that we will be using this information to select therapies for patients with wild-type tumors.

For a patient with rectal cancer, in whom the primary tumor and metastases are the same biologically, the biopsy at the time of diagnosis would be suitable for K-ras analysis. If the status is wild type, we might consider cetuximab with chemotherapy, either FOLFIRI or FOLFOX. I would choose FOLFOX if it was to be received concurrently with radiation therapy, because of the synergistic diarrheal toxicity with irinotecan.

We currently have a research trial in which we are intentionally administering cetuximab with radiation therapy. This is based on the preclinical data showing synergy between EGFR antibodies and radiation therapy — in addition to the positive data in head and neck cancer, albeit squamous cell — that suggests a survival advantage when cetuximab is added to standard radiation therapy and platinum chemotherapy.


Impact of K-ras testing on treatment decisions

Commentator: DANIEL HALLER, MD


A nice editorial by Charles Blanke was published in the Journal of Clinical Oncology on dual biologics and the evolving data. One data set showed a trend toward a worse outcome in progression-free survival and response when you add cetuximab to chemotherapy for patients with mutated K-ras tumors. We also know that patients with wild-type disease versus mutant always have better prognosis independent of the chemotherapy they receive.

A meeting was held of the FDA Oncology Drug Advisory Committee about a month ago, and basically they haven’t made a decision regarding K-ras testing. Apparently, at least some people feel we need formal prospective trials, because all of the data we have are retrospective and sometimes come from only subgroups, such as in the CRYSTAL trial, and not the whole patient population.

I‘ve seen the results of the EPIC trial, which evaluated second-line FOLFIRI with or without cetuximab in 5-FU/oxaliplatin failures. It’s only 300 out of 1,200 patients and only the subsets that were treated in the United States, so lots of biases can be built into it, but we don’t have the resources for large prospective trials. I don’t believe anyone feels they want to carry out a study of formal predictive testing — that is to treat both mutant and nonmutants and go through 2,400 more patients. It’s not that we only have data from one study. We have the panitumumab study, the cetuximab NCIC study, the CRYSTAL trial and the OPUS trial — every study shows the same effect.

It may not be great science in some respects, but we always conduct imperfect studies. To me, when we have a series of 15 or 20 large, somewhat flawed studies, all showing exactly the same effect on a forest plot, it’s not problematic. Additionally, when a biologic plausibility exists as to why it should be true — which there is — then it’s even stronger. If it were simply an oddball observation and no good biologist, not even Lee Ellis, could figure out why this could be true, then you might make a different decision.

We have to be careful when we talk to patients about treatment based on K-ras testing, because basically we’re taking away treatment. The good part is that they may not need to be exposed to side effects of a therapy that will not help them, but their initial reaction is to retract. We dealt with this at ASCO when we had an emergency meeting about the Intergroup trials and our patient advocates were there. Their response was that we had taken too long to accomplish this, and we explained that we didn’t want to change all the trials based on early verbal reports.

Patients want to be active and go in there and receive it. We need them to understand and buy into the fact that we’re not denying anyone anything. It’s like denying paclitaxel to a patient with colon cancer — it doesn’t work. If we could identify a subgroup who did respond to paclitaxel or gemcitabine, that would be nice. But it would be a small group, because it never shows up in any analysis, not even a smell of something.

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