Mast cells activation and high blood tryptase levels due to paclitaxel administration. Is Cremophor EL the culprit?

Abstract

Rationale: Although the cancer incidence continues to rise, cancer mortality has declined over the past decade, in large part due to more efficacious chemotherapeutic regimens thus, the ability to use first-line chemotherapeutic agents in the treatment of patients with cancer is crucial. Antineoplastic agents can potentially cause toxic and/or hypersensitivity reactions, that can have serious consequences. Anaphylaxis is a big pitfall in oncological patients; the most important aspect in diagnosing anaphylaxis is to precisely identify the offending agent to prevent future events. Paclitaxel (Taxol) is widely used as antitumor medication in the ovarian, breast, non-small-cell lung, and other cancers. Paclitaxel hypersensitivity reactions are frequently described in the literature, but fatalities are rarely reported. Due to the low solubility of paclitaxel, the compound requires dissolution in Cremophor EL, a derivative of castor oil. Patient concerns: A 79-year-old man was affected by high-grade non-papillary urothelial carcinoma and underwent a radical cystectomy and prostatectomy with locoregional lymphadenectomy. Diagnosis: Eight months later, relapse was detected, and penis amputation and left nephrostomy were performed. Multiple metastases to lymph nodes were detected. Interventions: Palliative chemotherapy was started with Paclitaxel (110 mg) infused at a rate of 50 mL/h. Despite premedication with cetirizine dihydrochloride, dexamethasone, ondansetron, ranitidine, 20 min after Paclitaxel infusion starts, the patient developed general distress, followed by cardiac arrest. Outcomes: The mechanism of fatal paclitaxel-associated hypersensitivity reaction is uncertain and its solvent vehicle Cremophor EL may be involved. Several mechanisms have been postulated: an IgE-mediated mast cell degranulation induced by paclitaxel or Cremophor EL, a non-IgE-mediated idiosyncratic mast cell degranulation by paclitaxel or by Cremophor EL, and complement activation. Severe hypersensitivity reactions with fatal outcome are considered rare. Lessons: The unpredictability and often dramatic reactions of Taxol cause substantial anxiety for doctors and caretakers. They also represent a significant logistic and financial burden on hospitals. Despite premedication, skin testing, and desensitization protocols administration of taxane-based, chemotherapy cannot be considered safe and severe to fatal hypersensitivity reactions cannot be prevented.

Remodeling tumor microenvironment with natural products to overcome drug resistance

“…Over the recent years, with the potential of mast cells being explored in cancer immunotherapy, extensive studies revealed that natural products could regulate the function of mast cells. Paclitaxel exerts antitumor effects in non-small cell lung cancer, breast cancer, ovarian cancer and several other cancers ( 156 ). But patients frequently suffer serious hypersensitivity reactions and painful sensory neuropathy during the paclitaxel chemotherapy ( 157 ).…”

“…But patients frequently suffer serious hypersensitivity reactions and painful sensory neuropathy during the paclitaxel chemotherapy ( 157 ). The occurrences of adverse reactions may be associate with paclitaxel activation mast cells by the following mechanisms: complement activation, non-IgE-mediated idiosyncratic mast cell degranulation by paclitaxel, and IgE-mediated mast cell degranulation induced by paclitaxel ( 156 ). A study reveals that quercetin has the potential to improve paclitaxel-induced pain produced by neuropathy ( 157 ).…”

Natural Taxanes: From Plant Composition to Human Pharmacology and Toxicity

“…The occurrence of a hypersensitivity reaction during the administration of paclitaxel is approximately 10% of patients, despite the administered prophylactic therapy with antihistamines and glucocorticoids [ 98 ]. The mechanism of the hypersensitivity reaction is not fully known and may occur immediately after the first administration, without prior sensitisation [ 99 ]. The hypersensitivity reaction is mainly caused by adjuvants that allow for the transport and transfer of hydrophobic paclitaxel into cells.…”

“…Considering that hypersensitivity response or anaphylactic reaction are potentially life-threatening conditions, it is recommended to start premedication with H1, H2 blockers and dexamethasone before administration of standard paclitaxel [ 98 ]. Despite the administered premedication, cases of fatal hypersensitivity reactions have been described [ 99 ]. Due to the fact that the administration of standard paclitaxel is associated with a hypersensitivity reaction, it is necessary to monitor vital functions during administration and to immediately stop administration at the appearance of the first symptoms.…”

Intravenous Cetirizine vs Intravenous Diphenhydramine for the Prevention of Hypersensitivity Infusion Reactions: Results of an Exploratory Phase 2 Study

“…occurring in up to 30% of patients who did not receive pretreatment with an antihistamine. 2,6 In clinical trials of this widely used cancer treatment, 2% to 4% of patients have developed severe hypersensitivity reactions and anaphylaxis, with cases of fatal reactions despite premedication. 2 Within the prescribing information for both rituximab and paclitaxel, the risk of fatal reactions is highlighted as a black box warning.…”