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Melanoma surveillance and survivorship

TL;DR — The only randomised trial of follow-up intensity in melanoma found that a reduced-frequency, stage-adjusted schedule was as safe as conventional follow-up: in 388 sentinel-node-negative patients randomised in the Netherlands and UK 2006–2016, 19.4% recurred with no difference between arms (HR 0.87, 95% CI 0.54–1.39, P = .57), no difference in any survival outcome (disease-free survival HR 1.00, 0.49–2.07, P = .99), and self-examination detected ~76% of recurrences in both arms (Moncrieff 2022, PMID 35866644). Nodal ultrasound is a good test with poor uptake: pooled sensitivity 0.879 (0.878–0.879) and specificity 0.969 (0.968–0.970) across 36 studies and 18,273 patients, but overall adherence to planned surveillance was 77.0% (76.0–78.1) and significantly lower in the US (Liu 2024, PMID 38635019). Circulating tumour DNA is the most active research direction, clinically validated as a prognostic biomarker in resected stage III disease within COMBI-AD (Syeda 2025, PMID 40250457). The survivorship burden is dominated by fear of recurrence, and by second primaries — 4.3% of patients with a first melanoma in situ developed a second primary invasive melanoma, which raised melanoma-specific mortality more than fourfold (adjusted HR 4.1, 3.6–4.6) (Patel 2023, PMID 37285145).

How intensively to follow up

Evidence Finding
MELFO randomised trial (Moncrieff 2022, PMID 35866644) 388 adults with sentinel-node-negative primary melanoma randomised 2006–2016 to conventional national-guideline follow-up (n = 196) or a reduced-frequency schedule (n = 192); quality of life the primary outcome. At 5 years: >97% satisfaction in both arms; no significant group effect on any patient-reported outcome; 75 of 388 (19.4%) recurred with no between-arm difference (HR 0.87, 0.54–1.39, P = .57); self-examination detected recurrence in 75.8% (experimental) and 76.2% (control) (P = .41); no difference in disease-free survival (HR 1.00, 0.49–2.07, P = .99)
Nodal ultrasound (Liu 2024, PMID 38635019) 36 studies, 18,273 patients, mean age 56.6 years, median follow-up 36 months at 4-monthly frequency. Pooled sensitivity 0.879, specificity 0.969, diagnostic OR 224.5 (223.1–225.9). Substantial absolute sensitivity gain over clinical examination alone, number needed to screen 2.95. Overall adherence 77.0% (76.0–78.1), significantly lower in the US
Guideline position European guideline recommends a structured, stage-based follow-up regimen to detect relapses and second primaries early, with lymph-node sonography from stage IB and whole-body CT or PET-CT plus brain MRI from stage IIB/C (Garbe 2025, PMID 39700658)

Two findings pull in opposite directions. MELFO shows that reduced-intensity follow-up is safe and that patient self-examination — not clinic visits — detects three quarters of recurrences (PMID 35866644). Ultrasound meta-analysis shows a highly accurate test whose real-world value is capped by adherence (PMID 38635019). Neither trial nor meta-analysis addresses the population in which surveillance intensity has changed most: patients on or after adjuvant therapy, where the recurrence pattern and the treatment options at recurrence both differ.

Nodal observation with ultrasound is also the comparator arm of MSLT-II, in which 80.2% of observed basins remained free of nodal recurrence at 10 years after sentinel-node biopsy alone (Crystal 2022, PMID 35921122) — see sentinel node and nodal management.

Does imaging frequency change what is found?

In a longitudinal cohort of 473 patients with resected stage IIIA–D melanoma at a tertiary referral centre 2000–2017 (IIIA 19%, IIIB 31%, IIIC 49%, IIID 1%), 30% underwent 3–4-monthly imaging, 10% 6-monthly and 60% 12-monthly. After a median 6.2 years, distant recurrence occurred in 252 patients (53%): 40% were detected by surveillance CT or PET/CT, 43% clinically, and 17% by another imaging modality (Dieng 2022, PMID 35142966). Even in stage III disease followed at a specialist centre, clinical detection accounts for a larger share of distant recurrences than scheduled cross-sectional imaging does — consistent with MELFO's finding in node-negative disease (PMID 35866644). Brain-specific surveillance has its own prospective dataset in advanced disease, with imaging every 6 weeks and cumulative incidence calculated at 12-week intervals (Wang 2014, PMID 24121189).

Circulating tumour DNA

Study Finding
COMBI-AD biomarker analysis (Syeda 2025, PMID 40250457) Analytically validated mutation-specific droplet digital PCR assays for BRAF V600E/V600K ctDNA applied to the intention-to-treat population of the randomised phase 3 adjuvant trial of dabrafenib plus trametinib in resected stage III melanoma; prespecified exploratory biomarker endpoint relating baseline post-resection ctDNA to survival outcomes
Stage III prospective multicentre (Palacios-Diaz 2025, PMID 40387867) BRAF, NRAS and TERT promoter mutations identified in tumour, then tracked in cell-free DNA at baseline, 4 weeks post-surgery and every 3–6 months. ctDNA detected in 21 of 48 patients (43.8%), associated with distant-site and multi-site recurrence
Advanced disease monitoring Tumour-informed liquid biopsies for monitoring advanced melanoma under checkpoint inhibition (PMID 39384805); ctDNA-based molecular residual disease detection for treatment monitoring in advanced melanoma (PMID 36869646)
Earlier-stage feasibility Personalised ctDNA detection in stage II and III melanoma (PMID 37040662); a study protocol for ctDNA surveillance in high-risk melanoma (PMID 39930781)
Implementation International expert survey on translating ctDNA into cutaneous melanoma care (PMID 41932032)
In uveal melanoma Longer overall survival on tebentafusp was associated with undetectable ctDNA (Piperno-Neumann 2026, PMID 42162665)
Randomised treatment guidance CAcTUS randomised 21 patients with advanced BRAF-mutant melanoma to standard investigator-selected sequencing or targeted-therapy induction followed by a switch to checkpoint blockade when plasma BRAF variant allele frequency fell by ≥80%. All critical results were returned within 7 days, establishing feasibility; the trial was not powered to establish a survival benefit (Lee 2026, PMID 42168180; NCT03808441)

ctDNA can drive a treatment decision, but outcome utility is not established. CAcTUS proves that a molecular threshold can prospectively trigger a switch within a randomised melanoma trial, but its 21-patient feasibility design does not show that acting on ctDNA improves progression-free or overall survival (PMID 42168180). The nearest outcome-oriented precedent remains colon cancer, where a randomised trial of ctDNA-guided adjuvant therapy has reported five-year outcomes (PMID 40055522). A separate randomised adaptive BRAF/MEK trial is registered but not yet recruiting (NCT06470880), while the stage IIB/C DETECTION trial terminated before randomisation (NCT04901988).

Second primaries

Finding Detail
After melanoma in situ Among 137,872 patients with a first-and-only melanoma in situ diagnosed 2000–2018 (mean age 61.9, 96.7% White, mean follow-up 6.6 years): 4.3% (6,751) developed a second primary invasive melanoma and 7.4% (11,628) a second primary MIS. Compared with those without a subsequent melanoma, melanoma-specific mortality risk was raised for a second invasive primary (adjusted HR 4.1, 3.6–4.6) and lowered for a second MIS (adjusted HR 0.7, 0.6–0.9) (Patel 2023, PMID 37285145)
Australian population cohort Risk of a second primary melanoma after a first primary has been quantified in a population-based Australian cohort (Ni 2023, PMID 36946230)
Personal history as a risk factor Personal history of melanoma is the strongest single input to melanoma risk prediction (relative risk 7.28/7.24 by sex) (Mar 2011, PMID 21605094)

The lowered mortality associated with a second in situ melanoma is a striking artefact: it identifies a population under active surveillance whose lesions are caught early, and it is one of the cleanest demonstrations of surveillance-related lead-time and length bias in this literature.

The prognosis of melanoma in situ itself

Fifteen-year melanoma-specific survival after a first-and-only melanoma in situ was 98.4% (95% CI 98.3–98.5), while 15-year relative survival was 112.4% (112.0–112.8) — i.e. these patients outlive demographically matched people without melanoma in situ. The melanoma-specific standardised mortality ratio was 1.89 (1.77–2.02) but the all-cause SMR was 0.68 (0.67–0.70). Melanoma-specific mortality risk was higher in patients ≥80 (7.4% vs 1.4% at 60–69; adjusted HR 8.2, 6.7–10.0) and with acral lentiginous histology (3.3% vs 0.9% for superficial spreading; HR 5.3, 2.3–12.3) (Patel 2023, PMID 37285145).

A relative survival above 100% is direct evidence of selection: people diagnosed with melanoma in situ are healthier and better-surveilled than the general population, which is the survivorship counterpart of the overdiagnosis argument.

Multiple primaries as a genetic-testing trigger

Second primary melanoma is not only a surveillance outcome; it is the commonest reason to consider germline testing. In two genomically ascertained cohorts totalling 696,665 individuals, pathogenic-variant prevalence in the eight major familial melanoma genes was 0.5–0.9% overall but exceeded the 2.5% threshold conventionally used to justify germline testing only among people with multiple cutaneous melanomas or a first melanoma before age 40 (Goldstein 2026, PMID 42201696). Personal history of melanoma is also the single strongest input to melanoma risk prediction (RR 7.28/7.24 by sex) (Mar 2011, PMID 21605094), and MITF p.E318K is found in multiple-primary patients independently of CDKN2A status (Potrony 2016, PMID 26650189). A patient developing a second primary therefore crosses two thresholds at once: intensified surveillance and a testing indication — see germline predisposition.

Living after melanoma

Domain Evidence
Fear of cancer recurrence Qualitative and survey study of 51 survivors of localised cutaneous melanoma (mean age 49.5, 67% female) recruited from an academic dermatology practice, using semistructured interviews and the Fear of Cancer Recurrence Inventory short form, with scores ≥13 of 36 identifying clinically significant fear (Mahama 2024, PMID 38353983)
Intervention MELACARE randomised trial, 153 patients with surgically treated stage IA–IIA melanoma at a Danish hospital, randomised to a nurse-led intervention combining skin-self-examination training and metacognitive strategies (n = 78) versus usual care (n = 75). At 6 months fear of recurrence was lower but not significantly so (−0.86, 95% CI −3.34 to 1.62); health-related quality of life (18%, 3–32) and patient activation (0.43, 0.15–0.71) improved significantly, as did confidence in self-examination (Hansen 2025, PMID 40504479)
Uveal melanoma survivors Seven-year distress trajectories (PMID 36848060); prediction of 2–5-year fear of recurrence from post-treatment symptoms and functional problems (PMID 34850324); a prospective study of anxiety, depression and fear of recurrence with attention to clinician communication (PMID 39548476)
Self-examination interventions Structured skin-self-examination skills training improved early detection of new melanomas by patients and partners in a randomised trial (Robinson 2016, PMID 27367303); digital and remote training approaches have been randomised (PMID 34637495; PMID 32761987; PMID 24418949); patients' own views about self-examination after treatment for localised melanoma have been studied (PMID 31090868)
Long-term treatment sequelae Chronic immune-related adverse events persisted in 43.2% of adjuvant anti-PD-1 recipients beyond 12 weeks after cessation (Patrinely 2021, PMID 33764387) — see immune-related adverse events; limb lymphoedema after nodal surgery has its own risk-factor literature (Gjorup 2021, PMID 33793386); long-term quality of life after isolated limb perfusion has been described (PMID 17300914)
Adjuvant-era survivorship The survivorship consequences of adjuvant immunotherapy in patients who would never have recurred have been argued explicitly (PMID 32388064)

The MELACARE result is the honest state of the evidence: a well-designed intervention improved quality of life, patient activation and self-examination confidence, but did not significantly reduce the fear of recurrence it targeted (PMID 40504479).

What the guidelines recommend, and on what basis

The European guideline proposes a structured, stage-based follow-up regimen "which in the experience of the guideline group covers the optimal requirements, although further studies may be considered" — an explicit statement that the schedule rests on expert experience rather than trial evidence (Garbe 2025, PMID 39700658). Its staging-investigation thresholds carry over into follow-up: no imaging for melanoma ≤0.8 mm, lymph-node sonography from stage IB, and whole-body CT or PET-CT plus brain MRI from stage IIB/C (PMID 39700658). ESMO's 2025 cutaneous guideline covers follow-up in its title scope (Amaral 2025, PMID 39550033), and the synthesis of where documents diverge is in guidelines.

Against that, the randomised evidence says reduced-intensity follow-up is safe (PMID 35866644), the observational evidence says clinical detection outperforms scheduled imaging for distant recurrence even in stage III (PMID 35142966), and the adherence evidence says a quarter of planned ultrasound surveillance does not happen (PMID 38635019). Every element of the recommended schedule is supported by consensus and contradicted or unsupported by the trial and cohort data.

Interpretation rules for this page

  • Self-examination detects most recurrences, in both arms of the only randomised follow-up trial (PMID 35866644).
  • A good surveillance test with 77% adherence is a 77%-adherence intervention, not an 88%-sensitivity one (PMID 38635019).
  • Relative survival above 100% signals selection, not protection (PMID 37285145).
  • A second in situ melanoma associating with lower mortality is a surveillance artefact, not a protective effect (PMID 37285145).
  • ctDNA is prognostic and treatment guidance is feasible, but no trial has shown an outcome benefit from acting on it (PMID 40250457; PMID 40387867; PMID 42168180).
  • MELFO enrolled sentinel-node-negative patients before the adjuvant-therapy era; its conclusions do not automatically transfer to stage III patients on or after adjuvant treatment (PMID 35866644).

Open questions

  • Does ctDNA-guided surveillance or adjuvant therapy improve outcomes in melanoma, beyond the treatment-switch feasibility shown by CAcTUS (PMID 42168180; PMID 40055522)?
  • What follow-up schedule is right for patients who have completed adjuvant therapy — a population MELFO did not include (PMID 35866644)?
  • Can nodal ultrasound adherence be raised enough for its diagnostic performance to matter in practice (PMID 38635019)?
  • What intervention actually reduces fear of recurrence, given that the best-designed melanoma trial to date did not (PMID 40504479; PMID 38353983)?
  • Should melanoma in situ be followed at all, given 15-year melanoma-specific survival of 98.4% and all-cause SMR 0.68 (PMID 37285145)?
  • What proportion of chronic immune-related adverse events resolve beyond five years, and what does that mean for survivorship planning (PMID 37535354)?

Where the survivorship burden actually falls

Burden Magnitude Source
Chronic immune-related events after adjuvant anti-PD-1 43.2% persisting >12 weeks after cessation; 96.4% grade 1–2, most unresolved Patrinely 2021, PMID 33764387
Lymphoedema after completion lymph-node dissection 24.1% Faries 2017, PMID 28591523
Second primary invasive melanoma after melanoma in situ 4.3%; raises melanoma-specific mortality more than fourfold (adjusted HR 4.1, 3.6–4.6) Patel 2023, PMID 37285145
Financial toxicity Significantly higher in patients under 65 (P < .001), correlated with quality of life Thom 2021, PMID 33103948
Years of life lost per metastatic patient 16–23 across twelve countries Thiam 2016, PMID 26531249
Fear of recurrence Not significantly reduced by the best-designed melanoma intervention trial to date Hansen 2025, PMID 40504479

Two of these are iatrogenic — chronic immune toxicity and lymphoedema — and both follow interventions whose survival benefit is either unproven (adjuvant therapy in stage IIB/IIC) or disproven (completion dissection). That is the sharpest statement of the survivorship problem this condition has.

References

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