Immune checkpoint inhibitors (CIs), in particular inhibitors of the cytotoxic T-lymphocyte-associated antigen 4 and programmed death 1 (PD-1), have revolutionized the treatment of advanced melanoma. Ipilimumab, nivolumab and pembrolizumab, alone or in combination (ipilimumab plus nivolumab) have led to dramatic improvements in survival. In some patients, CI therapy may lead to long-term survival,1 resulting in the emergence of a new population of cancer survivors.2

While some clinical trials have followed patients for as long as 5 years, most quality of life (QoL) evidence on CIs in melanoma is limited to 1 or 2 years follow-up time. Despite the common occurrence of immune-related adverse events (irAEs), good QoL is generally maintained in melanoma patients in CI clinical trials.3 However, patients treated outside of trials may have higher rates of adverse events and lower QoL.4 The clinical experiences and needs of long-term melanoma survivors treated with CI, including symptom burden, QoL and health services needs, are not well described.5 Such information is critical for optimizing care for this growing survivor group. Memorial Sloan Kettering Cancer Center (MSK) provides care to many long-term melanoma survivors who have been treated with CIs. We performed a cross-sectional study, accompanied by chart review, to measure symptom burden and long-term QoL in this cohort of patients.

We approached 274 eligible patients; 107 (39%) responded and agreed to participate. Non-responders were of similar age as participants (mean 63 vs 65 years) and were slightly more likely to be male (65% vs 57%). We were unable to collect other information about non-responders. One hundred and six patients completed the survey. Of those, 16 remained on CI treatment and were excluded, leaving 90 off-treatment participants for analysis.

Demographic characteristics are shown in table 1. Nearly all (93%) patients were white; 43% were female. The median age at time of survey was 65 years (IQR 54–74 years). All patients had a Charlson comorbidity index of 0 at treatment initiation and very few (7 (8%)) had pre-existing autoimmune illnesses (data not shown). Twenty-two per cent had received systemic antineoplastic therapy prior to CI; 12 (17%) had been treated with radiation therapy (RT) prior to CI and 13 (14%) received RT after CI initiation.

The most commonly received CI regimen was ipilimumab plus nivolumab (53%), followed by pembrolizumab (41%). Median length of CI treatment was 8 months (IQR: 2–24 months). Most participants (n=64, 71%) were not treated with CI within a clinical trial; 15 (17%) were treated only on a clinical trial protocol and 11 (12%) received CI both on and off protocol. The median time from initiation of CI therapy to survey completion was 40 months (IQR: 31–58 months) and the median time from the last dose of CI therapy to survey completion was 28 months (IQR: 17–40 months), with 15 patients (17%) off treatment <12 months, 22 (24%) from 12 to <24 months, 27 (30%) from 24 to <36 months, 7 (7.8%) from 36 to <48 months and 19 (21%) ≥48 months.

Table 2 shows all domains of PRO-CTCAE by time since last CI dose. The most commonly reported symptoms on the PRO-CTCAE were aching joints (17%), aching muscles (12%) and headache (6%), with no meaningful differences in frequency or severity based on time since treatment or receipt of combination versus single-agent therapy. PRO-CTCAE results also did not differ based on sex (table 3). Rates of difficulty with physical, role (eg, work around the home), emotional, cognitive or social functioning on the EORTC QLQ-C30 varied (table 4), with more difficulty with physical and work functioning in patients >3 years from CI completion.

Fatigue was common. Overall, 28% of patients reported being easily fatigued on the FSS, 27% that fatigue interferes with physical functioning, 22% that fatigue interfered with social functioning and 20% that fatigue causes frequent problems. The level of fatigue appeared highest in the group who had completed CI 24 to <36 months prior, with 26% in that group agreeing that fatigue causes frequent problems and 37% agreeing that it interferes with physical functioning (table 5), although across-group differences were not statistically significant. The overall FSS score was 19.5 (IQR: 12–35); FSS scores did not differ based on time since CI therapy (p=0.83) but were higher (suggesting more fatigue) in females than males (24 vs 18, p=0.034) and in patients who received combination therapy than in those who received only single-agent (20 vs 19, p=0.027). On the EORTC QLQ-C30, 11 (12%) patients reported difficulty sleeping; rates ranged from 5% to 19% across groups but differences were not significant, and 14% reported trouble taking a long walk (table 4).

Overall QOL was excellent, with a median EQ-5D-3L score of 5.5 (IQR: 5–7) and a median global health score (EORTC QLQ-C30) of 83%; global health scores did not differ based on time since treatment completion, receipt of combination therapy or sex. On the EORTC QLQ-C30, 11 (12%) patients reported difficulty sleeping; rates ranged from 5% to 19% across groups but differences were not significant, and 14% reported trouble taking a long walk (table 4). While few patients responded ‘yes’ on the EQ-5D-3L to having problems in any dimension, many reported ‘some or moderate’ problems with usual activities (23%), anxiety/depression (40%) and pain/discomfort (31%); these rates did not differ based on time since CI treatment or sex (table 6). Moderate problems with mobility and pain on the EQ-5D-3L appeared more prevalent in patients surviving longer since CI completion, (table 6), though differences were not statistically significant.

Most patients (n=77 (86%)) had seen a healthcare provider outside of MSK in the 12 months prior to the study, including a therapist (eg, mental, physical, speech) (n=14 (16%)), a nurse practitioner, physician assistant or certified registered nurse practitioner (6 (7%)) or a dentist (2 (2%)). Physicians outside MSK seen by participants included primary care physicians (PCPs) (37 (41%)), medical subspecialists (30 (33%)), surgeons (21 (23%)), dermatologists (20 (22%)), ophthalmologists (12 (13%)), oncologists (12 (13%)) and gynecologists (7 (8%)).

The most common irAEs at any time since CI initiation were rash (38%), colitis (27%), hypothyroidism (20%), hepatitis (17%) and hypophysitis (11%) (table 7). Musculoskeletal toxicities were more common among women compared with men (13% vs 2%); prevalences of other irAEs were similar in men and women; small numbers of patients with specific irAEs precluded performing formal statistical testing. Notably, patients with endocrine irAEs were more likely to report fatigue compared with those who did not experience endocrine problems (46% vs 21%.)

We found high rates of fatigue but otherwise moderate symptom burden and good QoL in patients with advanced melanoma currently off therapy and surviving at least 1 year after CI therapy initiation, despite a relatively high prevalence of having ever experienced an irAE. In the PRO-CTCAE, headache, aching joints and aching muscles were the most commonly reported symptoms in terms of both frequency and severity. Few patients reported definitive mental health problems like anxiety or depression, though many responses indicated ‘some’ or ‘moderate’ symptoms, and rates of sleep difficulties were overall similar to those in the general population.14

Notably, 28% of patients in our study reported being easily fatigued and 20% reported fatigue causing frequent problems. Our results are consistent with robust evidence that fatigue is a common problem across populations of cancer survivors with prevalence as high as 40% and is the most common adverse event in patients on CIs.15–19 Findings regarding fatigue in melanoma survivors are mixed. A study of survivors with metastatic melanoma found very high rates of fatigue (90%), but most patients were receiving ongoing treatment with CIs or BRAF-MEK inhibitors.20 A large study of long-term melanoma survivors found rates of fatigue that were comparable to the general population,21 but most had early stage disease. Our study is unique in evaluating long-term survivors of advanced melanoma, previously treated with CI and currently off treatment, including 53 patients surviving >2 years at the time of the survey; it reflects a population that is likely growing. Further, the higher rate of fatigue in women than men in our sample is notable. Findings regarding gender differences in fatigue in cancer survivors have been mixed,22–24 though some studies have found higher rates of fatigue in women22; such differences should be explored in future studies. Our findings of slightly higher fatigue scores in patients who had received combination therapy and that patients with endocrine irAEs may be more likely to be fatigued are interesting and important to address further in the future. As both oncologists and others care for the growing group of long-term cancer survivors treated with CIs, awareness about fatigue and its treatment is crucial.25

Our findings regarding QoL are reassuring and are consistent with clinical trials showing that patients on CI maintain QoL better than those treated with other agents.3 26 27 Our study, however, includes survivors no longer receiving treatment, reflects longer-term symptom burden and captures the experiences of patients treated both within and outside of clinical trials. One small study of long-term melanoma survivors treated with ipilimumab enrolled a similar population to ours and found generally excellent performance status after more than 2 years.2 Our study adds to this literature by assessing QoL and including patients treated with PD-1 and programmed death ligand 1 (PD-L1) in combination with ipilimumab, over half of whom were alive more than 2 years after CI completion.

A 2015 study of QoL in long-term melanoma survivors found poorer QoL and higher symptom burden than our study,28 but many of those patients were presumably treated before the widespread use of PD-1-based immunotherapy and may not be comparable. Population-based studies have found that long-term melanoma survivors had similar QoL compared with non-cancer controls,29 30 but it is likely that few in these cohorts had advanced disease. Comparisons with other long-term survivor groups are challenging, since there are few similar populations of patients with advanced disease and durable survival. Such populations might include survivors of lymphoma, in whom findings regarding QoL are mixed,31 and breast cancer, whose overall QoL appears comparable to controls but who may report impediments in functioning.32 In our study, global QoL exceeded that reported for the general population (median global health status 83 compared with 75 in the general population).8 Further, patients in our study rated their QoL as high despite substantial burden of fatigue. The observed QoL inflation may be due to altered expectations in the context of having faced life-threatening disease or patient selection.33

Musculoskeletal symptoms were the most common symptoms in our study. In clinical trials and observational studies of CIs, rates of musculoskeletal problems like arthralgia, myalgia and back pain have ranged widely, with rates of arthralgia as high as 43%.34 35 While clinical trials of CIs may underestimate rates of musculoskeletal irAEs,36 our study suggests that persistent musculoskeletal symptoms are moderately common in long-term survivors. While these symptoms were seldom reported as ‘severe’ on the PRO-CTCAE, the proportion of patients reporting at least some mobility problems on the EQ-5D-3L seemed to rise as patients survived longer after treatment (table 6). Further, while sex differences were not significant, we saw a trend toward higher rates of musculoskeletal symptoms in women than in men. Several studies have documented musculoskeletal problems in patients treated with CIs,35 though gender differences have not been described. As this group of survivors grows and patients live longer, future studies should further characterize gender-based differences and explore the evolution of musculoskeletal symptoms.

Fewer than half of patients in our sample (41%) reported having seen a PCP in the last year; we did not evaluate whether these represented new versus established relationships. The Institute of Medicine recommends collaboration between oncologists and PCPs to optimize care for cancer survivors,37 and survivors’ involvement with both an oncologist and a PCP is associated with higher quality care.38 PCPs, however, may lack adequate knowledge to deliver needed care.39 Future studies should evaluate the trajectory of patient relationships with PCPs. As the population of CI-treated cancer survivors grows, there will be a need to ensure patient access to primary care and to educate PCPs about potential long-term health effects of CI therapy.

Our study has important limitations. Our sample size is relatively small, and our response rate was modest, so our findings may imperfectly reflect the experiences of the broader patient population. Further, due to the small sample size, we were unable to apply multivariable models to examine the observed associations adjusted for potential confounding factors. Our patients were also healthy prior to CI therapy and approved by their oncologist to be approached, which may have biased our sample toward healthier and more satisfied patients. Second, participants in our study received various CI regimens, often more than one, and duration of therapy varied (with median 15 months). Symptoms and QoL are likely to differ based on the drug received and the duration of therapy, but our study was not powered to detect differences based on these factors and the cross-sectional nature of our study does not enable understanding of changes in symptoms and QoL over time. Further, we collected only basic information on utilization of other health services; future prospective studies should describe the specific services needed in this population. In addition, we surveyed only patients who had survived for at least 1 year since initiation of CI therapy so our findings reflect this specific group; experiences of patients who respond less well to treatment may differ substantially. Finally, all participants in our study were patients at a single institution and therefore may not be representative of metastatic melanoma patients across the nation. Long-term health outcomes data, including information on symptom burden and QoL, are needed from prospective studies of larger and more diverse cohorts of patients treated with CI therapy, which will likely come from studies other than those focused on melanoma.

In conclusion, our cross-sectional study found that patients with advanced melanoma who were off treatment and had survived at least 1 year after therapy with CI had good QoL. Skin and musculoskeletal symptoms, moderate problems with anxiety and depression, and fatigue were moderately prevalent but appeared not to severely impede function or QoL. Our findings are reassuring that this emerging population of cancer survivors can live not only longer but better than in years past.