Most patients with early stage melanoma in the United States are still treated primarily with surgery, but a new multisite study shows that people diagnosed at more advanced early stages often cycle through multiple lines of therapy, with some receiving as many as four different systemic drug regimens. The findings, drawn from a retrospective chart review at four large US cancer centers, offer one of the most detailed real-world pictures to date of how stage IB through IIC cutaneous melanoma is actually managed outside of clinical trials.
The study, published in the journal Drugs – Real World Outcomes, was conducted within medical oncology and dermatology departments at the University of Virginia Cancer Center, the University of California San Francisco, Mayo Clinic, and Cleveland Clinic. Researchers assembled two cohorts: an aggregate, site-level cohort of 7,285 patients newly diagnosed with stage I or II melanoma between 2018 and 2022, and a patient-level cohort of 398 adults with histologically confirmed stage IB–IIC melanoma diagnosed between 1 January 2018 and 24 months before the start of data collection at each site, with the latest such date being 3 July 2024. The final two years of each patient’s window were reserved exclusively for outcome assessment, and the study had a median follow-up of 57.6 months, roughly five years.
In the patient-level cohort, 56.3 percent of patients had stage IB disease, 21.1 percent stage IIA, 16.3 percent stage IIB, and 6.3 percent stage IIC. The aggregate cohort showed a similar picture across the broader population: stage IA accounted for 67.4 percent of the 7,285 patients, stage IB for 14.0 percent, stage IIA for 6.3 percent, stage IIB for 5.3 percent, and stage IIC for just 3.0 percent, with about 4 percent of unknown stage. The distribution remained relatively stable from 2018 to 2022, and the authors note that these proportions are consistent with large European registry studies from Germany and Denmark.
Treatment in the patient-level cohort was overwhelmingly surgical. Among the 398 patients, 98.5 percent received surgery, 92.0 percent underwent sentinel lymph node biopsy, 33.9 percent were managed with watchful waiting, 12.3 percent received systemic drug therapy, and 2.5 percent received radiotherapy. When the researchers examined lines of treatment, defined as continuous periods of melanoma management that could include one or more approaches, 99.0 percent of patients received at least one line, and nearly all of them, 99.5 percent, received surgery alone or in combination as their first line of treatment. Most patients were treated with surgery alone or surgery paired with watchful waiting.
That surgical dominance did not extend evenly across stages. Receipt of radiotherapy and systemic drug therapy during follow-up was significantly associated with diagnosis stage, increasing as disease advanced. Radiotherapy ranged from 1.3 percent among stage IB patients to 12.0 percent among those with stage IIC disease, while systemic drug therapy was given to 4.9 percent of stage IB patients but 40.0 percent of stage IIC patients. Among the 49 patients who received systemic therapy, anti-PD-1 immune checkpoint inhibitors formed the backbone, used by 81.6 percent, with nivolumab the single most administered agent at 65.3 percent and pembrolizumab at 22.4 percent. Nearly a third, 30.6 percent, received anti-CTLA-4 therapy, all of it with ipilimumab. BRAF and MEK inhibitors and intratumoral agents such as T-VEC played only a minor role.
Recurrence added a further layer of complexity. Overall, 59 patients, or 14.8 percent, experienced a recurrence during follow-up, and the risk rose sharply with stage: 7.1 percent of stage IB patients, 19.0 percent of stage IIA, 26.2 percent of stage IIB, and 40.0 percent of stage IIC. After recurrence, treatment patterns shifted markedly. Surgery and watchful waiting were significantly less frequent at or after recurrence in recurrent patients compared with nonrecurrent patients throughout follow-up, at 25.4 percent versus 98.2 percent for surgery and 10.2 percent versus 34.2 percent for watchful waiting. The opposite held for systemic drug therapy and radiotherapy, which were administered significantly more often at or after recurrence, at 66.1 percent versus 0.6 percent and 15.3 percent versus 0.3 percent, respectively. No recurrent patient received radiotherapy before their recurrence.
The number of treatment lines also climbed with stage. Sixteen percent of patients overall received two or more lines of treatment, but that proportion ranged from 8.9 percent in stage IB to 22.7 percent in stage IIA, 23.1 percent in stage IIB, and 40.0 percent in stage IIC. Six percent received three or more lines, again rising with stage to 20.0 percent among stage IIC patients. A Sankey diagram mapping the pathways of the 64 patients with more than one line of treatment showed that all of them began with surgery, but their second lines were far more heterogeneous, including systemic drug therapy alone in 45.3 percent of cases, additional surgeries, watchful waiting, and radiotherapy. Twenty-five patients proceeded to a third line, eight to a fourth, six to a fifth, two to a sixth, and one to a seventh. From the third line onward, patients often moved into programs involving multiple systemic drug therapies or combinations of radiotherapy and systemic therapy.
Patient and tumor characteristics also tracked with stage in ways the authors describe as consistent with prior research. Mean age at diagnosis was 63.4 years overall and increased significantly with advancing stage, as did body mass index. Tumor-related parameters varied substantially: mean Breslow thickness rose from 1.2 millimeters in stage IB to 7.4 millimeters in stage IIC, ulceration went from 2.7 percent to 100 percent, and the proportion of tumors with more than three mitoses per square millimeter climbed from 15.6 percent to 84.0 percent. Gender, race, performance status, comorbidities, Charlson comorbidity index score, and primary tumor location showed no significant association with stage.
The authors argue that their findings confirm guideline-concordant practice. Management of early stage melanoma in routine US practice remains mainly surgical, in alignment with National Comprehensive Cancer Network recommendations, which call for wide local excision with sentinel lymph node biopsy for appropriate categories, followed by observation for stage IB–IIA, and adjuvant anti-PD-1 therapy and/or radiotherapy for pathological stage IIB or IIC. The study period captures the introduction of adjuvant therapy for stage II melanoma, with the Food and Drug Administration approving pembrolizumab for adjuvant treatment of stage IIB or IIC disease at the end of 2021. The authors also note that the diversity of treatment sequences observed after the first line suggests that once disease recurs or progresses, there is no clearly established treatment pathway.
The study has limitations the authors acknowledge. Although the overall sample of 398 was adequate, the numbers of patients receiving more than one line of treatment, systemic drug therapy, radiotherapy, or experiencing recurrence were relatively small, limiting the power of stage-stratified and recurrence-based comparisons. Generalizability may be constrained because all four participating sites were academic centers in the United States, which may not represent all institutions managing early stage melanoma, and 18.3 percent of patients were lost to follow-up. Even so, with 75 percent of patients followed for more than roughly four years, the study offers a contemporary, real-world view of a disease that accounts for approximately 80 percent of melanoma cases. The authors conclude that the substantial treatment burden seen in high-risk early stage melanoma, particularly stages IIB and IIC, highlights an unmet need for novel therapies and better optimization of treatment sequences, and they call for future studies to assess the comparative effectiveness of treatment strategies and refine predictors of recurrence.
Subject of Research: Real-world treatment patterns and lines of therapy in early stage cutaneous melanoma
Article Title: Characteristics and Treatment Patterns of Early Stage Melanoma: Results from a Multisite Chart Review
Article References: Costello, C. M., Wei, M. L., Isaacs, J., Gaughan, E. M., Greene, A., So, A., Zhong, X., Majuelos-Melguizo, J., Gandhi, K., Rey, C., Delibes, A., Barnett, R., Fukunaga-Kalabis, M., Qizilbash, N., Shui, I. M., & Tan, X.-L. (2026). Characteristics and Treatment Patterns of Early Stage Melanoma: Results from a Multisite Chart Review. Drugs – Real World Outcomes. https://doi.org/10.1007/s40801-026-00583-5
Image Credits: AI Generated
DOI: 10.1007/s40801-026-00583-5
Keywords: melanoma, early stage melanoma, treatment patterns, chart review, immunotherapy, anti-PD-1, surgery, sentinel lymph node biopsy, recurrence, lines of treatment, radiotherapy, NCCN guidelines
News Source: Nathaniel Bowman. (October 28, 2026). Surgery Still Dominates Early Stage Melanoma Care, but Higher-Stage Patients Face Mounting Treatment Burden. Scienmag.
