color to the skin and protects its deeper layers from some of the harmful effects of ultraviolet rays from the sun. Because the majority of these affected cells still produce melanin, melanoma tumors often appear brown or black. But this is not always the case, with melanoma sometimes also appearing pink, tan or even white. Melanoma most often starts on the trunk (chest or back) in men and on the legs in women, but it can appear in other places as well. Having dark skin lowers the risk of melanoma, but a person with dark skin can still get the cancer. The discovery of genetic changes that underlie melanoma formation now provides a strong framework to develop therapies that antagonize several key molecular steps that lead to the malignant behavior of melanoma. The most commonly mutated signal transduction in melanoma is referred to as v-raf murine sarcoma viral oncogene (gene that causes cells to mutate) homolog B1 (BRAF). BRAF is part of the mitogen-activated protein kinase (MAPK) pathway, an intracellular signaling cascade that is implicated in the malignant behavior of a number of different cancers. BRAF mutations are more common in melanoma than other types of cancer. In its early stages, melanoma can almost always be cured. But it is likely to spread to other parts of the body if not caught early. Once it disseminates to distant sites and visceral organs, melanoma is almost invariably incurable, with a median survival time of eight to nine months and a three-year survival rate of only 10 to 15 percent. Overall, the lifetime risk of getting melanoma is about one in 50 for Caucasians, one in 1,000 for African Americans and one in 200 for Hispanics. The American Cancer Society’s estimate for melanoma in the United States for 2011 included about 70,230 new cases, with about 8,790 deaths from the tumor. The cancer accounts for less than 5 percent of skin cancer cases, but it causes most skin cancer deaths.
Mechanism of Action. Zelboraf is a potent inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. It also inhibits other kinase enzymes. Some mutations in the BRAF gene, including V600E, result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Adverse Effects. Most common adverse reactions (≥30 percent) during premarketing trials were arthralgia (joint pain), rash, alopecia, fatigue, photosensitivity reactions, nausea, itching and skin papilloma (benign tumors derived from epithelium). Warnings, Precautions and Contraindications. The following warnings and precautions are listed: • Cutaneous squamous cell carcinomas: In premarketing trials, these occurred in 24 percent of patients. Dermatologic evaluations should be performed prior to initiation of therapy and every two months while on therapy, and managed with excision and continued treatment without dose adjustment. • Serious hypersensitivity reactions: These, in addition to anaphylaxis, have been reported during and upon re-initiation of treatment. Zelboraf should be discontinued in patients who experience severe hypersensitivity reactions. • Severe dermatologic reactions: These, including StevensJohnson syndrome and toxic epidermal necrolysis, have been reported. Treatment in patients who experience severe dermatologic reactions should be discontinued. • QT prolongation: Electrocardiogram (ECG) and electrolytes should be monitored before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first three months of treatment, every three months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, the drug should be temporarily interrupted, electrolyte
Table 3 Major counseling points for Xalkori (crizotinib) capsules* This medicine is used to treat patients with locally advanced or metastatic non-small cell lung cancer. • Read the Patient Information leaflet before you start taking Xalkori and each time you get a refill. •Tell your doctor: -if you have any new or worsening symptoms of lung cancer, including trouble breathing or shortness of breath, cough with or without mucus, or fever. -if your skin or the whites of your eyes turn yellow; you feel tired; your urine turns dark or brown; you have nausea or vomiting, a decreased appetite, pain on the right side of your stomach; or you bleed or bruise more easily than normal. -about all other prescription and nonprescription (OTC) medicines, vitamin/mineral supplements, natural products and herbal remedies you are taking. The Patient Information leaflet has a list of medicines you should not take with Xalkori. • Periodic laboratory testing is important with Xalkori. Be sure to make all testing appointments. • WOMEN: Notify your doctor if you become or intend to become pregnant, or are breastfeeding. • Xalkori is usually taken twice a day with or without food. The manufacturer advises to avoid eating grapefruit or drinking grapefruit juice when taking Xalkori. • Nausea, diarrhea, vomiting and constipation may occur with Xalkori. Supportive care for treatment of these conditions may include nonprescription anti-emetic and/or antidiarrheal or laxative medications. • Use caution when driving or operating machinery if you experience blurred vision, dizziness, or tiredness while taking Xalkori. Report light flashes or floaters in your eyes to your doctor. • Store Xalkori at room temperature protected from heat. Do not use after the expiration date on the label. Properly discard unused medication. *Excerpted from the FDA-approved Patient Counseling Information.