Treating Advanced Melanoma: Current Insights and Opportunities

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Treating patients with advanced stage melanoma continues to be a therapeutic challenge. As the incidence of melanoma in certain population increases at a fast pace (2% to 7% annual increase in incidence rate in countries with a fair skinned population), researchers have determined that behavioral changes, changes in diagnostic criteria in histopathology, and possibly the change in the medicolegal climate play as factors in the increase in melanoma incidence.

Surgery is typically the treatment of choice, however when an inoperable tumor is presented it requires systemic therapy. Previously systemic therapy included the application of different chemotherapy regimens, either as monochemotherapy or as polychemotherapy, which can lead to sever toxicities and generally did not result in an improvement in a patient’s overall survival or progression-free survival.

While chemotherapeutic options for melanoma still exist, the development of targeted therapies, new drug options, and immunologic substances has revised the standard treatment guidelines for metastatic disease. Individualized targeted therapy has recently created incomparable response rates for patients with melanoma.

However, the early development of resistance is the major weakness of this therapy. Researchers are looking to develop a combination of various targeted substances that will aid in resistance and must continue to find new immunologic keys, sequence different therapies, and develop more targeting substances (while also developing a more advanced understanding of resistance mechanisms) to continue to improve the outlook for patients diagnosed with metastatic melanoma.

Melanoma disease in advanced stages still proves to be a therapeutic challenge
Melanoma disease in advanced stages still proves to be a therapeutic challenge

Abstract

Whereas thin melanomas have an excellent prognosis after sufficient surgical treatment, melanoma disease in advanced stages is still a therapeutic challenge. After decades of frustrating studies, new therapeutic strategies have come up in the past few years. On the one hand, increasing insights into the molecular aberrations in melanoma have led to specific “targeted” therapies to affect only the mutated tumor cells, as in many other types of cancers.

Today there are few “targeted” substances which are already approved and successfully used for single or combination therapy, but many others are under development. While on the other hand, nonpersonalized strategy substances have been developed successfully inducing an immunologic tumor response. Both kinds of therapy have been found to result in an improvement not only of the response rate, but also of the overall survival in metastatic disease, which represents a milestone in melanoma therapy.

However, using these therapies there is still much to learn regarding the effects, the side effects, and the limitations of these promising substances.

Keywords: melanoma, treatment, targeted therapy, immunotherapy, BRAF, CTLA-4

Introduction

In countries with a fair-skinned population, the incidence of melanoma is increasing faster than in any other type of cancer – a fact, which has led to the use of the term melanoma “epidemic”.1,2 The incidence rate per year is rising by 2%–7% annually – thus it doubles around every 10 years.3,4

This impressive rise in incidence may be due to several factors, including behavioral changes, better early detection by screening instruments, changes in diagnostic criteria in histopathology, and perhaps also the change in the medico-legal climate.2,5

Whereas surgical procedures are usually the treatment of choice with primary tumors, regional disease, and single metastases, an inoperable tumor manifestation requires a systemic therapy. For many years various chemotherapeutic regimen have been applied, either as monochemotherapy or as polychemotherapy, which in general did not result in an improvement of progression-free or overall survival, but sometimes in severe toxicities.6

The development of new substances, targeted therapies, and immunologic substances has completely changed the former treatment guidelines for metastatic disease in melanoma.2,7

This review focuses on the new development in therapy and future perspectives. Nevertheless, the chemotherapeutical procedures still remain an option in treating metastatic melanoma.

Targeted therapy

The number of mutations found in melanoma is high compared to the number in other metastatic tumors. This may be due to the fact that ultraviolet (UV) light is involved in the pathogenesis of melanoma.7

The analysis of the mutational status of melanoma disease clearly shows that the various clinical manifestations of melanoma also differ in their molecular changes, which subsequently will be of importance for therapies directed against tumors bearing a distinct mutation.

According to the findings of molecular studies in melanoma, the unifying concept of one melanoma disease which is mainly based on dermatopathologic criteria is outdated.8 However, the knowledge of the mutational landscape in melanoma alone does not help in the development of therapeutic strategies. Concerning the high rate of mutations it must be differentiated which mutation is causative in the disease (driver mutation) and which is only a bystander mutation (passenger mutation).8

Approval of single substances directed against mutated proteins has dramatically changed the options available in melanoma therapy. The most important task for the future will be to overcome primary and, even more important, secondary resistance to the targeted therapeutics. In addition, the understanding and management of the frequent side effects of these new therapies have to be improved.  

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