Chapter 081. Principles of Cancer Treatment (Part 16)

The taxanes include paclitaxel and docetaxel. These agents differ from the vinca alkaloids in that the taxanes stabilize microtubules against depolymerization. The "stabilized" microtubules function abnormally and are not able to undergo the normal dynamic changes of microtubule structure and function necessary for cell cycle completion. Taxanes are among the most broadly active antineoplastic agents for use in solid tumors, with evidence of activity in ovarian cancer, breast cancer, Kaposis sarcoma, and lung tumors. They are administered intravenously, and paclitaxel requires use of a Cremophor-containing vehicle that can cause hypersensitivity reactions. Premedication with dexamethasone (20 mg orally or intravenously...
Nội dung trích xuất từ tài liệu:
Chapter 081. Principles of Cancer Treatment (Part 16) Chapter 081. Principles of Cancer Treatment (Part 16) The taxanes include paclitaxel and docetaxel. These agents differ from thevinca alkaloids in that the taxanes stabilize microtubules against depolymerization.The stabilized microtubules function abnormally and are not able to undergo thenormal dynamic changes of microtubule structure and function necessary for cellcycle completion. Taxanes are among the most broadly active antineoplasticagents for use in solid tumors, with evidence of activity in ovarian cancer, breastcancer, Kaposis sarcoma, and lung tumors. They are administered intravenously,and paclitaxel requires use of a Cremophor-containing vehicle that can causehypersensitivity reactions. Premedication with dexamethasone (20 mg orally orintravenously 12 and 6 h before treatment) and diphenhydramine (50 mg) andcimetidine (300 mg), both 30 min before treatment, decreases but does noteliminate the risk of hypersensitivity reactions to the paclitaxel vehicle. Docetaxeluses a polysorbate 80 formulation, which can cause fluid retention in addition tohypersensitivity reactions, and dexamethasone premedication with or withoutantihistamines is frequently used. A protein-bound formulation of paclitaxel(called nab-paclitaxel) has at least equivalent antineoplastic activity and decreasedrisk of hypersensitivity reactions. Paclitaxel may also cause hypersensitivityreactions, myelosuppression, neurotoxicity in the form of glove-and-stockingnumbness, and paresthesia. Cardiac rhythm disturbances were observed in phase Iand II trials, most commonly asymptomatic bradycardia but also, much morerarely, varying degrees of heart block. These have not emerged as clinicallysignificant in the majority of patients. Docetaxel causes comparable degrees ofmyelosuppression and neuropathy. Hypersensitivity reactions, includingbronchospasm, dyspnea, and hypotension, are less frequent but occur to somedegree in up to 25% of patients. Fluid retention appears to result from a vascularleak syndrome that can aggravate preexisting effusions. Rash can complicatedocetaxel administration, appearing prominently as a pruritic maculopapular rashaffecting the forearms, but it has also been associated with fingernail ridging,breakdown, and skin discoloration. Stomatitis appears to be somewhat morefrequent than with paclitaxel. Estramustine was originally synthesized as a mustard derivative that mightbe useful in neoplasms that possessed estrogen receptors. However, no evidence ofinteraction with DNA was observed. Surprisingly, the drug caused metaphasearrest, and subsequent study revealed that it binds to microtubule-associatedproteins, resulting in abnormal microtubule function. Estramustine binds toestramustine-binding proteins (EMBPs), which are notably present in prostatetumor tissue. The drug is used as an oral formulation in patients with prostatecancer. Gastrointestinal and cardiovascular adverse effects related to the estrogenmoiety occur in up to 10% of patients, including worsened heart failure andthromboembolic phenomena. Gynecomastia and nipple tenderness can also occur. Hormonal Agents The family of steroid hormone receptor–related molecules has emerged asprominent targets for small molecules useful in cancer treatment. When bound totheir cognate ligands, these receptors can alter gene transcription and, in certaintissues, induce apoptosis. The pharmacologic effect is a mirror or parody of thenormal effects of the agent acting in nontransformed tissue, although the effects ontumors are mediated by indirect effects in some cases. Glucocorticoids are generally given in pulsed high doses in leukemiasand lymphomas, where they induce apoptosis in tumor cells. Cushings syndromeor inadvertent adrenal suppression on withdrawal from high-dose glucocorticoidscan be significant complications, along with infections common inimmunosuppressed patients, in particular Pneumocystis pneumonia, whichclassically appears a few days after completing a course of high-doseglucocorticoids. Tamoxifen is a partial estrogen receptor antagonist; it has a tenfold greaterantitumor activity in breast cancer patients whose tumors express estrogenreceptors than in those who have low or no levels of expression. Side effectsinclude a somewhat increased risk of estrogen-related cardiovascularcomplications, such as thromboembolic phenomena, and a small increasedincidence of endometrial carcinoma, which appears after chronic use (usually >5years). Progestational agents—including medroxyprogesterone acetate, androgensincluding fluoxymesterone (Halotestin), and, paradoxically, estrogens—haveap ...