Patient Demographics and Relapse Incidence
A total of 466 patients enrolled on an adjuvant immunotherapy trials were identified and evaluated. Of these, 115 (25%) had resected stage II disease, 328 (70%) had stage III, and 23 (5%) had stage IV disease. Sixty-three percent of patients were male, and 37% were female. The median patient age was 49 years. The majority of patients had a primary located on an extremity (41%), 36% had a primary located on the trunk, 15% had a head or neck primary, and 8% had a primary of unknown origin (Table 1).
Of the 466 patients, 225 (48%) developed disease progression during the 5-year observation period. For these patients, the median time from protocol enrollment to the date of identified tumor progression was 7 months. There were no differences in the rates or timing of relapses between the four adjuvant trials. Approximately 94% of relapses were detected by 3 years and 99% of relapses were noted by 4 years. Not surprisingly, stage IV patients were more likely to demonstrate early disease progression (Fig. 1).
Site of First Relapse
Table 3 documents the sites of disease progression as either local regional or systemic using the previously defined criteria for the 225 patients who developed relapse. The first relapse among stage II patients was locoregional in 52% of patients and systemic in 48% of patients. Among those with stage III disease, the site of tumor progression was locoregional in 32% of patients and systemic in 68% of patients. For patients with resected stage IV disease at protocol enrollment and who demonstrated tumor progression, the disease was identified as locoregional in 23% of patients and systemic in 77% of patients.
Table 3 Site of first recurrence
Method of Detection
The method by which disease progression was first detected was classified as by patient, by physician or lab analysis, or by CT imaging alone (Table 4). For the 225 individuals who recurred, 60 were detected by the patient (27%), 32 by physicians or labs (14%), and 131 by CT imaging alone (59%). For the 81 patients with local regional recurrence, 36 (45%) recurrences were patient-detected, 20 (25%) were detected by physician examination, and 24 (30%) were identified by imaging alone. Not surprisingly, patients and physicians were more likely to diagnose locoregional disease and less likely to detect progressive systemic disease.
Table 4 Method of detection by site and stage
As expected, CT imaging was the most effective method to detect systemic progression of melanoma. For the 144 patients who developed systemic recurrence, 107 (75%) were detected by imaging in an asymptomatic patient with normal labs and physical examination. Twenty-four (17%) recurrences were patient-detected. These individuals noted a new tumor and had concomitant metastatic disease detected or complained of pain, bleeding, or neurologic symptoms. Nine patients had their systemic disease detected by physician examination, and only three patients had abnormal laboratory finding which suggested disease progression. These individuals developed anemia from intestinal metastasis and are included in the physician-detected cohort. As noted in Table 4, two patients had metastatic disease detected by physical examination, but the medical record was unclear if this was by the patient’s or physician’s examination. Both of these patients were in the resected Stage IV cohort; one recurred with locoregional disease and one with systemic disease.
Serum LDH was routinely obtained at each follow-up evaluation. LDH elevation was recorded at least once in 13% of patients who remained free of disease during the observation period and in only 3.5% of patients at the time tumor progression was detected in patients with tumor progression. Neither LDH nor LFTs appeared to be useful for surveillance.
Detection of Brain Metastasis
Melanoma brain metastases were detected in 17 (4%) of 466 evaluable patients and in 7.5% of the 225 patients who developed progressive melanoma during surveillance. Given our brain surveillance strategy, it is not surprising that 14 of these patients presented with neurologic symptoms, including headache, visual changes, or seizures. The remaining three patients had brain disease identified as part of a complete metastatic survey that was initiated, because progression had been detected at other sites. Interestingly, 11 of the 17 patients with brain metastasis patients had brain-only disease. Sixteen of the 17 patients had stage III or resected stage IV disease at protocol entry.