melanoma
MELANOMA
Melanoma is a skin neoplasm that originates from malignant transformation of melanocytes.
It commonly occurs in the extremities of women and on trunk or head and neck in men.
Metastases are via lymphatic and hematogenous routes.

Pharmacotherapy

Clinical Trial

  • Considered candidates for ongoing clinical trials are patients w/ all stages of melanoma
  • Highly considered for patients due to the advances in the development of new drugs & combination of agents w/c help in reversing or interrupting aberrant molecular pathways that aid in the growth of the tumor

Systemic Therapy

  • Additional treatment modalities for patients w/ either resectable or unresectable disease
  • Preferred treatment modality for unresectable or systemic nodal recurrence & disseminated unresectable distant metastatic melanoma
  • Preferred regimens for advanced or metastatic disease include Ipilimumab, Vemurafenib, Dabrafenib, Dabrafenib w/ Trametinib, clinical trial, & high-dose Interleukin-2

Immunotherapy

  • Checkpoint inhibitors, eg Pembrolizumab (Lambrolizumab) & Nivolumab
    • Antibodies which inhibit programmed death (PD-1) receptors that diminish effector responses of T-cell against cancer
    • Pembrolizumab & Nivolumab had been approved for the treatment of advanced or unresectable melanoma unresponsive to other drugs & disease progression after therapy w/ Ipilimumab & BRAF inhibitor, if BRAF V600 positive
    • A large phase I trial had shown long-lasting clinical responses w/ low toxicity
    • Phase II & III trials have shown that Pembrolizumab has higher response rates & lesser toxicity compared to Ipilimumab
  • Interferon alfa
    • High-dose Interferon alfa-2b (IFN-a-2b) is an immunomodulating cytokine used for adjuvant treatment of melanoma stage IIB-III & nodal recurrences
    • Pegylated Interferon alfa-2b (peginterferon alfa-2b/PegIFN-a-2b) is an interferon formulation conjugated to polyethylene glycol for improved circulation & decreased immunogenicity
      • An alternative to high-dose non-pegylated interferon for adjuvant treatment of stage III disease that has been resected with microscopic or gross LN involvement
    • High-dose & pegylated Interferon alfa may be given to patients who had complete surgical resection but had a high risk for relapse
      • High-dose IFN-a is given for up to 1 yr or PegIFN-a-2b for up to 5 yr
    • Prospective, randomized, controlled trials w/ high-dose & pegylated Interferon alfa have not demonstrated increase in OS when compared w/ observation
    • Close patient monitoring should be done due to significant toxic side effects from both agents
  • Interleukin-2 (IL-2)
    • May be given to patients w/ brain metastases that are small and no significant peritumoral edema
    • Demonstrated durable complete response in few patients w/ metastatic melanoma that have been previously treated; however, randomized trials failed to show improvement in OS
    • High-dose IL-2 can cause serious cardiac & pulmonary side effects, thus is generally given for young healthy patients
  • Ipilimumab
    • A monoclonal antibody to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) that is considered the treatment of choice for unresectable or metastatic disease
      • Blocks CTLA-4 function in down regulating T-cell activation, thus allowing the immune system to attack tumor cells
    • High dose Ipilimumab is an alternative treatment option for sentinel node positive melanoma stage III & stage III w/ clinically positive node/s & as adjuvant therapy for nodal recurrences
    • Response rate is <20%; though it may take months for a clinical response to become discernible, this response, however, is durable
    • Has shown improvement in progression-free survival & OS in trials of patients w/ advanced or unresectable disease
    • When combined w/ Nivolumab for patients w/ metastatic or unresectable disease, may improve relapse-free survival but w/ increased toxicity compared to Nivolumab or Ipilimumab monotherapy
    • Indications for Ipilimumab reinduction are the following: Absence of remarkable systemic toxicity during previous therapy, relapse occurring after first clinical response, or progression following disease stability >3 mth
    • Close monitoring is needed as immune-mediated reactions may be severe eg colitis, hepatitis, skin inflammation

Targeted Therapy (Signal Transduction Inhibitors)

  • BRAF inhibitors, eg Vemurafenib & Dabrafenib
    • Inhibition of BRAF activity slows or stops proliferation of tumor cells & promotes apoptosis
    • Not to be used for wild-type BRAF melanoma but may instead give Ipilimumab
    • Vemurafenib is considered to be the treatment of choice for metastatic or unresectable melanoma that is BRAF V600E mutation positive
      • Response rate is 40-50% & may be seen days to weeks following therapy; however, median duration is 5-6 mth only
      • Monitoring for significant dermatologic reactions is advised
    • Dabrafenib may also be given for unresectable stage III disease, may develop episodic & recurrent fevers which are treated by drug discontinuation & use of antipyretic; monitoring for significant dermatologic reactions is also advised
    • Vemurafenib/Cobimetinib & Trametinib/Dabrafenib are preferred combination therapies for metastatic or unresectable melanoma
    • Vemurafenib & Ipilimumab combination is currently being tested in clinical trials to prevent resistance
    • Both Vemurafenib & Ipilimumab are available to patients w/ newly diagnosed & previously treated melanoma
  • MEK (mitogen-activated protein kinase) inhibitor, eg Cobimetinib, Trametinib
    • A MEK1 & MEK2 selective inhibitor that can control growth & induce cell death in some melanoma tumors w/ BRAF mutation; can be given in patients intolerant to BRAF inhibitor single-agent therapy
    • Trametinib/Dabrafenib combination therapy may be associated w/ fewer cutaneous toxicity than monotherapy
  • KIT inhibitor, eg Imatinib
    • C-KIT inhibitors are available in phase II & phase III trials for patients w/ unresectable stage III or IV mucosal or acral melanomas positive for the C-KIT mutation
    • A 23% response rate w/ Imatinib was seen in a phase II study of patients w/ metastatic melanoma positive for KIT mutation; however, limited duration of responses was shown
  • Multikinase inhibitor, eg Sorafenib
    • Active against the Raf/MEK/ERK pathway & the vascular endothelial growth-factor signaling
    • Sorafenib has minimal activity in melanoma as a single agent but combination studies continue as results of usage with Carboplatin plus Paclitaxel were encouraging

Chemotherapy

  • Eg Dacarbazine, Paclitaxel w/ or w/o Carboplatin, Temozolomide
  • Halts or slows down growth of cancer cells by interfering w/ the cells’ ability to reproduce
  • Generally not used as initial therapy for advanced disease as it is less effective than Ipilimumab & Vemurafenib
  • Dacarbazine (DTIC), a reference drug if clinical trial, immunotherapy, or new targeted drug is unavailable for the treatment of advanced or metastatic melanoma
  • Temozolomide is an oral alkylating agent that hydrolyzes to the same moiety as DTIC but has better CNS penetration
  • Other chemotherapeutic agent that has shown modest response rates for advanced or metastatic melanoma is Paclitaxel w/ or w/o Carboplatin
  • Polychemotherapy has shown no survival benefit when compared w/ monochemotherapy & is not considered first-line therapy
    • Tamoxifen addition to chemotherapy (CDBT regimen: Cisplatin, Dacarbazine, Carmustine, Tamoxifen) is ineffective & has shown no improvement in OS
  • Biochemotherapy is a combination of chemotherapy w/ IL-2 &/or Interferon alfa
    • When compared w/ chemotherapy, no impact on OS was demonstrated
    • Associated w/ increased toxic side effects
  • Recommended combination therapies for advanced or metastatic melanoma
    • Dacarbazine on days 1-3 plus Carmustine on day 1 plus Cisplatin on days 1-3; cycle is repeated w/ Dacarbazine & Cisplatin every 3 wk; repeat Carmustine cycle every 6 wk
    • Interferon alfa-2b (induction therapy w/ IV infusion on days 1-5, 8-12, & 15-19 followed by SC injection 3x wkly) plus Dacarbazine on days 22-26

Intralesional Injection

  • Intralesional injection w/ Talimogene laherparepvec (T-VEC), BCG, Interferon alfa or IL-2 & carbon dioxide laser ablation therapy may be options for local recurrence, satellite recurrence &/or stage III in-transit metastasis
  • T-VEC is also a treatment option for unresectable or systemic nodal recurrence, & disseminated unresectable distant metastatic disease
    • Associated w/ 16% response rate lasting >6 mth in highly selected patients w/ unresectable metastatic melanoma & Stage IV-m1a disease

Vaccination Therapy

  • A treatment option for patients w/ stage IV & recurrent melanoma that is currently under clinical evaluation

Others

  • For in-transit &/or satellite lesions of extremity melanoma, palliative local therapy w/ hyperthermic isolated limb perfusion w/ Melphalan w/ or w/o tumor necrosis factor-alpha has shown high rates of tumor response & palliation
    • However, impact on OS has not been shown in controlled studies
  • Topical Imiquimod is an immune response modifier that may also be used as an adjunct after excisional surgery
    • May be given for local, satellite &/or in-transit recurrence
    • Studies are limited by different treatment regimens & absence of long-term follow-up
    • The risk of an inflammatory reaction & a low threshold for a repeat biopsy to check for residual or recurrent disease should always be considered

Non-Pharmacological Therapy

Observation

  • An acceptable option when surgery is not possible
    • Though therapies directed toward reducing tumor burden may improve disease outcome, these treatment modalities have not been demonstrated to be superior to observation
Editor's Recommendations
Most Read Articles
07 May 2015
The treatment armamentarium of atopic dermatitis (AD) includes pharmaceuticals like emollients, topical corticosteroids, and topical calcineurin inhibitors. Recently available, medical devices are a newer class of topical, non-steroidal, semi-solid formulation for the treatment of AD and touted to possess emollient, anti-inflammatory, and anti-pruritic properties. To determine the role of medical devices in flare and remission management in AD, a panel of local experts from the field of dermatology, paediatric dermatology, and allergy convened to review the available evidence and highlights of the meeting are reported here.
5 days ago
Hydrochlorothiazide (HCTZ) appears to significantly increase the risks of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma (SCC), a recent study has shown.
24 Nov 2017
It appears that patients with psoriasis have lesser health-related quality of life (HRQoL) burden than those with hidradenitis suppurativa (HS), a recent study has found.
12 Nov 2017
Active and passive smoking are associated with atopic dermatitis, a new study from Korea reveals.