Melanoma Treatment and Curcumin Benefits

Melanoma

• Melanoma is a type of skin cancer that accounts for around 80% of all newly diagnosed cancers in Australia by the time people are 70.
• Two in three Australians will be diagnosed with skin cancer by the time they are 70.
• Basal cell carcinoma (BCC) is the most common type, making up 80% of skin cancers.
• It has a low metastatic potential but can be locally destructive.
• Squamous cell carcinoma (SCC) is the second most common skin cancer, comprising 20% of cases and can develop in sites of chronic wounds or scarring.

Learning Outcomes

• Identify the prevalence of different types of skin cancers
• Know the risk factors for skin cancers
• Recognise symptoms of BCC and SCC
• Know the prevention and treatments for BCC and SCC
• Understand the pathogenesis of cutaneous melanoma
• Appreciate treatments for cutaneous melanoma
• Compare and contrast target therapy with immunotherapy
• Know drug classes, names, and mode of action in cutaneous melanoma

Risk Factors

• Non-melanoma: UV exposure (especially early childhood), Male > Female
• Melanoma: UV, fair skin type, multiple atypical moles, family history of melanoma, genetic predisposition

BCC and SCC Manifestations

• Images of BCC and SCC are included showing the physical manifestations, including characteristics such as a locally destructive and slow-growing nature.

BCC/SCC Prevention and Treatments

• Prevention: Sun protection, oral nicotinamide (Vitamin B3), topical fluorouracil
• Treatment: Surgical excision, Mohs surgery, curettage and electrodesiccation, photodynamic therapy (PDT), cryosurgery, topical fluorouracil/imiquimod, radiation

Melanoma Manifestations

• Different types of melanoma are shown and their associated features
• Includes superficial spreading, nodular, lentigo maligna, acral lentiginous and mucosal melanoma

Melanoma Screening and Diagnosis

• People at increased risk for melanoma should be screened regularly.
• Screening involves a total body skin examination supported by dermoscopy or other imaging techniques.
• Screening is useful for early detection of all skin cancers.

Melanoma Pathophysiology

• Genetic level: Activating BRAF mutation, telomerase reverse transriptase mutation, cell cycle controlling genes mutations and their effect on the development of melanoma.
• Protein level: Over-stimulation of MAPK pathway, deletion, mutations in PTEN or tumour protein p53.

Target Therapy C-KIT

• A small number of melanomas have changes in the C-KIT gene.
• Clinical trials are testing drugs such as imatinib, dasatinib, and nilotinib as target therapy for C-KIT changes.
• Drug resistance is associated with the frequent presence of brain and central nervous system metastases.

Target Therapy Table

• Shows various types of inhibitors and their associated dosages.
• Includes dabrafenib combined with trametinib, Vemurafenib combined with cobimetinib, encorafenib combined with binimetinib, imatinib combined with nilotinib.

Pathophysiology- Adaptive Immune Resistance

• Checkpoint inhibition: Monoclonal antibodies such as ipilimumab against CTLA-4, enhancing T cell response against melanoma cells to prevent negative feedback

Immunotherapy Table

• Lists various immunotherapy agents and their respective approvals/phases of development
• Includes ipilimumab for CTLA-4, pembrolizumab, Nivolumab, Pidilizumab, Durvalumab, Atezolimab

Melanoma Genetic Alterations

• Four different genetic melanoma subtypes: BRAF mutant melanomas (50%), N-Ras, K-Ras, and H-Ras-mutant melanomas (25%), NF1-mutant (15%) and Triple-wild-type (10%) .
• Activating TERT-promoter mutations (30-80%)
• Altered tumor suppressors - CDKN2A, PTEN, P53

Melanoma Treatment By Stage

• Treating stage 0-1 melanoma: Surgery to remove the melanoma and a small margin of normal skin around.
• Treating stage II or above melanoma: Surgery + lymph node biopsy; If lymph node positive, target therapy/immunotherapy is required.

Target Therapy Considerations

• Rapid response within days to a few weeks.
• Favourable treatment outcomes with BRAF inhibitor + MEK inhibitor compared to monotherapy with a BRAF inhibitor.
• Good safety and tolerability profile, common side effects include nausea, diarrhoea, vomiting, arthralgia, fatigue, photosensitivity, increase in creatine kinase and liver transaminases, peripheral oedema, alopecia, and hyperkeratosis.

Immunotherapy Considerations

• CTLA4 inhibitor (ipilimumab): Demonstrated superior efficacy compared to chemotherapy, but caused a range of immune related adverse events (irAE)
• PD-1 blockers (nivolumab, pembrolizumab): Showed superior efficacy compared to ipilimumab and chemotherapy, with lower toxicity rates

Management- Challenge

• Multiple mechanisms of resistance against BRAF and MEK inhibitors have been identified.
• Immune inhibition of lymphocyte activation gene-3 (LAG-3) is often linked to managing PD-1 immunotherapy tolerance.

Combination Therapy

• Combining PD1 and PD-L1 leads to longer progression-free survival but has a higher rate of grade 3/4 adverse events compared with doublet therapies.
• Sequencing approach (giving one drug after the other) might result in similar survival as full combination therapy with less toxicity.

Sample Exam Questions

• Questions regarding each topic are presented in a sample exam format.

Rheumatoid Arthritis

• Learning Outcomes: describe inflammatory and immunological mechanisms, identify drug targets, understand DMARD drug selection, define mechanisms of action and toxicity of DMARDs.
• Practice Point: Advice for pharmacists' role in RA management
• Background: Symmetric polyarthritis of hands, wrists, and feet. Low-grade fevers, anemia (fatigue). Joint erosion and destruction may occur in RA, alongside systemic inflammation.
• Symptoms: Primarily affects the joints, with possible first symptoms in metacarpophalangeal, proximal interphalangeal, and wrist joints, leading to prolonged morning stiffness and pain.
• Common Presentations: Swollen, tender, stiff multiple symmetrical joints lasting for more than an hour in the morning or after inactivity. Chronic fatigue + fever + weight loss. Possible joint destruction and systemic inflammatory symptoms including fatigue and fever.
• Joint Changes: X-ray images showing the effects of RA on the joints, including joint swelling, destruction, and loss of joint space.
• Common Sites: Images illustrating common locations affected by RA, including the distal interphalangeal joints (DIP), proximal interphalangeal joints (PIP), and metacarpophalangeal joints (MCP).
• Risk Factors: Age (most common >60 years), Sex (women > men), Genetics (HLA genes encoding MHCII protein), Smoking (current or former), History of nulliparous births, Early life exposure to smoking or infections, and Obesity.
• Pathogenesis: The description of the underlying disease mechanisms, particularly the role of citrullination in immune system dysfunction and subsequent inflammatory response leading to joint damage from uncontrolled synovial tissues proliferation. Also includes the role of APCs, CD4+ T cells, and resulting autoantibodies (ACPA, RF) in disease progression.
• Pathogenesis Overview: Video showing the mechanistic details of RA (presumably a New England Journal of Medicine video)
• Induction of RA Pathogenesis: Specific diagram depicting stages of RA pathogenesis, including citrullination, macrophage presentation, B cell proliferation, and plasma cell production of autoantibodies.
• RA Pathogenesis: Diagram showing key cells (macrophages, T cells, B cells, fibroblast-like synoviocytes, osteoclasts) and cytokines (TNF, IL-1, IL-6) involved in the pathophysiology of RA.
• Antigen Presentation Dysfunction in Autoimmunity: Diagram highlighting the role of HLA-DRB1 variants in enhancing citrulline binding and leading to stronger T cell activation.
• Early B Cell Antigen Recognition and Autoantibody Production: Diagram showing the process of autoreactive B cell activation and the lack of central tolerance in RA patients.
• Microbiome Linkages with RA: Environmental risk factors such as respiratory diseases, smoking exposure, and periodontal/dental issues can contribute to tissue damage and further disease. High risk of disease with HLADRb1. Many bacteria can cause post-translational modification (PTM) such as citrullination, leading to autoantibodies (ACPA and IgG) in the sputum of RA patients.
• Joint Erosion: Diagram showing the mechanism of joint erosion, including inflammation with macrophage activation, excessive protease secretion damaging cartilage, bone erosion (osteoclast activity), and synovial hyperplasia.
• Linkages Between Cytokines and Symptoms: Diagram depicting the connection between various cytokines and clinical symptoms like inflammation, destructive changes, and systemic inflammation.
• Management of RA: Goals of therapy include symptom relief, modifying disease course, inducing and maintaining remission, and preventing relapses. Special considerations for pregnancy and co-morbidities.
• Considerations: Symptom relief, disease modification, induction of remission, maintaining remission, preventing relapses, and treatments for pregnancy and co-morbidities.
• Why is treatment of early RA Important?: Early treatment leads to reduced joint damage, reduced bone mineral density loss, and prevents disability.
• How to Differentiate Between MSK Conditions: Differentiating factors between RA and other joint diseases, including clinical history, disease extent, extra-articular symptoms, blood results, and joint aspiration.
• Treatment Strategy: Symptomatic treatments (non-pharmacological, analgesics, anti-inflammatory drugs, corticosteroids.) and Disease-Modifying Anti-Rheumatic Drugs (DMARDs) are initiated early, often in combination to improve long-term outcome and slow disease progression. This includes synthetic DMARDs (methotrexate, leflunomide, sulphasalazine, hydroxychloroquine) and biologics (antibodies to cellular processes or ligands).
• Methotrexate: Mechanism of action, dosages, adverse events, precautions, and practice points.
• Leflunomide: Mechanism of action, dosages, adverse events, precautions, and practice points.
• Sulfasalazine: Mechanism of action, dosages, adverse events, precautions, and practice points.
• Hydroxychloroquine: Mechanism of action, dosages, adverse events, precautions, and practice points.
• Efficacy Comparison: Comparison of various DMARD efficacy on the use of the PBS.
• Combination Rx: Risk and benefit of combining DMARDs including MTX, Hydroxychloroquine, and Sulfasalazine.
• Criteria for Biologics: Specific criteria are listed for use of biologics for rheumatoid arthritis treatment.
• Choice of First bDMARD for RA: Selection of a first-line biologic DMARD in rheumatoid arthritis patients, taking into consideration approval guidelines, patient characteristics and adherence factors. Cost of medication and prescription consideration are also included.
• Immunologic Targeting: Includes specific examples of biologics targeting different systems within the immune response (e.g. anti-CD19, anti-TNF).

Additional Topics

• Sample Exam Questions: Sample exam questions for both Melanoma and Rheumatoid Arthritis.
• Evidence-based Complementary Medicines for Osteoarthritis Pain and Disability 2024: Specific information on evidence and safety regarding CM use in osteoarthritis management and treatment.
• Glucosamine: Description of glucosamine sulfate and its naturally occurring source from synovial fluid as a supplementary aid in osteoarthritis treatment.
• Chondroitin: Overview of chondroitin, its source, proposed mechanisms of action, efficacy evidence (specifically in Cochrane review updated 2009), and safety considerations.
• Indian Frankincense (Boswellia serrata): Description of the composition of Indian frankincense, its active components, efficacy (specifically in clinical trials shown in the lecture), and safety precautions.
• Turmeric (Curcumin) : Overview of curcumin as an active constituent of the turmeric rhizome, the effect on inflammation, efficacy, clinical trials, adverse effects (particularly hepatotoxicity from recent data), and drug interactions.
• Pycnogenol: Overview of Pycnogenol, derivation, effects on matrix metalloproteinases (MMPs), and evidence regarding benefits in osteoarthritis patients.
• Methylsulfonylmethane (MSM): Characteristics of the compound, its application in osteoarthritis and its effect on inflammatory cytokines.
• Omega-3 Fatty Acids: Overview of the mechanism of action of Omega-3 fatty acids and its effects of inflammatory conditions.
• Case Studies (2023 and 2024): Specific cases of individuals who present to a pharmacy with distinct skin or joint conditions with specific details and the required questions to evaluate and provide advice.
• Contact Dermatitis: Definition, causes, typical symptoms, and treatment.
• Topical Corticosteroids: Indications, application, precautions, and commonly available types.
• Cutaneous Drug Reactions: An overview of the potential for a drug reaction to the skin based on their mechanism, type of response, severity, common triggers, and how to recognize clinical features and when to refer to the GP or dermatologist.