Melanoma

Melanoma is a malignant tumour arising from melanocytes, the pigment-producing cells normally found in the basal layer of the epidermis. It accounts for only about 4-5% of skin cancers but causes the large majority of skin-cancer deaths, and its incidence has risen faster than that of almost any other malignancy over recent decades.^[1] Median age at diagnosis is 45-55 years, with a predominance in males and in people of European ancestry, though melanoma occurs across all skin tones and, in patients with darker skin, is disproportionately likely to present late, at an acral or mucosal site, and at a more advanced, thicker stage.^[1][2]

Melanoma has several recognized clinicopathologic subtypes. Superficial spreading melanoma is the most common form in fair-skinned populations, typically arising in a pre-existing or new pigmented lesion with a slow radial (outward) growth phase before invading vertically. Nodular melanoma lacks this radial phase, presenting instead as a rapidly enlarging, often symmetric and uniformly coloured papule or nodule that frequently does not fit the ABCDE pattern described below - it is disproportionately responsible for thick, high-risk tumours at diagnosis. Lentigo maligna melanoma arises in chronically sun-damaged skin (face, scalp, neck) of older patients, evolving over years from a flat, tan-to-brown in-situ lesion. Acral lentiginous melanoma occurs on the palms, soles, and nail beds; it is not strongly UV-related, occurs at a broadly similar absolute incidence across skin tones, and - because it makes up a much larger proportion of melanoma in patients with darker skin, who are also less likely to be screened for melanoma at all - is a leading driver of the more advanced stage at diagnosis and worse outcomes seen in this population.

The single most important prognostic factor in localized melanoma is Breslow depth - the vertical thickness of the tumour measured in millimetres - which, along with ulceration and nodal status, drives both the surgical margin and the decision to pursue adjuvant systemic therapy (see Assessment and Diagnosis).^[3] Pharmacists are genuinely well positioned at several distinct points in the melanoma care pathway: opportunistic recognition of a concerning lesion during an unrelated encounter, practical sunscreen and sun-protection counselling that measurably reduces incident melanoma risk, and - for the growing number of patients now receiving adjuvant or metastatic immune checkpoint inhibitor or BRAF/MEK-inhibitor therapy - recognizing and counselling on a genuinely distinctive adverse-effect profile that differs fundamentally from cytotoxic chemotherapy.

Pigmented lesions demonstrating asymmetry, border irregularity, and colour variegation - the classic ABCDE morphology described below. (CDC/Carl Washington, MD, Emory University School of Medicine; Mona Saraiya, MD, MPH; Wikimedia Commons, public domain)

A melanoma lesion illustrating the irregular pigmentation and border that separate it from a benign, uniformly coloured mole. (National Cancer Institute, Wikimedia Commons, public domain)

The ABCDE criteria

The ABCDE mnemonic remains the standard bedside framework for evaluating a pigmented lesion:^[4]

• Asymmetry - one half of the lesion does not mirror the other.
• Border irregularity - edges are notched, scalloped, or poorly defined rather than smooth.
• Colour variegation - more than one shade of tan, brown, black, red, white, or blue within the same lesion.
• Diameter greater than 6 mm (roughly the size of a pencil eraser), though melanoma can be diagnosed at a smaller diameter.
• Evolving - any change in size, shape, colour, elevation, or a new symptom such as bleeding, itching, or crusting.

Diagnostic-accuracy data give a genuine sense of which features matter most: "evolving/enlargement" carried the strongest positive likelihood ratio of the 5 criteria (LR+ 8.4), and a lesion with 5 or more abnormal ABCDE-type findings present carried a positive likelihood ratio of 107 for melanoma - individual criteria are each only modestly informative on their own, and it is the combination and trajectory of change that matters most.^[4]

The "ugly duckling" sign

Not every melanoma fits the ABCDE pattern, and a purely criteria-based checklist can miss a genuinely dangerous lesion. The "ugly duckling" sign is a complementary, and often more practical, pattern-recognition approach: most people's individual nevi resemble one another in colour, size, and pattern (a person's own "signature nevus" phenotype), so a lesion that looks meaningfully different from a patient's other moles - the outlier - deserves particular scrutiny, even when that single lesion does not, in isolation, meet several ABCDE criteria. This is especially useful, and especially important, in a patient with many nevi or dysplastic (atypical) nevus syndrome, where dozens of individually atypical-looking moles can otherwise make it very difficult to know which single lesion is the one that actually matters.

Presentations that do not fit ABCDE - do not be reassured by their absence

• Nodular melanoma - often symmetric, uniformly pigmented (or entirely unpigmented), and round, so it fails most ABCDE criteria; instead, think "EFG" - Elevated, Firm to palpation, and Growing progressively over weeks. Nodular melanoma is disproportionately responsible for thick tumours at diagnosis precisely because it is missed by ABCDE-only screening.
• Amelanotic melanoma - pink, red, or skin-coloured, with little or no visible pigment; easily mistaken for a benign vascular lesion, a pyogenic granuloma, or a basal cell carcinoma. Any new, non-healing, or growing pink papule or nodule deserves the same scrutiny as a pigmented one.
• Acral lentiginous and subungual melanoma - a new or enlarging pigmented patch on the palm or sole, or a pigmented longitudinal streak in a nail. Hutchinson's sign - extension of nail-bed pigmentation onto the surrounding proximal or lateral nail fold skin - is a specific warning sign for subungual melanoma and should never be dismissed as a bruise or fungal discoloration without examination.
• Lentigo maligna - a large (often several centimetres), slowly enlarging, irregularly pigmented patch on chronically sun-damaged facial or scalp skin in an older patient; easy to under-call as ordinary sun damage given how slowly it evolves.

• Ultraviolet (UV) exposure - both cumulative lifetime sun exposure and, in particular, a history of intense intermittent exposure and sunburn in childhood and adolescence. A history of more than 5 severe sunburns is associated with an approximately 2-fold increase in melanoma risk, and indoor tanning bed use carries an independent, well-documented risk.^[2]
• Fair skin phototype (Fitzpatrick I-II) - skin that burns easily and tans poorly, often with red or blond hair, light eyes, and a tendency to freckle, carries the greatest UV-related risk; darker skin tones are meaningfully protected against UV-driven cutaneous melanoma subtypes but are not protected against the acral or mucosal subtypes, which are not UV-related.^[2]
• High nevus count - the number of common melanocytic nevi is itself an independent risk marker, and this risk compounds substantially with certain genetic backgrounds (individuals with 20 or more nevi and a high-risk MC1R genotype have been estimated to carry as much as a 25-fold increase in relative risk compared with those with very few nevi).^[2]
• Dysplastic (atypical) nevus syndrome / familial atypical multiple mole and melanoma (FAMMM) syndrome - patients with numerous clinically atypical nevi, particularly when at least 1 close relative has also had melanoma, carry a markedly elevated lifetime melanoma risk and need regular, often more frequent, total-body skin examination (see Monitoring and Follow-Up).^[2]
• Family history - a first-degree relative with melanoma raises risk; an estimated 5-10% of melanomas arise in a familial context, including germline CDKN2A pathogenic variants in some kindreds.^[2]
• Personal history of melanoma or other skin cancer - a prior melanoma is one of the strongest risk factors for a second, independent primary melanoma, part of why lifelong surveillance continues even after successful treatment (see Monitoring and Follow-Up).
• Immunosuppression - solid-organ transplant recipients on chronic immunosuppressive therapy carry a substantially elevated risk of melanoma, with pooled relative risk estimated at 5.27 for liver and heart transplant recipients and 2.54 for kidney transplant recipients compared with the general population; other immunosuppressed states (HIV, chronic lymphocytic leukemia, other hematologic malignancy, biologic immunosuppressive therapy) carry a similarly elevated, if less precisely quantified, risk.^[2]
• Older age - incidence rises with age, though melanoma is also one of the more common cancers diagnosed in younger adults, and any concerning lesion at any age warrants full evaluation.

Biopsy technique

For any lesion with genuine clinical suspicion, the preferred approach is a full-thickness excisional biopsy with narrow (1-3 mm) margins, taking the entire lesion down to subcutaneous fat. This is what allows an accurate Breslow depth measurement on the first pathology specimen, which in turn determines the surgical margin, the need for sentinel lymph node biopsy (SLNB), and eligibility for adjuvant therapy - all downstream decisions a partial (shave or punch) biopsy can compromise if it transects the base of the lesion. A wide local excision performed before histologic confirmation and staging should be avoided, since it can distort the lymphatic drainage pattern and compromise later sentinel node mapping.

Breslow depth and staging

Breslow depth - the vertical thickness of the tumour in millimetres, measured from the top of the granular layer of the epidermis to the deepest point of tumour invasion - is the single most important prognostic factor in primary cutaneous melanoma and the backbone of the American Joint Committee on Cancer (AJCC) 8th edition T-category staging:^[3]

^[3] Ulceration - loss of the overlying epidermis on histology - independently worsens prognosis within every T category. Mitotic rate, once part of the T1 definition, was removed as a formal staging criterion in the 8th edition but remains a reported, clinically relevant prognostic feature; lymphovascular invasion, tumour-infiltrating lymphocytes, and regression are similarly reported but not staging-defining. Overall stage groups this T category together with nodal (N) and metastatic (M) status: stage 0 (in situ) and stage I-II (localized, node-negative, subdivided by thickness and ulceration) are potentially curable by surgery alone; stage III reflects regional lymph node and/or in-transit metastasis; stage IV reflects distant metastatic spread. This T/N/M framework, not thickness alone, ultimately determines both prognosis and eligibility for adjuvant systemic therapy (see Choose Initial Treatment).

Sentinel lymph node biopsy and complete nodal dissection

Refer to the surgical oncology team for sentinel lymph node biopsy (SLNB) consideration for any lesion over 0.75 mm Breslow depth, or for a lesion of any thickness with associated ulceration, lymphovascular invasion, and/or significant mitotic activity - no single qualifier alone mandates or excludes SLNB, and the overall clinical picture should be reviewed by the surgical oncology team.^[1] SLNB should be performed only by surgeons specifically trained in the technique.^[1] While no individual-patient survival advantage from SLNB itself has been conclusively demonstrated, it provides valuable prognostic information, guides eligibility for adjuvant therapy and clinical trials, and randomized trial data show that a positive sentinel node predicts significantly worse disease-free and melanoma-specific survival than a negative one.^[1] Complete nodal dissection (CND) is the standard of care when SLNB is positive for macrometastasis or micrometastasis (with individualized consideration for isolated tumour cells), or when there is clinically apparent nodal metastasis (in which case SLNB itself is unnecessary, provided the metastatic work-up below is otherwise negative).^[1]

Molecular testing

BRAF mutation analysis should be considered for thick primary tumours and node-positive disease, since a BRAF V600E or V600K mutation - present in roughly 40-50% of cutaneous melanomas - opens the option of targeted BRAF/MEK inhibitor therapy alongside immunotherapy in both the adjuvant and metastatic settings (see Choose Initial Treatment).^[1] CKIT mutation analysis should be considered specifically for ocular and mucosal melanomas, where KIT mutations are more prevalent than in cutaneous disease and can open the option of imatinib in advanced, KIT-mutant disease.^[1]

Metastatic work-up

For higher-risk disease - greater than T4a, node-positive, recurrent, or with other clinical indication - order (or, if referring for systemic therapy, at least initiate) a metastatic work-up: CT of the chest, abdomen, and pelvis (or head and neck imaging specifically for head and neck melanoma), bone scan, liver function tests, complete blood count, lactate dehydrogenase (LDH), renal function panel, and electrolytes, alongside the BRAF mutation analysis above.^[1] LDH in particular carries independent prognostic weight in metastatic disease and is followed serially by the treating oncology team.

Differential diagnosis

• Dysplastic (atypical) nevus - can share ABCDE-type features with melanoma; the ugly duckling comparison against a patient's other nevi, and dermoscopy where available, help distinguish the 2, but low-threshold biopsy of any outlier lesion remains appropriate.
• Seborrheic keratosis - a "stuck-on," waxy, verrucous surface and well-demarcated border typically distinguish it, though heavily pigmented or irritated lesions can be mistaken for melanoma.
• Pigmented basal cell carcinoma - a pearly, telangiectatic border with pigment islands, rather than the diffuse variegated pigmentation of melanoma.
• Blue nevus and dermatofibroma - generally stable, symmetric, and long-standing, without the evolution history central to melanoma concern.
• Subungual hematoma - a key mimic of subungual melanoma; a hematoma grows out with the nail and does not extend onto the nail fold (no Hutchinson's sign), while a true pigmented streak that fails to grow out, or any nail-fold pigment extension, needs biopsy.
• Pyogenic granuloma - a mimic of amelanotic/nodular melanoma; both can present as a rapidly growing, friable, bleeding papule, and clinical distinction alone is unreliable - biopsy any lesion with this appearance.

• Achieve complete surgical excision with histologically clear margins for localized disease - the only curative treatment for melanoma confined to the skin and, where applicable, regional nodes.
• Accurately stage disease (Breslow depth, ulceration, mitotic rate, nodal status, and BRAF/CKIT mutation status where relevant) to correctly match the intensity of surgery, surveillance, and systemic therapy to the individual patient's actual risk.
• For high-risk resected disease, reduce recurrence risk with adjuvant systemic therapy while genuinely minimizing avoidable treatment-related toxicity - not simply choosing the most aggressive available regimen by default.
• For unresectable or metastatic disease, maximize response and survival with systemic therapy while promptly recognizing and managing its immune-related or targeted-therapy-related adverse effects, since early recognition materially changes outcomes for several of these toxicities.
• Support safe, informed self-management during systemic therapy - practical recognition of an emerging immune-related adverse event or a BRAF/MEK-inhibitor-specific toxicity (particularly dabrafenib-trametinib pyrexia) is something a patient and their pharmacist can genuinely act on together, days before a scheduled oncology visit.
• Reduce future melanoma risk and support early detection of both recurrence and a second primary melanoma through genuine, specific sun-protection counselling and structured surveillance.
• Support psychosocial wellbeing through a diagnosis that carries genuine cancer-related anxiety even at an early, highly curable stage.

Sun protection counselling - a genuine, high-yield pharmacist role

Sunscreen counselling is one of the most concrete, evidence-supported preventive actions a pharmacist can deliver in a routine encounter, and it is worth doing properly rather than as a passing "wear sunscreen" comment:

• Product selection - recommend a broad-spectrum (UVA and UVB) sunscreen with SPF 30 or higher for anyone over 6 months of age; both organic (chemical) filters and mineral filters (titanium dioxide, zinc oxide) are acceptable options, and mineral filters are often preferred for sensitive or reactive skin.^[9]
• Application amount - the amount actually matters: roughly 2 tablespoons (about 35 mL) to cover the entire body, plus a separate teaspoon specifically for the face and neck. Most people apply far less than this in practice, which meaningfully reduces the effective SPF achieved.^[9]
• Commonly missed sites - lips (use a lip balm with SPF), ears, the back of the neck, the top of the head (especially with thinning hair), and the tops of the feet are all frequently missed during self-application; specifically prompt patients to include them.^[9]
• Application technique - apply sunscreen before sun exposure, not once already outdoors, to allow it to bind to the skin; for spray formulations, spray onto the hands first and then rub in, rather than spraying directly onto the face.^[9]
• Reapplication - reapply after swimming, sweating, strenuous exercise, or towelling off, and at least every 2 hours with sustained outdoor exposure regardless of the product's stated water resistance.^[9]
• Comprehensive sun protection, not sunscreen alone - seeking shade and limiting outdoor time between 10 a.m. and 3 p.m. in summer, sun-protective clothing, wide-brimmed hats, and sunglasses all meaningfully add to sunscreen-only protection.^[9]
• Darker skin tones - sunscreen counselling should not stop at "you're less likely to burn." Patients with darker skin remain at real risk for UV-related skin damage and for the non-UV-related acral/mucosal melanoma subtypes, and can develop visible-light-induced pigmentary changes that a tinted, iron-oxide-containing sunscreen specifically helps prevent - a genuinely useful, often under-counselled product-selection point.^[9]
• Photosensitizing systemic therapy - patients on vemurafenib specifically need reinforced, strict photoprotection counselling, given a markedly increased and well-documented photosensitivity reaction with this agent (see Pharmacologic Treatment Options).

Opportunistic skin-check counselling

A community pharmacist is often one of the few healthcare contacts a patient has regularly and briefly - during a blood pressure check, an injection, a medication review, or simply picking up a prescription - and this creates a genuine, practical opportunity to notice a concerning lesion on visibly exposed skin (face, neck, forearms, hands) that the patient themselves may not have looked at closely, and to prompt a referral. Equally important is teaching patients a practical monthly self-examination routine: using a full-length mirror and a hand mirror (or a partner's help) to check the back, scalp, buttocks, and soles of the feet - sites patients very often skip - and photographing any borderline lesion to objectively track change over time rather than relying on memory.

Patient and caregiver education for systemic therapy

• Explain, in plain terms, what an immune-related adverse event is and why it differs fundamentally from a typical chemotherapy side effect - it can develop weeks to months into treatment, or even after treatment has stopped, and can affect essentially any organ system, so a new symptom in almost any body system deserves mention to the treating team rather than being dismissed as unrelated (see Red Flags and Monitoring and Follow-Up).
• For a patient starting dabrafenib plus trametinib, explain the pyrexia syndrome specifically and in advance - what to do at the first sign of fever or chills (hold both drugs, use an antipyretic, call the treating team) - so the patient is not caught off guard by a genuinely common and clearly manageable adverse effect.^[6]
• Reinforce that BRAF and MEK inhibitors in melanoma are always used as fixed, paired doses - never adjust one drug's dose or timing independently of the other without specific direction from the treating team.
• Set realistic expectations for a chronic surveillance schedule after treatment - regular skin, nodal, and (for higher-risk disease) imaging follow-up continues for years, not months, even after apparently successful treatment (see Monitoring and Follow-Up).

Skin of colour

Melanoma is genuinely less common in patients with darker skin, but this should not translate into a lower index of suspicion. Acral lentiginous and mucosal subtypes - which are not UV-related and occur at a broadly similar absolute incidence across skin tones - make up a much larger proportion of melanoma diagnosed in patients with darker skin, and are disproportionately diagnosed at a later, thicker, higher-risk stage, in part because they occur at less routinely examined sites (palms, soles, nail beds, mucosa) and in part because of a genuinely lower index of clinical suspicion for melanoma in this population.^[2] A full skin examination in a patient with darker skin should specifically and deliberately include the palms, soles, between the toes, and the nail beds; a new or changing pigmented nail streak, particularly with nail-fold extension (Hutchinson's sign), needs the same urgency as a classic pigmented lesion elsewhere (see Recognize the Condition). Sunscreen counselling remains genuinely relevant in this population (see Non-Pharmacologic Treatment) even though UV-driven cutaneous melanoma risk is lower.

Solid-organ transplant recipients and other chronically immunosuppressed patients

Chronic immunosuppression substantially raises baseline melanoma risk (see Risk Factors), which makes routine surveillance genuinely important in this population.^[2] If melanoma develops and immune checkpoint inhibitor therapy is being considered, this is a genuinely high-stakes decision that needs close, explicit coordination with the transplant team: checkpoint inhibitor therapy carries a real, well-documented risk of triggering acute graft rejection, and any reduction in baseline immunosuppression intended to allow the checkpoint inhibitor to work must be balanced individually against that rejection risk - this is not a decision oncology should make unilaterally, and a pharmacist reviewing a transplant recipient's regimen who notices a new checkpoint inhibitor order should confirm this coordination has genuinely happened.

Pregnancy

Wide local excision under local or regional anesthesia is generally considered safe during pregnancy and should not be delayed for a genuinely suspicious lesion. Sentinel lymph node biopsy technique needs modification in pregnancy - blue dye mapping is generally avoided given anaphylaxis risk and a theoretical concern about fetal dye exposure, and radioisotope dosing needs institution-specific adjustment. Melanoma is one of the few malignancies capable of metastasizing to the placenta and, rarely, the fetus, part of why a genuinely suspicious lesion in pregnancy should not be watched expectantly. Adjuvant and metastatic systemic therapy - both immune checkpoint inhibitors and BRAF/MEK inhibitors - is generally deferred during pregnancy given limited safety data, and managed collaboratively with maternal-fetal medicine when systemic treatment genuinely cannot wait.

Older adults

Lentigo maligna and lentigo maligna melanoma are disproportionately diagnosed in older patients on chronically sun-damaged skin, and are easy to under-call as ordinary age-related sun damage given how slowly they evolve (see Recognize the Condition). Comorbidity and polypharmacy in this population deserve real weight when choosing between an immune checkpoint inhibitor and a BRAF/MEK inhibitor combination for adjuvant or metastatic therapy - review for interacting medications (see Pharmacologic Treatment Options) and confirm the patient and any caregiver genuinely understand the self-monitoring expected of them.

Renal impairment

Immune checkpoint inhibitors are monoclonal antibodies and are not renally dose-adjusted, though immune-mediated nephritis is itself a recognized, if uncommon, irAE and needs its own monitoring (see Monitoring and Follow-Up). BRAF/MEK inhibitors are primarily hepatically metabolized and generally do not require renal dose adjustment, but volume status and electrolytes deserve closer attention in significant renal impairment given the diarrhea and edema these agents can cause.

Hepatic impairment

Dabrafenib, trametinib, encorafenib, binimetinib, vemurafenib, and cobimetinib are all primarily hepatically metabolized and may need dose adjustment or closer monitoring in significant hepatic impairment - confirm current product-monograph guidance for the specific agent. Checkpoint inhibitors are not hepatically dose-adjusted in the pharmacokinetic sense, but immune-mediated hepatitis is a recognized irAE and baseline/periodic liver enzyme monitoring is standard regardless of baseline hepatic function (see Monitoring and Follow-Up).

Children and adolescents

Pediatric melanoma is rare and often presents atypically - amelanotic, raised, and bleeding rather than following the classic ABCDE pattern - which has led to proposed pediatric-specific screening modifications (sometimes summarized as amelanotic, bleeding/bumps, uniform colour, and de novo/any diameter). Any persistently changing or bleeding skin lesion in a child deserves the same low threshold for biopsy referral as in an adult.

Post-treatment surveillance schedule

For high-risk resected melanoma (stage IIB through IV, rendered clinically disease-free by treatment), a 2020 consensus statement from Canadian melanoma specialists recommends a structured 5-year surveillance schedule:^[10]

• Clinical examination - full skin and regional nodal basin examination every 6 months throughout the entire 5-year period (11 visits in total): every 6 months during the first 2 years (the "intensive" phase, when approximately 47% of high-risk patients relapse, two-thirds of them asymptomatically), continuing every 6 months through years 3-5 (the "maintenance" phase).^[10]
• Systemic imaging (PET-CT preferred; routine CT is an acceptable substitute where PET-CT access is limited) - every 6 months during years 1-2, then annually during years 3-5.^[10]
• Brain MRI - annually throughout the full 5-year period.^[10]
• Regional nodal basin ultrasound - every 4-6 months during the first 2 years, then annually through year 5.^[10]

Lower-stage, lower-risk disease (stage 0 through IIA) generally warrants a less intensive schedule, built around regular clinician skin examination and reinforced monthly patient self-examination (see Non-Pharmacologic Treatment) rather than routine systemic imaging - confirm the specific schedule with the treating team, since it is individualized to stage and risk features.

Monitoring immune checkpoint inhibitor therapy

Immune-related adverse events (irAEs) can develop at essentially any point during treatment, and sometimes after treatment has already stopped; proactive, structured monitoring - not simply waiting for the patient to report a symptom - is standard practice:^[5]

• Dermatologic - rash and pruritus are often the earliest irAEs to appear; examine the skin at each visit.
• Gastrointestinal - ask specifically about stool frequency/consistency and abdominal pain at each visit; colitis can progress quickly and, rarely, perforate.
• Hepatic - liver enzymes (AST, ALT, bilirubin) before each treatment cycle.
• Endocrine - thyroid function (TSH, free T4) periodically throughout treatment (thyroiditis is among the most common irAEs); morning cortisol and, where indicated, ACTH stimulation testing if hypophysitis or primary adrenal insufficiency is suspected (headache, visual field change, fatigue, hypotension); blood glucose monitoring, since checkpoint-inhibitor-induced type 1 diabetes can present abruptly as diabetic ketoacidosis, including after only 1 or 2 doses - educate patients on hyperglycemia symptoms specifically for this reason.
• Pulmonary - ask about new cough, dyspnea, or hypoxia at every visit; pneumonitis, while uncommon, needs prompt imaging and specialist assessment.
• Cardiac - myocarditis is uncommon but carries a disproportionately high mortality among irAEs and can present early in treatment; a low threshold for troponin and ECG with any new cardiac symptom is appropriate (see Red Flags).
• Renal and rheumatologic/neurologic - baseline and periodic renal function; ask about new joint pain/swelling and any new neurologic symptom (weakness, numbness, unsteady gait) at each visit.

The general severity-based management framework: grade 1 toxicities are usually managed with continued therapy and closer monitoring; grade 2 toxicities generally warrant suspending the checkpoint inhibitor, with corticosteroids considered, and resuming once the toxicity has returned to grade 1 or better; grade 3 toxicities generally warrant suspending therapy and starting high-dose corticosteroids, tapered over at least 4-6 weeks; grade 4 toxicities generally warrant permanent discontinuation, with the notable exception of endocrinopathies that are adequately controlled with hormone replacement, where therapy can often continue.^[5]

Monitoring BRAF/MEK inhibitor therapy

• Dabrafenib-trametinib pyrexia - counsel every patient starting this combination on the pyrexia self-management plan before it ever occurs: hold both drugs at the first sign of fever (38 degrees C or higher) or chills/rigors/night sweats, use an antipyretic (acetaminophen up to 4 g/day, or ibuprofen), and restart both drugs together at the prior dose once symptom-free for at least 24 hours and off antipyretics; for a severe or complicated episode (hospitalization, or grade 2 or higher dehydration, hypotension, renal dysfunction, or confusion), restart at a reduced dose instead; for recurrent episodes less than 3 weeks apart, steroid prophylaxis (prednisone or dexamethasone) or a planned intermittent-dosing schedule should be considered before further dose reduction.^[6]
• Cardiac (MEK inhibitors - trametinib, binimetinib, cobimetinib) - baseline and periodic left ventricular ejection fraction assessment (echocardiogram or MUGA scan).
• Ophthalmologic (MEK inhibitors) - baseline and periodic ophthalmologic examination; report any new visual change promptly given the risk of retinal vein occlusion or serous retinopathy.
• QT interval (encorafenib, vemurafenib) - baseline and periodic ECG and electrolyte monitoring; review the patient's full medication list for other QT-prolonging drugs.
• Dermatologic (BRAF inhibitors, particularly vemurafenib) - routine skin examination for new squamous cell carcinoma or keratoacanthoma, a recognized class effect from paradoxical MAPK-pathway activation in BRAF-wild-type keratinocytes; reinforce photoprotection specifically for vemurafenib given its marked photosensitivity risk.

1. Positive or unclear margins after wide local excision: re-excise to achieve the recommended clinical margin; for lentigo maligna where negative margins genuinely cannot be achieved, or in a poor surgical candidate, consider a non-surgical alternative (topical imiquimod or radiation therapy) rather than repeated attempts at surgery alone.^[1]
2. Recurrence identified during structured post-treatment surveillance: re-stage with appropriate imaging and biopsy, and refer to medical oncology for adjuvant or systemic-therapy reassessment rather than treating the recurrence in isolation from the original staging.
3. Progression on first-line immunotherapy for unresectable/metastatic disease (PD-1-inhibitor refractory): combination checkpoint inhibitor therapy is the recommended next step, for either BRAF-mutant or BRAF-wild-type disease.^[8]
4. Progression on BRAF/MEK inhibitor therapy: switch to immunotherapy if not already tried, or to an alternative BRAF/MEK combination; genuinely refractory disease warrants consideration of a clinical trial.
5. Grade 3 or higher immune-related adverse event not improving on high-dose corticosteroids after approximately 3 days: escalate to organ-specific additional immunosuppression (for example, infliximab or a similar agent for steroid-refractory colitis) per specialist-directed protocol, generally alongside permanent discontinuation of the checkpoint inhibitor.^[5]
6. Recurrent (cluster) dabrafenib-trametinib pyrexia despite antipyretics and appropriate dose holds: add steroid prophylaxis or a planned intermittent-dosing schedule before resorting to permanent dose reduction.^[6]
7. Apparent lack of response, or unexpected toxicity, that does not fit the expected pattern for the regimen: confirm genuine adherence and correct administration before assuming true treatment failure - a missed infusion, an incorrectly paired BRAF/MEK dose, or an unaddressed practical barrier (transportation, cost, caregiver support) is a common and correctable explanation.

• Performing a shave or punch biopsy of a genuinely suspicious pigmented lesion when a full-thickness excisional biopsy is feasible, losing the ability to accurately measure Breslow depth on the first specimen.
• Reassuring a patient about a rapidly growing, firm, elevated, or non-pigmented lesion because it "doesn't fit ABCDE" - this is the classic nodular/amelanotic melanoma trap, and these subtypes are disproportionately responsible for thick, high-risk disease precisely because of this reasoning.
• Attributing a new or enlarging pigmented nail streak to trauma or fungal discoloration without examining for Hutchinson's sign or considering biopsy.
• Applying a lower index of suspicion for melanoma in a patient with darker skin, or skipping the palms, soles, and nail beds during a skin check in this population.
• Giving generic "wear sunscreen" advice without specific SPF, application-amount, and reapplication counselling - the difference between the SPF tested in a laboratory and the SPF a patient actually achieves is driven almost entirely by how much product is applied.
• Assuming a new gastrointestinal, dermatologic, endocrine, pulmonary, or cardiac symptom in a patient on checkpoint inhibitor therapy is unrelated to treatment (a virus, anxiety, deconditioning) rather than considering an immune-related adverse event.
• Continuing checkpoint inhibitor therapy through a clearly emerging grade 2 or higher immune-related adverse event rather than holding treatment and escalating management.
• Treating dabrafenib-trametinib pyrexia purely as an infection work-up without recognizing the class-associated pyrexia syndrome and the correct hold-both-drugs approach.
• Adjusting dabrafenib or trametinib (or any other paired BRAF/MEK inhibitor combination) independently of its partner drug, rather than as a fixed pair per the product-labelled reduction hierarchy.
• Missing the mandated baseline and periodic cardiac (LVEF) and ophthalmologic monitoring for a patient started on a MEK inhibitor.
• Defaulting to ipilimumab monotherapy in the adjuvant setting rather than nivolumab or pembrolizumab, given its clearly inferior efficacy and higher toxicity in this specific setting.
• Attributing new chest pain or palpitations in a checkpoint-inhibitor-treated patient to anxiety or deconditioning rather than considering myocarditis, a genuine, high-mortality oncologic emergency.
• Allowing immunosuppression changes or checkpoint inhibitor initiation in a transplant recipient to proceed without explicit coordination with the transplant team.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

BRAF/MEK Inhibitor Combinations (Targeted Therapy)

Always prescribed and dosed as a fixed BRAF-inhibitor-plus-MEK-inhibitor pair in melanoma - never as BRAF-inhibitor monotherapy, which drives resistance and paradoxical MAPK-pathway activation. Preferred for BRAF V600E/K-mutant disease when immunotherapy is unsuitable, already tried, or when a rapid response is clinically prioritized.

Immune Checkpoint Inhibitors

Immune-related adverse events (irAEs) can affect essentially any organ system and can develop weeks to months into treatment, or even after treatment has stopped - proactive, structured monitoring by organ system is standard practice, not simply waiting for the patient to report a symptom (see Monitoring and Follow-Up).

KIT-Targeted Therapy (Special Situation)

Reserved for confirmed, actionable KIT mutations, most often in mucosal, acral, or chronic-sun-damaged-skin melanoma subtypes; evidence base is more limited than for checkpoint inhibitor or BRAF/MEK inhibitor therapy.

Supportive Care for Treatment-Related Toxicity

Doses below support the specific toxicities discussed in this chapter and require individualized, patient-specific confirmation.