Metastatic Melanoma in the Older Patient

Immunologic Insights and Treatment Outcomes

Upendra P Hegde; Nitya Chakraborty; Bijay Mukherji; Jane M Grant Kels

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(2):185-193. 

In This Article

Abstract and Introduction

Abstract

Cutaneous melanoma (CM) is a highly curable skin cancer of melanocytes if diagnosed early. Unfortunately, its invasion into the deeper dermis increases the risk of it spreading to the lymph nodes and distant organs. Spread of metastatic melanoma (MM) to other organs is among one of the most dangerous conditions that is almost uniformly fatal for the majority of patients with the currently available treatment modalities. Since melanoma is an immunogenic tumor, developing novel immune strategies will continue to play a critical role in designing effective treatment modalities for those at high risk of recurrence and those with distant metastasis. While older age is believed to be a poor prognostic marker for CM, rapid expansion of the aging population and its projected increase in the coming decades is expected to result in a large number of elderly melanoma patients seeking treatment in all stages of disease. This will not only bring with it unique management challenges in this population, but also an increased burden on communities to provide financial and social resources. Comprehensive efforts will need to be directed towards early diagnosis, as well as developing safe and effective treatment. Renewed interest in the cancer immune surveillance theory coupled with recognition of aging-associated weaknesses in the immune system has put the spotlight on immunsenescence as a important risk factor for the rising incidence of CM in the aging population. Comprehensive assessment of the aging immune system might shed light, not only on weaknesses of individual components of the adaptive immune system, but also on the critical imbalances resulting from these weaknesses on anti-melanoma immunity. Identifying these imbalances might help harness novel immune-based treatment of MM in selected elderly patients. This article describes our experience of treating elderly patients with MM and the issues unique to them, with particular emphasis on insights into the aging immune system.

Introduction

Although squamous and basal cell carcinoma together account for more than 80% of all skin cancers, cutaneous melanoma (CM) attracts the most attention owing to its contribution to more than 85% of skin cancer mortality.[1] Intermittent exposure to an increasing intensity of UV light (UVL) derived from solar electromagnetic radiation is believed to be the most studied risk factor in its causation. Although the exact mechanism of UVL in the etiology of melanoma is controversial, the damage of melanocyte DNA coupled with impaired DNA repair and a tolerant anti-melanoma immunity is believed to lead to clonal evolution of melanoma. The important prognostic factors include depth of melanoma, presence of ulceration on microscopic examination, high mitotic rate, old age and presence of metastasis. Surgical excision of the tumor with negative margins is the standard of care. Those at risk of recurrence after surgical excision are patients with deeper melanomas and those with lymph node metastasis (stage IIB, IIC and III) who have a high risk of melanoma-specific mortality (30–65%) in the ensuing 10–15 years.[2] Patients with stage IV melanoma have uniformly poor outcomes, with a 5-year survival of less than 15%. Over the past 50 years, the increasing rate of melanoma incidence has risen rapidly in the Western hemisphere, from as low as one in 1500 subjects in the 1930s to a projected incidence of one in 49 and one in 73 for men and women, respectively, in 2010.[3,4] These statistics have led to aggressive social and legislative efforts directed towards patient education in regard to lifestyle and screening programs for early detection of CM. Although the success of such strategies has resulted in stabilization or even a decrease in the overall incidence of CM in younger patients, CM incidence continues to rise rapidly in the older population and particularly in older males.[5] The projected growth of the aging population is expected to increase the number of elderly melanoma patients seeking treatment for CM in all stages of the disease and is expected to result in an increased burden on communities to provide financial and social resources.[6] A number of clinical studies have reported older age as a poor prognostic marker of CM but very little has been written about the management of older patients with metastatic melanoma (MM) and their response to treatment. We have been studying immunologic characteristics of older melanoma patients, with particular emphasis on its relevance to MM in elderly patients. Our preliminary experience in treating older patients with MM suggests that, while this tumor is challenging to manage, some elderly patients have either an indolent course or respond dramatically to chemotherapeutic agents with durable responses. Although the aging-associated weaknesses of the immune system are believed to adversely impact treatment outcome of immunogenic tumor-like melanoma, imbalances between effector and regulatory components of the immune system reported to occur with aging might explain an indolent clinical course or the unusual responses observed following treatment of older patients with MM. Comprehensive examination of aging-associated changes in the immune system will help us to understand treatment outcomes and identify defects that are clinically relevant in older patients, leading to the design of successful immune-based treatment.

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