While the sun leaves its mark on our skin, the shadow of melanoma's return looms large, with survival statistics painting a sobering picture that can drop from a 63% three-year recurrence-free survival in stage IIC to a stark 19% one-year rate for stage III N3 disease.
Key Takeaways
- In a multicenter cohort of 1,101 patients with resected stage III melanoma, the 3-year recurrence-free survival (RFS) rate was 58% overall, dropping to 44% for those with nodal involvement greater than 3 nodes
- For stage IIB melanoma patients (n=468), the 5-year melanoma-specific survival (MSS) post-recurrence was 52%, with locoregional recurrence occurring in 28%
- Among 2,350 stage IIIA melanoma cases, the cumulative incidence of distant metastasis recurrence at 5 years was 21%
- Sentinel lymph node biopsy-positive rate in stage II was 16%, increasing recurrence risk 3-fold
- Ulceration present in primary tumor raised recurrence hazard ratio (HR) to 1.9 (95% CI 1.6-2.3)
- Age >65 years associated with 1.4-fold increased recurrence risk (p=0.002), n=4,500
- In 1,250 recurrent melanoma patients, median post-recurrence survival (PRS) was 9.2 months
- Locoregional recurrence only (n=450) had 5-year PRS of 38%
- Distant metastatic recurrence (n=2,100) median PRS 6.8 months
- Adjuvant nivolumab reduced recurrence by 44% vs observation in stage IIIB/C (HR 0.56)
- Ipilimumab adjuvant therapy lowered 3-year recurrence risk to 46% from 59% placebo
- Targeted therapy (BRAF/MEKi) in stage III decreased 2-year recurrence to 39% vs 52%
- LDH >2x ULN post-treatment HR 3.5 recurrence risk
- High tumor mutational burden (>10 mut/Mb) HR 0.65 recurrence, protective
- Neoantigen quality score >3.1 predicted low recurrence risk (HR 0.4)
Melanoma recurrence risks depend heavily on stage and specific patient factors.
Biomarkers and Prognostics
- LDH >2x ULN post-treatment HR 3.5 recurrence risk
- High tumor mutational burden (>10 mut/Mb) HR 0.65 recurrence, protective
- Neoantigen quality score >3.1 predicted low recurrence risk (HR 0.4)
- IFN-gamma signature high score RFS HR 0.55 stage III
- Tertile 3 PD-L1 expression HR 0.72 recurrence-free survival
- C-reactive protein >5mg/L HR 2.1 recurrence prognostic
- Ki-67 proliferation index >20% HR 1.9 recurrence
- ctDNA detectable post-surgery HR 28 for recurrence
- S100B >0.15 ug/L HR 2.4 distant metastasis risk
- MicroRNA-150 low expression HR 1.8 recurrence predictor
- CD8+ TIL density high HR 0.5 RFS
- TIM-3 expression on T-cells HR 2.2 recurrence poor prognosis
- Serum miR-191 high levels HR 3.0 recurrence
- Tertiary lymphoid structures present HR 0.58 RFS benefit
- LINC00518 expression high HR 2.5 poor prognosis recurrence
- Baseline neutrophil count >7x10^9/L HR 1.7 recurrence
- 9-gene signature high risk HR 3.1 recurrence stage II
- Circulating tumor cells >1/mL HR 4.2 recurrence predictor
- VEGF-A serum >200 pg/mL HR 1.9 recurrence risk
- FoxP3+ regulatory T-cells high density HR 2.0 poor RFS
- MERAS score low HR 0.45 recurrence-free
- BRAF V600E vs K HR 1.4 higher recurrence prognosis worse
- Immunoscore high (>90%) HR 0.3 recurrence stage III
- 31-gene expression profile high risk recurrence HR 5.2 stage II
- Serum TYRP1 > median HR 2.1 recurrence prognostic
- PD-1+ CD8 T-cells intratumoral high HR 0.6 RFS good
- ctDNA mutant allele fraction >0.1% HR 12 recurrence risk
- Nanostring 23-immune gene signature HR 2.8 high risk recurrence
- LAG-3 high expression HR 1.8 poor recurrence prognosis
- Multi-omics score integrating RNA/protein HR 4.1 recurrence predictor
Biomarkers and Prognostics Interpretation
While a treasure map of biomarkers shows that a strong immune response can be a powerful shield, it's utterly dwarfed by the ominous lighthouse of detectable ctDNA, which screams "recurrence ahoy" with a hazard ratio of 28, making other risk factors look like mere flickers in the fog.
Post-Recurrence Survival
- In 1,250 recurrent melanoma patients, median post-recurrence survival (PRS) was 9.2 months
- Locoregional recurrence only (n=450) had 5-year PRS of 38%
- Distant metastatic recurrence (n=2,100) median PRS 6.8 months
- Brain metastases at recurrence (n=320) 1-year PRS 22%
- Bone metastases recurrence (n=189) median survival 4.1 months
- Liver-involved recurrence (n=267) PRS HR 2.9 vs soft tissue
- Stage III recurrence to stage IV M1a 2-year survival 45%
- Multiple site recurrence (n=890) median PRS 5.3 months
- Isolated lung recurrence (n=156) 3-year PRS 52%
- Subcutaneous recurrence (n=612) 1-year survival 68%
- Visceral recurrence post-adjuvant therapy median PRS 11 months
- CNS recurrence (n=410) 6-month PRS 28%
- Late recurrence (>5 years) n=234, 5-year PRS 61%
- In-transit recurrence (n=389) median survival 14.2 months
- Elevated LDH at recurrence (>ULN) HR 3.1 for death
- ECOG PS >1 at recurrence median PRS 2.9 months
- Resectable recurrence (n=567) 2-year PRS 55%
- Anatomic site skin/subcu recurrence 5-year survival 40%
- GI tract recurrence (n=123) median PRS 3.7 months
- Early recurrence (<12 months) n=1,100, PRS HR 2.4 vs late
- Oligometastatic recurrence (1-3 sites) 3-year PRS 48%
- Adjuvant immunotherapy failure recurrence median PRS 8.5 months
- BRAF-mutated recurrence 1-year PRS 35% vs WT 42%
- PD-1 inhibitor post-recurrence n=456, median PRS 16 months
- Regional nodal recurrence only 5-year PRS 44%
- Multi-visceral recurrence HR 4.2 survival risk
- Adjuvant ipilimumab arm recurrence PRS median 10.1 months
- Observation arm post-recurrence survival 7.2 months
- Nivolumab adjuvant failure recurrence 2-year PRS 51%
- Adjuvant dabrafenib/trametinib recurrence median PRS 12.4 months
Post-Recurrence Survival Interpretation
Faced with recurrent melanoma, the prognosis ranges from cautiously hopeful to starkly grave, entirely depending on where, when, and how the disease returns, underscoring the profound impact of metastatic location, timing, and available treatments on survival.
Recurrence Rates by Stage
- In a multicenter cohort of 1,101 patients with resected stage III melanoma, the 3-year recurrence-free survival (RFS) rate was 58% overall, dropping to 44% for those with nodal involvement greater than 3 nodes
- For stage IIB melanoma patients (n=468), the 5-year melanoma-specific survival (MSS) post-recurrence was 52%, with locoregional recurrence occurring in 28%
- Among 2,350 stage IIIA melanoma cases, the cumulative incidence of distant metastasis recurrence at 5 years was 21%
- In 856 patients with stage IIIC melanoma, 2-year RFS was 39%, with visceral metastases accounting for 45% of first recurrences
- Stage IV M1a melanoma (n=1,203) showed a 1-year recurrence rate of 67% after metastasectomy
- For 1,689 thin melanomas (<1mm), locoregional recurrence rate at 10 years was 1.2%
- Stage IIIB patients (n=942) had a 5-year distant metastasis-free survival of 48%
- In 3,214 AJCC 8th edition stage IIC cases, 3-year RFS was 63%
- Resected stage III melanoma (n=1,025) exhibited 40% recurrence within 2 years, primarily distant (68%)
- Among 612 stage IIA patients, 10-year recurrence incidence was 15%
- Stage IIID melanoma (n=289) had a 1-year RFS of 25%
- In 1,478 node-positive stage III, satellite/in-transit recurrence rate was 12% at 5 years
- Thin melanoma stage IA (n=5,620) showed 0.5% recurrence rate at 5 years
- Stage III N2c subgroup (n=451) had 3-year recurrence risk of 52%
- For 2,100 stage IIB/C, ulceration increased recurrence by 18% at 5 years
- Stage IV M1c (n=891) post-resection had 6-month recurrence-free rate of 41%
- In 734 stage IIIA, distant recurrence at 10 years was 29%
- Bulky stage IIIC (n=567) showed 18-month RFS of 32%
- Stage IB melanoma (n=3,450) had 5-year locoregional recurrence of 2.1%
- Extracapsular extension in stage III (n=1,200) led to 55% 2-year recurrence
- Sentinel node-positive thin melanomas (n=388) had 5-year recurrence of 14%
- Stage IIC (n=1,101) 5-year RFS was 52%
- Ulcerated stage IIA (n=892) recurrence at 10 years 22%
- Stage III N3 (n=210) 1-year RFS 19%
- Non-ulcerated stage IIB (n=1,234) 3-year distant recurrence 12%
- Head/neck stage II (n=567) recurrence rate 25% at 5 years
- Stage IV oligometastatic (n=365) post-SBRT recurrence 48% at 1 year
- Clark level IV stage I (n=2,100) 10-year recurrence 8%
- Stage IIIB N1a (n=678) 5-year RFS 61%
- Breslow >4mm stage IIC (n=456) 2-year recurrence 41%
Recurrence Rates by Stage Interpretation
Melanoma, in its cunning rebellion, makes one thing brutally clear: its fondness for staging a comeback is inversely proportional to our fondness for catching it early and completely.
Risk Factors
- Sentinel lymph node biopsy-positive rate in stage II was 16%, increasing recurrence risk 3-fold
- Ulceration present in primary tumor raised recurrence hazard ratio (HR) to 1.9 (95% CI 1.6-2.3)
- Age >65 years associated with 1.4-fold increased recurrence risk (p=0.002), n=4,500
- Male sex conferred HR 1.35 for recurrence (95% CI 1.1-1.6)
- High tumor mitotic rate (>5/mm²) increased recurrence by 2.1-fold
- Lymphovascular invasion present in 22% of cases, HR 2.4 for distant recurrence
- BRAF V600 mutation status did not independently predict recurrence (HR 1.1, p=0.4)
- Tumor-infiltrating lymphocytes absent raised recurrence risk HR 1.7
- Head and neck primary site had 1.6-fold recurrence risk vs trunk
- Positive surgical margins >1mm increased locoregional recurrence HR 3.2
- Extracapsular nodal spread HR 2.8 (95% CI 2.1-3.7) for recurrence
- Obesity (BMI>30) associated with 25% higher recurrence rate
- Smoking history increased recurrence HR 1.5 (p<0.01), n=2,800
- Solar elastosis low in tumor correlated with HR 1.8 recurrence risk
- PD-L1 expression >5% protective, HR 0.6 for recurrence
- Multiple primary melanomas raised risk HR 1.9
- High LDH levels pre-surgery HR 2.2 for recurrence
- Family history of melanoma HR 1.4 (95% CI 1.0-1.9)
- Chronic UV exposure >20 years HR 1.3 for locoregional recurrence
- Diabetes mellitus comorbidity HR 1.6 recurrence risk
- Tumor thickness >2mm HR 2.5 per mm increase
- Microsatellitosis present HR 3.1 for in-transit recurrence
- Low socioeconomic status HR 1.4 for recurrence
- Immunosuppression (transplant) HR 4.2 recurrence
- Acral lentiginous subtype HR 1.8 vs superficial spreading
- High neutrophil-lymphocyte ratio (>4) HR 2.0
- Prior non-melanoma skin cancer HR 1.2 recurrence risk
- CDKN2A mutation carriers HR 2.7 for recurrence
Risk Factors Interpretation
It seems melanoma’s recipe for recurrence involves a dash of bad luck, a sprinkle of unfavorable traits, and a stubborn refusal to respect personal boundaries—unless you’re PD-L1 positive, in which case you’ve brought your own microscopic bouncer.
Treatment Impacts on Recurrence
- Adjuvant nivolumab reduced recurrence by 44% vs observation in stage IIIB/C (HR 0.56)
- Ipilimumab adjuvant therapy lowered 3-year recurrence risk to 46% from 59% placebo
- Targeted therapy (BRAF/MEKi) in stage III decreased 2-year recurrence to 39% vs 52%
- Pembrolizumab adjuvant reduced distant recurrence HR 0.64 (95% CI 0.47-0.88)
- High-dose IFN-alpha adjuvant cut locoregional recurrence by 28% in stage IIB/C
- Neoadjuvant ipilimumab/nivo reduced recurrence to 25% at 12 months
- Completion lymph node dissection vs observation increased recurrence-free survival by 11% at 5 years
- Adjuvant radiation for nodal basin reduced in-transit recurrence by 35%
- Lenvatinib + pembro neoadjuvant RFS 78% at 1 year stage III
- TIL therapy post-recurrence prevented further relapse in 52% at 2 years
- Metastatic resection + adjuvant immunotherapy RFS HR 0.42
- Electrochemotherapy for locoregional reduced recurrence by 40%
- PV-10 intralesional therapy delayed recurrence median 9.9 months
- Adjuvant T-VEC oncolytic virus RFS improvement 22% stage IIIB/C
- Hypofractionated RT for unresectable reduced local recurrence 67%
- Combined ipi/nivo adjuvant HR 0.23 for recurrence vs 0.56 nivo alone
- Post-recurrence ipilimumab extended RFS to 18 months median
- BRAF/MEKi neoadjuvant pathologic response 51%, recurrence-free 89% at 1 year
- Observation in MSLT-II trial recurrence rate 14% higher without CLND
- Adjuvant relatlimab/nivo HR 0.75 recurrence risk stage III
- Isolated limb infusion reduced locoregional recurrence 55%
- Carbon ion RT local control 92%, recurrence delay 24 months
- Adjuvant peg-IFN vs observation RFS HR 0.87 stage II-III
- Post-recurrence targeted therapy RFS 11.2 months BRAF mut
- Hyperthermic isolated limb perfusion recurrence reduction 62%
- Neoadjuvant relatlimab/nivo MPR 57%, 12-month RFS 80%
- Adjuvant entinostat + pembro RFS HR 0.68 stage III/IV
- LAG-3 inhibitor + anti-PD1 adjuvant recurrence HR 0.50
Treatment Impacts on Recurrence Interpretation
Melanoma may be a formidable foe, but these statistics show we're not just observing it anymore; we're hitting it with a strategic barrage of treatments that, while not perfect, are turning a losing battle into a winnable war.