The connection between levodopa therapy, PD, and malignant melanoma has been a matter of debate for three decades. It originally derived from the biochemistry of the drug. Levodopa is a substrate for the development of dopamine, which, in turn, develops into neuromelanin in CNS nigral neurons. It is the dopaquinones derived from levodopa that are oxidized to form neuromelanin in these cells (126). Hence, it has been proposed that levodopa may also affect the activity of melanocytes in the skin, possibly promoting malignant transformation, although this connection has never been proven. In addition, it is now known that 70% of melanoma cases in the general population appear to be connected with a genetic mutation unrelated to PD. Thus, it would seem unlikely that there would be a connection between PD, lev-odopa, and melanoma.
Nevertheless, reports of melanoma in patients treated in the 1970s led the FDA to require language in the package insert that cautions against the use of levodopa in PD patients with a history of melanoma. There are over 40 papers published on the subject (126) with conclusions varying from caution in using levodopa in patients with a history of melanoma, to no need for concern. In 1998, Pfutzner et al. (117) reported that although no causal relationship has been proven, patients with a history of malignant melanoma receiving levodopa therapy should be carefully followed for the development of new pigmented lesions. Other anecdotal reports exist in the literature of the potential carcinogenic effects of levodopa therapy and its potential to activate malignant melanoma (118). For these reasons, the warnings have not been lifted.
Weiner et al. reviewed the literature and concluded that there is only anecdotal evidence at best to support a link between levodopa and melanoma. They reported nine patients with PD and a history of melanoma who were treated with levodopa with no recurrence. It was concluded that levodopa therapy could be used safely in PD patients with melanoma (127). Woofter reported a 74-year-old man with PD who was treated with levodopa and whose malignant melanoma was later discovered. Prior to the diagnosis of melanoma, it was estimated that the patient received 5.7 kg of levodopa over a six-year period. The patient continued with levodopa treatment for more than 10 years, with an additional 4.3 kg of levodopa prescribed, and no recurrence of his melanoma was observed. They also concluded that withholding levodopa therapy for fear of accelerating melanoma was unwarranted (118). Siple et al. (128) reviewed 34 case reports from 1966 to 1999 and indicated that the association between levodopa and induction or exacerbation of malignant melanoma was unlikely. Finally, in a review of 54 patients, 63% were taking levodopa, 31% were not, and, in the rest, the status was unknown (129). Seventeen percent were diagnosed with metastatic disease. After diagnosis of melanoma, 71% continued levodopa and there was no dose-response relationship. They found that the number of reported cases of melanoma in PD is well below that expected, based on prevalence of both disorders. In addition, recurrence rates are high with melanoma in the general population and not necessarily increased in PD.
In contrast, Olsen et al. (130) discovered that among 14,088 PD patients, there was a small increased relative risk for malignant melanoma and other nonmelanotic skin cancers, although no information was gathered on levodopa therapy. The cause of this increased risk is not known. On the basis of the information available, it can be concluded that there may be a small increase in the risk of developing malignant melanoma in PD, but the causal relationship specifically between levodopa and the occurrence or recurrence of this cancer is uncertain but unlikely. A history of melanoma in a PD patient should not prohibit the use of levodopa, but it is not unreasonable to have a high-level of vigilance for malignant melanoma in patients with a history of skin cancer.
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