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

Health related quality of life outcomes for unresectable stage III or IV melanoma patients... Background: In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial’s 12 week treatment induction period. Methods: The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). Results: In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p< 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain. Conclusions: Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients. Trial registration: Clinicaltrials.gov identification number NCT00094653 Keywords: Ipilimumab, Randomized clinical trial, EORTC QLQ-C30, Advanced melanoma, Health-related quality of life * Correspondence: dennis.revicki@unitedbiosource.com United BioSource Corporation, 7101 Wisconsin Avenue, Suite 600, Bethesda, MD 20814, USA Full list of author information is available at the end of the article © 2012 Revicki et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 2 of 8 http://www.hqlo.com/content/10/1/66 Introduction respectively [9]. Immune-related adverse events were the Advanced melanoma is a serious and life threatening can- most frequently reported drug-related adverse events [9]. cer which has an impact on health-related quality of life The immune-related adverse events of ipilimumab are (HRQL). According to the American Cancer Society, there managed through administration of systemic glucocorti- were an estimated 68,130 new cases of melanoma and coids and other immunosuppressant agents along with ad- 8,700 deaths in the US in 2010, which accounts for almost herence to treatment according to well established three-fourths of all skin cancer deaths [1]. The median guidelines [39,40]. The majority of these immune-related overall survival for patients with untreated advanced mel- adverse events occurred during the induction period of anoma ranges between 6 to 9 months [1-6]. Cornish et al. ipilimumab treatment. This report summarizes the HRQL recently demonstrated that the impact of melanoma on outcomes during the 12 week treatment induction period patient HRQL is comparable with other cancers [7]. of the ipilimumab Phase III clinical trial (MDX010-20). Until the recent approvals for vemurafenib and ipilimu- Assessment of the effects of ipilimumab in relation to mab, none of the currently approved treatments for overall HRQL is important and will allow oncologists to advanced melanoma have shown overall survival benefit appropriately educate patients on the risks and benefits of [3,8-18]. The focus of current treatment is on improving treatment with this agent. survival, managing symptoms, and improving HRQL out- comes [2,19]. Studies have shown that melanoma impacts Methods psychological functioning (i.e., anxiety, depression, and Study design vulnerability) [20-24]. In studies of advanced melanoma Study MDX010-20 was conducted in accordance with patients receiving treatment, melanoma patients also International Conference on Harmonisation-Good Clin- reported significant impairments in physical functioning ical Practices and the Declaration of Helsinki. The study and fatigue symptoms [20,25,26]. Treatment-related was approved by local regulatory authorities and institu- HRQL outcomes vary by HRQL instrument, study meth- tional review boards and Ethics Committees at the partici- ods and design, study dropout rates, and disease progres- pating sites, and all subjects provided written consent. sion rates. These factors need to be taken into The Phase III clinical trial (MDX010-20) was a double- consideration when interpreting the findings of HRQL blind, fixed dose study in 676 previously treated patients studies in advanced melanoma. with advanced stage III or IV melanoma [9]. Patients in Several clinical trials comparing treatments for advanced this trial were randomized 3:1:1 to receive either ipilimu- melanoma have included HRQL measures [14,20,26-36]. mab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; In general, these clinical studies demonstrate varied 1 mg q3w x 4 doses; ipilimumab plus gpl00, n = 403); HRQL and symptom effects for different treatments, al- gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimu- though the earliest studies demonstrate significant impair- mab + placebo (ipilimumab alone, n = 137). The main in- ment to functioning [34,35]. However, most of these clusion criteria were men and women aged ≥18 years, studies have considerable dropout rates and results are histological confirmed advanced stage III or IV melanoma, often restricted to the initial weeks of the clinical trial Eastern Cooperative Oncology Group (ECOG) perform- study. Dropouts are frequently observed in patients with ance status of 0 or 1, and life expectancy of at least four significant toxicity or disease progression, and these miss- months. Key exclusion criteria included active symptom- ing data can make the follow-up HRQL outcomes appear atic or asymptomatic untreated central nervous system better than they are in reality [37]. (CNS) metastasis, primary ocular melanoma, or pregnant Ipilimumab is an anti-CTLA-4 monoclonal antibody or breastfeeding women. Patients with stable, pre-treated with anti-tumor activity and has demonstrated statistically CNS metastases were allowed in the study. 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 Treatment regimen safety data corresponding to the Phase II and III clinical Ipilimumab, at a dose of 3 mg per kilogram of body trials in advanced melanoma have been reported else- weight, was administered with or without gp100 every where [9,12,38]. Overall, ipilimumab, alone or in combin- three weeks for up to four treatments (induction) [9]. In ation with gp100, was tolerable in subjects with advanced the gp100 groups, patients received two modified HLA- metastatic melanoma with a generally manageable safety A* 0201-restricted peptides with incomplete Freund’s profile, which is consistent with safety demonstrated in adjuvant (Montanide ISA-51): a gp100:209-217(210M) previous studies of ipilimumab [9]. Study drug-related ad- peptide, 1 mg injected in the right anterior thigh, and a verse events, regardless of etiology, were severe (≥ Grade gp100:280-288(288V) peptide, 1 mg injected in the left 3) for 19.5%, 26.0%, and 12.1% of subjects treated with ipi- anterior thigh. These injections were given immediately limumab plus gp100, ipilimumab alone, and gp100 alone, after the intravenous infusion of ipilimumab or placebo. Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 3 of 8 http://www.hqlo.com/content/10/1/66 Treatment was started on day 1 of Week 1, and add- and gp100 alone (n = 136) treatment arms. Participants itional treatment was received at Weeks 4, 7, and 10 if from all three arms (total n = 676) had a mean age of there was no intolerable toxicity, no rapidly progressive 56.2 ± 57.0 years and 59% were male (Table 1). The ma- disease, and no significant decline in performance status. jority of participants had M1C stage at entry (n = 483; This included patients who developed new lesions and/or 71.4%) and almost all had an ECOG performance status experienced growth in baseline lesions. Patients were score of 0 or 1 (n = 665; 98.4%). All of the participants offered additional courses of therapy (reinduction) if they had received prior treatment for advanced melanoma. had stable disease after Week 12 or a confirmed partial or Twelve percent of participants (n = 82; 12.1%) had CNS complete response and no dose-limiting toxicity, or if they metastases at baseline. had disease progression with their assigned treatment regimen [9]. HRQL outcomes In the Phase III study (MDX010-20), 95% had baseline Health-related quality of life measure HRQL assessments and Week 12 assessments were HRQL was evaluated using the European Organization available for 236 (62%), 85 (65%), and 80 (61%) of the for Research and Treatment of Cancer Quality of Life patients treated with ipilimumab plus gp100, ipilimumab Questionnaire (EORTC QLQ-C30) [41,42]. The EORTC alone, and gp100 alone, respectively. Missing HRQL data QLQ-C30 contains subscales for global health status, at baseline were due to administrative errors. Reasons and physical, emotional, role, cognitive, and social func- for missing Week 12 data were primarily due to disease tion, with higher scores indicating better functioning progression, adverse events, or death [9]. There were no [41,42]. Symptom subscales include pain, nausea/vomit- differences in demographic or relevant clinical character- ing, fatigue, dyspnea, appetite loss, insomnia, diarrhea, istics between those study patients with complete and and constipation (higher scores indicate greater symp- missing Week 12 HRQL assessments. There were differ- tom severity). Extensive evidence is available supporting ences in baseline EORTC QLQ-C30 scores for global, the reliability, validity, and responsiveness of the EORTC physical, role, emotional, and social function scores and QLQ-C30 in different cancer populations [42,43]. In the for fatigue, nausea, pain, dyspnea, sleep, appetite, and Phase III trial (MDX010-20), HRQL outcomes were self- constipation scores between those with and without administered at the clinical centers before any clinical Week 12 assessments. procedures or physician interactions, including any dis- cussion of imaging studies at baseline and Week 12. Table 1 Baseline demographics and clinical characteristics Phase III (MDX010-20) Statistical analyses Ipilimumab Ipilimumab gp100 Total Baseline to Week 12 changes in EORTC QLQ-C30 func- plus gp100 Alone Alone tion, global health status and symptom scores were calcu- (N = 403) (N = 137) (N = 136) (N = 676) lated. Analysis of variance models were used to compare Age (years), mean 55.6 56.8 57.4 56.2 treatment differences for the HRQL outcomes. Since there Gender, n (%) is clinical interest in effectiveness and risks in older oncol- Male 247 (61) 81 (59) 73 (54) 401 (59) ogy patients, post hoc subgroup analysis of EORTC QLQ- Melanoma stage, C30 data by age (<65 years versus ≥65 years) was also n (%) conducted, and these analyses were compared to the M0 5 (1.2) 1 (0.7) 4 (2.9) 10 (1.5) results from the total sample (i.e., combined age group). M1a 37 (9.2) 14 (10.2) 11 (8.1) 62 (9.2) Descriptive analyses are reported for the data, and no stat- M1b 76 (18.9) 22 (16.1) 23 (16.9) 121 (17.9) istical tests were performed due to the ad hoc nature and relatively small sample sizes. Interpretations of the mean M1c 285 (70.7) 100 (73.0) 98 (72.1) 483 (71.4) change in scores were categorized as “no change” (0–5 Prior treatment 403 (100.0) 137 (100.0) 136 (100.0) 676 (100.0) points), “alittle” (5–10 points), “moderate” (10–20 points), for advanced melanoma, n (%) and “very much” (>20 points), based on Osoba et al. [44]. ECOG PS, n (%) When function and symptom scores showed either “no change” or “little change,” they were interpreted as reflect- 0 233 (57.8) 72 (52.6) 70 (51.5) 375 (55.5) ing no or minimal impact on patient HRQL [44]. 1 165 (40.9) 64 (46.7) 61 (44.9) 290 (42.9) 2 or 3 5 (1.2) 1 (0.7) 4 (2.9) 10 (1.4) Results Missing 0 0 1 (0.7) 1 (0.1) Demographic and clinical characteristics CNS metastases 46 (11.4) 15 (10.9) 21 (15.4) 82 (12.1) Patients were randomly assigned to either the ipilimu- at baseline, n (%) mab plus gp100 (n = 403), ipilimumab alone (n = 137), Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 4 of 8 http://www.hqlo.com/content/10/1/66 When HRQL outcomes were evaluated, most observed none to small impairments in functional outcomes and baseline to Week 12 changes were no greater than minimal symptom scores, while the older age group reported a in the “a little” impairment category (Figures 1 and 2). similar pattern of changes for most of the outcomes. There was a statistically significant difference in constipa- Older patients reported moderate impairments in role tion scores between the ipilimumab plus gp100 and the function, global health, fatigue and sleep disturbance. In gp100 alone groups (p< 0.05) and between the ipilimumab the ipilimumab alone subgroup of patients <65 years, alone and gp100 alone groups (p< 0.05). None of the other the impairment changes in functional outcomes and differences in HRQL scores between the three treatments symptom scores were none to small for most scores, ex- were statistically significant. cept for fatigue and appetite loss. For patients aged For the ipilimumab plus gp100 arm, the observed impair- ≥65 years, in the ipilimumab alone group, moderate or ments were in the “no change” or “alittle” categories for greater impairments were seen in social function and physical, role, emotional, cognitive, and social function, glo- global health, which differed somewhat from the younger bal health, nausea, pain, dyspnea, sleep disturbance, appetite age group. More symptom effects were observed in those loss, constipation, and diarrhea subscales. For the ipilimu- ≥65 years for dyspnea and diarrhea compared with the mab alone group, the observed impairments were in the <65 age group. These findings need to be interpreted cau- “no change” or “alittle” categories for the physical, emo- tiously given the smaller sample size. tional, cognitive, and social function, the global health, nau- sea, pain, dyspnea, constipation, and diarrhea subscales. For Discussion the gp100 alone group, the observed impairments were in Ipilimumab at 3 mg/kg monotherapy, whether combined the “no change” or “alittle” categories for the cognitive and with gp100 vaccine or not, was associated with a 19% to social function, nausea, dyspnea, and diarrhea subscales. In 36% reduction in the rate of disease progression and, the gp100 alone group, moderate to large impairments were more importantly, had increased overall survival com- seen for global health, role function, fatigue, and pain. pared with the gp100 vaccine alone group in patients Due to interest from clinicians in the analysis of with previously treated advanced melanoma [9]. In gen- results for older oncology patients, results from the post eral, the HRQL results for the ipilimumab groups dem- hoc subgroup analysis of EORTC QLQ-C30 data were onstrate that ipilimumab treatment is associated with also compared by two age groups: patients aged minimal impairments on functioning and symptoms <65 years and those ≥65 years (Table 2). For patients during the treatment induction period. The only statisti- <65 years, in the ipilimumab plus gp100 arm, there were cally significant difference between ipilimumab and Figure 1 Baseline to Week 12 endpoint changes in EORTC QLQ-C30 function and global health status scores. * For the functioning and global health scales, improvements are indicated by positive scores. ** p> 0.05 for all comparisons. Mean change in scores were categorized as “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 5 of 8 http://www.hqlo.com/content/10/1/66 Figure 2 Baseline to Week 12 endpoint changes in EORTC QLQ-C30 symptom scores. * For symptom scales, improvements are indicated by negative scores. ** p< 0.05 versus gp100 group. *** p> 0.05 for all comparisons (except for Constipation with p< 0.05). Mean change in scores were categorized as “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). gp100 vaccine was for constipation, and this finding may reported increased pain, fatigue, dyspnea, and decreased be due to increased rate of colitis in the ipilimumab physical and role function compared with the ipilimu- groups (5.3-7.6% versus 0.8%) [9]. Most of the observed mab group. changes were in the range of “no change” or minimal After 12 weeks of treatment with ipilimumab, only fa- impairments, which indicates that HRQL was main- tigue, sleep disturbance, and appetite loss showed mod- tained during the treatment induction period. Function- erate impairments. However, there was no significant ing and symptom scores did not improve during negative impact on physical, emotional, cognitive, and treatment; only the overall HRQL of these patients was social functioning and global health status in the ipili- negatively impacted to a small extent. The gp100 group mumab treated groups. These findings indicate that Table 2 Baseline to week 12 endpoint changes in EORTC QLQ-C30 scores by age groups Ipilimumab plus gp100 Ipilimumab plus gp100 Ipilimumab Alone Ipilimumab Alone < 65 years ≥ 65 years < 65 years ≥ 65 years (N = 170) (N = 66) (N = 59) (N = 26) Physical function −6.2 −9.5 −4.3 −9.3 Role function −9.8 −11.7 −11 −12.9 Emotional function −0.8 −6.2 −2.2 −9.3 Cognitive function −3.9 −4.7 −3.6 −8.8 Social function −5.4 −7.4 −6 −12.3 Global health −6.5 −12.1 −6 −17 Fatigue 9 14.2 12.4 12.1 Nausea/vomiting 5.3 7.3 4.9 3.1 Pain 7.2 6.4 10 7.4 Dyspnea 2 8.1 2.1 12.5 Sleep disturbance 5 10.4 8.8 12.9 Appetite loss 9.4 9.6 12.9 11.7 Constipation 3.8 6 2.3 −0.4 Diarrhea 6.2 7.7 7.7 13.5 Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 6 of 8 http://www.hqlo.com/content/10/1/66 HRQL outcomes were minimally impaired by ipilimu- treatment as possibly better or comparable to those mab treatment. Therefore, the trade-offs between observed in these other clinical trials. extended survival and HRQL may be acceptable to Clinicians are concerned about the effects of treatment patients and their clinicians [45]. Given that few treat- on elderly (i.e., ≥65 years of age) advanced melanoma ments for advanced melanoma (i.e., vemurafenib and ipi- patients [46,47]. Although overall survival is comparable limumab) are associated with improvements in overall for patients aged <65 and ≥65 years (for ipilimumab survival [9,10,12,13], these HRQL results for ipilimumab plus gp100 versus gp100 alone, hazard ratio was 0.70 are very encouraging. and 0.69 for <65 years and ≥65 years, respectively; for We identified three studies that used the EORTC ipilimumab alone versus gp100 alone, hazard ratio was QLQ-C30 comparing treatments for advanced melan- 0.65 and 0.61 for <65 years and ≥65 years, respectively) oma [14,32,34]. Study design and methods are summar- [9], we evaluated differences in HRQL outcomes by age ized in Additional file 1 Table A1. Two of these studies group. For the ipilimumab plus gp100, results were com- reported higher rates of missing HRQL data at follow- parable for both age groups, although those ≥65 years up compared with ipilimumab plus gp100 or ipilimu- reported more impairment in role function, global mab alone (Additional file 1 Table A2). Disease progres- health, and sleep disturbance. For the ipilimumab alone sion rates were somewhat greater in the comparison groups, the results for functional outcome and symptom studies, ranging from 61% to 74% (Additional file 1 scores were comparable, except that those ≥65 years Table A2). For the EORTC QLQ-C30 functional out- reported more impairment in social function, dyspnea, comes, dacarbazine-videsine-cisplatin and dacarbazine- sleep disturbance, and diarrhea. videsine treated groups demonstrated worse global health The HRQL results from the current ipilimumab study and physical, role, and social function compared with ipili- should be interpreted considering the following limita- mumab plus gp100 or ipilimumab alone groups (Additional tions. HRQL endpoint data were available for only 61% to file 2 Figure A1). For the symptom outcomes, dacarbazine- 65% of patients randomized into the clinical trial. Disease videsine-cisplatin and dacarbazine-videsine treated progression was the most common reason for discontinu- groups demonstrated worse fatigue, nausea/vomiting, ation of study drug (24% of subjects in the ipilimumab and appetite loss and similar pain compared with ipilimu- plus gp100 group; 16% in the ipilimumab alone group; mab plus gp100 and ipilimumab alone groups (Additional and 33% in the gp100 alone group). Rates of discontinu- file 3 Figure A2). The studies by Avril et al. [14] and ation of study drug due to adverse events were greatest for Kiebert et al. [32] showed changes in EORTC QLQ-C30 ipilimumab alone (13%) compared with ipilimumab plus function and symptom scores comparable to the ipilimu- gp100 (9%) and gp100 alone (4%). However, there were mab plus gp100 and ipilimumab alone treatment groups. comparable completion rates of the EORTC QLQ-C30 Overall, the ipilimumab HRQL effects we observed may across treatment arms in the current study (MDX010-20), be better or comparable to those observed in these other so these missing data may not impact the interpretation of clinical trials, as supported by little meaningful impair- the HRQL results. Missing HRQL data is a significant ment in functioning and symptoms during the treatment problem for oncology studies, and patients who complete induction period. follow-up assessments are less likely to experience severe The comparison of HRQL outcomes between the ipili- toxicity and are more likely to have better response to mumab clinical trials and these other studies should be treatment [37]. Finally, although EORTC QLQ-C30 is an interpreted cautiously given the differences in methods, internationally validated, widely used questionnaire for disease progression, and dropout rates. Significant differ- assessing the HRQL in oncology, melanoma specific ences in mechanism of action and known toxicity pro- HRQL questions might not have been addressed. files of chemotherapy and ipilimumab may contribute to observed differences in HRQL between the chemother- Conclusions apy and ipilimumab. In addition, ipilimumab’s demon- In conclusion, ipilimumab at 3 mg/kg with and without strated efficacy compared to the general lack of gp100 vaccine does not have a significant negative im- chemotherapy activity in this disease is another consid- pact on HRQL in patients completing the baseline and eration for observed differences. Week 12 follow-up, during the treatment induction In the Phase II study for ipilimumab [38], mean phase compared with gp100 alone. Ipilimumab treat- changes from baseline to Week 12 for the 3 mg/kg arm ment results in little to no impairment in HRQL out- generally indicated little or no negative impact to patient comes in advanced melanoma patients. The improved HRQL across the EORTC QLQ-C30 subscales for global survival observed in the ipilimumab treated groups does health status, function, and symptoms. These Phase II not come with a significant burden on HRQL for results are similar to the Phase III (MDX010-20) results patients in this analysis. Further research is needed to and add further support to the effects of ipilimumab determine the long term impact of ipilimumab treatment Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 7 of 8 http://www.hqlo.com/content/10/1/66 on HRQL outcomes. In addition, further analyses are 06492, USA. Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ08540, USA. needed to better understand the impact of serious adverse events on HRQL in ipilimumab treated patients. Received: 23 November 2011 Accepted: 17 May 2012 Published: 13 June 2012 Additional files References 1. American Cancer Society: Cancer Facts & Figures 2010. Atlanta: American Additional file 1: Methodology for comparison with other melanoma Cancer Society; 2010. clinical trials. A systematic search of review articles and clinical trial 2. Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N articles was conducted in order to compare the HRQL findings from the Engl J Med 2004, 351:998–1012. ipilimumab studies to other published clinical trials in advanced 3. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick melanoma that included the EORTC QLQ-C30. 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Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Abbreviations Aamdal S, Cebon J, Coates A, et al: Randomized phase III study of CNS: Central Nervous System; DTIC: Dacarbazine; ECOG: Eastern Cooperative temozolomide versus dacarbazine in the treatment of patients with Oncology Group; EORTC QLQ-C30: European Organization for Research and advanced metastatic malignant melanoma. J Clin Oncol 2000, 18:158–166. Treatment of Cancer Quality of Life Core Questionnaire; FACT: Functional 6. Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Assessment of Cancer Therapy; HRQL: Health-Related Quality of Life; Sondak VK, Atkins MB, Eisenhauer EA, et al: Meta-analysis of phase II I.V.: Intravenous. cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II Competing interests trials. J Clin Oncol 2008, 26:527–534. DAR and SS are employees of United BioSource Corporation and have 7. Cornish D, Holterhues C, van de Poll-Franse LV, Coebergh JW, Nijsten T: A research support from Bristol-Myers Squibb (BMS). AJMV is on the BMS systematic review of health-related quality of life in cutaneous advisory board and has been paid honoraria by BMS. PL is a consultant to melanoma. Ann Oncol 2009, 20(suppl 6):vi51–vi58. BMS, has been a member of BMS Speakers Bureau, and has received 8. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, honoraria from BMS to attend international conferences. PL has undertaken Sznol M, Parkinson D, Hawkins M, et al: High-dose recombinant a number of unpaid academic projects with BMS around treatment of interleukin 2 therapy for patients with metastatic melanoma: analysis of melanoma and also this study; which have been or are being submitted for 270 patients treated between 1985 and 1993. J Clin Oncol 1999, publication. CL has received honoraria from BMS for ipilimumab 17:2105–2116. development. GL is a consultant for GlaxoSmithKline, Genentech, and BMS 9. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, and has received honoraria from BMS. CHO has consulted for BMS, received Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival honoraria from BMS, and has received an unrestricted grant from BMS for a with ipilimumab in patients with metastatic melanoma. N Engl J Med clinical trial using ipilimumab. MM declares that she has no competing 2010, 363:711–723. interests. AH is an employee with BMS, holds a leadership position with the 10. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Cancer Immunotherapy Consortium, and owns stocks in BMS. SW is an Dummer R, Garbe C, Testori A, Maio M, et al: Improved survival with employee with and owns stock in BMS. SK is an employee with, owns stock vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med in, and has research funding from BMS. 2011, 364:2507–2516. 11. Trinh VA: Current management of metastatic melanoma. Am J Health Syst Authors' contributions Pharm 2008, 65(suppl 9):S3–S8. DAR participated in data analysis and interpretation and manuscript writing. 12. Robert C, Thomas L, Bondarenko I, O'Day S, DJ M, Garbe C, Lebbe C, Baurain AJMV participated in data analysis and interpretation and manuscript writing. JF, Testori A, Grob JJ, et al: Ipilimumab plus dacarbazine for previously PL participated in the collection and assembly of data, data analysis and untreated metastatic melanoma. N Engl J Med 2011, 364:2517–2526. interpretation, and manuscript writing. CL participated in the conception and 13. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur design and manuscript writing. GL participated in data analysis and GA, Hutson TE, Moschos SJ, Flaherty KT, et al: Survival in BRAF V600- interpretation and manuscript writing. CHO participated in the conception mutant advanced melanoma treated with vemurafenib. N Engl J Med and design and manuscript writing. SS participated in manuscript writing 2012, 366:707–714. and provided project management and administrative support. MM 14. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal participated in data analysis and interpretation and manuscript writing. AH M, Neuber K, Bieber T, Gilde K, et al: Fotemustine compared with participated in data analysis and interpretation and manuscript writing. SW dacarbazine in patients with disseminated malignant melanoma: a participated in conception and design and manuscript writing. SK phase III study. J Clin Oncol 2004, 22:1118–1125. participated in the conception and design, collection and assembly of data 15. Patel P, Suciu S, Mortier L, Kruit W, Robert C, Schadendorf D, Keilholz E, and manuscript writing. All authors read and approved the final manuscript. 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Quirt I, Verma S, Petrella T, Bak K, Charette M: Temozolomide for the for unresectable stage III or IV melanoma patients receiving ipilimumab treatment of metastatic melanoma: a systematic review. Oncologist 2007, treatment. Health and Quality of Life Outcomes 2012 10:66. 12:1114–1123. 31. Paterson AG, Trask PC, Wagner LI, Esper P, Redman B: Validation of the FACT-BRM with interferon-alpha treated melanoma patients. Qual Life Res 2005, 14:133–139. 32. Kiebert GM, Jonas DL, Middleton MR: Health-related quality of life in patients with advanced metastatic melanoma: results of a randomized phase III study comparing temozolomide with dacarbazine. Cancer Invest 2003, 21:821–829. 33. Young AM, Marsden J, Goodman A, Burton A, Dunn JA: Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma. Clin Oncol (R Coll Radiol) 2001, 13:458–465. 34. Sigurdardottir V, Bolund C, Sullivan M: Quality of life evaluation by the EORTC questionnaire technique in patients with generalized malignant melanoma on chemotherapy. Acta Oncol 1996, 35:149–158. Submit your next manuscript to BioMed Central 35. Chiarion-Sileni V, Del Bianco P, De Salvo GL, Lo Re G, Romanini A, Labianca and take full advantage of: R, Nortilli R, Corgna E, Dalla Palma M, Lo Presti G, Ridolfi R: Quality of life evaluation in a randomised trial of chemotherapy versus bio- • Convenient online submission chemotherapy in advanced melanoma patients. Eur J Cancer 2003, • Thorough peer review 39:1577–1585. 36. Beusterien KM, Ackerman SJ, Plante K, Glaspy J, Naredi P, Wood D, Gehlsen K, • No space constraints or color figure charges Agarwala SS: The health-related quality-of-life impact of histamine • Immediate publication on acceptance dihydrochloride plus interleukin-2 compared with interleukin-2 alone in patients with metastatic melanoma. Support Care Cancer 2003, 11:304–312. • Inclusion in PubMed, CAS, Scopus and Google Scholar 37. Fairclough DL: Summary measures and statistics for comparison of • Research which is freely available for redistribution quality of life in a clinical trial of cancer therapy. Stat Med 1997, 16:1197–1209. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Health and Quality of Life Outcomes Springer Journals

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

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Springer Journals
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Copyright © 2012 by Revicki et al.; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Quality of Life Research; Quality of Life Research
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1477-7525
DOI
10.1186/1477-7525-10-66
pmid
22694829
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Abstract

Background: In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial’s 12 week treatment induction period. Methods: The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). Results: In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p< 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain. Conclusions: Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients. Trial registration: Clinicaltrials.gov identification number NCT00094653 Keywords: Ipilimumab, Randomized clinical trial, EORTC QLQ-C30, Advanced melanoma, Health-related quality of life * Correspondence: dennis.revicki@unitedbiosource.com United BioSource Corporation, 7101 Wisconsin Avenue, Suite 600, Bethesda, MD 20814, USA Full list of author information is available at the end of the article © 2012 Revicki et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 2 of 8 http://www.hqlo.com/content/10/1/66 Introduction respectively [9]. Immune-related adverse events were the Advanced melanoma is a serious and life threatening can- most frequently reported drug-related adverse events [9]. cer which has an impact on health-related quality of life The immune-related adverse events of ipilimumab are (HRQL). According to the American Cancer Society, there managed through administration of systemic glucocorti- were an estimated 68,130 new cases of melanoma and coids and other immunosuppressant agents along with ad- 8,700 deaths in the US in 2010, which accounts for almost herence to treatment according to well established three-fourths of all skin cancer deaths [1]. The median guidelines [39,40]. The majority of these immune-related overall survival for patients with untreated advanced mel- adverse events occurred during the induction period of anoma ranges between 6 to 9 months [1-6]. Cornish et al. ipilimumab treatment. This report summarizes the HRQL recently demonstrated that the impact of melanoma on outcomes during the 12 week treatment induction period patient HRQL is comparable with other cancers [7]. of the ipilimumab Phase III clinical trial (MDX010-20). Until the recent approvals for vemurafenib and ipilimu- Assessment of the effects of ipilimumab in relation to mab, none of the currently approved treatments for overall HRQL is important and will allow oncologists to advanced melanoma have shown overall survival benefit appropriately educate patients on the risks and benefits of [3,8-18]. The focus of current treatment is on improving treatment with this agent. survival, managing symptoms, and improving HRQL out- comes [2,19]. Studies have shown that melanoma impacts Methods psychological functioning (i.e., anxiety, depression, and Study design vulnerability) [20-24]. In studies of advanced melanoma Study MDX010-20 was conducted in accordance with patients receiving treatment, melanoma patients also International Conference on Harmonisation-Good Clin- reported significant impairments in physical functioning ical Practices and the Declaration of Helsinki. The study and fatigue symptoms [20,25,26]. Treatment-related was approved by local regulatory authorities and institu- HRQL outcomes vary by HRQL instrument, study meth- tional review boards and Ethics Committees at the partici- ods and design, study dropout rates, and disease progres- pating sites, and all subjects provided written consent. sion rates. These factors need to be taken into The Phase III clinical trial (MDX010-20) was a double- consideration when interpreting the findings of HRQL blind, fixed dose study in 676 previously treated patients studies in advanced melanoma. with advanced stage III or IV melanoma [9]. Patients in Several clinical trials comparing treatments for advanced this trial were randomized 3:1:1 to receive either ipilimu- melanoma have included HRQL measures [14,20,26-36]. mab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; In general, these clinical studies demonstrate varied 1 mg q3w x 4 doses; ipilimumab plus gpl00, n = 403); HRQL and symptom effects for different treatments, al- gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimu- though the earliest studies demonstrate significant impair- mab + placebo (ipilimumab alone, n = 137). The main in- ment to functioning [34,35]. However, most of these clusion criteria were men and women aged ≥18 years, studies have considerable dropout rates and results are histological confirmed advanced stage III or IV melanoma, often restricted to the initial weeks of the clinical trial Eastern Cooperative Oncology Group (ECOG) perform- study. Dropouts are frequently observed in patients with ance status of 0 or 1, and life expectancy of at least four significant toxicity or disease progression, and these miss- months. Key exclusion criteria included active symptom- ing data can make the follow-up HRQL outcomes appear atic or asymptomatic untreated central nervous system better than they are in reality [37]. (CNS) metastasis, primary ocular melanoma, or pregnant Ipilimumab is an anti-CTLA-4 monoclonal antibody or breastfeeding women. Patients with stable, pre-treated with anti-tumor activity and has demonstrated statistically CNS metastases were allowed in the study. 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 Treatment regimen safety data corresponding to the Phase II and III clinical Ipilimumab, at a dose of 3 mg per kilogram of body trials in advanced melanoma have been reported else- weight, was administered with or without gp100 every where [9,12,38]. Overall, ipilimumab, alone or in combin- three weeks for up to four treatments (induction) [9]. In ation with gp100, was tolerable in subjects with advanced the gp100 groups, patients received two modified HLA- metastatic melanoma with a generally manageable safety A* 0201-restricted peptides with incomplete Freund’s profile, which is consistent with safety demonstrated in adjuvant (Montanide ISA-51): a gp100:209-217(210M) previous studies of ipilimumab [9]. Study drug-related ad- peptide, 1 mg injected in the right anterior thigh, and a verse events, regardless of etiology, were severe (≥ Grade gp100:280-288(288V) peptide, 1 mg injected in the left 3) for 19.5%, 26.0%, and 12.1% of subjects treated with ipi- anterior thigh. These injections were given immediately limumab plus gp100, ipilimumab alone, and gp100 alone, after the intravenous infusion of ipilimumab or placebo. Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 3 of 8 http://www.hqlo.com/content/10/1/66 Treatment was started on day 1 of Week 1, and add- and gp100 alone (n = 136) treatment arms. Participants itional treatment was received at Weeks 4, 7, and 10 if from all three arms (total n = 676) had a mean age of there was no intolerable toxicity, no rapidly progressive 56.2 ± 57.0 years and 59% were male (Table 1). The ma- disease, and no significant decline in performance status. jority of participants had M1C stage at entry (n = 483; This included patients who developed new lesions and/or 71.4%) and almost all had an ECOG performance status experienced growth in baseline lesions. Patients were score of 0 or 1 (n = 665; 98.4%). All of the participants offered additional courses of therapy (reinduction) if they had received prior treatment for advanced melanoma. had stable disease after Week 12 or a confirmed partial or Twelve percent of participants (n = 82; 12.1%) had CNS complete response and no dose-limiting toxicity, or if they metastases at baseline. had disease progression with their assigned treatment regimen [9]. HRQL outcomes In the Phase III study (MDX010-20), 95% had baseline Health-related quality of life measure HRQL assessments and Week 12 assessments were HRQL was evaluated using the European Organization available for 236 (62%), 85 (65%), and 80 (61%) of the for Research and Treatment of Cancer Quality of Life patients treated with ipilimumab plus gp100, ipilimumab Questionnaire (EORTC QLQ-C30) [41,42]. The EORTC alone, and gp100 alone, respectively. Missing HRQL data QLQ-C30 contains subscales for global health status, at baseline were due to administrative errors. Reasons and physical, emotional, role, cognitive, and social func- for missing Week 12 data were primarily due to disease tion, with higher scores indicating better functioning progression, adverse events, or death [9]. There were no [41,42]. Symptom subscales include pain, nausea/vomit- differences in demographic or relevant clinical character- ing, fatigue, dyspnea, appetite loss, insomnia, diarrhea, istics between those study patients with complete and and constipation (higher scores indicate greater symp- missing Week 12 HRQL assessments. There were differ- tom severity). Extensive evidence is available supporting ences in baseline EORTC QLQ-C30 scores for global, the reliability, validity, and responsiveness of the EORTC physical, role, emotional, and social function scores and QLQ-C30 in different cancer populations [42,43]. In the for fatigue, nausea, pain, dyspnea, sleep, appetite, and Phase III trial (MDX010-20), HRQL outcomes were self- constipation scores between those with and without administered at the clinical centers before any clinical Week 12 assessments. procedures or physician interactions, including any dis- cussion of imaging studies at baseline and Week 12. Table 1 Baseline demographics and clinical characteristics Phase III (MDX010-20) Statistical analyses Ipilimumab Ipilimumab gp100 Total Baseline to Week 12 changes in EORTC QLQ-C30 func- plus gp100 Alone Alone tion, global health status and symptom scores were calcu- (N = 403) (N = 137) (N = 136) (N = 676) lated. Analysis of variance models were used to compare Age (years), mean 55.6 56.8 57.4 56.2 treatment differences for the HRQL outcomes. Since there Gender, n (%) is clinical interest in effectiveness and risks in older oncol- Male 247 (61) 81 (59) 73 (54) 401 (59) ogy patients, post hoc subgroup analysis of EORTC QLQ- Melanoma stage, C30 data by age (<65 years versus ≥65 years) was also n (%) conducted, and these analyses were compared to the M0 5 (1.2) 1 (0.7) 4 (2.9) 10 (1.5) results from the total sample (i.e., combined age group). M1a 37 (9.2) 14 (10.2) 11 (8.1) 62 (9.2) Descriptive analyses are reported for the data, and no stat- M1b 76 (18.9) 22 (16.1) 23 (16.9) 121 (17.9) istical tests were performed due to the ad hoc nature and relatively small sample sizes. Interpretations of the mean M1c 285 (70.7) 100 (73.0) 98 (72.1) 483 (71.4) change in scores were categorized as “no change” (0–5 Prior treatment 403 (100.0) 137 (100.0) 136 (100.0) 676 (100.0) points), “alittle” (5–10 points), “moderate” (10–20 points), for advanced melanoma, n (%) and “very much” (>20 points), based on Osoba et al. [44]. ECOG PS, n (%) When function and symptom scores showed either “no change” or “little change,” they were interpreted as reflect- 0 233 (57.8) 72 (52.6) 70 (51.5) 375 (55.5) ing no or minimal impact on patient HRQL [44]. 1 165 (40.9) 64 (46.7) 61 (44.9) 290 (42.9) 2 or 3 5 (1.2) 1 (0.7) 4 (2.9) 10 (1.4) Results Missing 0 0 1 (0.7) 1 (0.1) Demographic and clinical characteristics CNS metastases 46 (11.4) 15 (10.9) 21 (15.4) 82 (12.1) Patients were randomly assigned to either the ipilimu- at baseline, n (%) mab plus gp100 (n = 403), ipilimumab alone (n = 137), Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 4 of 8 http://www.hqlo.com/content/10/1/66 When HRQL outcomes were evaluated, most observed none to small impairments in functional outcomes and baseline to Week 12 changes were no greater than minimal symptom scores, while the older age group reported a in the “a little” impairment category (Figures 1 and 2). similar pattern of changes for most of the outcomes. There was a statistically significant difference in constipa- Older patients reported moderate impairments in role tion scores between the ipilimumab plus gp100 and the function, global health, fatigue and sleep disturbance. In gp100 alone groups (p< 0.05) and between the ipilimumab the ipilimumab alone subgroup of patients <65 years, alone and gp100 alone groups (p< 0.05). None of the other the impairment changes in functional outcomes and differences in HRQL scores between the three treatments symptom scores were none to small for most scores, ex- were statistically significant. cept for fatigue and appetite loss. For patients aged For the ipilimumab plus gp100 arm, the observed impair- ≥65 years, in the ipilimumab alone group, moderate or ments were in the “no change” or “alittle” categories for greater impairments were seen in social function and physical, role, emotional, cognitive, and social function, glo- global health, which differed somewhat from the younger bal health, nausea, pain, dyspnea, sleep disturbance, appetite age group. More symptom effects were observed in those loss, constipation, and diarrhea subscales. For the ipilimu- ≥65 years for dyspnea and diarrhea compared with the mab alone group, the observed impairments were in the <65 age group. These findings need to be interpreted cau- “no change” or “alittle” categories for the physical, emo- tiously given the smaller sample size. tional, cognitive, and social function, the global health, nau- sea, pain, dyspnea, constipation, and diarrhea subscales. For Discussion the gp100 alone group, the observed impairments were in Ipilimumab at 3 mg/kg monotherapy, whether combined the “no change” or “alittle” categories for the cognitive and with gp100 vaccine or not, was associated with a 19% to social function, nausea, dyspnea, and diarrhea subscales. In 36% reduction in the rate of disease progression and, the gp100 alone group, moderate to large impairments were more importantly, had increased overall survival com- seen for global health, role function, fatigue, and pain. pared with the gp100 vaccine alone group in patients Due to interest from clinicians in the analysis of with previously treated advanced melanoma [9]. In gen- results for older oncology patients, results from the post eral, the HRQL results for the ipilimumab groups dem- hoc subgroup analysis of EORTC QLQ-C30 data were onstrate that ipilimumab treatment is associated with also compared by two age groups: patients aged minimal impairments on functioning and symptoms <65 years and those ≥65 years (Table 2). For patients during the treatment induction period. The only statisti- <65 years, in the ipilimumab plus gp100 arm, there were cally significant difference between ipilimumab and Figure 1 Baseline to Week 12 endpoint changes in EORTC QLQ-C30 function and global health status scores. * For the functioning and global health scales, improvements are indicated by positive scores. ** p> 0.05 for all comparisons. Mean change in scores were categorized as “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 5 of 8 http://www.hqlo.com/content/10/1/66 Figure 2 Baseline to Week 12 endpoint changes in EORTC QLQ-C30 symptom scores. * For symptom scales, improvements are indicated by negative scores. ** p< 0.05 versus gp100 group. *** p> 0.05 for all comparisons (except for Constipation with p< 0.05). Mean change in scores were categorized as “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20). gp100 vaccine was for constipation, and this finding may reported increased pain, fatigue, dyspnea, and decreased be due to increased rate of colitis in the ipilimumab physical and role function compared with the ipilimu- groups (5.3-7.6% versus 0.8%) [9]. Most of the observed mab group. changes were in the range of “no change” or minimal After 12 weeks of treatment with ipilimumab, only fa- impairments, which indicates that HRQL was main- tigue, sleep disturbance, and appetite loss showed mod- tained during the treatment induction period. Function- erate impairments. However, there was no significant ing and symptom scores did not improve during negative impact on physical, emotional, cognitive, and treatment; only the overall HRQL of these patients was social functioning and global health status in the ipili- negatively impacted to a small extent. The gp100 group mumab treated groups. These findings indicate that Table 2 Baseline to week 12 endpoint changes in EORTC QLQ-C30 scores by age groups Ipilimumab plus gp100 Ipilimumab plus gp100 Ipilimumab Alone Ipilimumab Alone < 65 years ≥ 65 years < 65 years ≥ 65 years (N = 170) (N = 66) (N = 59) (N = 26) Physical function −6.2 −9.5 −4.3 −9.3 Role function −9.8 −11.7 −11 −12.9 Emotional function −0.8 −6.2 −2.2 −9.3 Cognitive function −3.9 −4.7 −3.6 −8.8 Social function −5.4 −7.4 −6 −12.3 Global health −6.5 −12.1 −6 −17 Fatigue 9 14.2 12.4 12.1 Nausea/vomiting 5.3 7.3 4.9 3.1 Pain 7.2 6.4 10 7.4 Dyspnea 2 8.1 2.1 12.5 Sleep disturbance 5 10.4 8.8 12.9 Appetite loss 9.4 9.6 12.9 11.7 Constipation 3.8 6 2.3 −0.4 Diarrhea 6.2 7.7 7.7 13.5 Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 6 of 8 http://www.hqlo.com/content/10/1/66 HRQL outcomes were minimally impaired by ipilimu- treatment as possibly better or comparable to those mab treatment. Therefore, the trade-offs between observed in these other clinical trials. extended survival and HRQL may be acceptable to Clinicians are concerned about the effects of treatment patients and their clinicians [45]. Given that few treat- on elderly (i.e., ≥65 years of age) advanced melanoma ments for advanced melanoma (i.e., vemurafenib and ipi- patients [46,47]. Although overall survival is comparable limumab) are associated with improvements in overall for patients aged <65 and ≥65 years (for ipilimumab survival [9,10,12,13], these HRQL results for ipilimumab plus gp100 versus gp100 alone, hazard ratio was 0.70 are very encouraging. and 0.69 for <65 years and ≥65 years, respectively; for We identified three studies that used the EORTC ipilimumab alone versus gp100 alone, hazard ratio was QLQ-C30 comparing treatments for advanced melan- 0.65 and 0.61 for <65 years and ≥65 years, respectively) oma [14,32,34]. Study design and methods are summar- [9], we evaluated differences in HRQL outcomes by age ized in Additional file 1 Table A1. Two of these studies group. For the ipilimumab plus gp100, results were com- reported higher rates of missing HRQL data at follow- parable for both age groups, although those ≥65 years up compared with ipilimumab plus gp100 or ipilimu- reported more impairment in role function, global mab alone (Additional file 1 Table A2). Disease progres- health, and sleep disturbance. For the ipilimumab alone sion rates were somewhat greater in the comparison groups, the results for functional outcome and symptom studies, ranging from 61% to 74% (Additional file 1 scores were comparable, except that those ≥65 years Table A2). For the EORTC QLQ-C30 functional out- reported more impairment in social function, dyspnea, comes, dacarbazine-videsine-cisplatin and dacarbazine- sleep disturbance, and diarrhea. videsine treated groups demonstrated worse global health The HRQL results from the current ipilimumab study and physical, role, and social function compared with ipili- should be interpreted considering the following limita- mumab plus gp100 or ipilimumab alone groups (Additional tions. HRQL endpoint data were available for only 61% to file 2 Figure A1). For the symptom outcomes, dacarbazine- 65% of patients randomized into the clinical trial. Disease videsine-cisplatin and dacarbazine-videsine treated progression was the most common reason for discontinu- groups demonstrated worse fatigue, nausea/vomiting, ation of study drug (24% of subjects in the ipilimumab and appetite loss and similar pain compared with ipilimu- plus gp100 group; 16% in the ipilimumab alone group; mab plus gp100 and ipilimumab alone groups (Additional and 33% in the gp100 alone group). Rates of discontinu- file 3 Figure A2). The studies by Avril et al. [14] and ation of study drug due to adverse events were greatest for Kiebert et al. [32] showed changes in EORTC QLQ-C30 ipilimumab alone (13%) compared with ipilimumab plus function and symptom scores comparable to the ipilimu- gp100 (9%) and gp100 alone (4%). However, there were mab plus gp100 and ipilimumab alone treatment groups. comparable completion rates of the EORTC QLQ-C30 Overall, the ipilimumab HRQL effects we observed may across treatment arms in the current study (MDX010-20), be better or comparable to those observed in these other so these missing data may not impact the interpretation of clinical trials, as supported by little meaningful impair- the HRQL results. Missing HRQL data is a significant ment in functioning and symptoms during the treatment problem for oncology studies, and patients who complete induction period. follow-up assessments are less likely to experience severe The comparison of HRQL outcomes between the ipili- toxicity and are more likely to have better response to mumab clinical trials and these other studies should be treatment [37]. Finally, although EORTC QLQ-C30 is an interpreted cautiously given the differences in methods, internationally validated, widely used questionnaire for disease progression, and dropout rates. Significant differ- assessing the HRQL in oncology, melanoma specific ences in mechanism of action and known toxicity pro- HRQL questions might not have been addressed. files of chemotherapy and ipilimumab may contribute to observed differences in HRQL between the chemother- Conclusions apy and ipilimumab. In addition, ipilimumab’s demon- In conclusion, ipilimumab at 3 mg/kg with and without strated efficacy compared to the general lack of gp100 vaccine does not have a significant negative im- chemotherapy activity in this disease is another consid- pact on HRQL in patients completing the baseline and eration for observed differences. Week 12 follow-up, during the treatment induction In the Phase II study for ipilimumab [38], mean phase compared with gp100 alone. Ipilimumab treat- changes from baseline to Week 12 for the 3 mg/kg arm ment results in little to no impairment in HRQL out- generally indicated little or no negative impact to patient comes in advanced melanoma patients. The improved HRQL across the EORTC QLQ-C30 subscales for global survival observed in the ipilimumab treated groups does health status, function, and symptoms. These Phase II not come with a significant burden on HRQL for results are similar to the Phase III (MDX010-20) results patients in this analysis. Further research is needed to and add further support to the effects of ipilimumab determine the long term impact of ipilimumab treatment Revicki et al. Health and Quality of Life Outcomes 2012, 10:66 Page 7 of 8 http://www.hqlo.com/content/10/1/66 on HRQL outcomes. In addition, further analyses are 06492, USA. Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ08540, USA. needed to better understand the impact of serious adverse events on HRQL in ipilimumab treated patients. Received: 23 November 2011 Accepted: 17 May 2012 Published: 13 June 2012 Additional files References 1. American Cancer Society: Cancer Facts & Figures 2010. Atlanta: American Additional file 1: Methodology for comparison with other melanoma Cancer Society; 2010. clinical trials. A systematic search of review articles and clinical trial 2. Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N articles was conducted in order to compare the HRQL findings from the Engl J Med 2004, 351:998–1012. ipilimumab studies to other published clinical trials in advanced 3. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, Pavlick melanoma that included the EORTC QLQ-C30. 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Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Abbreviations Aamdal S, Cebon J, Coates A, et al: Randomized phase III study of CNS: Central Nervous System; DTIC: Dacarbazine; ECOG: Eastern Cooperative temozolomide versus dacarbazine in the treatment of patients with Oncology Group; EORTC QLQ-C30: European Organization for Research and advanced metastatic malignant melanoma. J Clin Oncol 2000, 18:158–166. Treatment of Cancer Quality of Life Core Questionnaire; FACT: Functional 6. Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Assessment of Cancer Therapy; HRQL: Health-Related Quality of Life; Sondak VK, Atkins MB, Eisenhauer EA, et al: Meta-analysis of phase II I.V.: Intravenous. cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II Competing interests trials. J Clin Oncol 2008, 26:527–534. DAR and SS are employees of United BioSource Corporation and have 7. Cornish D, Holterhues C, van de Poll-Franse LV, Coebergh JW, Nijsten T: A research support from Bristol-Myers Squibb (BMS). AJMV is on the BMS systematic review of health-related quality of life in cutaneous advisory board and has been paid honoraria by BMS. PL is a consultant to melanoma. Ann Oncol 2009, 20(suppl 6):vi51–vi58. BMS, has been a member of BMS Speakers Bureau, and has received 8. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, honoraria from BMS to attend international conferences. PL has undertaken Sznol M, Parkinson D, Hawkins M, et al: High-dose recombinant a number of unpaid academic projects with BMS around treatment of interleukin 2 therapy for patients with metastatic melanoma: analysis of melanoma and also this study; which have been or are being submitted for 270 patients treated between 1985 and 1993. J Clin Oncol 1999, publication. CL has received honoraria from BMS for ipilimumab 17:2105–2116. development. GL is a consultant for GlaxoSmithKline, Genentech, and BMS 9. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, and has received honoraria from BMS. CHO has consulted for BMS, received Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival honoraria from BMS, and has received an unrestricted grant from BMS for a with ipilimumab in patients with metastatic melanoma. N Engl J Med clinical trial using ipilimumab. MM declares that she has no competing 2010, 363:711–723. interests. AH is an employee with BMS, holds a leadership position with the 10. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Cancer Immunotherapy Consortium, and owns stocks in BMS. SW is an Dummer R, Garbe C, Testori A, Maio M, et al: Improved survival with employee with and owns stock in BMS. SK is an employee with, owns stock vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med in, and has research funding from BMS. 2011, 364:2507–2516. 11. Trinh VA: Current management of metastatic melanoma. Am J Health Syst Authors' contributions Pharm 2008, 65(suppl 9):S3–S8. DAR participated in data analysis and interpretation and manuscript writing. 12. Robert C, Thomas L, Bondarenko I, O'Day S, DJ M, Garbe C, Lebbe C, Baurain AJMV participated in data analysis and interpretation and manuscript writing. JF, Testori A, Grob JJ, et al: Ipilimumab plus dacarbazine for previously PL participated in the collection and assembly of data, data analysis and untreated metastatic melanoma. N Engl J Med 2011, 364:2517–2526. interpretation, and manuscript writing. CL participated in the conception and 13. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur design and manuscript writing. GL participated in data analysis and GA, Hutson TE, Moschos SJ, Flaherty KT, et al: Survival in BRAF V600- interpretation and manuscript writing. 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