Browse Day: November 1, 2007

Treatments for Anal Cancer 3

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.

Treatments for Anal Cancer 2

Now there are other data that show some important aspects of this regimen and these studies just point out that it’s important to intercalate the radiation and chemotherapy, in other words, to give them together not to give them sequentially. And that radiation combined with chemotherapy is better than chemotherapy alone at a higher dose. Very similar to studies done on esophageal cancer. But the original Wayne State experience with 122 patients showed a complete response rate of 93%. What they tried to do at Memorial-Sloan-Kettering was to give 5-FU mitomycin as an induction therapy then follow it by radiation, and that was not nearly as effective. I think everyone would agree with that. Princess Margaret in Toronto also did a study that was a randomization between 5-FU, mitomycin and what is a more standard dose of radiation these days, the 5,000 centigray versus 6,000 centigray alone and showed that the combined modality therapy was better than the higher dose of radiation therapy alone. So I think we’ve come to believe that that’s correct. What this slide is showing is that if you look at tumors that are greater than 4 cm you have a considerably higher relapse rate. So you want smaller tumors to treat.

Now this is a randomized study that was published about two years ago. It was a randomized study that was published in the JCO and it was from EUROTC and essentially it was comparing radiation alone to a mitomycin/radiation therapy arm. What it showed was local regional control was better with the combined modality therapy versus radiation alone. It also showed that colostomy-free survival was better with radiation therapy combined with chemotherapy than radiation therapy alone. This is important because obviously again we are talking about sphincter sparing. Now the next slide is interesting because what it shows is the overall survival is no different. That gets back to this whole issue of keeping the abdominoperineal resection in reserve because it can salvage at least 50% of patients who don’t respond to combined modality therapy. But I think that randomized studies like this have been very helpful in convincing us that there is no doubt that the combined modality approach with 5-FU, mitomycin C and radiation is the standard of care for patients with anal cancer.

Now many people are concerned about mitomycin. Mitomycin is certainly a very old drug and mitomycin sort of from the word go had gotten a bad reputation. Because mitomycin was developed at a time in the 1960’s when the standard way to do a phase I study was to give daily doses of the therapy until you got toxicity and then see what happens. Of course all of you who have used mitomycin can imagine that after three or four weeks of giving low doses of mitomycin, when the platelets finally got down, they were never going to come back. So it was not a … the pharmacokinetics of the drug and the way, the timing of myelo-suppression wasn’t well understood. And of course mitomycin is also associated particularly in patients with minimal disease, with a hemolytic uremic syndrome which can be essentially a TTP-like syndrome, and people can die of it in renal failure. The thing that is particularly concerning is that it tends to occur in patients with minimal disease.

Treatments for Anal Cancer.

What about the results? The standard therapy for anal cancer, before 20 years ago -18-20 years ago – was abdominoperineal resection. Obviously abdominoperineal resection is something that can’t be taken too lightly since you are removing the whole anorectal mechanism and you leave a patient with a permanent colostomy. In a review of some 460 patients this was done with, what I consider as relatively high – and of course these were patients treated in the 60’s and 70’s – with relatively high operative mortality. The cure rate was about 50% with this procedure. So it’s important in one sense to be absolutely sure – particularly in the context of taking the Boards – that you never want to do an abdominoperineal resection as the first line therapy for a patient with anal cancer. But the other thing is to keep abdominoperineal resection in your back pocket, because as I’ll show you, it’s still an effective salvage rate for patients who recur or who don’t respond.

Looking at radiation therapy alone in the treatment of patients with anal cancer, and you get a local control rate of somewhere from 60-70% and a five year survival rate of somewhere around 50-65%. So radiation alone has some benefit. Now the radiation therapists are in a sense like chemotherapists in that if a little radiation is good someone is always going to say, “Well, a lot of radiation is better.” These are data from France from Papillion, and what he did was to do brachytherapy or interstitial radiation in patients with anal cancer, and he had some 64 patients and he was able to render about two-thirds of them without any evidence of disease. However, there was a significant incidence of radionecrosis that occurred. And the other thing that is not mentioned in this slide, which I think is an important consideration to keep, what we are talking about is the potential for sphincter-sparing surgery here. Now if you spare the sphincter but it doesn’t work, you haven’t done the patient any favors really. So you need to look at functional benefit in these patients, after whatever sphincter-sparing approach you are going to use. With this much radiation many people would agree, we would be very concerned about the function of the residual sphincter.

Well, when the modern era arrived where data, using the combination of mitomycin, 5-FU and radiation in patients with basaloid and squamous cancers of the anus. The original work was done at Wayne State University by Dr. Nigro and his colleagues. Many people picked up on it and initially the combination of 5-FU, mitomycin and radiation was used in patients with larger anal cancers, or patients who were thought to be very poor surgical risks, or patients who refused to have abdominoperineal resections. What was found was that this tended to be very effective therapy. The way it’s given, and the way it’s given still, is interesting because there are all kinds of innovations in combined modality therapy and people are constantly looking at how best to modulate the radiation-chemotherapy, for example in esophageal cancer. What’s happened is that in the early 1980’s, late 1970’s, we stumbled upon this and it works real well and people are reluctant to leave it. I’ll show you that we are looking at new approaches but it’s like MOP chemotherapy in Hodgkin’s disease. You have to have a real good reason to want to change it. This therapy is really quite simple to give. You give a gram per M2 (meter square) per day for 96 hours of 5-FU by continuous infusion, and most people do this now with a pump as an outpatient. It used to be that the patient would come to the hospital. Mitomycin C is given on the first day, either 10 or 15 mg. For many people 10 mg is probably plenty. Radiation has changed somewhat in that the radiation dose has been increased. Most radiation oncologists give about 5,000 centigray. In this original study, one of these studies from San Francisco by Flamm et all, there were 11 patients who were treated and they ran ED and had a very good response; essentially 100% response rate.