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Mucositis and Targeted Therapies

Small Molecules - Targeted Therapy for Cancer

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As new drugs are developed and used for cancer therapy, new patient toxicities are being noted. Targeted therapies are usually given in conjunction with more traditional chemotherapy drugs. Thus, toxicities can be a combination of either or both therapies. Mucosal injury from targeted anti-cancer therapies were studied by Keefe and Gibson, who conducted a literature review of some 700 papers. Mucosal injury was not a primary endpoint in the studies, and, thus, there was inadequate results on the mechanism of the drug and prediction of toxicities. Mouth ulcers and diarrhea were prominent.

Of cancer chemotherapy, side effects include nausea, vomiting, hair loss, gastrointestinal symptoms (diarrhea, constipation), and cytopenias (low blood counts).

One of the goals of targeted therapy is to have treatments with fewer side effects than chemotherapy or radiation therapy. Good examples are Rituximab and trastuzumab, Cetuximab, and Gefitinib/Tarceva. These targeted therapies are usually monoclonal antibodies or small molecules (tyrosine kinase inhibitors). Hypersensitivity reactions and organ systems being affected are well-known. The underlying mechanisms are not well understood thus far.

The mucosa is a lining covering various parts of the body. They cover digestive tract and exits (mouth or anus), respiratory passages, and general urinary passages in contrast to serous membranes that cover closed body cavities or synovial membranes that cover joints and skin, which covers the body. The mucosal membrane can secrete mucous and absorb water, salts, and other solutes.

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Diarrhea, which is common from chemotherapy - there is no scientific evidence thus far of mucosal damage from targeted therapies.

Capecitabine is an anti-metabolite that is comparable to fluorouracil in the tumor cell and may cause skin changes, diarrhea and coronary artery spasm.

The majority of monoclonal antibodies (bevasizumab, trastuzumab, Mylotarg) can induce diarrhea without oral mucositis as a major side effect. There is very little literature on the side effects of Rituximab. The goal of the monoclonal antibody therapy is to cause apoptosis induction, anti-angiogenesis or tyrosine kinase inhibition, all of which can damage the mucosa.

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF). It prevents the binding of VEGF to its receptor and can help improve the efficacy of chemotherapy regimens with little added toxicity in metastatic colon cancer.

There may be grade I ulcerations with bleeding in the radiotherapy field. There is no known mechanism on how the monoclonal antibody relates to the mucositis, but it is considered safe.

Small Molecules - Targeted Therapy for Cancer
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These are inhibitors of signal transduction, which is similar to monoclonal antibodies, although they act downstream to the cell surface receptor.

With tyrosine kinase inhibitors, diarrhea is a dose-limiting toxicity for most small molecule inhibitors of EGFR tyrosine kinase, such as gefitinib and erlotinib (Tarceva) that acts by inhibiting the receptor tyrosine kinase activity, which is the protein product of the EGFR gene. It interferes with the singling pathway of cell proliferation, inhibition of EGFR that's associated with tyrosine kinase, and appears to be a novel approach to the treatment of solid tumors.

Use of gefitinib in the elderly NSCLC patients was well-tolerated with a grade I-II diarrhea in 24% of patients and in 2-5%, grade IV diarrhea. The mechanism was not known, and it was generally well-tolerated.

In conclusion, mucosal toxicity is seen in targeted anti-cancer therapy, but the mechanisms and results of therapy need more study. Some of the toxicities were related to combinations with chemotherapy.

Keefe, D. M. K., and Gibson, R. J., "Mucosal Injury from Targeted Anti-cancer Therapy," Supportive Care in Cancer, 15:483-490, 2007.

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First appeared July 31, 2007; updated August 10, 2007