Taxane Toxicity

Etiology

Taxane toxicity is common primarily because the drugs are extensively prescribed in oncology and have peculiar molecular structures. Paclitaxel was first separated from the bark of the tree Taxus brevifolia, although presently, synthetic and semi-synthetic forms of the compounds are increasingly used. Similarly, the motivation to identify further taxanes led to the discovery of docetaxel from the needles of the abundantly available tree Taxus baccata.

The effective delivery and distribution of paclitaxel and docetaxel require the support of solvents which include chromophore-ethanol and polysorbate 80, respectively. Natural sources and solvents are mainly responsible for infusion-related hypersensitivity reactions. Recent evidence has suggested that some of these reactions might be IgE-mediated.[7] 

Nab-paclitaxel is the nano-particle formulation of paclitaxel which is bound to the albumin during travel through the blood and therefore doesn't cause hypersensitivity during infusion.[8] Cabazitaxel was developed to overcome the resistance faced by paclitaxel and docetaxel. Its structure is similar to docetaxel, and thus the risk of hypersensitivity reactions is the same.[5]

Paclitaxel has the principal toxicity of neuropathy which presents in gloves and stocking distribution and can become permanent if left untreated. The neuropathy pattern is usually sensory and occurs due to axonal degeneration and demyelination. Neutropenia and mucositis are other side effects of paclitaxel which are dependent on the duration of exposure to the drug.[9] Cardiac disturbances, especially bradycardia, have been noted during paclitaxel infusion, but these are usually benign, and no cause has been identified.[10]

Docetaxel has a unique toxicity of fluid retention. It is cumulative and is believed to be due to increased capillary permeability. Neutropenia is docetaxel's dose-limiting toxicity, which is more common with 3-weekly regimens. The neuropathy is less severe with docetaxel than with paclitaxel, likely due to structural differences.[11]

Nab-paclitaxel is extensively distributed in the plasma due to its unique combination with albumin. The volume of distribution and bioavailability is thus higher than paclitaxel. This results in improved drug efficacy at the cost of more prevalence of neutropenia and sensory neuropathy.[12]

Epidemiology

Initially, hypersensitivity reactions were noticed in 30% of patients who received paclitaxel and docetaxel; however, the use of premedication has decreased the incidence to 1 to 2%. Typically, these occur within the first 10 minutes during the first or second infusion, and the incidence is negligible afterward.[7]

The incidence of bradycardia with paclitaxel is about 30%, while 30 to 40% of patients experience mucositis. Skin rash and onycholysis are relatively less common and occur in 5 to 10% of patients.[13]

Docetaxel results in characteristic skin toxicity in about 80% of patients.[14]

The incidence of haematologic toxicity is very high, with cabazitaxel with neutropenia being observed in greater than 90% of patients.[5]

History and Physical

Hypersensitivity reactions are experienced immediately after starting the drug. Minor reactions are observed in 40% of cases and cause urticaria or skin rash. Significant reactions comprise nausea, vomiting, flushing, urticaria, shortness of breath, wheezing, tachycardia, hypotension, and abdominal or chest pain.[7]

Neuropathy presents as a tingling sensation in hands and feet with numbness. Rarely, the patient may also complain of motor weakness and urinary or fecal incontinence. Examination typically reveals sensory loss in gloves and stocking distribution. Motor and autonomic examinations are often unremarkable.[15]

Mucositis can be caused by all the taxanes and is characterized by oral ulcers, nausea, vomiting, and diarrhea.

Docetaxel-induced fluid retention is often characterized by pedal and ankle edema, weight gain, abdominal distension, shortness of breath, and facial swelling.[16]

Skin toxicity is a common side effect of docetaxel. Most patients experience mild dermatitis, nail discoloration, and alopecia; however, the severe spectrum of toxicity results in hand and foot desquamation, onycholysis, and erythroderma.[16]

Cardiac abnormalities with paclitaxel are benign, and bradycardia is the most common incidental finding.[13]

Ophthalmic toxicity, though uncommon (1 to 2%), could come in many forms, including meibomian gland dysfunction, cystoid macular edema, and canalicular obstruction.[17] These toxicities can be addressed without discontinuing therapy.

Evaluation

Complete blood count and liver function tests are typically prescribed with 3-weekly infusions to detect neutropenia, thrombocytopenia, and elevation of liver transaminases. There are no proven guidelines for routine blood tests in weekly drug regimens, and institutional policies should be followed. 

Recent studies have noted a genetic predisposition to taxane toxicity.[18] Cytochrome P450 (CYP3A4 and CYP3A5) metabolizes docetaxel into inactive compounds that are cleared from the body. Though rare (0.2% homozygous), some variants have reduced or less-of-function. This causes compound retention and augments its toxicity. Other medications reportedly do not worsen the situation, but other genetic anomalies (e.g., SLCO1B3, ABCC2, ABCB1) are thought to compound the problem. 

Taxane skin testing is an effective method to identify IgE-mediated hypersensitivity reactions.[7]

The suspicion of neutropenic enterocolitis can be confirmed through ultrasonography abdomen to evaluate the gut thickness.

The investigation of neuropathy includes nerve conduction studies to confirm axonal damage.

Treatment / Management

The majority of toxicities associated with taxanes are reversible with appropriate and timely management. Both prophylactic measures and treatment modalities help counter adverse events.

Hypersensitivity reactions can be prevented by using prophylactic steroids and premedication. The typical docetaxel regimens include 3-weekly infusions, and prophylactic steroids are recommended for 72 hours, starting 24 hours before the drug administration. The dose of dexamethasone is 8mg bid. Cabazitaxel is used as a single agent given every three weeks. The dose of dexamethasone is 10mg daily through all the cycles of cabazitaxel.[19] 

In the case of paclitaxel, dexamethasone is given 20mg, 12 and 6 hours before drug administration. Apart from steroids, the premedication is given 30 minutes before starting the taxane infusion and usually includes diphenhydramine 50mg IV and cimetidine 300mg IV or any other H2-blockers. Nab-paclitaxel is the only taxane that doesn't require routine use of prophylactic steroids or premedication.

If a major hypersensitivity reaction occurs despite premedication, immediately stop the infusion and give high-dose steroids. The minor reactions don't need any medication. Life-threatening anaphylactic reactions may require adrenaline. Symptoms usually resolve within 15 minutes. Taxane skin testing and the severity of hypersensitivity reaction dictate the re-introduction of the drug, which could include rapid drug desensitization or graded exposure. Rapid desensitization is safe and effective with premedication given 30 minutes before rechallenge.[20] Patients with severe reactions to paclitaxel are at increased risk of similar reactions to docetaxel. Nab-paclitaxel can be prescribed in such situations.

Taxane-induced neurotoxicity can be challenging to treat. There is no convincing evidence that any antidotes are effective at ameliorating the existing complaints or helping prevent the onset of neuropathy. Neuropathic pain is less responsive to conventional non-opioid and opioid analgesics. The preferred management of painful neuropathy revolves around antidepressants. Tricyclic antidepressants (TCAs) have been used historically preferred in this context.

Agents like amitriptyline, doxepin, imipramine, and nortriptyline have analgesic effects, and the dose required for pain relief is much less than the one used for depression.[21] However, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are increasingly being used for chemotherapy-related neurotoxicity. Duloxetine belongs to the SNRIs group and has proven efficacy in relieving diabetic neuropathy.[22](A1)

Clinically, it has been the preferred agent to treat taxane neuropathy, particularly the painful disease.[23] Anticonvulsants like gabapentin and pregabalin reduce the pain intensity in noncancer neuropathy.[22] However, a recent systematic review failed to demonstrate conclusive evidence of the benefit of pregabalin in cancer patients.[24] Local anesthetics and corticosteroids can be co-administrated with other drugs to relieve neuropathic pain.[25] (A1)

Hilotherapy has had some success in treating Taxane-peripheral neuropathy.[26] This modality involves thermally-generated water cuffs that provide a constant temperature over an affected limb, hand, or feet. 

Neutropenia is the main dose-limiting toxicity of docetaxel, while it is also frequently seen with paclitaxel. Docetaxel should not be given if the absolute neutrophil count is less than 1500/mm3.[11] The severity of neutropenia has been established through clinical trials for the vast majority of chemotherapy agents. The expected risk of neutropenia above 20% warrants the prophylactic use of granulocyte colony-stimulating growth factors (G-CSF).[27] (A1)

Docetaxel-containing regimens given every three weeks fall into this high-risk category and require routine G-CSF prescription. If patients have ANC of <1500/mm^3 despite G-CSF and no active complaints, it's best to delay the therapy. Patients with low ANC and fever should be managed as neutropenic sepsis on an outdoor or indoor basis, according to the MASCC score.[28](B3)

The chief purpose of steroids prophylaxis in docetaxel is the prevention of fluid retention rather than hypersensitivity reactions, although it helps with both. Severe ascites or pleural effusion can be treated with diuretics like furosemide, and fluid paracentesis is rarely needed.[16] Dexamethasone use also prevents skin toxicity which is the major problem with docetaxel. Treatment of established skin rash includes topical steroids, emollients, vitamin A, and dermatology opinion.[29]

The paclitaxel-associated bradycardia is an incidental finding that doesn't require cardiac monitoring during therapy. Often, no active management or cardiologist opinion is needed. 

Taxane-induced arthralgias and myalgias have been found to have a possible ideal treatment with flupirtine.[30] One study noted above 93% incidence of arthralgia/myalgia, but there was an improvement with the administration of this analgesic. It provides analgesia through the blockade of glutamate-N-methyl-D-aspartate receptors.[31] It is non-opioid with few side effects.

Differential Diagnosis

Hypersensitivity Reactions

• Allergic sinusitis
• Urticaria
• Angioedema
• Anaphylaxis to dietary or environmental factors
• Anxiety disorder
• Pulmonary embolism
• Myocardial infarction

Neuropathy

• Alcoholism
• Diabetes mellitus
• Pernicious anemia
• Dietary deficiencies
• Hypothyroidism
• Lyme disease
• HIV

Fluid Retention

• Hypoalbuminemia
• Congestive cardiac failure
• Chronic liver failure
• Chronic kidney disease

Prognosis

Although the rate of taxane-induced adverse events is high, there is often full recovery, except for neuropathy. Patients with diabetes or a history of alcohol abuse are more prone to develop persistent neurotoxicity. Early and prompt management of both neuropathy and comorbidities often avoids long-term disability.   

Complications

The irreversible complications of taxane therapy are rare. The combination of doxorubicin and paclitaxel is associated with a higher risk of congestive cardiac failure, which could be persistent. Similarly, there are reports of scleroderma-like cutaneous syndrome with taxanes, particularly docetaxel.[14] 

The rare sequelae of long-term therapy could also lead to pneumonitis. A recent study noted that, save for neutropenia, Taxane toxicity was generally manageable with premedications, monitoring, and close reactive care.[32] 

Discontinuing a chemotherapy agent with significant potential benefit to the patient over an "event" was generally viewed with disdain.