Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study

Summary

Background

Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant—a neurokinin receptor inhibitor—for management of severe pruritus induced by biological drugs.

Methods

In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552.

Findings

Median VAS in the refractory group was 8·00 (95% CI 7·93–8·57) at baseline and 1·00 (0·00–2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43–8·37) at baseline and 0·00 (0·06–1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred.

Interpretation

Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials.

Funding

None.

Introduction

Drugs that target EGFR (cetuximab, erlotinib, gefitinib, panitumumab), multikinase inhibitors (sunitinib, sorafenib), and EGFR/HER2 tyrosine-kinase inhibitors (lapatinib) are used for treatment of several tumours, including lung, breast, head and neck, colorectal, renal, and hepatocellular cancer.

Common dermatological side-effects associated with these drugs are hair loss and changes in colour, radiation dermatitis, skin rash, pruritus, mucositis, xerosis or fissures and paronychia, and hand and foot syndrome. The incidence of pruritus induced by anti-EGFR antibodies and tyrosine-kinase inhibitors varies: 10–16% for cetuximab, 57–69% for panitumumab, 9–13% for erlotinib, 8–9% for gefitinib, 1% for sunitinib, and 28–45% for lapatinib.1, 2, 3, 4 Onset of pruritus rarely necessitates dose modifications or discontinuation of cancer treatment, but it can have a substantial effect on quality of life, mostly when associated with pain and infections.5, 6, 7

The pathogenesis of pruritus during treatment with anti-EGFR antibodies or tyrosine-kinase inhibitors is not completely understood. Substance P is an important neuromediator of pruritus. It activates mast cells through neurokinin receptors, inducing release of pruritogens. Neurokinin 1 receptor is a G-protein-coupled receptor, mainly activated by substance P, located in the plasma membrane of inflammatory cells and the central and peripheral nervous systems. The keratinocytes of patients with chronic pruritus have an increased number of neurokinin 1 receptors.⁸ Moreover, patients with prurigo nodularis have an increased number of nerve fibres positive for substance P.⁹ Anti-EGFR antibodies or tyrosine-kinase inhibitors might induce secretion of stem cell factors and increase the number of dermal mast cells in skin rashes.¹⁰

Aprepitant is an oral neurokinin 1 receptor antagonist that blocks mast-cell degranulation caused by neurokinin 1 receptor.11, 12 It is used for prevention of acute and delayed nausea or vomiting caused by highly emetogenic chemotherapy and for prevention of postoperative nausea and vomiting. Aprepitant inhibits acute and delayed emesis induced by cytotoxic chemotherapy by blocking binding of substance P to receptors in neurons and increases activity of 5-hydroxytryptamine (5-HT) 3 receptor antagonists and the corticosteroid dexamethasone.

Aprepitant has been investigated as a possible treatment for pruritus refractory to conventional treatment (antihistamines, corticosteroids, and antiepileptic drugs) in patients with diseases including Sézary syndrome,¹³ erythrodermic cutaneous T-cell lymphoma,¹⁴ chronic kidney disease,¹⁵ and solid tumours.¹⁶

In 2010, we reported the off-label use of aprepitant for treatment of pruritus in two patients with stage IV non-small-cell lung cancer receiving erlotinib. Both patients recovered from pruritus 24 h after first administration of aprepitant and after 2 months of treatment with erlotinib plus aprepitant prophylaxis no further episodes of severe pruritus occurred (though the rash persisted).17, 18, 19 On the basis of these findings, we designed a pilot study to assess the effects of aprepitant for management of pruritus caused by biological drug treatment.