An explorative study to assess the association between health-related quality of life and the recommended phase II dose in a phase I trial: idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma

Amélie Anota, Mathieu Boulin, Sandrine Dabakuyo-Yonli, Patrick Hillon, Jean-Pierre Cercueil, Anne Minello, Jean-Louis Jouve, Xavier Paoletti, Laurent Bedenne, Boris Guiu, Franck Bonnetain, Amélie Anota, Mathieu Boulin, Sandrine Dabakuyo-Yonli, Patrick Hillon, Jean-Pierre Cercueil, Anne Minello, Jean-Louis Jouve, Xavier Paoletti, Laurent Bedenne, Boris Guiu, Franck Bonnetain

Abstract

Objectives: The objective of this study was to explore the association between health-related quality of life (HRQoL) and the recommended phase 2 dose in a phase I clinical trial according to the Time to HRQoL deterioration approach (TTD).

Setting: This is a phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads performed in cirrhotic patients with hepatocellular carcinoma. Patients had to complete the EORTC QLQ-C30 HRQoL questionnaire at baseline and at days 15, 30 and 60 after TACE.

Participants: Patients aged ≥18 years with HCC unsuitable for curative treatments were evaluated for the study (N=21).

Primary and secondary outcome measurements: The primary objective was to determine the maximum tolerated dose (MTD) of idarubicin loaded after a single TACE session. MTD was defined as the dose level closest to that causing dose-limiting toxicity in 20% of patients. HRQoL was the secondary end point.

Results: Between March 2010 and March 2011, 9, 6 and 6 patients were included at idarubicin dose levels of 5, 10 and 15 mg, respectively. Calculated MTD of idarubicin was 10 mg. At the 10 mg idarubicin dose, patients presented a longer TTD than at 5 mg, for global health status (HR=0.91 (95% CI 0.18 to 4.72)), physical functioning (HR=0.38 (0.04 to 3.22)), fatigue (HR=0.67 (0.18 to 2.56)) and pain (HR=0.47 (0.05 to 4.24)).

Conclusions: These HRQoL results were consistent with the estimated MTD, with a median TTD for global health status of 41 days (21 to NA) at 5 mg, 23 days (20 to NA) at 10 mg and 25 days (17 to NA) at 15 mg. These results show the importance of studying HRQoL in phase I trials.

Trial registration number: NCT01040559; Post-results.

Keywords: Health-related Quality of Life; longitudinal analysis; oncology clinical trial; phase I; time to deterioration.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Consort diagram. ITT: intent to treat; mITT: modified intent to treat (ie, patients with at least the baseline HRQoL score); GHS, Global Health Status; PF, physical functioning; FA, fatigue; PA: pain.
Figure 2
Figure 2
Kaplan-Meier survival curves according to idarubicin dose level for the four-targeted dimensions of the QLQ-C30 regarding the time to Health-related quality of life score deterioration with a 5-point minimal clinically important difference.

References

    1. Ferlay J, Shin HR, Bray F et al. . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. 10.1002/ijc.25516
    1. Wood TF, Rose DM, Chung M et al. . Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol 2000;7:593–600. 10.1007/BF02725339
    1. Eltawil KM, Berry R, Abdolell M et al. . Quality of life and survival analysis of patients undergoing transarterial chemoembolization for primary hepatic malignancies: a prospective cohort study. HPB (Oxford) 2012;14:341–50. 10.1111/j.1477-2574.2012.00455.x
    1. Ahmed S, de Souza NN, Qiao W et al. . Quality of life in hepatocellular carcinoma patients treated with transarterial chemoembolization. HPB Surg 2016;2016:6120143 10.1155/2016/6120143
    1. Doffoël M, Bonnetain F, Bouché O et al. . Multicentre randomised phase III trial comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402). Eur J Cancer 2008;44:528–38. 10.1016/j.ejca.2008.01.004
    1. Boulin M, Guiu S, Chauffert B et al. . Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma. Anticancer Drugs 2011;22:741–8. 10.1097/CAD.0b013e328346a0c5
    1. Boulin M, Hillon P, Cercueil JP et al. . Idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma: results of the IDASPHERE phase I trial. Aliment Pharmacol Ther 2014;39:1301–13. 10.1111/apt.12746
    1. National Cancer Institute. Common Terminology Criteria for Adverse Events v3. 0 (CTCAE). Cancer Therapy Evaluation Program, 2006.
    1. Postel-Vinay S, Arkenau HT, Olmos D et al. . Clinical benefit in phase-I trials of novel molecularly targeted agents: does dose matter? Br J Cancer 2009;100:1373–8. 10.1038/sj.bjc.6605030
    1. Le Tourneau C, Razak AR, Gan HK et al. . Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: a review of the literature. Eur J Cancer 2011;47:1468–75. 10.1016/j.ejca.2011.03.016
    1. Basch E. Patient-reported outcomes in drug safety evaluation. Ann Oncol 2009;20:1905–6. 10.1093/annonc/mdp542
    1. Verweij J, Disis ML, Cannistra SA. Phase I studies of drug combinations. J Clin Oncol 2010;28:4545–6. 10.1200/JCO.2010.30.6282
    1. Stephenson CM, Levin RD, Spector T et al. . Phase I clinical trial to evaluate the safety, tolerability and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol 2013;72:139–46. 10.1007/s00280-013-2179-9
    1. Rouanne M, Massard C, Hollebecque A et al. . Evaluation of sexuality, health-related quality-of-life and depression in advanced cancer patients: a prospective study in a phase I clinical trial unit of predominantly targeted anticancer drugs. Eur J Cancer 2013;49:431–8. 10.1016/j.ejca.2012.08.008
    1. Anota A, Hamidou Z, Paget-Bailly S et al. . Time to health-related quality of life score deterioration as a modality of longitudinal analysis for health-related quality of life studies in oncology: do we need RECIST for quality of life to achieve standardization? Qual Life Res 2015;24:5–18. 10.1007/s11136-013-0583-6
    1. Bonnetain F, Dahan L, Maillard E et al. . Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. Eur J Cancer 2010;46:2753–62. 10.1016/j.ejca.2010.07.023
    1. Hamidou Z, Dabakuyo TS, Mercier M et al. . Time to deterioration in quality of life score as a modality of longitudinal analysis in patients with breast cancer. Oncologist 2011;16:1458–68. 10.1634/theoncologist.2011-0085
    1. Bruix J, Sherman M, Llovet JM et al. . Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–30.
    1. O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 1990;46:33–48. 10.2307/2531628
    1. O'Quigley J, Shen LZ. Continual reassessment method: a likelihood approach. Biometrics 1996;52:673–84. 10.2307/2532905
    1. Aaronson NK, Ahmedzai S, Bergman B et al. . The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76. 10.1093/jnci/85.5.365
    1. Fayers PM, Aaronson NK, Bjordal K et al. . EORTC QLQ-C30 scoring manual. 3rd edn Brussels: EORTC; 2001 ed2001 2001.
    1. Osoba D, Rodrigues G, Myles J et al. . Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139–44.
    1. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–5.
    1. Llovet JM, Bruix J. Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000;32:679–80. 10.1053/jhep.2000.16475
    1. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329–38. 10.1055/s-2007-1007122
    1. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika 1982;69:239–41. 10.1093/biomet/69.1.239
    1. Atkinson TM, Li Y, Coffey CW et al. . Reliability of adverse symptom event reporting by clinicians. Qual Life Res 2012;21:1159–64. 10.1007/s11136-011-0031-4
    1. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med 2010;362:865–9. 10.1056/NEJMp0911494
    1. Basch E, Reeve BB, Mitchell SA et al. . Development of The National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst 2014;106:pii: dju244 10.1093/jnci/dju244
    1. Dueck AC, Mendoza TR, Mitchell SA et al. . Validity and reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol 2015;1:1051–9. 10.1001/jamaoncol.2015.2639
    1. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther 2001;8:181–6. 10.1097/00045391-200105000-00006

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi