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New Treatments for Colon Cancer

Capecitabine. Itís approved for breast cancer. I donít think it is approved yet for colorectal, but it has certainly been tested in colorectal as Iíll show you. A second, which is close to approval, is UFT. UFT is a combination of uracil and dorofor , which is an old Russian prodrug with the leucovorin. Again, the principle is the same. A slow release of 5FU into the blood. And the third involves an inhibitor of DPD, the enzyme that degrades 5FU, so that if you give an oral dose of 5FU itís essentially 100% absorbed, which it is not without this inhibitor. And the level is maintained. The dose of 5FU in this combination is extremely low. If you gave a conventional dose of 5FU with ethynyluracil you would kill the patient. But with the right dose of 5FU this colon cancer.

One trial that was reported at ASCO this year, between capecitabine and 5FU leucovorin on the Mayo schedule. The response rate with the FU leucovorin was a little bit below what has been reported for FU leucovorin, lower than the average 21% of the metaanalysis I showed you, but not outside the range of some of the trials that have been done. The capecitabine is also a bit below what you expect for infusional 5FU but this is a plausible result.

Going on now to what do you do after 5FU fails? Because it will fail. Generally in substantially less than a year. You have very limited options because of the inherent drug resistance in these tumors. Irinotecan, or CPT-11 is really the only useful drug that is now available. It also has a response rate of around 20%. It is more toxic than 5FU. Diarrhea being the main problem, but neutropenia and nausea as well. But patients do tolerate it and itís a very useful drug for patients who are not responsive to 5FU. There is a French drug, oxaliplatin, which hopefully will become available in the not too distant future. Also has a response rate of around 20%.

Combination chemotherapy. Until the last very few years, people have tried a zillion different combinations, mainly based on 5FU in colorectal cancer. None was ever superior to 5FU monotherapy. With the availability of these two new drugs, CPT-11 and oxaliplatin, we are now beginning to see combination trials that show better results than monotherapy. 5FU leucovorin plus CPT-11 the response rate is higher and both survival and progression free survival are longer.

What is unanswered is, what is the right strategy? Do you use 5FU leucovorin or infusional 5FU or one of the prodrugs, when we have them, initially? And take advantage of the lower toxicity. And then go to CPT-11 and/or oxaliplatin on failure. Does that make survival worse? Is the survival difference worth the added toxicity of the combination? These are questions that really havenít been fully answered. The other thing that hasnít been tested yet is protracted 5FU with CPT-11. One of the major toxicities of CPT-11 is neutropenia. Protracted 5FU gives no neutropenia. So that particular toxicity doesnít overlap in this combination and this would be a more rational combination to try than FU leucovorin where you still have the myelotoxicity of the bolus 5FU schedule. So eventually, the protracted 5FU will be replaced by the prodrugs.

Regional chemotherapy is useful in patients sometimes, very selected patients, with exclusive hepatic disease. Response rates average around 50%. Other regional approaches; chemoembolization, cryosurgery, can be used for isolated hepatic mets. Electrocoagulation is now available. Alcohol injection is not quite as good.

Guidelines for therapy. Dukes A or B cancers, surgery. Adjuvant therapy is not required in these patients unless they have other adverse indicators. Dukes C patients get surgery with adjuvant therapy. Rectal, A and B1 get surgery no adjuvant. Remember the sphincter-sparing options for low stage. Dukes B2 and C combined, chemoradiotherapy as adjuvant following surgery. Preop chemoradiotherapy is now being evaluated and we use that already. For recurrent or metastatic, chemo but remember to resect isolated liver.