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.