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Melanoma

Table of Contents
1 Disease Overview
        1.1 Types
        1.2 Risk Factors and Prevention
        1.3 Screening
        1.4 History, Symptoms and Signs
        1.5 Diagnosis and Tumour Assessment
2 Staging
3 Stage Grouping
4 Treatment Modalities
        4.1 Surgery
        4.2 Chemotherapy
        4.3 Radiation Therapy
        4.4 Biological Therapy or Immunotherapy
        4.5 Treatment of Metastatic Melanoma
        4.6 Clinical Trials
        4.7 Palliative Therapy
5 Follow-up
        5.1 Stage 0
        5.2 Stage IA
        5.3 Stage IB-IV
6 Pivotal Trials

Disease Overview

    Melanoma originates in melanocytes or cells developing from melanocytes. This malignancy may develop from a precursor lesion, or in apparently normal skin. Typically, melanomas first grow radially, then vertically; once the cells invade the dermis, they tend to metastasize. Approximately one out of 58 men and one out of 82 women will be diagnosed with melanoma in their lifetimes. Melanoma affects all age groups and is the leading cause of death from cutaneous malignancies. In 2010, Statistics Canada estimated 5300 new cases and 920 deaths accounts for 1% to 2% of all cancer deaths in Canada.

Types

  • Superficial spreading melanoma (SSM): This sub-type comprises of 70% of cutaneous melanomas, and often develops from a dysplastic nevus, which can be found anywhere on the body. Typically, after a long period of stability, the nevus may enlarge, ulcerate, or change colour.
  • Nodular melanoma (NM): This sub-type makes up 10% to 15% of melanomas and is found in any body area. The lesions, which tend to be symmetrical and brown or black (about 5% are amelanotic), are high-risk malignancies, as they rapidly advance to the vertical growth phase.
  • Lentigo maligna melanoma (LMM): This melanoma sub-type makes up 10% to 15% of all melanomas and is usually found on sun-exposed skin. The lesions arise from precursor lesions, tend to be large, and may be hypopigmented.
  • Acral lentiginous melanoma (ALM): These aggressive melanomas are found on the palms, soles, and subungual areas.
  • Mucosal lentiginous melanoma (MLM): These lesions, which make up approximately 3% of melanomas, may occur on any mucosal surface. They are often diagnosed at an advanced disease stage in elderly patients, and their behaviour is aggressive.

Risk Factors and Prevention

    The most important melanoma risk factor is exposure to ultraviolet radiation, especially severe sunburns. Other strong risk factors are a changing mole, dysplastic nevi in familial melanoma, and more than 50 nevi. Factors moderately increasing risk are family members with melanoma, previous melanoma, sporadic dysplastic nevi, and congenital nevus. Risk is slightly increased by immunosuppression, sun sensitivity, history of severe blistering sunburns, and freckling. The most important preventive strategy is avoidance of sun exposure and sunburn. The proportion of melanomas that develop from menanocytic nevi ranges from 18% to 85%. 10% of melanoma patients have a family history of the disease.

Screening

    No screening tests or programs are available. Regular skin examination, however, is important to early detection and curative surgery.

History, Symptoms and Signs

    Family and personal history of melanoma or other skin cancer, and of irregular, prominent moles is important. In addition, a personal history of sun exposure and of any changes in an existing mole is important. Signs of melanoma may include change in size, shape, colour or symmetry of a mole; ulceration of a mole; development of a skin lesion, or changes in lymph nodes.

Diagnosis and Tumour Assessment

    Definitive diagnosis is based on a complete excisional biopsy of a suggestive lesion, including all skin layers and subcutaneous fat and a 1-2 mm margin of healthy skin. Regional lymph node dissection is indicated in patients with enlarged lymph nodes but without evidence of distant spread.

    Prognosis depends on melanoma type, lesion thickness, ulceration, and nodal status at diagnosis. Laboratory investigation includes hematology, complete chemistry panel and lactic dehydrogenase, which may be elevated in metastatic disease. Imaging studies are needed if advanced disease is suspected.


Staging

    Stages I and II is localized primary melanoma to the skin, stage III melanoma is regional involvement, and stage IV is metastatic disease beyond regional lymph nodes. It is estimated 82% to 85% of melanoma patients present with stages I or II, 10% to 13% present with stage III, and 2% to 5% present with stage IV.

*Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).

**Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.


Stage Grouping


Treatment Modalities

Surgery

    Surgery to remove the tumour is the primary treatment of all stages of melanoma. A decision to have surgery depends on the size, thickness of the melanoma and the location of the lesion.

    For melanomas less than 1 mm in thickness without ulceration or Clarks level II-III, a wide excision of the primary melanoma should be performed. No further treatment is required.If the melanoma is greater than 1 mm, or < 1 mm with ulceration, or Clarks level IV-V, wide excision and possibly sentinel lymph node biopsy should be considered. If a positive SLN is found, completion of axillary lymph node dissection should be done, and patients should consider a clinical trial, adjuvant interferon treatment, or observation. When SLN is negative and the melanoma is > 4 mm, consider a clinical trial, adjuvant interferon treatment, or observation.

Chemotherapy

    Chemotherapy has shown modest activity in treatment of melanomas. For metastatic melanoma, the median survival is only nine months, although this depends on many factors. Treatment options for metastatic melanoma include observation, resection of solitary metastasis, dacarbazine-based or temzolamide-based therapy. There is no evidence that combination therapy is better than single agent treatment for patients with metastatic melanoma. For melanoma on a leg or arm, chemotherapy drugs may be put directly into the bloodstream of that limb.

Radiation Therapy

    Radiation therapy may be used to help control melanoma that has spread to other parts of the body. It can also help relieve pain or other symptoms.

Biological Therapy or Immunotherapy

    Biological therapy can target specific cells without damaging healthy cells. Side effects of biological therapy can be mild or severe, depending on the type of treatment. Interferon therapy may be considered as adjuvant therapy following surgery for patients with primary melanomas that are more than 4 mm, for patients with stage III, or node positive disease. Interleukin-2 (IL-2) is a potent T cell activator and is used for metastatic melanoma. It is usually associated with serious side effects which is dose related due to capillary leak syndrome. Most of the side effects are self-limiting and resolve when the drug is discontinued.

    Vaccine therapy is a type of biologic therapy. Cancer vaccines work by helping the immune system recognize and attack specific types of cancer cells.

Treatment of Metastatic Melanoma

    Metastatic melanoma can affect virtually any organ of the body; most common sites are lung, skin, liver, and brain. Traditionally, melanoma has been a challenging disease to treat because chemotherapy is typically not effective and cytokine therapy, such as high-dose interleukin-2 (HD IL-2), only helps a small percentage of patients. Highlighting the futility of early approaches to the development of effective therapies for melanoma, from 1976 to 2011 the U.S. Food and Drug Administration (FDA) approved only dacarbazine and HD IL-2 for the treatment of melanoma. Median survival with dacarbazine ranged from 5-11 months. HD IL-2 caused some durable remissions but treatment had serious toxicity and were done in specialized centres.

    Over the past decade, however, great advances in molecular-targeted and immune-targeted therapies have led to a therapeutic revolution. Since 2011, six agents, three molecular targeted therapies (vemurafenib, dabrafenib, trametinib), and three immunotherapies (ipilimumab, pembrolizumab, nivolumab) have regulatory approval. A 2011 practice changing trials of Vemurafenib, a potent and selective BRAF inhibitor, showed promising results compared to standard therapy with dacarbazine in BRIM III. Response rate was 48% compared to 5%, and median overall survival with vemurafenib was 13.6 vs 9.7 months with dacarbazine.

    Three immunomodulatory drugs have been approved for metastatic melanoma (ipilimumab-CTLA4 inhibitor, pembrolizumab, nivolumab-PD1 inhibitor). There are ongoing clinical trials with immunomodulation in melanoma and other cancers.

    Patients should be encouraged to participate in clinical trials as this new field of precision medicine evolves and we change the natural history of metastatic disease with durable responses and survival. The use of novel molecular targeted therapies, alone or in combination, holds great promise for the treatment of melanoma, but is not without challenges.

    Wolchok et al presented the results of a randomized, double-blind, phase III trial designed to evaluate Nivo combined with IPI or NIVO alone vs IPI alone in MEL. At a minimum follow-up of 9 months, NIVO + IPI and NIVO alone significantly improved PFS and ORR vs IPI (Table). Grade 3-4 drug-related adverse events (AEs) occurred in 55.0%, 16.3%, and 27.3% of pts in the NIVO + IPI, NIVO, and IPI arms, respectively (most commonly diarrhea [9.3%, 2.2%, 6.1%], increased lipase [8.6%, 3.5%, 3.9%], increased alanine aminotransferase [8.3%, 1.3%, 1.6%], and colitis [7.7%, 0.6%, 8.7%]). Drug-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of pts in the NIVO + IPI, NIVO, and IPI arms, with 0, 1, and 1 drug-related deaths, respectively. NIVO + IPI and NIVO alone had superior clinical activity vs IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents (J Clin Oncol 33, 2015 [suppl; abstr LBA1]).

Clinical Trials

    Patients are to be encouraged to participate in ongoing clinical trials of new chemotherapy, biologic therapy, and/or targeted therapy with monoclonal antibodies, or vaccine therapy.

Palliative Therapy

    For advanced stage melanoma, palliative therapy may be considered to relieve the symptoms and reduce the suffering. Palliative cancer therapies are given together with other cancer treatments.


Follow-up

    For patients with no evidence of disease, melanoma stage determines the follow-up schedule and recommended examinations.

Stage 0

  • Skin examination: annually for life
  • Self-examination of skin: monthly for life

Stage IA

  • History and physical focused on skin and lymph nodes: every 3 to 12 months for five years, then annually as indicated
  • Skin examination: annually for life
  • Self-examination of skin and lymph nodes: monthly for life

Stage IB-IV

  • History and physical focused on skin and lymph nodes: every 3 to 6 months for two years, then every 3 to 12 months for two years, then annually as indicated
  • Optional: Chest radiography, lactic dehydrogenase and hematology every 6 to 12 months (routine imaging is not recommended for stage IB or IIA)
  • CT scans: if clinically indicated or to screen for recurrent or metastatic disease in stages IIB to IV
  • Skin examination: annually for life
  • Self-examination of skin and lymph nodes: monthly for life

Pivotal Trials

Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17

Kirkwood JM, Ibrahim J, Sondak V. et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of Intergroup Trial E1690/S9111/C9190. J. Clin Oncol. 2000; 18(12):2444-2458


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