Colorectal Cancer Update for Surgeons 2007 (1)

DR HOCHSTER: Studies conducted in rectal cancer have convincingly demonstrated that administering chemotherapy and radiation therapy preoperatively, rather than postoperatively, is well tolerated and has fewer long-term complications. It has not been shown to improve survival, although it may lead to a better result with respect to local failure.

In general, patients who are candidates for adjuvant therapy should receive neoadjuvant chemoradiation therapy, and I believe that is rapidly becoming the standard of practice across the United States.If a patient has T3 disease or lymph nodes that are positive as detected by ultrasound or CAT scan, there’s no question he or she should receive neoadjuvant chemoradiation therapy.

The standard treatment regimen in this setting is continuous infusion 5-FU with radiation therapy. Studies suggest that capecitabine might be as efficacious as 5-FU, and that concept is currently being investigated in a randomized trial. Randomized trials are also evaluating whether oxaliplatin should be added to 5-FU in the preoperative setting.

Colorectal Cancer Update GI Think Tank 2007

DR HALLER: I wear two different hats regarding the use of oxaliplatin as neoadjuvant therapy for rectal cancer: one as a person who conducted a Phase I/II trial in this area and uses it off protocol and another as the GI Intergroup co-chair with a protocol specifically addressing this question.

Separate Phase I or Phase II studies evaluating this agent in this setting have been conducted worldwide, and some clear conclusions have emerged. First, it is evident that you can add oxaliplatin to a fluoropyrimidine and radiation therapy on a weekly or biweekly schedule or once every three weeks and at different doses. The dose depends on whether you consider oxaliplatin a radiosensitizer, a systemic agent or both. That is, you’re administering adjuvant therapy and local therapy to make the radiation therapy work better.

If you want to use oxaliplatin as a radiosensitizer, you probably want to use it more frequently, as in CALGB-89901. If you believe it’s more of a systemic agent, you certainly want to administer the maximal dose.

It turns out that if you administer oxaliplatin weekly, not everybody completes the dosing. So although the total dose that could be delivered is high, the actual dose administered with the weekly regimens is much lower than with the every two-week or every three-week regimens. We have defaulted to a weekly regimen because the CALGB data suggested that oxaliplatin was more of a radiosensitizer.

In the German preoperative trial, the pathologic complete response (CR) rate was found to correlate with disease-free survival. For patients who have received radiation therapy alone or radiation therapy with 5-FU, the pathologic CR rate is in the range of about eight to 10 percent. In the 5-FU/oxaliplatin studies, the pathologic CR rates range anywhere from about 18 percent to 48 percent.

Colorectal Cancer Update 2007 (5)

DR GOLDBERG: In rectal cancer, preoperative chemotherapy and radiation therapy seems to have become the “MO” for most patients. The only time when that isn’t the case is if you have an early lesion — a T2/N0 or even a T3/N0 lesion.

The next step is to try to add sensitizers to 5-FU. A number of studies have evaluated the agents that are active in advanced disease as radiation sensitizers. I believe the NSABP-R-04 trial evaluating capecitabine versus 5-FU with or without oxaliplatin is an important study. It’ll help us know whether adding a second radiation sensitizer preoperatively will be useful.

The intriguing data from Chris Willett on bevacizumab obviously need to be evaluated in a larger patient population. The data on cetuximab with radiation therapy that came from the head and neck cancer physicians are also intriguing. But we also had a study from the German Rectal Study Group showing that cetuximab didn’t appear to be a radiation sensitizer in rectal cancer.

I am seeing patients for second opinions who are receiving 5-FU and oxaliplatin as a radiation sensitizer, and I believe that’s premature. I’m not doing that in my practice. I’m trying to enroll people on the NSABP-R-04 trial.

Colorectal Cancer Update 2007 (4)

DR CHRISTOPHER H CRANE: The optimal way to administer either infusional 5-FU or capecitabine with radiation therapy is to make dosage adjustments for Grade II toxicities, such as diarrhea or nausea. With infusional 5-FU, we would interrupt the therapy and allow the patient a couple of days for it to resolve.

Once it resolved, we would start back with a 25 percent dose reduction. The best way to minimize toxicity is to modulate the dose based on how the patient tolerates the therapy. When using any radiosensitizer, as in the NSABP-R-04 trial in rectal cancer, efficacy is the most important consideration. How do we prove the efficacy of a radiosensitizer?

Basically, we’re using neoadjuvant chemotherapy and radiation therapy together, which have independent toxicities. We want to use systemic doses of chemotherapy, if we can do so safely, with radiation therapy. From that perspective, the X-ACT study adjuvant data provide enough information to administer capecitabine with radiation therapy.

We conducted a matched-pair analysis, published last year, of infusional 5-FU versus capecitabine in combination with radiation therapy. We had approximately 90 patients in each group, and they were matched for T and N stage. The patients receiving capecitabine had less low-grade mucositis and diarrhea with a slightly numerically improved pathologic CR rate.

So the use of capecitabine is something we’ve adopted as a general platform from which to incorporate novel targeted agents with chemoradiation therapy regimens in upper and lower gastrointestinal cancer — liver, hepatobiliary, pancreatic and anal tumors.

Oxaliplatin has been incorporated into the NSABP-R-04 trial because it has been proven in the adjuvant setting, which makes it interesting to use with radiation therapy. Its value may be that it’s a radiosensitizer or that it’s being used earlier in the treatment. It’s a worthwhile drug to study in the neoadjuvant setting, and NSABP-R-04 was improved when they added oxaliplatin as the second part of a two-by-two randomization.

I believe it’s acceptable to use oxaliplatin-based chemoradiation therapy off protocol if it’s done selectively, carefully and with close monitoring because the rates of Grade III gastrointestinal toxicity, mainly diarrhea, will be higher.

Colorectal Cancer Update 2006 (5)

DR GROTHEY: All of the patients who were candidates for the neoadjuvant approach in the German trial — which set the standard treatment for rectal cancer — received postoperative chemotherapy.

We make our decision to treat based on clinical evidence, and the data we have right now suggest we should administer postoperative adjuvant therapy for rectal cancer.

I receive questions from colleagues asking, “I have a patient who had an excellent response to neoadjuvant radiochemotherapy. Does this patient need postoperative treatment?” I say yes, because the response with neoadjuvant therapy indicates that the tumor is chemosensitive — or at least treatment sensitive.

So the rationale is to use this information and try to control the disease systemically because patients most likely succumb to their systemic metastatic spread, not to local recurrence, if they experience recurrence.

Overall, I suggest that patients receive postoperative chemotherapy even if they responded to neoadjuvant therapy. Then, the standard treatment has, for most purposes, moved to FOLFOX again based on the experiences in colon cancer — and I believe most of us would use an approach that combines six weeks of neoadjuvant radiochemotherapy, surgery and four months of FOLFOX chemotherapy afterward in the absence of clinical data.

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