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UntitledMelanoma, Parkinson’s disease and levodopa:causal or spurious link? A review of the literatureRoberto Zanettia, Dora Loriab and Stefano Rossoa Since the early 1970s, a number of case reports have correlation between social class and melanoma risk; (5) suggested that levodopa therapy for Parkinson’s disease the relationship between the risk of Parkinson’s disease increases the risk of cutaneous malignant melanoma. As and the risk of melanoma may be due to a common genetic yet, no formal epidemiological study has been conducted profile or it can be attributed to a confounding role of social to verify this hypothesis. To elucidate the relationship class, associated with both melanoma and Parkinson’s between levodopa and the risk of cutaneous malignant disease possibly through an inverse relationship with melanoma, a systematic literature search using tobacco smoking. Melanoma Res 16:201–206 computerized bibliographic databases was done. This review presents the case history evidence for and againstthe hypothesis of a causal association, and explores possible epidemiological, genetic, social, biochemical and Keywords: causality, levodopa, melanoma, Parkinson’s disease, smoking toxicological factors that may increase the risk of melanoma in Parkinson’s disease patients. All the case aPiedmont Cancer Registry, Center for Oncology, Turin, Italy and bInstitute of reports in the literature were considered. We concluded Oncology AH Roffo, Buenos Aires, Argentina that (1) there is no epidemiological or experimentalevidence of a causal role of levodopa in increasing the risk Correspondence and requests for reprints to Roberto Zanetti, MD, PhD, of melanoma incidence or progression; (2) there is good Piedmont Cancer Registry, CPO-Centre for Oncology Prevention, Via SanFrancesco da Paola, 31, 10123 Torino, Italy evidence of an excess risk of melanoma in patients with Tel: + 39 011 6333870; fax: + 39 011 6333861; e-mail: [email protected] Parkinson’s disease; (3) there is good evidence of aprotective effect of tobacco smoking on the risk for Received 9 June 2005 Accepted 24 February 2006 Parkinson’s disease; (4) there is good evidence of positive association with melanoma risk, and the toxicology of Levodopa treatment for Parkinson’s disease (PD) was levodopa with respect to melanocytic cells. In addition, introduced at the end of the 1960s. In 1972, Skibba et al.
the review presents possible explanations for the associa-  described a case of skin melanoma in a patient with tion between PD, levodopa and CMM, and questions PD. Since then, numerous case reports of a similar nature whether this association is causal or produced by other No formal epidemiological study of the hypothesis that levodopa therapy increases the risk of melanoma devel- opment has, however, been undertaken. A cohort study in As indicated above, the first case mentioned in the Danish PD patients  found a consistent increase of literature was reported by Skibba et al.  in 1972. The melanomas. Common steps in the metabolic pathways of patient, a 50-year-old man already affected by PD, was levodopa and melanin synthesis also suggest potential for diagnosed with melanoma in the left scapular area before interaction, although this has not been confirmed levodopa treatment. This was treated with surgical experimentally. Despite the paucity of data, the prescrib- removal and a skin transplant; there was no evidence of ing information of levodopa drug includes a warning of a metastasis. In September 1971, the patient started possible increased risk of occurrence or progression of levodopa treatment. In January of the following year, melanoma during treatment, and recommends a prudent some pigmented nodules were removed from the approach to use in PD patients with a previous history of transplant area, with a diagnosis of recurring melanoma.
Levodopa treatment was interrupted at the end ofJanuary 1972.
The present review examines what is relevant to theassociation between levodopa and melanoma: the case Further cases were reported in the literature and report studies on melanomas during levodopa treatment, summarized by Lieberman and Shupack . The authors the epidemiology and aetiology of cutaneous malignant presented the highest dosages of levodopa but not the melanoma (CMM), the aetiology of PD and the length of treatment, which varied from a few weeks to Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
several months. The data show that, in four of the five bibliography and the 50 participants mentioned by the cases, melanoma actually preceded levodopa treatment author come from an unpublished source (files of a by 2–88 months. One death occurred as a result of rapid levodopa manufacturer), thereby making a strict compar- clinical evolution (6 months between bleeding of a ison impossible. We believe that, independently of their naevus and death from diffuse metastasis) and two cases exhaustiveness, the case reports mentioned by Pfu in which melanoma had not recurred following treatment.
and Przybilla  and quoted in the present review In another case, recurrence is not documented.
represent the majority of this type of investigation.
Subsequently, another report linking the occurrence of superficial spreading melanoma without metastasis with The incidence of melanoma is well documented by the levodopa in a PD patient is considered to be questionable world network of cancer registries. Since the early 1960s, because levodopa treatment was not actually started the incidence has shown the fastest increase among owing to the presence of the melanoma .
tumours, matched only recently by prostate cancer. Datafrom the Surveillance, Epidemiology and End Results The final case report published in this period (1970s) programme showed that the increase of CMM incidence was presented by Sober and Wick . In this case, a in North America was particularly high in men, reaching a 48-year-old man was diagnosed with melanoma 6 years level of more than 40 cases per 100 000 in several areas in after the onset of PD and the beginning of levodopa 1999 . In European men (1993–1997), CMM treatment. One year after the melanoma diagnosis, the incidence was as high as 17 cases per 100 000 in patient had not had a recurrence or metastasis.
Switzerland, 10 in Denmark, nine in the Netherlandsand more than seven in Finland, England and Scotland; The state-of-the-art at this point is well summarized in rates were slightly lower in women. Rates in southern the letters exchanged in JAMA in 1979 by Fermaglich and Europe were lower still, but with a consistent increase Delaney  on one side and Sober and Wick  on the compared with earlier data: doubling in Spain from other. Fermaglich and Delaney  stated that the 2.2 in 1983–1987 to four cases per 100 000 in the period available evidence suggests a risk of melanoma progres- 1993–1997, for example, and increasing by about 30% in sion associated with the use of levodopa, and they Italy in the same period, from five to seven cases per recommend its proscription, suggesting bromocriptine as 100 000 . In fact, mortality in developed countries an alternative treatment. In contrast, Sober and Wick  showed increasing trends only till the end of the 1980s, regard the evidence (including experimental results) as when it stabilized or started to decline slightly. At insufficient. Nevertheless, they agree upon a cautious present, mortality rates are 2.8 and 1.3 in men and approach until there is clear epidemiological evidence on women in North America, 1.6 and 1.2 in Europe, and five Further case reports were published in the 1980s and Knowledge of the aetiology of melanoma derives 1990s and in more recent years. As in the first group of substantially from good case–control studies conducted case reports, the melanoma sometimes followed and from the 1980s onwards in America [23–27], Australia sometimes preceded levodopa treatment [6–19].
[28,29] and Europe [30–33]. These studies show that theaetiology consists of complex interactions between It must be noted that some of these case reports are genetic characteristics (i.e. skin phenotype), social and ‘negative’ in terms of a link between levodopa and environmental factors (e.g. exposure to sunlight).
melanoma. For example, the paper by Weiner et al. presented nine melanoma cases in levodopa-treated PD All the indicators of pale complexion and sensitivity to patients; in only one case did the melanoma recur.
sunlight are associated with a 2–4-fold increased risk of Woofter and Manyam  described the case of a man melanoma. Moreover, specific population subgroups with who died at the age of 97 years, after having taken 4.3 kg a collection of risk factors, such as people with red hair, of levodopa in the 15 years following the melanoma blue eyes, a tendency to sunburn, and with a large number of freckles and naevi have observed relative risksup to 10 times that of the population average. Number of The case reports included above, with the exception of sunburns and age at first sunburn can be considered as those of Wobbes and Bonenkamp , are also reported intermediate indicators of skin sensibility and sun ¨tzner and Przybilla  in their 1997 review of the literature. In 2000, Siple et al.  found 34 case reportson Medline within 1999, and counted a total of melanoma and sun exposure were observed early on in were, however, not completely listed in the article’s the research on this topic. First, there is a protective Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Melanoma, Parkinson’s disease and levodopa Zanetti et al.
effect of persistent tanning from chronic sun exposure, Kessler and Diamond  published a second large-scale observed in cohorts of outdoor workers [31,32]. Second, case–control study in 1971 analysing 468 cases (and as there is an increasing risk of melanoma with higher social many controls) with a valid interview. Less strong class. Factors such as opportunities for intermittent sun protective effects of smoking than those in the study exposure on holidays, during seaside sojourns and water by Nefzger et al.  were found (RR: 0.66). The sports are (even more so in the past) positively related to proportion of smokers in the control group was somewhat an increase of melanoma risk and to social class.
lower than that of the general population (contrary to thatin the study by Nefzger et al.  in which it was slightlyhigher), and this can explain the differences between the Aetiological epidemiology of Parkinson’s disease and association with melanoma riskNotwithstanding Subsequently, several other studies were conducted, epidemiological studies, the aetiology of PD remains which differed in design, quality and scale. In general, substantially unknown. Studies have focused on different however, investigators came to the conclusion that factors and have been of varying size and quality [34–39].
tobacco smoking or tobacco-related cancers were inver-sely related to PD. Morens et al.  provide a complete Reviews have been conducted by Morens et al. , review of 34 studies published up to 1995.
Tanner and Ben-Shlomo  and Fiala et al. .
More recent case–control studies in PD patients clearly confirmed the decreased risk in smokers [48,49].
concerns the protective effect of tobacco smoking.
Epidemiological The most important study with respect to melanoma risk relationship, and the hypothesis is supported by a is a cohort study conducted in Denmark between 1977 credible biological mechanism. Consequently, the rela- and 1999 in which data from 14 088 patients with a PD tionship between tobacco smoking and risk of PD is diagnosis were linked with the Danish Cancer Registry examined in depth in this review because, in our opinion, incidence files . Apart from strongly confirming the it also explains the apparent association between PD and deficit in tobacco-related cancers, this study found a clear excess of cutaneous melanoma risk (RR 1.95; confidenceinterval: 1.4–2.6). This excess of melanoma risk could be The first formal evidence of an inverse relationship explained by the inverse relationship between tobacco between tobacco smoking and PD risk is derived from smoking and social class, especially in men, whereas the Dorn’s study on American war veterans . Smoking risk of melanoma is positively correlated with this habits of a large cohort of American war veterans were variable. If tobacco smoking protects against PD, PD established through a mailed questionnaire and revealed a patients would tend to belong to a higher social class and net mortality deficit (mortality ratio 0.36) from PD in smokers compared with nonsmokers. When presentingthis highly surprising result, the authors excluded two Biochemical relationship between levodopa possible artefacts, namely that PD symptoms lead to cessation of smoking and that PD might be obscured as a It is well known that pigmented neurons, containing cause of death in death certificates by other concurrent neuromelanin and high amounts of iron, are typically lost causes associated with tobacco. The same negative in PD. In contrast, neurons that survive are free of relationship was also noted in other large studies on neuromelanin and contain low amounts of iron .
tobacco consumption, specifically those by Doll and Peto on British medical doctors and by Hammond  on One of the important functions of cutaneous melanin is one million Americans. Indeed, the final results of Doll its role in the determination of phenotypic appearance.
and Peto  confirmed the protective effect of tobacco More than 80 genetic loci that regulate mammalian pigmentation are known, and a summary of the biochem-ical control of melanogenesis has been published .
A case–control study was later carried out by Nefzger et al.
, with 198 cases and 198 controls being analysed.
The fact that levodopa is an intermediate in the A protective effect was found for tobacco consumption biosynthesis of melanins necessitates investigation of [relative risk (RR) 0.33–0.44] and the data showed a good the suggested link between levodopa and malignancies consistency for the different modalities and durations of arising from melanocytic cells. The biochemical pathway exposure to tobacco. Of note, the patients’ education responsible for the production of several pigments in levels and job titles were found to be higher than those of mammalian melanocytes is quite well established  Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
melanoma should not be regarded as a contraindication toantiparkinsonian therapy.
DiscussionBy definition, case reports are descriptive and not demonstrative or conclusive. When they signal a possible association that implies a risk, this should lead to thedesign and performance of adequate formal studies totest the hypothesis. In the case of levodopa and melanoma, this has not happened and, over the last 30 years, even more case reports have monotonouslyappeared. Even assuming, however, that there is no Mechanism of formation of phaeomelanins and eumelanins. Common increased melanoma risk following levodopa treatment, steps in the metabolic pathway of levodopa and melanins.
the real number of cases of random association betweenlevodopa and melanoma would have been enormouslyhigher than the few dozens identified by case reports,given the growing incidence of melanoma in the general In-vitro studiesIt has been shown that levodopa, an amino acid that is not population and the growing PD prevalence that is treated normally found in cellular proteins, is incorporated into with levodopa. This argument has already been expressed different cell lines and melanoma cells . When the by Sober and Wick  in their letter in 1979, and toxicity of levodopa on melanoma cells was discovered, it repeated by Rampen  in his letter in 1998.
led to the consideration of its therapeutic potential. It hasbeen shown that levodopa blocks cell proliferation in all Moreover, some case reports are spurious and even phases of the cell cycle . Clement et al.  advised contradictory. This is the case with those publications caution when extrapolating results of culture assays to reporting melanoma before the beginning of levodopa treatment and those in which melanoma did not progressover the course of treatment. Nevertheless, the falseimpression of an association persists and a further case report in a similar vein was published in 2002 .
In animalsA few earlier studies investigate the effect of levodopa onexperimental tumours. In one, levodopa at high dosage While the evidence for a role of levodopa in increasing the enhanced the survival time of animals bearing melanoma risk of melanoma or its progression is completely and mammary carcinoma but did not have any effect on inconsistent, as also discussed by Fiala et al.  in their review of a long series of published case reports, there isgood evidence of a positive association between melano-ma incidence and PD. This evidence is mainly based on Other antitumour assays demonstrate that levodopa and the results of the Danish PD cohort study , in which dopamine, the principal levodopa catabolite, are capable the association between PD and melanoma is very high of prolonging the survival of mice .
(standardized incidence ratio: 2.35) within the first yearafter PD diagnosis and decreases in subsequent periods, implying that the association is not due to PD treatment, Melanocytes have a ‘nonvital’ role in adult humans, so but to some pre-existing causal or confounding factor.
potential toxicity to normal melanocytes is not a serious A causal relationship would mean that a common factor problem. The possibility of using these agents to act could cause both the destruction of substantia nigra selectively on cells with mature phenotypes (like neurons and the neoplastic transformation of cutaneous melanoma cells), in combination with other neoplastic melanocytes, rather than that PD could directly cause drugs, appears interesting. More details can be found in a CMM or vice versa. A common genetic pattern could be review by Wick . In 1991, Gurney et al.  responsible for both diseases and so explain their attempted to treat malignant melanoma with high association. Or, alternatively, the association may be due concentrations of levodopa but, in the 17 metastatic to a third external factor associated with both PD and melanoma patients given oral levodopa/carbidopa, no CMM. At least one such factor exists, and that is social clinical response was shown. Nevertheless, no patient in class. Indeed, there is good evidence that this is this study experienced an increase in tumour growth positively associated with melanoma, probably through a following treatment. According to the authors, while greater recreational sun exposure habit among the levodopa/carbidopa may be regarded as an ineffective wealthier participants. Similarly, there are direct ele- treatment for metastatic melanoma, a previous history of ments (in the study by Nefzger et al.  for instance) of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Melanoma, Parkinson’s disease and levodopa Zanetti et al.
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