We know that 5-FU is a good radiation sensitizer. We also know that cisplatin is a radiation sensitizer. Widely used with radiation in other sites in the GI tract, esophageal especially. So what about 5-FU platinum radiation versus mitomycin? Well, we don’t know the answer versus mitomycin really, but we do know in a couple of studies – and these are studies with locally recurring disease – that there was a 55% complete response rate. Then in patients in a study from France from Bordeaux, Rene Brunet, using 5-FU platinum and radiation in patients with primary tumor had results that were very similar; complete response rates of about 82%, similar to what you would expect with mitomycin. There now is an active RTOG Inner Group study that many of you can certainly participate in that looks at the standard arm of 5-FU mitomycin versus an experimental arm of 5-FU platinum and radiation. The way the 5-FU platinum is given here is it’s given as an induction initially and then followed, and then given concurrently with the radiation. So this study, which is accruing patients fairly rapidly, will look at the comparison of mitomycin versus cisplatin as a radiation sensitizer.
Now just to remind you again of the point of abdominoperineal resection, these are a collection of patients from various series in the literature, pointing out that about one-half to two-thirds of patients who have recurred or who have not had a complete response with anal cancer can be salvaged with abdominoperineal resection. Of course the price you pay is they have a permanent colostomy. But it is an effective therapy and certainly would be something to suggest to patients who have recurred.
The current therapies for anal cancer for the very unusual tumors, the T-1’s the T-2’s, small tumors, local resection is certainly the reasonable thing to do. For more advanced tumors or tumors of higher grade the 5-FU mitomycin and 5-FU platinum it can be done. Many people use 5-FU platinum and there are a whole host of other radiation sensitization issues. The heart of this combined modality therapy is radiation sensitization, really. Whenever the radiation at a lower dose with a sensitizer is compared to higher dose radiation, the lower dose with the sensitizer works. So one could say, “Well, we know that the best radiation sensitization, for example in adjuvant therapy for rectal cancer, is low dose continuous infusion 5-FU. What about that?” These continuous infusion 5-FU regimens are of course only 96 hours per gram per M2 and that’s a perfectly reasonable question to ask. Obviously the other question with radiation sensitization is that everything we have talked about here requires intravenous therapy. What about capecitabine or UFT or one of the other oral fluorinated pyrimidine’s as a radiation sensitizer? And that would certainly be a reasonable thing to ask, and I think one of the problems … if this were esophageal cancer where nothing was working very well – and you are talking about marginal differences with combined modality therapy – people would jump to asking those questions. But since we have the analogy here of MOP chemotherapy in Hodgkin’s disease, people are a little reluctant to move far from the 5-FU mitomycin or 5-FU platinum standard therapy. So I think innovation will be relatively slow.
This is in your handout actually, sort of an algorithm of how to approach these patients. Obviously a tissue diagnosis is important and there can be confusion with tissue diagnosis. Many patients who are seen by particularly primary care physicians who have an anal fullness or what appears to be an anal mass, or misdiagnosed -for example – as having hemorrhoids and there may be misdiagnosis for awhile. The anorectal surgeons, the colorectal surgeons are very much in tune to this disease, and particularly now in a … like in Greenwich Village in New York we have a large population of gay males and it’s a very common diagnosis, so we are very tuned into it. But it’s important to make a diagnosis in people. The standard therapy is still 5-FU mitomycin. If the patient has a complete response, and complete response by clinical exam, in other words, for six weeks after you’ve finished your therapy you can do a rectal exam and you can’t feel anything abnormal – when this slide was made two years ago most people would biopsy. Now many people are saying, “Why biopsy? Because a deep biopsy may have some compromise on anal sphincter. Just follow the patient. The likelihood is that they won’t have any disease. And just follow them and if you find anything that appears abnormal, begin to biopsy. But the vast majority of these patients are cured. If they are not cured, if they have a PR or a CR and they have a macroscopic recurrence or a macroscopic failure to respond, then many people would go directly to an AP resection. If they have microscopic disease or smaller amounts of disease, or they’ve had an 80% response or something like that, then there are a variety of investigational approaches that have been used. Many people would add 5-FU platinum in then to try to get chemotherapy cyto-reduction of a patient who is failing. Local excision plus brachytherapy is something that is done, and again the risk here is that you end up with a dysfunctional sphincter. If none of these things work, then one could go again to the APR, the abdominoperineal resection.