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 . 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%) . 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 . 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.  and Kiebert et al.  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 , 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) , 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 . 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.