NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim

Jeffrey J Kirshner, Maxwell C McDonald 3rd, Flavio Kruter, Andrew S Guinigundo, Linda Vanni, Cathy L Maxwell, Maureen Reiner, Terry E Upchurch, Jacob Garcia, Phuong Khanh Morrow, Jeffrey J Kirshner, Maxwell C McDonald 3rd, Flavio Kruter, Andrew S Guinigundo, Linda Vanni, Cathy L Maxwell, Maureen Reiner, Terry E Upchurch, Jacob Garcia, Phuong Khanh Morrow

Abstract

Purpose: Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on pegfilgrastim-associated bone pain.

Methods: In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I-III breast cancer and an ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2-4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles.

Results: Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all-grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment-related AEs and discontinuations than naproxen.

Conclusions: Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim.

Clinical trial registration: ClinicalTrials.gov ; NCT01712009.

Keywords: Bone pain; Breast cancer; Granulocyte colony-stimulating factor; Loratadine; Naproxen; Pegfilgrastim.

Conflict of interest statement

Conflict of interest

Jeffrey J Kirshner has no relationships to disclose. Maxwell C McDonald III reports a relationship with Merck (speakers’ bureau). Flavio Kruter has no relationships to disclose. Andrew S Guinigundo reports relationships with Oncology Hematology Care Inc./US Oncology (employment), Amgen (consultancy, speakers’ bureau, travel expenses), Celgene (speakers’ bureau), Genentech (consultancy, speakers’ bureau), Merck (speakers’ bureau), and Pfizer (speakers’ bureau). Linda Vanni reports relationships with Ascension Providence (employment), Collegium (consultancy), Daiichi Sankyo (consultancy), and The Medicine Shop (consultancy, speakers’ bureau). Cathy L Maxwell reports a relationship with Amgen (consultancy, honoraria, speakers’ bureau, travel expenses). Maureen Reiner, Terry E Upchurch, Jacob Garcia, and Phuong Khanh Morrow report a relationship with Amgen (employment, stock/stock options).

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all individual participants included in this study.

Figures

Fig. 1
Fig. 1
Study schema. Following screening and randomization, patients received chemotherapy followed 24–72 h later by pegfilgrastim. Patients initiated treatment with naproxen or loratadine on the same day they received pegfilgrastim. Data on bone pain AEs were collected on day 1 of cycles 2, 3, and 4 and at the safety follow-up visit. Patients completed bone pain surveys and bone pain medication logs once per day for 5 days, beginning the day they received pegfilgrastim in cycles 1–4. BID twice a day, QD once a day
Fig. 2
Fig. 2
AUC for patient-reported bone pain (scale 0–10) by cycle and across all cycles. Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 through 5 of each cycle. Numerical values for the means and the 95% CIs are noted. Mean AUC across cycles was the average of AUCs across the cycles. AUC area under the curve, CI confidence interval, L loratadine, N naproxen, NP no prophylaxis

References

    1. Pettengell R, Schwenkglenks M, Leonard R, Bosly A, Paridaens R, Constenla M, Szucs TD, Jackisch C, Impact of Neutropenia in Chemotherapy-European Study Group Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study. Support Care Cancer. 2008;16:1299–1309. doi: 10.1007/s00520-008-0430-4.
    1. Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C, European Organisation for Research and Treatment of Cancer 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47:8–32. doi: 10.1016/j.ejca.2010.10.013.
    1. Schilling MB, Parks C, Deeter RG. Costs and outcomes associated with hospitalized cancer patients with neutropenic complications: a retrospective study. Exp Ther Med. 2011;2:859–866. doi: 10.3892/etm.2011.312.
    1. Lyman GH, Kuderer NM, Djulbegovic B. Prophylactic granulocyte colony-stimulating factor in patients receiving dose-intensive cancer chemotherapy: a meta-analysis. Am J Med. 2002;112:406–411. doi: 10.1016/S0002-9343(02)01036-7.
    1. Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL, Neumann TA, Schwartzberg LS. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23:1178–1184. doi: 10.1200/JCO.2005.09.102.
    1. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25:3158–3167. doi: 10.1200/JCO.2006.08.8823.
    1. Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, Kris M, Grous J, Picozzi V, Rausch G, Smith R, Gradishar W, Yahanda A, Vincent M, Stewart M, Glaspy J. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991;325:164–170. doi: 10.1056/NEJM199107183250305.
    1. Neulasta® (pegfilgrastim) prescribing information. Amgen
    1. Crawford J. Safety and efficacy of pegfilgrastim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy. 2003;23:15S–19S. doi: 10.1592/phco.23.9.15S.32889.
    1. Kubista E, Glaspy J, Holmes FA, Green MD, Hackett J, Neumann T, Pegfilgrastim Study Group Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer. Clin Breast Cancer. 2003;3:391–398. doi: 10.3816/CBC.2003.n.003.
    1. Kirshner JJ, Hickok J, Hofman M. Pegfilgrastim-induced bone pain: incidence, risk factors, and management in a community practice. Community Oncol. 2007;4:455–459. doi: 10.1016/S1548-5315(11)70107-3.
    1. Pinto L, Liu Z, Doan Q, Bernal M, Dubois R, Lyman G. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin. 2007;23:2283–2295. doi: 10.1185/030079907X219599.
    1. Sierra J, Harms R, Mo M, Vogel C (2009) Evaluation of reported bone pain in patients (pts) receiving chemotherapy in pegfilgrastim clinical trials. J Clin Oncol 27(15_suppl): Abstract 9621
    1. Gregory SA, Schwartzberg LS, Mo M, Sierra J, Vogel C. Evaluation of reported bone pain in cancer patients receiving chemotherapy in pegfilgrastim clinical trials: a retrospective analysis. Commun Oncol. 2010;7:297–308. doi: 10.1016/S1548-5315(11)70402-8.
    1. Lambertini M, Del Mastro L, Bellodi A, Pronzato P. The five “Ws” for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs) Crit Rev Oncol Hematol. 2014;89:112–128. doi: 10.1016/j.critrevonc.2013.08.006.
    1. Dulisse B, Li X, Gayle JA, Barron RL, Ernst FR, Rothman KJ, Legg JC, Kaye JA. A retrospective study of the clinical and economic burden during hospitalizations among cancer patients with febrile neutropenia. J Med Econ. 2013;16:720–735. doi: 10.3111/13696998.2013.782034.
    1. Crawford J, Dale DC, Kuderer NM, Culakova E, Poniewierski MS, Wolff D, Lyman GH. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Cancer Netw. 2008;6:109–118. doi: 10.6004/jnccn.2008.0012.
    1. Lyman GH, Dale DC, Tomita D, Whittaker S, Crawford J. A retrospective evaluation of chemotherapy dose intensity and supportive care for early-stage breast cancer in a curative setting. Breast Cancer Res Treat. 2013;139:863–872. doi: 10.1007/s10549-013-2582-2.
    1. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Cancer Netw. 2009;7:99–108. doi: 10.6004/jnccn.2009.0009.
    1. Kirshner JJ, Heckler CE, Dakhil SR, Hopkins JO, Coles C, Morrow GR (2010) Prevention of pegfilgrastim-induced bone pain (PIP): a URCC CCOP randomized, double-blind, placebo-controlled trial of 510 cancer patients. J Clin Oncol 28 (15_suppl):Abstract 9014
    1. Kirshner JJ, Heckler CE, Tiffany S, Reichel C, McAuliffe C, Morrow GR (2011) A phase II study of loratidine (L) to prevent pegfilgrastim-induced pain (PIP). J Clin Oncol 29 (15_suppl):Abstract e19704
    1. Kirshner JJ, Heckler CE, Janelsins MC, Dakhil SR, Hopkins JO, Coles C, Morrow GR. Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the University of Rochester Cancer Center Clinical Community Oncology Program Research Base. J Clin Oncol. 2012;30:1974–1979. doi: 10.1200/JCO.2011.37.8364.
    1. Kirshner JJ, Heckler CE, Reichel C, Morrow GR (2012) A phase II study of loratidine (L) and naproxen (N) to prevent pegfilgrastim-induced pain (PIP). J Clin Oncol 30 (15_suppl):Abstract e19510
    1. Romeo C, Li Q, Copeland L. Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: a case report. J Oncol Pharm Pract. 2015;21:301–304. doi: 10.1177/1078155214527858.
    1. Gewandter J, Heckler C, Kirshner J, Roscoe J, Morrow G. Naproxen reduces chemotherapy and pegfilgrastim-induced sleep disturbance possibly mediated through reduced bone pain. J Pain. 2012;13:S65. doi: 10.1016/j.jpain.2012.01.271.
    1. Little RJA, Rubin DB. Statistical analysis with missing data. Hoboken: Wiley; 2002.
    1. Culakova E, Thota R, Poniewierski MS, Kuderer NM, Wogu AF, Dale DC, Crawford J, Lyman GH. Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study. Cancer Med. 2014;3:434–444. doi: 10.1002/cam4.200.
    1. Langeberg WJ, Siozon CC, Page JH, Morrow PK, Chia VM. Use of pegfilgrastim primary prophylaxis and risk of infection, by chemotherapy cycle and regimen, among patients with breast cancer or non-Hodgkin’s lymphoma. Support Care Cancer. 2014;22:2167–2175. doi: 10.1007/s00520-014-2184-5.
    1. Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Muss HB, Green MR, Norton L, Frei E., 3rd Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998;90:1205–1211. doi: 10.1093/jnci/90.16.1205.
    1. Leonard RC, Miles D, Thomas R, Nussey F, UK Breast Cancer Neutropenia Audit Grou Impact of neutropenia on delivering planned adjuvant chemotherapy: UK audit of primary breast cancer patients. Br J Cancer. 2003;89:2062–2068. doi: 10.1038/sj.bjc.6601279.
    1. Sivendran S, Galsky MD. Adverse event reporting in oncology clinical trials—lost in translation? Expert Opin Drug Saf. 2016;15:893–896. doi: 10.1080/14740338.2016.1175429.
    1. Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010;362:865–869. doi: 10.1056/NEJMp0911494.
    1. Basch E, Jia X, Heller G, Barz A, Sit L, Fruscione M, Appawu M, Iasonos A, Atkinson T, Goldfarb S, Culkin A, Kris MG, Schrag D. Adverse symptom event reporting by patients vs clinicians: relationships with clinical outcomes. J Natl Cancer Inst. 2009;101:1624–1632. doi: 10.1093/jnci/djp386.
    1. Atkinson TM, Li Y, Coffey CW, Sit L, Shaw M, Lavene D, Bennett AV, Fruscione M, Rogak L, Hay J, Gönen M, Schrag D, Basch E. Reliability of adverse symptom event reporting by clinicians. Qual Life Res. 2012;21:1159–1164. doi: 10.1007/s11136-011-0031-4.
    1. Di Maio M, Basch E, Bryce J, Perrone F. Patient-reported outcomes in the evaluation of toxicity of anticancer treatments. Nat Rev Clin Oncol. 2016;13:319–325. doi: 10.1038/nrclinonc.2015.222.
    1. Black N. Patient reported outcome measures could help transform healthcare. BMJ. 2013;346:f167. doi: 10.1136/bmj.f167.
    1. Basch E, Rogak LJ, Dueck AC. Methods for implementing and reporting patient-reported outcome (PRO) measures of symptomatic adverse events in cancer clinical trials. Clin Ther. 2016;38:821–830. doi: 10.1016/j.clinthera.2016.03.011.
    1. Basch E. Patient-reported outcomes—harnessing patients’ voices to improve clinical care. N Engl J Med. 2017;376:105–108. doi: 10.1056/NEJMp1611252.
    1. Moore K, Haroz R. When hydromorphone is not working, try loratadine: an emergency department case of loratadine as abortive therapy for severe pegfilgrastim-induced bone pain. J Emerg Med. 2017;52:e29–e31. doi: 10.1016/j.jemermed.2016.08.018.
    1. Pawloski PA, Larsen M, Thoresen A, Giordana MD. Pegfilgrastim use and bone pain: a cohort study of community-based cancer patients. J Oncol Pharm Pract. 2016;22:423–429. doi: 10.1177/1078155215585188.
    1. Moukharskaya J, Abrams DM, Ashikaga T, Khan F, Schwartz J, Wilson K, Verschraegen C, Openshaw T, Valentine J, Eneman J, Unger P, Ades S. Randomized phase II study of loratadine for the prevention of bone pain caused by pegfilgrastim. Support Care Cancer. 2016;24:3085–3093.
    1. Gavioli E, Abrams M. Prevention of granulocyte-colony stimulating factor (G-CSF) induced bone pain using double histamine blockade. Support Care Cancer. 2017;25:817–822. doi: 10.1007/s00520-016-3465-y.

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