Why does melasma worsen in a woman of reproductive age with darker skin undergoing chemotherapy (e.g., cyclophosphamide, doxorubicin, 5‑fluorouracil, taxanes)?

Why Melasma Worsens After Chemotherapy

Chemotherapy-induced melasma worsening in women of reproductive age with darker skin occurs primarily through direct melanocyte stimulation by chemotherapeutic agents (particularly cyclophosphamide, doxorubicin, 5-fluorouracil, and taxanes), combined with baseline hormonal influences and genetic predisposition to hyperpigmentation that are already present in this population.

Mechanisms of Chemotherapy-Induced Hyperpigmentation

Direct Melanocyte Activation

• Chemotherapeutic agents, particularly anthracyclines (doxorubicin) and alkylating agents (cyclophosphamide), directly stimulate melanocyte activity and upregulate melanin synthesis pathways 1
• These drugs trigger the Wnt/β-catenin, PI3K/Akt, and cAMP/PKA signaling pathways that regulate melanogenesis, leading to increased melanin production in both epidermal and dermal layers 1
• The cytotoxic stress from chemotherapy induces inflammatory mediators and oxidative stress, both of which are proven contributors to melasma pathogenesis 1

Hormonal and Genetic Susceptibility

• Women of reproductive age already have baseline hormonal variations that predispose them to melasma, and chemotherapy can further dysregulate sex hormones 2
• Darker skin types (Fitzpatrick III-VI) have inherently higher melanocyte activity and nearly 300 genes differentially expressed in melasma-affected skin compared to healthy skin, making them more vulnerable to chemotherapy-triggered hyperpigmentation 3, 4
• Genetic predisposition combined with chemotherapy exposure creates a "perfect storm" for melasma development or worsening 2, 4

Drug-Specific Considerations

• Taxanes (paclitaxel, docetaxel) and platinum compounds have emerging evidence of causing pigmentary changes, though they are considered relatively safe regarding other toxicities 5
• 5-fluorouracil, anthracyclines, and cyclophosphamide—commonly used in breast cancer regimens—all have documented effects on melanin production 5
• The combination regimens (AC, TAC, dose-dense AC followed by paclitaxel) expose patients to multiple melanocyte-stimulating agents sequentially 5

Clinical Implications and Management

Prevention During Chemotherapy

• Strict photoprotection is mandatory: apply broad-spectrum SPF 50+ sunscreen daily, reapply every 2-3 hours during outdoor exposure, and use wide-brimmed hats (>3 inches) and UV-protective clothing 6, 7, 8
• UV radiation synergistically worsens chemotherapy-induced hyperpigmentation by upregulating melanocyte-specific genes and stimulating melanin synthesis 1
• Counsel patients to avoid tanning beds completely and seek shade during peak UV hours (10 a.m. to 4 p.m.) 7, 8

Treatment After Chemotherapy Completion

• Begin triple combination cream (hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%) once chemotherapy is completed and blood counts have recovered 6, 7, 9
• This remains the most effective treatment for melasma with the strongest evidence base 9
• For refractory cases, consider oral tranexamic acid 250 mg twice daily as adjunctive therapy 6, 7, 8, 9

Advanced Procedural Options

• Intradermal platelet-rich plasma (PRP) injections (4 sessions spaced 2-3 weeks apart) demonstrate superior efficacy with mean mMASI score reduction of 45.67% 7, 8
• PRP combined with oral tranexamic acid shows 90.48% total efficacy compared to 73.68% for tranexamic acid alone 7, 8
• Microneedling may be more effective than intradermal PRP injections for delivering treatments to hyperpigmented skin 6, 7, 8

Critical Pitfalls to Avoid

• Never use laser therapy in patients with Fitzpatrick skin types IV-VI due to markedly higher risk of burns, post-inflammatory hyperpigmentation, and permanent hypopigmentation 7
• Do not initiate aggressive topical treatments during active chemotherapy when skin barrier function is compromised 3
• Avoid prolonged corticosteroid use beyond 2 months due to risk of skin atrophy 6
• Recognize that melasma is a chronic condition requiring maintenance therapy every 6 months even after initial improvement 7, 8
• Counsel patients that genetic factors and ongoing hormonal influences may limit treatment success, requiring realistic expectations 6, 8

Monitoring and Long-Term Management

• Measure treatment efficacy using modified Melasma Area and Severity Index (mMASI) scores to objectively track improvement 7, 8
• Decreases in MASI >60-90% indicate moderate improvement; >90% indicates excellent response 7, 8
• Maintenance treatments are essential as chemotherapy-induced melasma has high recurrence rates similar to hormonally-induced melasma 7, 8
• Advise patients to avoid smoking, which worsens melasma and impairs treatment outcomes 6, 7, 8