Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment

Advanced melanoma is a serious and life threatening cancer which has an impact on health-related quality of life (HRQL). According to the American Cancer Society, there were an estimated 68,130 new cases of melanoma and 8,700 deaths in the US in 2010, which accounts for almost three-fourths of all skin cancer deaths [1]. The median overall survival for patients with untreated advanced melanoma ranges between 6 to 9 months [1‐6]. Cornish et al. recently demonstrated that the impact of melanoma on patient HRQL is comparable with other cancers [7].

Until the recent approvals for vemurafenib and ipilimumab, none of the currently approved treatments for advanced melanoma have shown overall survival benefit [3, 8‐18]. The focus of current treatment is on improving survival, managing symptoms, and improving HRQL outcomes [2, 19]. Studies have shown that melanoma impacts psychological functioning (i.e., anxiety, depression, and vulnerability) [20‐24]. In studies of advanced melanoma patients receiving treatment, melanoma patients also reported significant impairments in physical functioning and fatigue symptoms [20, 25, 26]. Treatment-related HRQL outcomes vary by HRQL instrument, study methods and design, study dropout rates, and disease progression rates. These factors need to be taken into consideration when interpreting the findings of HRQL studies in advanced melanoma.

Several clinical trials comparing treatments for advanced melanoma have included HRQL measures [14, 20, 26‐36]. In general, these clinical studies demonstrate varied HRQL and symptom effects for different treatments, although the earliest studies demonstrate significant impairment to functioning [34, 35]. However, most of these studies have considerable dropout rates and results are often restricted to the initial weeks of the clinical trial study. Dropouts are frequently observed in patients with significant toxicity or disease progression, and these missing data can make the follow-up HRQL outcomes appear better than they are in reality [37].

Ipilimumab is an anti-CTLA-4 monoclonal antibody with anti-tumor activity and has demonstrated statistically significant improvement in overall survival in a Phase III study (MDX010-20) in patients with previously treated unresectable stage III or IV melanoma [9]. Efficacy and safety data corresponding to the Phase II and III clinical trials in advanced melanoma have been reported elsewhere [9, 12, 38]. Overall, ipilimumab, alone or in combination with gp100, was tolerable in subjects with advanced metastatic melanoma with a generally manageable safety profile, which is consistent with safety demonstrated in previous studies of ipilimumab [9]. Study drug-related adverse events, regardless of etiology, were severe (≥ Grade 3) for 19.5%, 26.0%, and 12.1% of subjects treated with ipilimumab plus gp100, ipilimumab alone, and gp100 alone, respectively [9]. Immune-related adverse events were the most frequently reported drug-related adverse events [9]. The immune-related adverse events of ipilimumab are managed through administration of systemic glucocorticoids and other immunosuppressant agents along with adherence to treatment according to well established guidelines [39, 40]. The majority of these immune-related adverse events occurred during the induction period of ipilimumab treatment. This report summarizes the HRQL outcomes during the 12 week treatment induction period of the ipilimumab Phase III clinical trial (MDX010-20). Assessment of the effects of ipilimumab in relation to overall HRQL is important and will allow oncologists to appropriately educate patients on the risks and benefits of treatment with this agent.

Ipilimumab at 3 mg/kg monotherapy, whether combined with gp100 vaccine or not, was associated with a 19% to 36% reduction in the rate of disease progression and, more importantly, had increased overall survival compared with the gp100 vaccine alone group in patients with previously treated advanced melanoma [9]. In general, the HRQL results for the ipilimumab groups demonstrate that ipilimumab treatment is associated with minimal impairments on functioning and symptoms during the treatment induction period. The only statistically significant difference between ipilimumab and gp100 vaccine was for constipation, and this finding may be due to increased rate of colitis in the ipilimumab groups (5.3-7.6% versus 0.8%) [9]. Most of the observed changes were in the range of “no change” or minimal impairments, which indicates that HRQL was maintained during the treatment induction period. Functioning and symptom scores did not improve during treatment; only the overall HRQL of these patients was negatively impacted to a small extent. The gp100 group reported increased pain, fatigue, dyspnea, and decreased physical and role function compared with the ipilimumab group.

After 12 weeks of treatment with ipilimumab, only fatigue, sleep disturbance, and appetite loss showed moderate impairments. However, there was no significant negative impact on physical, emotional, cognitive, and social functioning and global health status in the ipilimumab treated groups. These findings indicate that HRQL outcomes were minimally impaired by ipilimumab treatment. Therefore, the trade-offs between extended survival and HRQL may be acceptable to patients and their clinicians [45]. Given that few treatments for advanced melanoma (i.e., vemurafenib and ipilimumab) are associated with improvements in overall survival [9, 10, 12, 13], these HRQL results for ipilimumab are very encouraging.

We identified three studies that used the EORTC QLQ-C30 comparing treatments for advanced melanoma [14, 32, 34]. Study design and methods are summarized in Additional file 1 Table A1. Two of these studies reported higher rates of missing HRQL data at follow-up compared with ipilimumab plus gp100 or ipilimumab alone (Additional file 1 Table A2). Disease progression rates were somewhat greater in the comparison studies, ranging from 61% to 74% (Additional file 1 Table A2). For the EORTC QLQ-C30 functional outcomes, dacarbazine-videsine-cisplatin and dacarbazine-videsine treated groups demonstrated worse global health and physical, role, and social function compared with ipilimumab plus gp100 or ipilimumab alone groups (Additional file 2 Figure A1). For the symptom outcomes, dacarbazine-videsine-cisplatin and dacarbazine-videsine treated groups demonstrated worse fatigue, nausea/vomiting, and appetite loss and similar pain compared with ipilimumab plus gp100 and ipilimumab alone groups (Additional file 3 Figure A2). The studies by Avril et al. [14] and Kiebert et al. [32] showed changes in EORTC QLQ-C30 function and symptom scores comparable to the ipilimumab plus gp100 and ipilimumab alone treatment groups. Overall, the ipilimumab HRQL effects we observed may be better or comparable to those observed in these other clinical trials, as supported by little meaningful impairment in functioning and symptoms during the treatment induction period.

The comparison of HRQL outcomes between the ipilimumab clinical trials and these other studies should be interpreted cautiously given the differences in methods, disease progression, and dropout rates. Significant differences in mechanism of action and known toxicity profiles of chemotherapy and ipilimumab may contribute to observed differences in HRQL between the chemotherapy and ipilimumab. In addition, ipilimumab’s demonstrated efficacy compared to the general lack of chemotherapy activity in this disease is another consideration for observed differences.

In the Phase II study for ipilimumab [38], mean changes from baseline to Week 12 for the 3 mg/kg arm generally indicated little or no negative impact to patient HRQL across the EORTC QLQ-C30 subscales for global health status, function, and symptoms. These Phase II results are similar to the Phase III (MDX010-20) results and add further support to the effects of ipilimumab treatment as possibly better or comparable to those observed in these other clinical trials.

Clinicians are concerned about the effects of treatment on elderly (i.e., ≥65 years of age) advanced melanoma patients [46, 47]. Although overall survival is comparable for patients aged <65 and ≥65 years (for ipilimumab plus gp100 versus gp100 alone, hazard ratio was 0.70 and 0.69 for <65 years and ≥65 years, respectively; for ipilimumab alone versus gp100 alone, hazard ratio was 0.65 and 0.61 for <65 years and ≥65 years, respectively) [9], we evaluated differences in HRQL outcomes by age group. For the ipilimumab plus gp100, results were comparable for both age groups, although those ≥65 years reported more impairment in role function, global health, and sleep disturbance. For the ipilimumab alone groups, the results for functional outcome and symptom scores were comparable, except that those ≥65 years reported more impairment in social function, dyspnea, sleep disturbance, and diarrhea.

The HRQL results from the current ipilimumab study should be interpreted considering the following limitations. HRQL endpoint data were available for only 61% to 65% of patients randomized into the clinical trial. Disease progression was the most common reason for discontinuation of study drug (24% of subjects in the ipilimumab plus gp100 group; 16% in the ipilimumab alone group; and 33% in the gp100 alone group). Rates of discontinuation of study drug due to adverse events were greatest for ipilimumab alone (13%) compared with ipilimumab plus gp100 (9%) and gp100 alone (4%). However, there were comparable completion rates of the EORTC QLQ-C30 across treatment arms in the current study (MDX010-20), so these missing data may not impact the interpretation of the HRQL results. Missing HRQL data is a significant problem for oncology studies, and patients who complete follow-up assessments are less likely to experience severe toxicity and are more likely to have better response to treatment [37]. Finally, although EORTC QLQ-C30 is an internationally validated, widely used questionnaire for assessing the HRQL in oncology, melanoma specific HRQL questions might not have been addressed.

In conclusion, ipilimumab at 3 mg/kg with and without gp100 vaccine does not have a significant negative impact on HRQL in patients completing the baseline and Week 12 follow-up, during the treatment induction phase compared with gp100 alone. Ipilimumab treatment results in little to no impairment in HRQL outcomes in advanced melanoma patients. The improved survival observed in the ipilimumab treated groups does not come with a significant burden on HRQL for patients in this analysis. Further research is needed to determine the long term impact of ipilimumab treatment on HRQL outcomes. In addition, further analyses are needed to better understand the impact of serious adverse events on HRQL in ipilimumab treated patients.