Incidence of fatigue and low-dose corticosteroid use in prostate cancer patients receiving systemic treatment: a meta-analysis of randomized controlled trials
- 21 Downloads
Cancer-related fatigue (CRF) is a complex condition that is reported in > 50% of cancer patients. In men with castration-resistant prostate cancer (CRPC), CRF was reported in 12–21% of patients. Approved systemic therapy against CRPC is commonly administered in combination with androgen-deprivation treatment (ADT) and, in some cases, with daily, low-dose corticosteroids. Importantly, the use of low-dose corticosteroids is associated with multiple negative effects, including reduced muscle mass. On these grounds, we hypothesized that the chronic use of corticosteroids may increase the incidence of fatigue in patients with prostate cancer.
We reviewed all randomized trials published during the last 15 years conducted in patients with prostate cancer receiving systemic treatment and we performed a sub-group analysis to gather insights regarding the potential differences in the incidence of fatigue in patients receiving vs. not receiving daily corticosteroids as part of their systemic anti-neoplastic regimen.
Overall, 22,734 men enrolled in prospective randomized phase II and III trials were evaluable for fatigue. Estimated pooled incidence of grade 1–2 fatigue was 30.89% (95% CI = 25.34–36.74), while estimated pooled incidence of grade 3–4 fatigue was reported in 3.90% (95% CI = 2.91–5.02). Sub-group analysis showed that grade 3–4 fatigue was approximately double in patients who received daily corticosteroids as part of their anti-neoplastic treatment (5.58; 95% CI = 4.33–6.98) vs. those who did not (2.67%; 95% CI = 1.53–4.11).
Our findings highlight the need for ad hoc-designed prospective clinical trials to investigate whether the benefits associated with low-dose, daily corticosteroids outweigh the risks associated with corticosteroid-related adverse events such as fatigue.
KeywordsProstate cancer Meta-analysis Fatigue Corticosteroids
Ferro: Project development; Manuscript editing. Di Lorenzo: Project development; Manuscript editing. de Cobelli: Project development; Manuscript editing. Bruzzese: Data analysis. Pignataro: Data collection. Borghesi: Project development. Musi: Project development. Vartolomei: Project development. Cosimato: Data collection. Serino: Data collection. Ieluzzi: Data collection. Terracciano Project development. Damiano Project development; Manuscript editing. Cantiello Project development; Manuscript editing. Mistretta Project development; Manuscript editing. Muto Project development; Manuscript editing. Lucarelli Project development; Manuscript editing. De Placido Project development; Manuscript editing. Buonerba Project development; Data management; Manuscript writing.
Compliance with ethical standards
Conflict of interest
No relevant conflicts by any of the authors are to be disclosed.
The authors have no potential conflicts of interest to disclose relevant to this work. This work is a systematic review of published data, so it does not directly involve human participants and/or animals, not did it require any informed consent or ethics committee approval.
- 5.Jaquet P, Gunz G, Saveanu A et al (2005) BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide. J Endocrinol Investig 28:21–27. https://doi.org/10.1056/NEJMoa1209096 CrossRefGoogle Scholar
- 10.Woratanarat T, Woratanarat P (2011) Six thinking hats technique for evaluation and strategic formulation in postgraduate medical teaching system. Indian J Public Heal Res Dev 2:108–110Google Scholar
- 14.Yu EY, Li H, Higano CS et al (2015) SWOG S0925: a randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. J Clin Oncol 33:1601–1608. https://doi.org/10.1200/JCO.2014.59.4127 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Petrylak DP, Vogelzang NJ, Budnik N et al (2015) Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 16:417–425. https://doi.org/10.1016/S1470-2045(15)70025-2 CrossRefPubMedGoogle Scholar
- 16.Saad F, Fizazi K, Jinga V et al (2015) Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol 16:338–348. https://doi.org/10.1016/S1470-2045(15)70027-6 CrossRefPubMedGoogle Scholar
- 17.Fizazi K, Jones R, Oudard S et al (2015) Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol 33(7):723–731. https://doi.org/10.1200/JCO.2014.56.5119 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Azad AA, Beardsley EK, Hotte SJ et al (2014) A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer. Invest New Drugs 32:746–752. https://doi.org/10.1007/s10637-014-0091-8 CrossRefPubMedGoogle Scholar
- 20.Freytag SO, Stricker H, Lu M et al (2014) Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 89:268–276. https://doi.org/10.1016/j.ijrobp.2014.02.034 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Michaelson MD, Oudard S, Houede N et al (2014) Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol 32:76–82. https://doi.org/10.1200/JCO.2012.48.5268 CrossRefPubMedGoogle Scholar
- 24.Araujo JC, Trudel GC, Saad F et al (2013) Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol 14:1307–1316. https://doi.org/10.1016/S1470-2045(13)70479-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Dreicer R, Garcia J, Rini B et al (2013) A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer. Invest New Drugs 31:1044–1050. https://doi.org/10.1007/s10637-013-9940-0 CrossRefPubMedGoogle Scholar
- 26.Fleming MT, Sonpavde G, Kolodziej M et al (2012) Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 10:6–14. https://doi.org/10.1016/j.clgc.2011.11.003 CrossRefPubMedGoogle Scholar
- 27.Ward JE, Karrison T, Chatta G et al (2012) A randomized, phase II study of pazopanib in castrate-sensitive prostate cancer: a University of Chicago Phase II Consortium/Department of Defense Prostate Cancer Clinical Trials Consortium study. Prostate Cancer Prostatic Dis 15:87–92. https://doi.org/10.1038/pcan.2011.49 CrossRefPubMedGoogle Scholar
- 28.Bradley DA, Daignault S, Ryan CJ et al (2011) Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs 29:1432–1440. https://doi.org/10.1007/s10637-010-9420-8 CrossRefPubMedGoogle Scholar
- 33.De Bono JS, Oudard S, Ozguroglu M et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376:1147–1154. https://doi.org/10.1016/S0140-6736(10)61389-X CrossRefPubMedGoogle Scholar
- 37.James ND, Caty A, Borre M et al (2009) Safety and efficacy of the specific endothelin—a receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 Trial. Eur Urol 55:1112–1123. https://doi.org/10.1016/j.eururo.2008.11.002 CrossRefPubMedGoogle Scholar
- 38.Figg WD, Hussain MH, Gulley JL et al (2009) A double-blind randomized crossover study of oral thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation. J Urol 181:1104–1113. https://doi.org/10.1016/j.juro.2008.11.026 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Machiels JP, Mazzeo F, Clausse M et al (2008) Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer. J Clin Oncol 26:5261–5268. https://doi.org/10.1200/JCO.2008.16.9524 CrossRefPubMedGoogle Scholar
- 41.Caffo O, Sava T, Comploj E et al (2008) Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: Results of a multicentre, randomized phase II trial. BJU Int 102:1080–1085. https://doi.org/10.1111/j.1464-410X.2008.07779.x CrossRefPubMedGoogle Scholar
- 42.Attia S, Eickhoff J, Wilding G et al (2008) Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer. Clin Cancer Res 14:2437–2443. https://doi.org/10.1158/1078-0432.CCR-07-4274 CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Galsky MD, Small EJ, Oh WK et al (2005) Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 23:1439–1446. https://doi.org/10.1200/JCO.2005.09.042 CrossRefPubMedGoogle Scholar
- 51.Shore ND, Chowdhury S, Villers A et al (2016) Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 17:153–163. https://doi.org/10.1016/S1470-2045(15)00518-5 CrossRefPubMedGoogle Scholar
- 53.Cathomas R, Crabb SJ, Mark M et al (2016) Orteronel switch maintenance therapy in metastatic castration resistant prostate cancer after first-line docetaxel: a multicenter, randomized, double-blind, placebo-controlled trial (SAKK 08/11). Prostate 76:1519–1527. https://doi.org/10.1002/pros.23236 CrossRefPubMedGoogle Scholar
- 54.Chi KN, Higano CS, Blumenstein B et al (2017) Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol 18:473–485. https://doi.org/10.1016/S1470-2045(17)30168-7 CrossRefPubMedGoogle Scholar
- 56.Antonarakis ES, Tagawa ST, Galletti G et al (2017) Randomized, noncomparative, phase II trial of early switch from docetaxel to cabazitaxel or vice versa, with integrated biomarker analysis, in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. J Clin Oncol 35:3181–3188. https://doi.org/10.1200/JCO.2017.72.4138 CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Beer TM, Hotte SJ, Saad F et al (2017) Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol 18:1532–1542. https://doi.org/10.1016/S1470-2045(17)30605-8 CrossRefPubMedGoogle Scholar
- 58.Eisenberger M, Hardy-Bessard AC, Kim CS et al (2017) Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer - PROSELICA. J Clin Oncol 35:3198–3206. https://doi.org/10.1200/JCO.2016.72.1076 CrossRefPubMedGoogle Scholar
- 62.Beer TM, Kwon ED, Drake CG et al (2017) Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 35:40–47. https://doi.org/10.1200/JCO.2016.69.1584 CrossRefPubMedGoogle Scholar
- 67.Tannock IF, Osoba D, Stockler MR et al (1996) Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14:1756–1764. https://doi.org/10.1200/JCO.19126.96.36.1996 CrossRefPubMedGoogle Scholar
- 71.Buonerba C, Bosso D, De Placido S, Di Lorenzo G (2017) 841TiPA randomized phase II study comparing cabazitaxel/prednisone to cabazitaxel alone for second-line chemotherapy in men with metastatic castrate resistant prostate cancer (mCRPC): CABACARE. Ann Oncol 28:mdx370.058–mdx370.058. https://doi.org/10.1093/annonc/mdx370.058 CrossRefGoogle Scholar