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Malignant melanoma in elderly patients: biological, surgical and medical issues Expert Rev. Anticancer Ther. 15(1), 101–108 (2015)
Alessia E Russo*1,2, Francesco Ferrau`2, Giovanna Antonelli2, Domenico Priolo2, James A McCubrey3 and Massimo Libra1 1 Department of Biomedical Sciences, Section of Pathology and Oncology, Laboratory of Translational Oncology and Functional Genomics, University of Catania, 85 Androne Avenue, Catania 95124, Italy 2 Department of Medical Oncology, San Vincenzo Hospital, Taormina (Messina) 98039, Italy 3 Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA *Author for correspondence: Tel.: +39 094 258 9322 Fax: +39 094 252 215 [email protected]
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Malignant melanoma is an aggressive tumor with a poor prognosis for patients with advanced disease. Over the last decades, its incidence and mortality has increased in elderly population, impacting significantly on healthcare costs, considering the increase in average age of the world population. Older age is recognized as an independent poor prognostic factor for melanoma, but the scientific community now is wondering if elderly melanoma patients have worse outcome because they are not receiving the same treatment as their younger counterparts. This article summarizes current data on elderly melanoma prevention and early detection and its subsequent management, underling the differences observed between older and younger patients. It also describes age-associated alterations in immunity and how these may impact on anti-melanoma response. KEYWORDS: age-related immune system imbalances • elderly patients • melanoma • multimorbidity • physician prejudice • practice bias
Elderly people are frequently diagnosed with cancer, including skin cancers [1]. Among these, cutaneous melanoma represents the most aggressive cancer type. In its early stages, melanoma can be surgically removed and cured, leading to 5-year survival rates exceeding 90% [2]. However, metastatic melanoma is refractory to current therapies and has a very poor prognosis, with a median survival rate of 6 months [3]. Its incidence has increased dramatically worldwide over the last 50 years [4] and is increasing in older patients, especially in developed countries where the older population is rapidly rising [5–7]. In Europe, the highest estimated mortality and incidence rates by age for melanoma are observed at more than 75 years old. In detail, the mortality rate at more than 75 years old per 100,000 is 17.6 in men and 10.5 in women. While, the incidence rates in the population more than 75 years old are 49.6 and 31.5 for men and women, respectively. A similar trend is observed in the USA as well. Of note, only the incidence rate in women until 50 years old in Europe is higher than in men (16 vs 12.5) [8]. The high incidence rate of melanoma in women might be explained by UV exposure, such as sunbeds, one of the major risk factors. Indication for a
10.1586/14737140.2015.961426
direct UV mutagenic effect in melanoma development remains controversial. It is possible that BRAF mutations could arise from error prone replication of UV-damaged DNA [9]. It is known that BRAF alterations play an important role in melanoma development [10–13]. Higher frequency of BRAFV600E mutation in melanoma of the trunk from indoor workers compared with outdoor workers was recently observed [14], suggesting that this mutation may be associated with an intermittent exposure to the sun, as usually the trunk is a sun-protected body site [14]. A group of American authors sought to assess healthcare resources consumed by melanoma in the over 65-year-old population and they found that the economic burden in the elderly population was significant, particularly in late-stage disease [15]. Therefore, prevention and early detection efforts may significantly reduce the economic burden in this patient setting, if they are proved to be effective. Until recently, age itself was thought to be an independent prognostic factor for a worse outcome in melanoma [16–18], but now the scientific community is speculating, considering results of recent studies that have observed age-related variations at every step of
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` , Antonelli, Priolo, McCubrey & Libra Russo, Ferrau
melanoma management [19–23], if these disparities could affect to the worse outcome in the elderly. Because melanoma is an immunogenic tumor, interaction between immune system aging and melanoma could influence many aspects of tumor biology in older individuals [24]. Of note, in the elderly, the progressive deterioration of the immune system, comprising cellular and molecular alterations, influences both innate and adaptive immunity [25–28]. An aim of this review article is to discuss the effect of immune system aging on anti-melanoma response. Several differences, observed in the management of melanoma, between older individuals and younger ones, are also discussed. We identified previous reports on melanoma and elderly published in English in the last 20 years through a MEDLINE search strategy based on the following words (all fields): ‘melanoma’ and ‘elderly or old patients’ and ‘immunity’. Interaction of the aging immune system with the melanoma
The increased incidence of cancer in elderly may be, in part, explained by the deregulated function of immune system affecting older people that may influence both the reaction against infectious agents and the anti-tumor defense. It was described that the apoptotic process in elderly is weaker than in young subjects. Spaulding et al. observed that senescent CD8+ T-cell cultures show reduced apoptosis in response to a wide variety of treatments and diminished caspase-3 activity compared with quiescent early passage cultures from the same donor [29]. Moreover, T-cell replicative senescence is also associated with increased Bcl-2 expression, which may contribute to the prolonged survival of senescent CD8+ T cells present in the cultures [29]. However, the nature of the immunological effectors, which induce apoptosis, is still debated. Since melanoma is a chemoresistant but highly immunogenic tumor [30,31], an increased body of evidence shows the efficacy of immune strategies in order to control melanoma growth, invasion and metastasis. Although, it has been hypothesized that in elderly patients the immune system is compromised and therefore these patients cannot benefit from immunological therapies [32,33], conflicting data have been generated. According to some clinical experiences, metastatic melanoma appears to have a more indolent clinical course in elderly patients, and the response to traditional chemotherapy is often more durable in these patients than in younger ones [24]; other authors have noted that the interval between metastatic melanoma diagnosis and death was shorter in younger subjects than in older patients [JOWELLA P ET AL., UNPUBLISHED OBSERVATIONS]; a case report described the aggressive clinical course of metastatic melanoma in two very elderly patients who died within 3 weeks of the diagnosis [34]. It has been observed that age does not impair the efficacy of high-dose IL-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma [35–37]. Clinical benefits from melanoma vaccines and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody treatment have also been 102
demonstrated in clinical trials including elderly patients [38,39]. Therefore, these data suggest that aging-associated changes of the immune system should not exclusively be viewed in the context of the immune system’s progressive functional decline. Aging is associated with increased levels of circulating proinflammatory cytokines (TNF-a, IFN-g) produced by NK cells, macrophages and T NK cells in response to chronic antigenic stress [40,41]. A predominantly proinflammatory cytokine profile leads to poor coordination between CD4, CD8 and B lymphocytes and the resulting Th1/Th2 cytokine imbalance in favor of Th1 production [42]. Cytotoxic T-lymphocyte activity under Th1 condition, along with a relatively weaker inhibitory system could lead to a better anti-tumor immunity [43]. This pathophysiological background could explain the indolent clinical course of melanoma and durable responses to systemic chemotherapy observed in vivo in some elderly patients. Conversely, in younger individuals, where effector immune responses are probably highly regulated, the predominantly Th2 response could favor immune tolerance and perhaps a reduced antitumor immunity. Finally, in very elderly subjects the imbalance seems to result from effector T-cell disadvantage [44] and for this reason very elderly subjects are at highest risk of infections and malignancies such as melanoma. A fine balance between effector T-cell response, profile of generated cytokines and immune regulation will therefore help to determine the effect of the aging immune system on anti-tumor activities. Therefore, a better understanding of the role of immune system imbalances will be needed in order to develop effective immune strategies to be used on selected elderly patients affected by melanoma. An immunological window could be identified to select older and oldest melanoma patients for properly enrolling them in immunotherapeutic trials. Why is melanoma mortality only increasing in the elderly?
Melanoma-related mortality continues to rise in elderly people, despite the fact that anti-melanoma immunity seems to be more efficient in them because of age-related immune system imbalances. Why? Older age is recognized as an independent poor prognostic factor in melanoma patients. Analyzing data from 399 melanoma patients submitted to sentinel lymph node biopsy (SLNB) from 1996 to 2003 at the National Cancer Institute of Naples, Caraco et al. observed a favorable outcome in older patients in terms of disease-free survival and overall survival and no differences between the younger and older group in terms of incidence of lymph node metastases [16]. Other investigators found that age, stage at diagnosis, sex and melanoma detection by a dermatologist were all predictive of improved survival on multivariate analysis in a population of over 2000 patients [17]. An analysis of prognostic factors among 17,600 melanoma patients demonstrated that increasing age was an independent adverse prognostic factor for overall survival and within each thickness subgroup [18]. However, there are some limitations to these studies. First, they are not prospective, randomized clinical trials; second, Expert Rev. Anticancer Ther. 15(1), (2015)
Malignant melanoma in elderly patients
they didn’t take account of a number of age-associated confounding factors. Moreover, recent studies have observed differences at every step of melanoma management between old and young patients [19–23]; currently, the scientific community is wondering if these disparities could adversely affect the outcome in elderly melanoma patients.
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Age-related disparities in melanoma prevention & early detection
At diagnosis, elderly melanoma patients present with thicker and more frequently ulcerated tumors compared with younger patients [45–48,18]. These features, known to contribute to poor outcome, may result from longer delays to diagnosis in elderly patients because of multiple factors: • Older people participate in skin cancer screening programs less often than younger patients because of the relative lack of access to specialist care services, cognitive impairment, depression, social isolation and active comorbidities [20]. Furthermore, screening campaigns for melanoma are generally aimed at the younger age groups [49]. • Older people are less attentive to changes on their skin compared with younger individuals both due to lower awareness levels regarding melanoma and also due to the diminished vision that occurs with advancing age. However, even selfskin examination is not sufficient because melanoma often develops on ‘hidden’ areas of the body, such as the back, the scalp, the nape of the neck and the posterior surface of the ears. • The high incidence of nodular melanomas in the elderly thwarts early detection efforts because this histological subtype develops de novo and very quickly [50]. On the other hand, all patients are less able to detect changes in melanoma, independent of their age, if these changes occur over a very long period of time [51], as it happens in the case of lentigo maligna, a melanoma histological type that occurs more frequently in elderly patients [52]. All these data suggest that it is extremely important to invest resources to strengthen access to early diagnostic services for the elderly. Of course, screening campaigns for melanoma remain the best strategy to prevent this devastating disease both for the young and elderly alike. Furthermore, many investigators are focusing on the role of prognostic factors in melanoma development and progression. Among these, serum lactate dehydrogenase, protein S-100 b, melanoma-inhibiting activity, matrix metalloproteinase-2 and TGF-b may correlate with melanoma progression [53,54]. Age-related disparities in surgical management of primitive melanoma
A significant proportion of patients with thick melanomas do not undergo lymph node staging with SLNB, despite the fact that it has been recommended by guidelines since 1998 and supported by retrospective and prospective institutional data [55–65]. Martinez et al. studied 1981 patients who underwent surgery for informahealthcare.com
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thick primary cutaneous melanoma from 2004 to 2008 and compared patients 60 years. They found that probability of receiving a SLNB was inversely proportional with age, with patients aged 60 years and older having a decreased likelihood of undergoing a SLNB [21]. Ciocan et al. examined 1621 patients with stage I or II melanoma who underwent SLNB in 2004 and 2008 in five regions of northeast France and similarly found decreased use of SLN biopsy among elderly patients compared with the younger group [19]. There are several possible explanations for this discrepancy. For example, multimorbidity could have precluded the use of SLNB in older patients. Low frequency of SLN metastasis in elderly melanomas reported by the literature could also have affected the decision to whether or not to perform a SLNB in these patients [66–68]. Changes in lymphatic function that accompany aging, such as destruction of lymphatic channels and an increase in fat composition of lymph nodes [69,70] may limit nodal trapping of tumor cells during metastatic migration, determining a reduced nodal positivity and increased in-transit disease or even a preferential hematogenous spread in elderly melanoma patients [71,72]. Some retrospective studies have also reported on the decreased use of complete lymph node dissection in the elderly with melanoma metastatic to the sentinel lymph node than in younger patients [22,23]. The cause of this disparity is likely to be multifactorial. The morbidity of lymphadenectomy, especially inguinal, likely plays a significant role in influencing physician recommendation for complete lymph node dissection in elderly patients [73]. This is supported by the observation that patients with lower extremity melanomas are less likely to undergo complete lymph node dissection than patients with melanomas of the trunk [23]. A severe pre-existing illness, use of anti-coagulation therapy or the necessity of taking care of a disabled partner could also strongly influence the decision to perform the procedure. Moreover, part of scientific community is not in total agreement on the therapeutic utility of completion lymph node dissection in melanoma metastatic to the sentinel lymph node. Recent publications have noted an increased probability of developing distant metastases rather than a regional nodal relapse in patients with positive sentinel lymph node [74–76]. However complete lymph node dissection should remain a standard approach for nodal metastasis in melanoma, regardless of patient age, until the results of an ongoing international randomized clinical trial evaluating the potential survival benefit of complete lymphadenectomy is available [77]. Analyzing incident cases of primary melanoma in 1621 patients with stage I or II melanoma in 2004 and 2008 in five regions of northeast France, Ciocan et al. observed a delay beyond 6weeks to perform definitive surgical excision for primary melanoma and a higher rate of positive margins after enlarged resection in older patients than in younger ones [19]. Malignant melanoma of the head and neck and lentigo maligna melanoma, most common in the elderly [78–80], often develop around eyes, nose and mouth, influencing the surgeon to opt for more conservative surgery to limit complications. However, 103
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optimal excision margins for primary cutaneous melanoma significantly reduce mortality [81]. Prolonged delays in definitive excision, probably due to poor patient compliance, also influenced by physician prejudice, and inadequate margins of excision represent two important practice biases in this patient setting [82].
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Age-related disparities in non-surgical management of melanoma
Ciocan et al. have observed that adjuvant therapy for melanoma was less frequently performed on older patients and was prematurely stopped in a higher proportion of this population [19]. Analyzing data from 1081 patients diagnosed with melanoma stages 0–III between April and June 2008 in Germany, other authors have instead reported a low rate of adjuvant treatment initiations in all eligible patients, regardless of age [83]. In any case, despite these conflicting data, it is reasonable to presume that the combination of several factors, such as severe comorbidities amplifying the possibility of treatment complication, the risk of significant side effects from therapy, lowering patients’ quality of life and dissuading them from continuing therapy, and uncertainty of clinical benefit obtained after treatment, discourage clinicians from proposing substantial treatment for older patients. It is a well-known issue that melanoma is an immune responsive disease. The US FDA has approved several new immunological-based drugs for the treatment of metastatic melanoma. The first is ipilimumab, a monoclonal antibody directed against CTLA-4; CTLA-4, also known as CD152, is a member of the immunoglobulin superfamily, which is expressed on the surface of activated CD4+ and CD8+ T cells. Its interaction with B7-1 (also known as CD80) or B7-2 (also known as CD86), ligands expressed on antigen-presenting cells, transmits an inhibitory signal to T cells that contributes to immune homeostasis. CTLA-4 inhibitory signal blockade using ipilimumab allows an uninhibited expansion of effector T lymphocytes, resulting in tumor regression demonstrated in preclinical studies and confirmed in large randomized human clinical trials. The clinical benefit was seen in all patients, regardless of age [84,85]. The second class of agents recently approved by the FDA is for the treatment of metastatic melanomas that carry BRAF gene mutation, and includes vemurafenib and dabrafenib. Targeting mutated BRAF protein, these drugs interrupt signaling through the aberrant MAPK pathway inducing tumor cell death. In a Phase III randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation, vemurafenib treatment improved rates of overall and progression-free survival in all patients, regardless of age [86]. As previously reported, age-related comorbidities and risk of significant side effects from therapy may influence the clinician’s decision to dispense adjuvant or metastatic therapies. However, the benefits or toxicities of new treatments are indeed still uncertain, not only because the elderly population is not 104
adequately represented in clinical trials, due to advanced age and comorbidities in themselves exclusion criteria from enrollment, but also because different side effects, comorbidities, the use of multiple diverse drugs and other aspects typical of elderly population make results from clinical trials in younger patients not directly comparable. Therefore, clinical trials for this setting of patients are urgently needed to provide better treatment. Conclusion
It has been suggested that older age is an independent poor prognostic factor in melanoma patients by several retrospective studies. However, these studies do not take account of a number of age-associated confounding factors that interfere with optimal management of elderly patients with melanoma. Therefore, the scientific community is now wondering whether older patients with melanoma have a worse outcome because they are not receiving the same treatment as their younger counterparts. Currently, there are no efficient frailty indexes to properly assess elderly patients and so age is often used as a surrogate marker of frailty. A comprehensive geriatric assessment is, therefore, required in order to identify elderly patients most likely to benefit from melanoma treatment. It will also be necessary to develop a screening program focused on the elderly, considering the increase in average age of world population, in order to improve early diagnosis and survival, and at the same time, to decrease surgical morbidity and public healthcare costs. Immunosenescence is characterized by a series of imbalances among effector T-cell responses, profile of generated cytokines and immune regulation. In older individuals, the imbalance would appear to weight in favor of effector T cells. This could explain the indolent clinical course of melanoma and durable responses to systemic chemotherapy observed in vivo in some elderly patients. A better understanding of aging-related immune system imbalances will be needed in order to develop effective immune strategies to be used on selected elderly melanoma patients. It will be also important, in the future, to improve the number of eligible elderly patients in clinical trials, aiming to extend even to them all the benefits experienced using immune-based treatment strategies on patients with melanoma. Expert commentary & five-year view
In the last few years, clinical oncologists are starting to shift their attention on elderly patients, in order to better define the modality of clinical approach and care. At the same time, the molecular approach is going to become the mainstay for therapeutic decision-making in cancer patients in general, and melanoma in particular. These two issues will presumably answer the growing expectations of both clinical researchers and therapists. Advanced melanoma patients have until recently suffered the lack of meaningful innovations, but it now seems that research and clinic are going to gain very important improvement, so oncologists could offer substantially renewed chances of care, if not cure. Expert Rev. Anticancer Ther. 15(1), (2015)
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Malignant melanoma in elderly patients
Elderly melanoma patients seem to carry a worse prognosis compared with their younger counterparts, probably related to lower awareness regarding the disease from both patients and physicians, later intervention and general underutilization of currently achievable therapeutic opportunities. In light of the immunogenic nature of melanoma, a more comprehensive understanding of immunological issues will help in selecting the appropriate treatment for the select patient in the proper timing of disease’s natural history, regardless of age. Furthermore, in this contest, a larger proportion of elderly melanoma patients could gain the benefit to be included in clinical trials exploring the role of novel molecular targeted therapies. The most promising approach for reducing melanoma mortality rates is early detection and prompt treatment. In the elderly, the total body skin examination, performed by physician or dermatologist, is an appropriate opportunity for the identification of cutaneous melanoma at early stage [87]. Skin cancer is a
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highly responsive cancer type for a screening program taking into account that the treatment of earlier disease is much more effective than treatment of later disease. Public health organizations should do more to promote screening campaigns as the time spent on examinations in the physician’s office is minimal and can save long-term healthcare costs. These campaigns are also appropriate in older patients who cannot take advantage of more aggressive therapies for melanoma. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Malignant melanoma is an aggressive tumor with a poor prognosis for patients with advanced disease. • Over the last decades, melanoma’s incidence and mortality has increased in the elderly population. • Considering the increase in average age of world population, metastatic melanoma is impacting significantly on healthcare costs. • Anti-melanoma immunity seems to be more efficient in elderly because of age-related immune system imbalances. In very elderly subjects, instead, the imbalance seems to be to effector T-cell disadvantage. The identification of this immunological window will allow the selection of older and oldest melanoma patients for properly enrolling them in immunotherapeutic trials. • Older age is recognized as a poor prognostic factor for melanoma, but now the scientific community is wondering whether elderly melanoma patients have worse outcomes because they are not receiving the same treatment as their younger counterparts. • Prolonged delays in definitive excision for primary melanoma and inadequate margins of excision represent two important practice biases in elderly patients. • It is extremely important to invest resources to strengthen access to early diagnostic services for the elderly. • Early detection of melanoma by screening in the aging population is essential to reduce melanoma mortality. • It will be necessary to improve the number of eligible elderly patients in clinical trials to provide better evidence for their treatment.
References
5.
Papers of special note have been highlighted as: • of interest •• of considerable interest
Tsai S, Balch C, Lange J. Epidemiology and treatment of melanoma in elderly patients. Nat Rev Clin Oncol 2010;7(3):148-52
6.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics.2014. CA Cancer. J Clin 2014; 64(1):9-29
7.
Department of Economic and Social Affairs Population Division. World population prospects the 2006 revision highlights. United Nations Publications; New York, NY, USA: 2007
8.
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon, France; 2013. Available from: http:// globocan.iarc.fr [Last accessed 11 May 2014]
1.
2.
Malaguarnera G, Giordano M, Cappellani A, et al. Skin cancers in elderly patients. Anticancer Agents Med Chem 2013;13(9):1406-11 Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature 2007;445(7130):851-7
3.
Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355(1):51-65
4.
MacKie RM, Hauschild A, Eggermont AM. Epidemiology of invasive cutaneous melanoma. Ann Onco 2009;20(Suppl 6): vi1-7
informahealthcare.com
9.
Thomas NE, Berwick M, Cordeiro-Stone M. Could BRAF mutations in melanocytic lesions arise from DNA damage induced by ultraviolet radiation? J Invest Dermatol 2006;126(8): 1693-6
10.
Libra M, Malaponte G, Navolanic PM, et al. Analysis of. BRAF mutation in primary and metastatic melanoma. Cell Cycle 2005;4(10):382-1384
11.
Cardile V, Malaponte G, Loreto C, et al. Raf kinase inhibitor protein (RKIP) and phospho-RKIP expression in melanomas. Acta Histochem 2013;115(8):795-802
12.
Maira F, Catania A, Candido S, et al. Molecular targeted therapy in melanoma: a way to reverse resistance to conventional drugs. Curr Drug Deliv 2012;9(1):7-29
13.
Russo AE, Torrisi E, Bevelacqua Y, et al. Melanoma: molecular pathogenesis and
105
Review
` , Antonelli, Priolo, McCubrey & Libra Russo, Ferrau
emerging target therapies (Review). Int J Oncol 2009;34(6):1481-9 14.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
15.
Candido S, Rapisarda V, Marconi A, et al. Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure. Oncol Rep 2014;31(3):1079-82 Seidler AM, Pennie ML, Veledar E, et al. Economic burden of melanoma in the elderly population: population-based analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Arch Dermatol 2010;146(3):249-56
••
Assesses healthcare resources consumed by the USA population 65 years or older with melanoma.
16.
Caraco C, Marone U, Botti G, et al. Age as predictor in patients with cutaneous melanoma submitted to sentinel lymph node biopsy. Eur J Surg Oncol 2006;32(9): 970-3
17.
Pennie ML, Soon SL, Risser JB, et al. Melanoma outcomes for Medicare patients: association of stage and survival with detection by a dermatologist vs a non dermatologist. Arch Dermatol 2007;143(4): 488-94
18.
Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19(16):3622-34
•
19.
••
20.
Describes predictors of survival outcomes in a large number of melanoma patients, incorporating results into the American Joint Committee on Cancer melanoma staging system. Ciocan D, Barbe C, Aubin F, et al. Distinctive features of melanoma and its management in elderly patients: a population-based study in France. JAMA Dermatol 2013;149(10):1150-7 Analyses 1621 melanomas diagnosed in 2004 and 2008 in five regions of northeast France and reports differences between older and younger patients concerning the initial characteristics and the subsequent management of their melanoma. Geller AC, Sober AJ, Zhang Z, et al. Strategies for improving melanoma education and screening for men age >or= 50 years: findings from the American Academy of Dermatological National Skin Cancer Screening Program. Cancer 2002; 95(7):1554-61
106
21.
Martinez SR, Shah DR, Yang AD, et al. Sentinel lymph node biopsy in patients with thick primary cutaneous melanoma: patterns of use and underuse utilizing a population-based model. ISRN Dermatol 2013;2013:315609
••
Describes a decreased likelihood of receiving sentinel lymph node biopsy for advancing age $60 years in patients with thick primary cutaneous melanoma.
22.
Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol 2008;15(6):1566-76
23.
•
Shah DR, Yang AD, Maverakis E, Martinez SR. Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis. J Surg Res 2013;185(1):240-4 Retrospective analysis of patients with melanoma metastatic to the sentinel lymph node from The Surveillance, Epidemiology, and End Results database that reports on decreased use of complete lymph node dissection in the elderly than in younger patients.
24.
Hegde UP, Grant-Kels JM. Metastatic melanoma in the older patient: special considerations. Clin Dermatol 2013;31(3): 311-16
25.
Malaguarnera L, Ferlito L, Di Mauro S, et al. Immunosenescence and cancer: a review. Arch Gerontol Geriatr 2001;32(2): 77-93
26.
Malaguarnera L, Cristaldi E, Malaguarnera M. The role of immunity in elderly cancer. Crit Rev Oncol Hematol 2010;74(1):40-60
27.
Malaguarnera M, Cristaldi E, Romano G, Malaguarnera L. Autoimmunity in the elderly: implications for cancer. J Cancer Res Ther 2012;8(4):520-7
28.
Motta M, Ferlito L, Malaguarnera L, et al. Alterations of the lymphocytic set-up in elderly patients with cancer. Arch Gerontol Geriatr 2003;36(1):7-14
29.
Spaulding C, Guo W, Effros RB. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 1999;34(5):633-44
30.
Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene 2003;22(20):3138-51
31.
Mukherji B. Immunology of melanoma. Clin Dermatol 2013;31(2):156-65
32.
Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immun Ageing 2008;5:11
33.
Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des 2013;19(9):1680-98
34.
Van der Meijden WA, van Bruchem-Visser RL, Thio HB, van der Cammen TJ. Melanomas more serious in the elderly. Ned Tijdschr Geneeskd 2010;154:A1535
35.
Clark JM, Kelley B, Titze J, et al. Clinical and safety profile of high-dose interleukin2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma. Oncology 2013;84:123-6
36.
Atzpodien J, Wandert T, Reitz M. Age does not impair the efficacy of immunotherapy in patients with metastatic renal cell carcinoma. Crit Rev Oncol Hematol 2005; 55(3):193-9
•
In this study, age does not impair the efficacy of high-dose IL-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma suggesting that immune therapy could be harnessed in older patients.
37.
Quan W Jr, Ramirez M, Taylor C, et al. Administration of high-dose continuous infusion interleukin-2 to patients age 70 or over. Cancer Biother. Radiopharm 2005; 20(1):11-15
38.
Tagawa ST, Cheung E, Banta W, et al. Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma. Cancer 2006;106(6):1353-7
39.
Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23(35): 8968-77
40.
Pawelec G, Solana R, Remarque E, Mariani E. Impact of aging on innate immunity. J Leukoc Biol 1998;64(6):703-12
•
Describes age-associated alterations in innate immunity and how these may also impact on adaptive immunity.
41.
Salminen A, Huuskonen J, Ojala J, et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 2008;7(2):83-105
42.
Hegde UP, Chakraborty N, Kerr P, Grant-Kels JM. Melanoma in the elderly
Expert Rev. Anticancer Ther. 15(1), (2015)
Malignant melanoma in elderly patients
patient: relevance of the aging immune system. Clin Dermatol 2009;27(6):537-44 43.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
44.
••
45.
Hegde UP, Chhabra A, Chakraborty NG. Lack of T reg cell function and melanoma tumor antigen-specific responses in some elderly patients. [Abstract 248]. Presented at 99th Annual Meeting of American Association of Cancer Research; 12 - 16 April 2008; San Diego, CA, USA Hegde UP, Chakraborty N, Mukherji B, Grant Kels JM. Metastatic melanoma in the older patient: immunologic insights and treatment outcomes. Expert Rev Pharmacoecon Outcomes Res 2011;11(2): 185-93 In this study, imbalances between the components of the aging immune system are believed to be relevant in determining natural history and outcomes of older melanoma patients following treatment. Cohen HJ, Cox E, Manton K, Woodbury M. Malignant melanoma in the elderly. J Clin Oncol 1987;5(1):100-6
46.
Averbook BJ, Russo LJ, Mansour EG. A long-term analysis of 620 patients with malignant melanoma at a major referral center. Surgery 1998;124(4):746-56
47.
MacKie RM. Malignant melanoma: clinical variants and prognostic indicators. Clin Exp Dermatol 2000;25(6):471-5
48.
49.
50.
51.
Ramesh HS, Pope D, Gennari R, Audisio RA. Optimising surgical management of elderly cancer patients. World J Surg Oncol 2005;3:17
development and progression. Oncol Rep 2010;24(1):81-7
Review
67.
Sondak VK, Taylor JM, Sabel MS, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from the generation of a probabilistic model. Ann Surg Oncol 2004; 11(3):247-58
55.
Houghton A, Coit D, Bloomer W, et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Williston Park) 1998;12(7A): 153-77
68.
56.
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27(36):6199-206
Bleicher RJ, Essner R, Foshag LJ, et al. Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas. J Clin Oncol 2003;21(7):1326-31
69.
57.
Covarelli P, Vedovati MC, Becattini C, et al. The sentinel node biopsy in patients with thick melanoma: outcome analysis from a single-institution database. In Vivo 2011;25(3):439-43
Fenske NA, Lober CW. Structural and functional changes of normal aging skin. J Am Acad Dermatol 1986;15(4 Pt 1): 571-85
70.
Luscieti P, Hubschmid T, Cottier H, et al. Human lymph node morphology as a function of age and site. J Clin Pathol 1980;33(5):454-61
71.
Conway WC, Faries MB, Nicholl MB, et al. Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol 2009; 16(6):1548-52
72.
Sassen S, Shaw HM, Colman MH, et al. The complex relationships between sentinel node positivity, patient age, and primary tumor desmoplasia: analysis of 2303 melanoma patients treated at a single center. Ann Surg Oncol 2008;15(2):630-7
73.
Guggenheim MM, Hug U, Jung FJ, et al. Morbidity and recurrence after completion lymph node dissection following sentinel lymph node biopsy in cutaneous malignant melanoma. Ann Surg 2008;247(4):687-93
74.
Kingham TP, Panageas KS, Ariyan CE, et al. Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol 2010;17(2):514-20
58.
59.
60.
61.
Ferrone CR, Panageas KS, Busam K, et al. Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9(7):637-45 Gershenwald JE, Mansfield PF, Lee JE, Ross MI. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or = 4 mm) primary melanoma. Ann Surg Oncol 2000;7(2):160-5 Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatol Ges 2008;6(3):198-203 Jacobs IA, Chang CK, Salti GI. Role of sentinel lymph node biopsy in patients with thick (>4mm) primary melanoma. Am Surg 2004;70(1):59-62
Kelly JW. Melanoma in the elderly a neglected public health challenge. Med J Aust 1998;169(8):403-4
62.
Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Melanoma Res 2010;20(3):163-70
Ra JH, McMasters KM, Spitz FR. Should all melanoma patients undergo sentinel lymph node biopsy? Curr Opin Oncol 2006;18(2):185-8
75.
63.
Rondelli F, Vedovati MC, Becattini C, et al. Prognostic role of sentinel node biopsy in patients with thick melanoma: a meta-analysis. J Eur Acad Dermatol Venereol 2012;26(5):560-5
Leong SP. Role of selective sentinel lymph node dissection in head and neck melanoma. J Surg Oncol 2011;104(4):361-8
76.
Vermeeren L, van der Ent FW, Sastrowijoto PS, Hulsewe´ KW. Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33(11): 2464-8
Willis AI, Ridge JA. Discordant lymphatic drainage patterns revealed by serial lymphoscintigraphy in cutaneous head and neck malignancies. Head Neck 2007;29(11): 979-85
77.
MSLT-II. Complete lymph node dissection or observation in treating patients with localized melanoma and sentinel node metastases who have undergone sentinel lymphadenectomy (MSLT-ii). Available from: www.clinicaltrials.gov/ct/show/ nct00389571?order=1
78.
Hoersch B, Leiter U, Garbe C. Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol 2006;155(4):771-7
Hanrahan PF, Hersey P, D’Este CA. Factors involved in presentation of older people with thick melanoma. Med J Aust 1998;169(8):410-14
52.
Kallini JR, Jain SK, Khachemoune A. Lentigo maligna: review of salient characteristics and management. Am J Clin Dermatol 2013;14(6):473-80
53.
Perrotta R, Bevelacqua Y, Malaguarnera G, et al. Serum markers of cutaneous melanoma. Front Biosci (Elite Ed) 2010;2: 1115-22
54.
Malaponte G, Zacchia A, Bevelacqua Y, et al. Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-beta in melanoma
informahealthcare.com
64.
65.
66.
Essner R, Chung MH, Bleicher R, et al. Prognostic implications of thick (‡4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002; 9(8):754-61 Chao C, Martin RC II, Ross MI, et al. Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 2004;11(3):259-64
107
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
Review
` , Antonelli, Priolo, McCubrey & Libra Russo, Ferrau
79.
Whiteman DC, Stickley M, Watt P, et al. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol 2006; 24(19):3172-7
80.
Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009;27(1):3-9
81.
Haigh PI, DiFronzo LA, McCready DR. Optimal excision margins for primary cutaneous melanoma: a systematic review and meta-analysis. Can J Surg 2003;46(6): 419-26
82.
Albertini JG, Countryman NB. Practice gaps: delayed treatment and inadequate surgical margins for invasive melanoma in elderly patients. JAMA Dermatol 2013; 149(10):1158
108
83.
84.
••
Livingstone E, Windemuth-Kieselbach C, Eigentler TK, et al. A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up. Eur J Cancer 2011;47(13):1977-89 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23 In this Phase III trial, the humanized monoclonal antibody ipilimumab exhibited a survival benefit in patients with previously treated metastatic melanoma.
85.
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517-26
86.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507-16
87.
Wolf J, Harris R, Ferris LK. Screening for Melanoma in Aging Patients. Cutis 2013;91:81-6
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Malignant melanoma in elderly patients: biological, surgical and medical issues Expert Rev. Anticancer Ther. 15(1), 101–108 (2015)
Alessia E Russo*1,2, Francesco Ferrau`2, Giovanna Antonelli2, Domenico Priolo2, James A McCubrey3 and Massimo Libra1 1 Department of Biomedical Sciences, Section of Pathology and Oncology, Laboratory of Translational Oncology and Functional Genomics, University of Catania, 85 Androne Avenue, Catania 95124, Italy 2 Department of Medical Oncology, San Vincenzo Hospital, Taormina (Messina) 98039, Italy 3 Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA *Author for correspondence: Tel.: +39 094 258 9322 Fax: +39 094 252 215 [email protected]
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Malignant melanoma is an aggressive tumor with a poor prognosis for patients with advanced disease. Over the last decades, its incidence and mortality has increased in elderly population, impacting significantly on healthcare costs, considering the increase in average age of the world population. Older age is recognized as an independent poor prognostic factor for melanoma, but the scientific community now is wondering if elderly melanoma patients have worse outcome because they are not receiving the same treatment as their younger counterparts. This article summarizes current data on elderly melanoma prevention and early detection and its subsequent management, underling the differences observed between older and younger patients. It also describes age-associated alterations in immunity and how these may impact on anti-melanoma response. KEYWORDS: age-related immune system imbalances • elderly patients • melanoma • multimorbidity • physician prejudice • practice bias
Elderly people are frequently diagnosed with cancer, including skin cancers [1]. Among these, cutaneous melanoma represents the most aggressive cancer type. In its early stages, melanoma can be surgically removed and cured, leading to 5-year survival rates exceeding 90% [2]. However, metastatic melanoma is refractory to current therapies and has a very poor prognosis, with a median survival rate of 6 months [3]. Its incidence has increased dramatically worldwide over the last 50 years [4] and is increasing in older patients, especially in developed countries where the older population is rapidly rising [5–7]. In Europe, the highest estimated mortality and incidence rates by age for melanoma are observed at more than 75 years old. In detail, the mortality rate at more than 75 years old per 100,000 is 17.6 in men and 10.5 in women. While, the incidence rates in the population more than 75 years old are 49.6 and 31.5 for men and women, respectively. A similar trend is observed in the USA as well. Of note, only the incidence rate in women until 50 years old in Europe is higher than in men (16 vs 12.5) [8]. The high incidence rate of melanoma in women might be explained by UV exposure, such as sunbeds, one of the major risk factors. Indication for a
10.1586/14737140.2015.961426
direct UV mutagenic effect in melanoma development remains controversial. It is possible that BRAF mutations could arise from error prone replication of UV-damaged DNA [9]. It is known that BRAF alterations play an important role in melanoma development [10–13]. Higher frequency of BRAFV600E mutation in melanoma of the trunk from indoor workers compared with outdoor workers was recently observed [14], suggesting that this mutation may be associated with an intermittent exposure to the sun, as usually the trunk is a sun-protected body site [14]. A group of American authors sought to assess healthcare resources consumed by melanoma in the over 65-year-old population and they found that the economic burden in the elderly population was significant, particularly in late-stage disease [15]. Therefore, prevention and early detection efforts may significantly reduce the economic burden in this patient setting, if they are proved to be effective. Until recently, age itself was thought to be an independent prognostic factor for a worse outcome in melanoma [16–18], but now the scientific community is speculating, considering results of recent studies that have observed age-related variations at every step of
2015 Informa UK Ltd
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melanoma management [19–23], if these disparities could affect to the worse outcome in the elderly. Because melanoma is an immunogenic tumor, interaction between immune system aging and melanoma could influence many aspects of tumor biology in older individuals [24]. Of note, in the elderly, the progressive deterioration of the immune system, comprising cellular and molecular alterations, influences both innate and adaptive immunity [25–28]. An aim of this review article is to discuss the effect of immune system aging on anti-melanoma response. Several differences, observed in the management of melanoma, between older individuals and younger ones, are also discussed. We identified previous reports on melanoma and elderly published in English in the last 20 years through a MEDLINE search strategy based on the following words (all fields): ‘melanoma’ and ‘elderly or old patients’ and ‘immunity’. Interaction of the aging immune system with the melanoma
The increased incidence of cancer in elderly may be, in part, explained by the deregulated function of immune system affecting older people that may influence both the reaction against infectious agents and the anti-tumor defense. It was described that the apoptotic process in elderly is weaker than in young subjects. Spaulding et al. observed that senescent CD8+ T-cell cultures show reduced apoptosis in response to a wide variety of treatments and diminished caspase-3 activity compared with quiescent early passage cultures from the same donor [29]. Moreover, T-cell replicative senescence is also associated with increased Bcl-2 expression, which may contribute to the prolonged survival of senescent CD8+ T cells present in the cultures [29]. However, the nature of the immunological effectors, which induce apoptosis, is still debated. Since melanoma is a chemoresistant but highly immunogenic tumor [30,31], an increased body of evidence shows the efficacy of immune strategies in order to control melanoma growth, invasion and metastasis. Although, it has been hypothesized that in elderly patients the immune system is compromised and therefore these patients cannot benefit from immunological therapies [32,33], conflicting data have been generated. According to some clinical experiences, metastatic melanoma appears to have a more indolent clinical course in elderly patients, and the response to traditional chemotherapy is often more durable in these patients than in younger ones [24]; other authors have noted that the interval between metastatic melanoma diagnosis and death was shorter in younger subjects than in older patients [JOWELLA P ET AL., UNPUBLISHED OBSERVATIONS]; a case report described the aggressive clinical course of metastatic melanoma in two very elderly patients who died within 3 weeks of the diagnosis [34]. It has been observed that age does not impair the efficacy of high-dose IL-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma [35–37]. Clinical benefits from melanoma vaccines and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody treatment have also been 102
demonstrated in clinical trials including elderly patients [38,39]. Therefore, these data suggest that aging-associated changes of the immune system should not exclusively be viewed in the context of the immune system’s progressive functional decline. Aging is associated with increased levels of circulating proinflammatory cytokines (TNF-a, IFN-g) produced by NK cells, macrophages and T NK cells in response to chronic antigenic stress [40,41]. A predominantly proinflammatory cytokine profile leads to poor coordination between CD4, CD8 and B lymphocytes and the resulting Th1/Th2 cytokine imbalance in favor of Th1 production [42]. Cytotoxic T-lymphocyte activity under Th1 condition, along with a relatively weaker inhibitory system could lead to a better anti-tumor immunity [43]. This pathophysiological background could explain the indolent clinical course of melanoma and durable responses to systemic chemotherapy observed in vivo in some elderly patients. Conversely, in younger individuals, where effector immune responses are probably highly regulated, the predominantly Th2 response could favor immune tolerance and perhaps a reduced antitumor immunity. Finally, in very elderly subjects the imbalance seems to result from effector T-cell disadvantage [44] and for this reason very elderly subjects are at highest risk of infections and malignancies such as melanoma. A fine balance between effector T-cell response, profile of generated cytokines and immune regulation will therefore help to determine the effect of the aging immune system on anti-tumor activities. Therefore, a better understanding of the role of immune system imbalances will be needed in order to develop effective immune strategies to be used on selected elderly patients affected by melanoma. An immunological window could be identified to select older and oldest melanoma patients for properly enrolling them in immunotherapeutic trials. Why is melanoma mortality only increasing in the elderly?
Melanoma-related mortality continues to rise in elderly people, despite the fact that anti-melanoma immunity seems to be more efficient in them because of age-related immune system imbalances. Why? Older age is recognized as an independent poor prognostic factor in melanoma patients. Analyzing data from 399 melanoma patients submitted to sentinel lymph node biopsy (SLNB) from 1996 to 2003 at the National Cancer Institute of Naples, Caraco et al. observed a favorable outcome in older patients in terms of disease-free survival and overall survival and no differences between the younger and older group in terms of incidence of lymph node metastases [16]. Other investigators found that age, stage at diagnosis, sex and melanoma detection by a dermatologist were all predictive of improved survival on multivariate analysis in a population of over 2000 patients [17]. An analysis of prognostic factors among 17,600 melanoma patients demonstrated that increasing age was an independent adverse prognostic factor for overall survival and within each thickness subgroup [18]. However, there are some limitations to these studies. First, they are not prospective, randomized clinical trials; second, Expert Rev. Anticancer Ther. 15(1), (2015)
Malignant melanoma in elderly patients
they didn’t take account of a number of age-associated confounding factors. Moreover, recent studies have observed differences at every step of melanoma management between old and young patients [19–23]; currently, the scientific community is wondering if these disparities could adversely affect the outcome in elderly melanoma patients.
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Age-related disparities in melanoma prevention & early detection
At diagnosis, elderly melanoma patients present with thicker and more frequently ulcerated tumors compared with younger patients [45–48,18]. These features, known to contribute to poor outcome, may result from longer delays to diagnosis in elderly patients because of multiple factors: • Older people participate in skin cancer screening programs less often than younger patients because of the relative lack of access to specialist care services, cognitive impairment, depression, social isolation and active comorbidities [20]. Furthermore, screening campaigns for melanoma are generally aimed at the younger age groups [49]. • Older people are less attentive to changes on their skin compared with younger individuals both due to lower awareness levels regarding melanoma and also due to the diminished vision that occurs with advancing age. However, even selfskin examination is not sufficient because melanoma often develops on ‘hidden’ areas of the body, such as the back, the scalp, the nape of the neck and the posterior surface of the ears. • The high incidence of nodular melanomas in the elderly thwarts early detection efforts because this histological subtype develops de novo and very quickly [50]. On the other hand, all patients are less able to detect changes in melanoma, independent of their age, if these changes occur over a very long period of time [51], as it happens in the case of lentigo maligna, a melanoma histological type that occurs more frequently in elderly patients [52]. All these data suggest that it is extremely important to invest resources to strengthen access to early diagnostic services for the elderly. Of course, screening campaigns for melanoma remain the best strategy to prevent this devastating disease both for the young and elderly alike. Furthermore, many investigators are focusing on the role of prognostic factors in melanoma development and progression. Among these, serum lactate dehydrogenase, protein S-100 b, melanoma-inhibiting activity, matrix metalloproteinase-2 and TGF-b may correlate with melanoma progression [53,54]. Age-related disparities in surgical management of primitive melanoma
A significant proportion of patients with thick melanomas do not undergo lymph node staging with SLNB, despite the fact that it has been recommended by guidelines since 1998 and supported by retrospective and prospective institutional data [55–65]. Martinez et al. studied 1981 patients who underwent surgery for informahealthcare.com
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thick primary cutaneous melanoma from 2004 to 2008 and compared patients 60 years. They found that probability of receiving a SLNB was inversely proportional with age, with patients aged 60 years and older having a decreased likelihood of undergoing a SLNB [21]. Ciocan et al. examined 1621 patients with stage I or II melanoma who underwent SLNB in 2004 and 2008 in five regions of northeast France and similarly found decreased use of SLN biopsy among elderly patients compared with the younger group [19]. There are several possible explanations for this discrepancy. For example, multimorbidity could have precluded the use of SLNB in older patients. Low frequency of SLN metastasis in elderly melanomas reported by the literature could also have affected the decision to whether or not to perform a SLNB in these patients [66–68]. Changes in lymphatic function that accompany aging, such as destruction of lymphatic channels and an increase in fat composition of lymph nodes [69,70] may limit nodal trapping of tumor cells during metastatic migration, determining a reduced nodal positivity and increased in-transit disease or even a preferential hematogenous spread in elderly melanoma patients [71,72]. Some retrospective studies have also reported on the decreased use of complete lymph node dissection in the elderly with melanoma metastatic to the sentinel lymph node than in younger patients [22,23]. The cause of this disparity is likely to be multifactorial. The morbidity of lymphadenectomy, especially inguinal, likely plays a significant role in influencing physician recommendation for complete lymph node dissection in elderly patients [73]. This is supported by the observation that patients with lower extremity melanomas are less likely to undergo complete lymph node dissection than patients with melanomas of the trunk [23]. A severe pre-existing illness, use of anti-coagulation therapy or the necessity of taking care of a disabled partner could also strongly influence the decision to perform the procedure. Moreover, part of scientific community is not in total agreement on the therapeutic utility of completion lymph node dissection in melanoma metastatic to the sentinel lymph node. Recent publications have noted an increased probability of developing distant metastases rather than a regional nodal relapse in patients with positive sentinel lymph node [74–76]. However complete lymph node dissection should remain a standard approach for nodal metastasis in melanoma, regardless of patient age, until the results of an ongoing international randomized clinical trial evaluating the potential survival benefit of complete lymphadenectomy is available [77]. Analyzing incident cases of primary melanoma in 1621 patients with stage I or II melanoma in 2004 and 2008 in five regions of northeast France, Ciocan et al. observed a delay beyond 6weeks to perform definitive surgical excision for primary melanoma and a higher rate of positive margins after enlarged resection in older patients than in younger ones [19]. Malignant melanoma of the head and neck and lentigo maligna melanoma, most common in the elderly [78–80], often develop around eyes, nose and mouth, influencing the surgeon to opt for more conservative surgery to limit complications. However, 103
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optimal excision margins for primary cutaneous melanoma significantly reduce mortality [81]. Prolonged delays in definitive excision, probably due to poor patient compliance, also influenced by physician prejudice, and inadequate margins of excision represent two important practice biases in this patient setting [82].
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Age-related disparities in non-surgical management of melanoma
Ciocan et al. have observed that adjuvant therapy for melanoma was less frequently performed on older patients and was prematurely stopped in a higher proportion of this population [19]. Analyzing data from 1081 patients diagnosed with melanoma stages 0–III between April and June 2008 in Germany, other authors have instead reported a low rate of adjuvant treatment initiations in all eligible patients, regardless of age [83]. In any case, despite these conflicting data, it is reasonable to presume that the combination of several factors, such as severe comorbidities amplifying the possibility of treatment complication, the risk of significant side effects from therapy, lowering patients’ quality of life and dissuading them from continuing therapy, and uncertainty of clinical benefit obtained after treatment, discourage clinicians from proposing substantial treatment for older patients. It is a well-known issue that melanoma is an immune responsive disease. The US FDA has approved several new immunological-based drugs for the treatment of metastatic melanoma. The first is ipilimumab, a monoclonal antibody directed against CTLA-4; CTLA-4, also known as CD152, is a member of the immunoglobulin superfamily, which is expressed on the surface of activated CD4+ and CD8+ T cells. Its interaction with B7-1 (also known as CD80) or B7-2 (also known as CD86), ligands expressed on antigen-presenting cells, transmits an inhibitory signal to T cells that contributes to immune homeostasis. CTLA-4 inhibitory signal blockade using ipilimumab allows an uninhibited expansion of effector T lymphocytes, resulting in tumor regression demonstrated in preclinical studies and confirmed in large randomized human clinical trials. The clinical benefit was seen in all patients, regardless of age [84,85]. The second class of agents recently approved by the FDA is for the treatment of metastatic melanomas that carry BRAF gene mutation, and includes vemurafenib and dabrafenib. Targeting mutated BRAF protein, these drugs interrupt signaling through the aberrant MAPK pathway inducing tumor cell death. In a Phase III randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation, vemurafenib treatment improved rates of overall and progression-free survival in all patients, regardless of age [86]. As previously reported, age-related comorbidities and risk of significant side effects from therapy may influence the clinician’s decision to dispense adjuvant or metastatic therapies. However, the benefits or toxicities of new treatments are indeed still uncertain, not only because the elderly population is not 104
adequately represented in clinical trials, due to advanced age and comorbidities in themselves exclusion criteria from enrollment, but also because different side effects, comorbidities, the use of multiple diverse drugs and other aspects typical of elderly population make results from clinical trials in younger patients not directly comparable. Therefore, clinical trials for this setting of patients are urgently needed to provide better treatment. Conclusion
It has been suggested that older age is an independent poor prognostic factor in melanoma patients by several retrospective studies. However, these studies do not take account of a number of age-associated confounding factors that interfere with optimal management of elderly patients with melanoma. Therefore, the scientific community is now wondering whether older patients with melanoma have a worse outcome because they are not receiving the same treatment as their younger counterparts. Currently, there are no efficient frailty indexes to properly assess elderly patients and so age is often used as a surrogate marker of frailty. A comprehensive geriatric assessment is, therefore, required in order to identify elderly patients most likely to benefit from melanoma treatment. It will also be necessary to develop a screening program focused on the elderly, considering the increase in average age of world population, in order to improve early diagnosis and survival, and at the same time, to decrease surgical morbidity and public healthcare costs. Immunosenescence is characterized by a series of imbalances among effector T-cell responses, profile of generated cytokines and immune regulation. In older individuals, the imbalance would appear to weight in favor of effector T cells. This could explain the indolent clinical course of melanoma and durable responses to systemic chemotherapy observed in vivo in some elderly patients. A better understanding of aging-related immune system imbalances will be needed in order to develop effective immune strategies to be used on selected elderly melanoma patients. It will be also important, in the future, to improve the number of eligible elderly patients in clinical trials, aiming to extend even to them all the benefits experienced using immune-based treatment strategies on patients with melanoma. Expert commentary & five-year view
In the last few years, clinical oncologists are starting to shift their attention on elderly patients, in order to better define the modality of clinical approach and care. At the same time, the molecular approach is going to become the mainstay for therapeutic decision-making in cancer patients in general, and melanoma in particular. These two issues will presumably answer the growing expectations of both clinical researchers and therapists. Advanced melanoma patients have until recently suffered the lack of meaningful innovations, but it now seems that research and clinic are going to gain very important improvement, so oncologists could offer substantially renewed chances of care, if not cure. Expert Rev. Anticancer Ther. 15(1), (2015)
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Malignant melanoma in elderly patients
Elderly melanoma patients seem to carry a worse prognosis compared with their younger counterparts, probably related to lower awareness regarding the disease from both patients and physicians, later intervention and general underutilization of currently achievable therapeutic opportunities. In light of the immunogenic nature of melanoma, a more comprehensive understanding of immunological issues will help in selecting the appropriate treatment for the select patient in the proper timing of disease’s natural history, regardless of age. Furthermore, in this contest, a larger proportion of elderly melanoma patients could gain the benefit to be included in clinical trials exploring the role of novel molecular targeted therapies. The most promising approach for reducing melanoma mortality rates is early detection and prompt treatment. In the elderly, the total body skin examination, performed by physician or dermatologist, is an appropriate opportunity for the identification of cutaneous melanoma at early stage [87]. Skin cancer is a
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highly responsive cancer type for a screening program taking into account that the treatment of earlier disease is much more effective than treatment of later disease. Public health organizations should do more to promote screening campaigns as the time spent on examinations in the physician’s office is minimal and can save long-term healthcare costs. These campaigns are also appropriate in older patients who cannot take advantage of more aggressive therapies for melanoma. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Malignant melanoma is an aggressive tumor with a poor prognosis for patients with advanced disease. • Over the last decades, melanoma’s incidence and mortality has increased in the elderly population. • Considering the increase in average age of world population, metastatic melanoma is impacting significantly on healthcare costs. • Anti-melanoma immunity seems to be more efficient in elderly because of age-related immune system imbalances. In very elderly subjects, instead, the imbalance seems to be to effector T-cell disadvantage. The identification of this immunological window will allow the selection of older and oldest melanoma patients for properly enrolling them in immunotherapeutic trials. • Older age is recognized as a poor prognostic factor for melanoma, but now the scientific community is wondering whether elderly melanoma patients have worse outcomes because they are not receiving the same treatment as their younger counterparts. • Prolonged delays in definitive excision for primary melanoma and inadequate margins of excision represent two important practice biases in elderly patients. • It is extremely important to invest resources to strengthen access to early diagnostic services for the elderly. • Early detection of melanoma by screening in the aging population is essential to reduce melanoma mortality. • It will be necessary to improve the number of eligible elderly patients in clinical trials to provide better evidence for their treatment.
References
5.
Papers of special note have been highlighted as: • of interest •• of considerable interest
Tsai S, Balch C, Lange J. Epidemiology and treatment of melanoma in elderly patients. Nat Rev Clin Oncol 2010;7(3):148-52
6.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics.2014. CA Cancer. J Clin 2014; 64(1):9-29
7.
Department of Economic and Social Affairs Population Division. World population prospects the 2006 revision highlights. United Nations Publications; New York, NY, USA: 2007
8.
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. International Agency for Research on Cancer, Lyon, France; 2013. Available from: http:// globocan.iarc.fr [Last accessed 11 May 2014]
1.
2.
Malaguarnera G, Giordano M, Cappellani A, et al. Skin cancers in elderly patients. Anticancer Agents Med Chem 2013;13(9):1406-11 Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature 2007;445(7130):851-7
3.
Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med 2006;355(1):51-65
4.
MacKie RM, Hauschild A, Eggermont AM. Epidemiology of invasive cutaneous melanoma. Ann Onco 2009;20(Suppl 6): vi1-7
informahealthcare.com
9.
Thomas NE, Berwick M, Cordeiro-Stone M. Could BRAF mutations in melanocytic lesions arise from DNA damage induced by ultraviolet radiation? J Invest Dermatol 2006;126(8): 1693-6
10.
Libra M, Malaponte G, Navolanic PM, et al. Analysis of. BRAF mutation in primary and metastatic melanoma. Cell Cycle 2005;4(10):382-1384
11.
Cardile V, Malaponte G, Loreto C, et al. Raf kinase inhibitor protein (RKIP) and phospho-RKIP expression in melanomas. Acta Histochem 2013;115(8):795-802
12.
Maira F, Catania A, Candido S, et al. Molecular targeted therapy in melanoma: a way to reverse resistance to conventional drugs. Curr Drug Deliv 2012;9(1):7-29
13.
Russo AE, Torrisi E, Bevelacqua Y, et al. Melanoma: molecular pathogenesis and
105
Review
` , Antonelli, Priolo, McCubrey & Libra Russo, Ferrau
emerging target therapies (Review). Int J Oncol 2009;34(6):1481-9 14.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
15.
Candido S, Rapisarda V, Marconi A, et al. Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure. Oncol Rep 2014;31(3):1079-82 Seidler AM, Pennie ML, Veledar E, et al. Economic burden of melanoma in the elderly population: population-based analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Arch Dermatol 2010;146(3):249-56
••
Assesses healthcare resources consumed by the USA population 65 years or older with melanoma.
16.
Caraco C, Marone U, Botti G, et al. Age as predictor in patients with cutaneous melanoma submitted to sentinel lymph node biopsy. Eur J Surg Oncol 2006;32(9): 970-3
17.
Pennie ML, Soon SL, Risser JB, et al. Melanoma outcomes for Medicare patients: association of stage and survival with detection by a dermatologist vs a non dermatologist. Arch Dermatol 2007;143(4): 488-94
18.
Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001;19(16):3622-34
•
19.
••
20.
Describes predictors of survival outcomes in a large number of melanoma patients, incorporating results into the American Joint Committee on Cancer melanoma staging system. Ciocan D, Barbe C, Aubin F, et al. Distinctive features of melanoma and its management in elderly patients: a population-based study in France. JAMA Dermatol 2013;149(10):1150-7 Analyses 1621 melanomas diagnosed in 2004 and 2008 in five regions of northeast France and reports differences between older and younger patients concerning the initial characteristics and the subsequent management of their melanoma. Geller AC, Sober AJ, Zhang Z, et al. Strategies for improving melanoma education and screening for men age >or= 50 years: findings from the American Academy of Dermatological National Skin Cancer Screening Program. Cancer 2002; 95(7):1554-61
106
21.
Martinez SR, Shah DR, Yang AD, et al. Sentinel lymph node biopsy in patients with thick primary cutaneous melanoma: patterns of use and underuse utilizing a population-based model. ISRN Dermatol 2013;2013:315609
••
Describes a decreased likelihood of receiving sentinel lymph node biopsy for advancing age $60 years in patients with thick primary cutaneous melanoma.
22.
Bilimoria KY, Balch CM, Bentrem DJ, et al. Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol 2008;15(6):1566-76
23.
•
Shah DR, Yang AD, Maverakis E, Martinez SR. Age-related disparities in use of completion lymphadenectomy for melanoma sentinel lymph node metastasis. J Surg Res 2013;185(1):240-4 Retrospective analysis of patients with melanoma metastatic to the sentinel lymph node from The Surveillance, Epidemiology, and End Results database that reports on decreased use of complete lymph node dissection in the elderly than in younger patients.
24.
Hegde UP, Grant-Kels JM. Metastatic melanoma in the older patient: special considerations. Clin Dermatol 2013;31(3): 311-16
25.
Malaguarnera L, Ferlito L, Di Mauro S, et al. Immunosenescence and cancer: a review. Arch Gerontol Geriatr 2001;32(2): 77-93
26.
Malaguarnera L, Cristaldi E, Malaguarnera M. The role of immunity in elderly cancer. Crit Rev Oncol Hematol 2010;74(1):40-60
27.
Malaguarnera M, Cristaldi E, Romano G, Malaguarnera L. Autoimmunity in the elderly: implications for cancer. J Cancer Res Ther 2012;8(4):520-7
28.
Motta M, Ferlito L, Malaguarnera L, et al. Alterations of the lymphocytic set-up in elderly patients with cancer. Arch Gerontol Geriatr 2003;36(1):7-14
29.
Spaulding C, Guo W, Effros RB. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 1999;34(5):633-44
30.
Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene 2003;22(20):3138-51
31.
Mukherji B. Immunology of melanoma. Clin Dermatol 2013;31(2):156-65
32.
Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immun Ageing 2008;5:11
33.
Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des 2013;19(9):1680-98
34.
Van der Meijden WA, van Bruchem-Visser RL, Thio HB, van der Cammen TJ. Melanomas more serious in the elderly. Ned Tijdschr Geneeskd 2010;154:A1535
35.
Clark JM, Kelley B, Titze J, et al. Clinical and safety profile of high-dose interleukin2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma. Oncology 2013;84:123-6
36.
Atzpodien J, Wandert T, Reitz M. Age does not impair the efficacy of immunotherapy in patients with metastatic renal cell carcinoma. Crit Rev Oncol Hematol 2005; 55(3):193-9
•
In this study, age does not impair the efficacy of high-dose IL-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma suggesting that immune therapy could be harnessed in older patients.
37.
Quan W Jr, Ramirez M, Taylor C, et al. Administration of high-dose continuous infusion interleukin-2 to patients age 70 or over. Cancer Biother. Radiopharm 2005; 20(1):11-15
38.
Tagawa ST, Cheung E, Banta W, et al. Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma. Cancer 2006;106(6):1353-7
39.
Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23(35): 8968-77
40.
Pawelec G, Solana R, Remarque E, Mariani E. Impact of aging on innate immunity. J Leukoc Biol 1998;64(6):703-12
•
Describes age-associated alterations in innate immunity and how these may also impact on adaptive immunity.
41.
Salminen A, Huuskonen J, Ojala J, et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 2008;7(2):83-105
42.
Hegde UP, Chakraborty N, Kerr P, Grant-Kels JM. Melanoma in the elderly
Expert Rev. Anticancer Ther. 15(1), (2015)
Malignant melanoma in elderly patients
patient: relevance of the aging immune system. Clin Dermatol 2009;27(6):537-44 43.
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
44.
••
45.
Hegde UP, Chhabra A, Chakraborty NG. Lack of T reg cell function and melanoma tumor antigen-specific responses in some elderly patients. [Abstract 248]. Presented at 99th Annual Meeting of American Association of Cancer Research; 12 - 16 April 2008; San Diego, CA, USA Hegde UP, Chakraborty N, Mukherji B, Grant Kels JM. Metastatic melanoma in the older patient: immunologic insights and treatment outcomes. Expert Rev Pharmacoecon Outcomes Res 2011;11(2): 185-93 In this study, imbalances between the components of the aging immune system are believed to be relevant in determining natural history and outcomes of older melanoma patients following treatment. Cohen HJ, Cox E, Manton K, Woodbury M. Malignant melanoma in the elderly. J Clin Oncol 1987;5(1):100-6
46.
Averbook BJ, Russo LJ, Mansour EG. A long-term analysis of 620 patients with malignant melanoma at a major referral center. Surgery 1998;124(4):746-56
47.
MacKie RM. Malignant melanoma: clinical variants and prognostic indicators. Clin Exp Dermatol 2000;25(6):471-5
48.
49.
50.
51.
Ramesh HS, Pope D, Gennari R, Audisio RA. Optimising surgical management of elderly cancer patients. World J Surg Oncol 2005;3:17
development and progression. Oncol Rep 2010;24(1):81-7
Review
67.
Sondak VK, Taylor JM, Sabel MS, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from the generation of a probabilistic model. Ann Surg Oncol 2004; 11(3):247-58
55.
Houghton A, Coit D, Bloomer W, et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology (Williston Park) 1998;12(7A): 153-77
68.
56.
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27(36):6199-206
Bleicher RJ, Essner R, Foshag LJ, et al. Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas. J Clin Oncol 2003;21(7):1326-31
69.
57.
Covarelli P, Vedovati MC, Becattini C, et al. The sentinel node biopsy in patients with thick melanoma: outcome analysis from a single-institution database. In Vivo 2011;25(3):439-43
Fenske NA, Lober CW. Structural and functional changes of normal aging skin. J Am Acad Dermatol 1986;15(4 Pt 1): 571-85
70.
Luscieti P, Hubschmid T, Cottier H, et al. Human lymph node morphology as a function of age and site. J Clin Pathol 1980;33(5):454-61
71.
Conway WC, Faries MB, Nicholl MB, et al. Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol 2009; 16(6):1548-52
72.
Sassen S, Shaw HM, Colman MH, et al. The complex relationships between sentinel node positivity, patient age, and primary tumor desmoplasia: analysis of 2303 melanoma patients treated at a single center. Ann Surg Oncol 2008;15(2):630-7
73.
Guggenheim MM, Hug U, Jung FJ, et al. Morbidity and recurrence after completion lymph node dissection following sentinel lymph node biopsy in cutaneous malignant melanoma. Ann Surg 2008;247(4):687-93
74.
Kingham TP, Panageas KS, Ariyan CE, et al. Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol 2010;17(2):514-20
58.
59.
60.
61.
Ferrone CR, Panageas KS, Busam K, et al. Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 2002;9(7):637-45 Gershenwald JE, Mansfield PF, Lee JE, Ross MI. Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (> or = 4 mm) primary melanoma. Ann Surg Oncol 2000;7(2):160-5 Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatol Ges 2008;6(3):198-203 Jacobs IA, Chang CK, Salti GI. Role of sentinel lymph node biopsy in patients with thick (>4mm) primary melanoma. Am Surg 2004;70(1):59-62
Kelly JW. Melanoma in the elderly a neglected public health challenge. Med J Aust 1998;169(8):403-4
62.
Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Melanoma Res 2010;20(3):163-70
Ra JH, McMasters KM, Spitz FR. Should all melanoma patients undergo sentinel lymph node biopsy? Curr Opin Oncol 2006;18(2):185-8
75.
63.
Rondelli F, Vedovati MC, Becattini C, et al. Prognostic role of sentinel node biopsy in patients with thick melanoma: a meta-analysis. J Eur Acad Dermatol Venereol 2012;26(5):560-5
Leong SP. Role of selective sentinel lymph node dissection in head and neck melanoma. J Surg Oncol 2011;104(4):361-8
76.
Vermeeren L, van der Ent FW, Sastrowijoto PS, Hulsewe´ KW. Thick melanoma: prognostic value of positive sentinel nodes. World J Surg 2009;33(11): 2464-8
Willis AI, Ridge JA. Discordant lymphatic drainage patterns revealed by serial lymphoscintigraphy in cutaneous head and neck malignancies. Head Neck 2007;29(11): 979-85
77.
MSLT-II. Complete lymph node dissection or observation in treating patients with localized melanoma and sentinel node metastases who have undergone sentinel lymphadenectomy (MSLT-ii). Available from: www.clinicaltrials.gov/ct/show/ nct00389571?order=1
78.
Hoersch B, Leiter U, Garbe C. Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol 2006;155(4):771-7
Hanrahan PF, Hersey P, D’Este CA. Factors involved in presentation of older people with thick melanoma. Med J Aust 1998;169(8):410-14
52.
Kallini JR, Jain SK, Khachemoune A. Lentigo maligna: review of salient characteristics and management. Am J Clin Dermatol 2013;14(6):473-80
53.
Perrotta R, Bevelacqua Y, Malaguarnera G, et al. Serum markers of cutaneous melanoma. Front Biosci (Elite Ed) 2010;2: 1115-22
54.
Malaponte G, Zacchia A, Bevelacqua Y, et al. Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-beta in melanoma
informahealthcare.com
64.
65.
66.
Essner R, Chung MH, Bleicher R, et al. Prognostic implications of thick (‡4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy. Ann Surg Oncol 2002; 9(8):754-61 Chao C, Martin RC II, Ross MI, et al. Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 2004;11(3):259-64
107
Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Korea University on 01/04/15 For personal use only.
Review
` , Antonelli, Priolo, McCubrey & Libra Russo, Ferrau
79.
Whiteman DC, Stickley M, Watt P, et al. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol 2006; 24(19):3172-7
80.
Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009;27(1):3-9
81.
Haigh PI, DiFronzo LA, McCready DR. Optimal excision margins for primary cutaneous melanoma: a systematic review and meta-analysis. Can J Surg 2003;46(6): 419-26
82.
Albertini JG, Countryman NB. Practice gaps: delayed treatment and inadequate surgical margins for invasive melanoma in elderly patients. JAMA Dermatol 2013; 149(10):1158
108
83.
84.
••
Livingstone E, Windemuth-Kieselbach C, Eigentler TK, et al. A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up. Eur J Cancer 2011;47(13):1977-89 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23 In this Phase III trial, the humanized monoclonal antibody ipilimumab exhibited a survival benefit in patients with previously treated metastatic melanoma.
85.
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517-26
86.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507-16
87.
Wolf J, Harris R, Ferris LK. Screening for Melanoma in Aging Patients. Cutis 2013;91:81-6
Expert Rev. Anticancer Ther. 15(1), (2015)
