Various chemotherapeutic, supportive care, and preventative agents used in the oncology setting utilize polysorbate 80 in their formulations, including docetaxel (Taxotere®, Sanofi-Aventis US LLC), the biologicals epoetin alfa (Epogen®, Amgen Inc.; Procrit®, Amgen Inc.) and darbepoetin alfa (Aranesp®, Amgen Inc.), and the antiemetic fosaprepitant IV (Emend® IV, Merck, Sharp & Dohme). Certain adverse events (both systemic and ISAE) occur with these drugs, in which polysorbate 80 may be implicated. There are some challenges in evaluating the literature on this topic, as attribution of adverse events to polysorbate 80 is confounded by its administration with the pharmacologically active agent and by the heterogeneity of reporting of these adverse events in clinical trials. However, there is evidence to implicate polysorbate 80 in systemic and administration-site reactions.
Docetaxel is a taxane that inhibits cell replication by stabilizing the microtubule cytoskeleton [7, 41]. To solubilize this agent for clinical use, it has been formulated using polysorbate 80. An injection concentrate (20 mg/ml) comprises 20 mg of docetaxel in 1 ml at a 50/50 (V/V) ratio of polysorbate 80/dehydrated alcohol. Currently, docetaxel is indicated for the treatment of several cancers, including locally advanced or metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer, hormone-refractory prostate cancer, gastric adenocarcinoma, and squamous cell carcinoma of the head and neck .
Docetaxel has been associated with a number of ISAEs and systemic reactions [7, 42, 43], including hypersensitivity [3, 7], fluid retention [3, 7], cutaneous reactions [7, 44], gastrointestinal adverse events , and peripheral neuropathy [3, 7]. In clinical trials in patients with cancer, the incidence of ISAEs has been reported to be 3–4% .
The presence of polysorbate 80 in the IV formulation of docetaxel has been implicated in hypersensitivity systemic reactions (HSRs) that were observed in the early clinical studies [3, 45]. In those studies, the incidence of HSRs ranged from 5% to 40%, with most events being grade 2 in severity on the four-point scale of the National Cancer Institute common toxicity criteria . Severe HSRs or, very rarely, fatal anaphylaxis have been reported in patients treated with docetaxel . Polysorbate 80 and the oleic acid released by its metabolism have been implicated in the HSRs seen with docetaxel therapy . Consequently, patients treated with the conventional formulation of docetaxel are premedicated with oral corticosteroids .
Developments in formulating docetaxel IV without polysorbate 80 include dendrimer (Dep) docetaxel [47, 48] and nanosomal docetaxel lipid suspension [22, 49]. In one study, the diminished potential for HSRs with the novel nanosomal docetaxel lipid suspension, compared with the conventional docetaxel formulation, reduced the requirement for premedication with corticosteroids .
Supportive Care: Epoetin Alfa, Darbepoetin Alfa
A number of subcutaneous and IV formulations of erythropoietin-stimulating agents (ESAs) contain polysorbate 80. Darbepoetin alfa  is formulated with polysorbate 80 in the US. Outside the US, epoetin alfa (Eprex®, Janssen-Cilag Ltd; Erypo®, Biocon Limited)  is formulated with polysorbate 80, instead of human serum albumin, to avoid potential contamination by human immunodeficiency virus and Creutzfeldt-Jakob disease-causing prions . These ESAs are indicated for the treatment of anemia and to reduce transfusion requirements in patients receiving myelosuppressive chemotherapy for cancer [9, 10, 52]. They act by stimulating erythropoiesis by the same mechanism as endogenous erythropoietin.
Adverse events associated with darbepoetin alfa in patients with cancer include abdominal pain, edema, and thrombovascular events . HSRs, including cases of rash, anaphylactic reactions, and angioneurotic edema, have been reported with epoetin alfa . In particular, the inclusion of polysorbate 80 in one epoetin alfa formulation has been associated with antibody-mediated pure red cell aplasia (PRCA) in patients with chronic kidney disease .
Supportive Care: Fosaprepitant (Emend IV)
Aprepitant is a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK-1) receptors that was first developed for oral administration [53, 54]. Aprepitant was approved in 2003 for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy . Subsequently, an IV prodrug formulation (fosaprepitant; Emend IV) was approved in 2008; this formulation includes polysorbate 80 . Because NK-1 antagonists target another important neurotransmitter/receptor involved in the emetogenic pathway, they complement 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists and enhance control of chemotherapy-induced nausea and vomiting [55, 56].
Most adverse events associated with fosaprepitant are mild to moderate in severity [57,58,59,60,61,62,63,64]. The most common adverse reactions (≥ 2%) reported with fosaprepitant include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in the extremities . No fosaprepitant-associated deaths have been reported in prospective studies.
However, HSRs and ISAEs have been associated with fosaprepitant infusion, and in recent updates, labeling for fosaprepitant was changed to include a warning regarding its potential association with HSRs during or shortly after infusion, including anaphylaxis and anaphylactic shock. Symptoms such as flushing, erythema, dyspnea, hypotension, and syncope have also been reported. ISAEs such as thrombophlebitis, necrosis, and vasculitis were reported with anthracycline-based chemotherapy administration .
Several ISAEs have been associated with the use of fosaprepitant, including infusion-site pain, erythema, swelling, venous hardening or induration, and phlebitis or thrombophlebitis. Because of heterogeneity in reporting, wide ranges of ISAE incidences have been published (Table 2) [57,58,59,60,61,62,63,64]. For example, fosaprepitant, compared with aprepitant, was associated with an overall ISAE incidence of 2.2% vs. 0.4%, respectively, of patients in a phase III trial . Most of the ISAEs were mild to moderate, with 0.2% of fosaprepitant recipients reporting severe infusion-site pain and 0.8% reporting thrombophlebitis . In another phase III trial, the incidence of ISAEs was 24% in those treated with fosaprepitant vs. 12% in those who did not receive fosaprepitant (p < 0.01); no severe ISAEs were reported in this trial .
Retrospective trials, compared with prospective trials, reported even higher incidences of ISAEs with fosaprepitant (Table 2) [60,61,62,63,64]. The reported incidence of ISAEs ranged from 28% to 96% with fosaprepitant, with pain being the most frequently reported ISAE. The reasons proposed for the higher incidence of ISAEs in the retrospective trials, compared with the prospective trials, include the increased number of fosaprepitant injections associated with additional rounds of chemotherapy [60, 61, 63], increased concentration of fosaprepitant used in each dose , increased speed of delivery of each dose , and use of peripheral venous access rather than central venous access [60,61,62,63,64]. Interestingly, changing the administration route of fosaprepitant from peripheral injection to central venous injection reduced the risk of developing ISAEs [61,62,63].
The use of anthracycline, compared with non-anthracycline, chemotherapy regimens also appears to be implicated in the increased incidence of ISAEs; patients receiving anthracycline-based chemotherapy have higher ISAE incidences than those receiving platinum-based chemotherapy [60,61,62,63,64]. In one retrospective trial, in which 42% of fosaprepitant recipients experienced ISAEs , those ISAEs appeared to be confined to patients treated with an anthracycline-based chemotherapy regimen [odds ratio (OR) 12.95; 95% CI 5.74–29.20; p < 0.001] and were not associated with a cisplatin-based chemotherapy regimen (OR 0.78; 95% CI 0.20–3.05; p = 0.717). Similarly, another retrospective study reported fosaprepitant-associated ISAE incidences of 34% in anthracycline plus cyclophosphamide-treated patients compared with 8% in platinum-treated patients . A recent retrospective review of ISAEs and HSRs associated with fosaprepitant in patients receiving anthracycline plus cyclophosphamide-based chemotherapy via peripheral IV line identified ISAEs and/or HSRs in 28% of patient charts reviewed .
The mechanism of vascular damage associated with fosaprepitant has not been precisely determined, but polysorbate 80 may be implicated. Polysorbate 80 has been associated with increased membrane permeability , and its combination with anthracyclines, which are also associated with an increase in vascular damage , may compound the effect . Consequently, fosaprepitant injections through veins already damaged by anthracycline, or vice versa, may result in a greater frequency of ISAEs or skin induration .
Changes in Practice at Specific Institutions
Following the inclusion of fosaprepitant in the Mayo Clinic (Rochester, MN, USA) practice guidelines for highly emetogenic chemotherapy in January 2011, chemotherapy nurses began to notice more frequent ISAEs, particularly in patients receiving anthracycline regimens (Fig. 2a) . A retrospective electronic medical records review of anthracycline-treated patients revealed a higher ISAE incidence with fosaprepitant vs. oral aprepitant (35% vs. 2%) . Consequently, in 2015, the Mayo Clinic guidelines were changed back to recommend the use of oral aprepitant in patients receiving anthracycline-based regimens, with oral aprepitant becoming routinely used from that time forward (Fig. 2b).
A retrospective study of patient medical records was also conducted at the James Cancer Center (Columbus, OH, USA) , including patients who received fosaprepitant infusion via a peripheral line. The study included 150 patients who received 333 doses of fosaprepitant and a median of 2 fosaprepitant doses (range 1–7). ISAEs were reported in 15% of patients, with 50 reactions occurring in 43 unique patients. These ISAEs were grade 2 or less in severity and resolved within a few minutes to a few hours in most patients, although in 24% of patients ISAEs had a median duration of 14 days. Multivariate analyses per event identified increased age, location of the IV line (hand vs. forearm or antecubital fossa), and IV infusion rate < 100 ml/h as risk factors for ISAEs. Management strategies that had been used to treat these ISAEs included placement of new IV lines and warming the affected area for 15–20 min at least four times each day for the first 24–48 h. Management strategies that were used to prevent future ISAEs included switching to oral aprepitant, switching to a different antiemetic regimen, prolonging the duration of fosaprepitant infusion, diluting fosaprepitant to 0.6 mg/ml for the next infusion, and placement of implanted ports. Because of the high incidence of ISAEs identified, the distress caused to patients, and the dissatisfaction with this issue reported by nursing staff, this institution changed its antiemetic protocol. Fosaprepitant was diluted in 250 ml rather than 150 ml of 0.9% sodium chloride base solution and was administered over 30 min rather than 20 min for all patients. Physicians were encouraged to use oral aprepitant or a different antiemetic regimen for patients who were to receive fosaprepitant via a peripheral line or who had experienced ISAEs with previous fosaprepitant infusion .