Melanoma is a dangerous form of skin cancer. The CDC reports that in 2012 almost 68,000 people in the U.S. were diagnosed with melanoma of the skin (1), with a rate of up to 23.6 per 100,000 people in the state of Maine (5). Melanoma has sometimes been associated with other diseases or medications. Increased risk of melanoma in Parkinson disease (PD) was first raised as a concern in 1972 with the report of a PD patient who experienced recurrent bouts of this potentially fatal disease while being treated with levodopa (2). This introduced the question as to whether the case represented a random correlation or an important link between the two diseases. There was also concern of a possible link between levodopa and melanoma because levodopa can convert into melanin, a pigment found both in the dopamine-producing cells of the substantia nigra, and in melanocytes, the cells which can become the tumor of melanoma.
The risk is not clear however. Not all cases of either condition are reported. The best we can do is study the available reports, epidemiology, and disease databases. One case-control study evaluated 862 malignant melanoma cases, compared with 862 age- and sex-matched controls to detect the incidence of PD among melanoma sufferers (3). Among the melanoma patients, 25 (2.9%) had PD. Among the controls, 11 had PD (1.3%). Thus, the odds of having PD was over twofold greater if one had melanoma versus those who did not. A meta-analysis (the combination of multiple studies) using the National Institute of Health (NIH) Medline search engine found that between 1972 and 2010 just over 50 cases of melanoma in PD had been reported in the worldwide medical literature (4). One chart review of 409 PD patients found two with melanoma where 0.3 would have been expected based upon incidence among the same age group (5).
Does levodopa raise the risk of melanoma?
Some authors included information about whether or not people were taking levodopa. A cross-sectional survey (6) to determine the frequency of skin cancers at 12 medical centers in Israel found 9 out of 1,395 patients had biopsy-proven melanoma, 14 had melanoma in their medical history (6 occurring prior to, 8 after PD diagnosis). Twenty patients total (1.4%) had a current or prior melanoma, with an overall rate of melanoma 4.4 times greater than expected for these patients. Melanoma did not correlate with PD duration, PD stage, or the duration of levodopa treatment. In North America, 2,106 PD patients underwent full skin examination with a dermatologist and 346 patients had biopsy of suspicious-looking pigmented skin lesions (7). Twenty biopsies confirmed in situ melanoma (0.95%), and four had invasive melanoma (0.19%). There was no observation of a relationship between levodopa use and melanoma. The DATATOP patient cohort (800 patents entered between 1987 and 1988), followed until 1994, yielded five melanoma cases (1.5 would have been expected, considering the age and gender of the group). Malignant melanoma was diagnosed in two of the patients prior to starting levodopa. The evaluators could not come to any conclusion regarding association between levodopa use and melanoma incidence (8).
Although there have been case reports of patients who started levodopa prior to onset of melanoma, there have also been cases in which patients who remained on levodopa had no recurrence or exacerbation of melanoma. And, no formal relationship between the two has been established in the lab. One epidemiological study attempted to determine if levodopa was causative (9). In this prospective study of 1,099 patients from the Melanoma Clinical Cooperative Group, a single patient was taking levodopa at time of diagnosis. The authors found no role for the induction of melanoma. The link is still not clear (10) and levodopa has not been found to be carcinogenic (cancer-causing) otherwise.
A prospective study of 157,036 people without PD at baseline as part of the Health Professional Follow-up Study and the Nurses’ Health Study took place over a 14-20 year follow-up (11). 616 cases of PD developed. A history of melanoma in a first-degree relative revealed relative risk of 1.85. The authors concluded that PD and melanoma “share common genetic components,” though genes were not identified.
In 2007, some experts considered the ongoing questions and cited the absence of convincing proof of an interaction between levodopa and melanoma, though still offering the following advice: “it would seem prudent not to treat with levodopa if other anti-Parkinson agents remain effective (12).”
In 2009, investigators reviewed five published studies exploring the associations between melanoma, PD, and levodopa (13). They noted the increased risk of melanoma is already present before PD is diagnosed, that as it is unlikely that levodopa plays any role in this phenomenon. The authors noted that while there is a need for further investigation, they also recommended removal of the warning from the drug insert leaflet, noting it might “lead to unnecessary fear on the part of the patients and physician resistance to prescribing this medication.”
Still, the current prescribing information for Sinemet from Merck Pharmaceuticals indicates in regards to reported cases of melanoma in PD, “whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear….patients and providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).”
Other anti-Parkinson medications
Azilect (rasagiline) is a monoamine oxidase B inhibitor, which boosts dopamine in the brain. The Azilect prescribing information notes, “The increased incidence of melanoma in the Azilect development program was comparable to the increased risk observed in the Parkinson’s disease populations examined in epidemiological studies.” In the lab, rasagiline has been found to actually decrease melanoma growth, and has been tested as a therapy in lab animals (13).
Requip (ropinirole), Mirapex (pramipexole), Neupro (rotigotine) are dopamine agonists. A PubMed search for each generic name and the term “melanoma” yielded zero citations. Prescribing information of ropinirole is silent regarding melanoma; whereas prescribing information of rotigotine and pramipexole note that there is a general two- to six-fold higher risk of melanoma in PD but the connection with drugs is unclear.
Summary
The incidence melanoma among PD patients is at least twice that of the general population, though still in the low single digits. And, if one has melanoma, the risk of developing PD is double that of the general population also. Thus, it would seem that there is a common risk or genetic cause for the two diseases, though the link has not been identified. In spite of the fact that levodopa can covert to melanin, the pigment of melanocytes and melanoma cells, there is no proof that levodopa causes or stimulates melanoma growth. The growth of melanoma seems dependent on genes, not the amount of melanin present. Still, some experts suggest it might be prudent to avoid levodopa in the melanoma patient if possible, and some recommend discarding the warning about levodopa and the risk of melanoma altogether.
1. http://www.cdc.gov/cancer/skin/statistics/
2. Skibba et al. Multiple primary melanoma following administration of levodopa. Arch Pahol 1972;93:556-61.
3. Rigel et al. Evaluation of Parkinson’s disease (PD) prevalence in patients with malignant melanoma. Mov Disord 2006;21:S58.
4. Ferrira, et al. Skin cancer and Parkinson’s disease. Movement Disorders 2010;25(2);139-48.
5. Jansson B, Jankovic J. Low cancer rates among patients with Parkinson’s disease. Ann Neurol. 1985;17(5);505-09.
6. Inzelberg, et al. High prevalence of malignant melanoma in Israeli patients with Parkinson’s disease. J Neural Transm 2011;118(8):1199-207.
7. Bertoni et al. Parkinson’s disease and melanoma: an epidemiologic evaluation. Ann Neurol 2006;60(Suppl 3):S71-72).
8. Constantinescu et al. Malignant melanoma in early Parkinson’s disease: the DATATOP trial. Mov Disord 2007;22:720-22.
9. Sober A, Wick M. Levodopa therapy and malignant melanoma. JAMA 1978;240:554-555.
10. Disse et al. A review of the association between Parkinson disease and malignant melanoma. Dermatol Surg 2016;42:(2)11-46.
11. Gao, et al. Family history of melanoma and Parkinson disease risk. Neurology. 2009;73(16):1286-91.
12. Fahn S, Jankovic J. Principles and Practice of Movement Disorders 2007, chapter 6,131.
13. Vermeij et al. Parkinson’s disease, levodopa-use and the risk of melanoma. Parkinsonism Relat Disord. 2009;15(8):551-3.
14. Meier-Davis, et al. Comparison of oral and transdermal administration of rasagiline mesylate on human melanoma tumor growth in vivo. Cutan Ocul Toxico 2012;31(4):312-17.
