Continuing Education Activity

Docetaxel is an antineoplastic agent used in the management of multiple metastatic and non-resectable tumor types. It is a newer agent from the taxane family. This activity will outline the indications, mechanism of action, and administration of docetaxel. The expected adverse events, potential toxicities, and contraindications will all be discussed as well.

Objectives:

• Identify the mechanism of action of docetaxel.
• Describe the potential adverse effects of docetaxel.
• Review the appropriate eligibility screening for treatment with docetaxel.
• Summarize the interprofessional team involved in the appropriate administration of docetaxel, as well as the management of those taking it.

Indications

In combination with cisplatin, docetaxel has approval as a first-line agent in the treatment of prostate cancer.[1] It is the standard of care in patients with castration-resistant prostate cancer for palliation and prolongation of life.[2] Single-dose docetaxel is generally first-line therapy in patients with non-small cell lung cancers and poor performance status.[1] Docetaxel is especially effective in preventing progression and extending survival in patients with non-small cell lung cancer with metastatic disease, as it has a good tolerability profile. Docetaxel serves as a standard adjunct agent in breast cancer treatment, demonstrating significant improvements in survival in high-risk patients regardless of prognostic factors such as estrogen receptor expression, the degree of nodal involvement, age, menopause status, and schedule of administration.[3] Finally, together with oxaliplatin and capecitabine, docetaxel completes the triple-agent combination therapy known as the TEX regimen and is indicated for treating advanced gastric cancer.[4]

Mechanism of Action

Docetaxel is a second-generation chemotherapeutic agent of the taxane family.[1] A derivative of paclitaxel, the first taxane to hit the market, docetaxel’s primary mechanism of action is to bind beta-tubulin, enhancing its proliferation and stabilizing its conformation.[2] Doing so inhibits the proper assembly of microtubules into the mitotic spindle, arresting the cell cycling during G2/M. Docetaxel also reduces the expression of the BCL2 gene, an anti-apoptotic gene often overexpressed by cancer cells conferring enhanced survival. By downregulating this gene, tumor cells can more readily undergo apoptosis.[1]

Administration

When administered intravenously, docetaxel's possible dosing schedules have considerable variability. Administration can be a one-time single dose or as regular doses given at increments varying from once weekly to once every five weeks.[1][5] The dosing regimen depends on the cancer type and level of treatment aggressiveness.[6][3] Weekly administration is generally mainly restricted to the palliation of patients with metastatic disease.[7] The mechanism of administration of docetaxel plays a role in minimizing potential toxicity.[8][9] Administering the drug by loading it onto liposomes or micelles enhances the selective uptake by cancer cells expressing specific cellular markers, optimizing intracellular concentration.[8]

Dosing for some approved indications is as follows; these are general guidelines and institutional protocols to verify dosing, pre-medication, and toxicity-related dose adjustments.

• Breast cancer - 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle; give six cycles as part of a multi-drug chemotherapy regimen. 
  • For locally advanced or metastatic disease monotherapy: 60 to 100 mg/m^2 on the first day of a 21-day cycle.
  • For metastatic disease in combination therapy with capecitabine: 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle (for anthracycline-resistant disease.)
• Non-small cell lung cancer (locally or advanced metastatic disease) - 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle; use with cisplatin in treatment-naive patients or as monotherapy for platinum-resistant disease.
• Prostatic cancer - 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle; give up to ten cycles with 5 mg prednisone orally twice daily.
  • Off-label dosing for metastatic castration-resistant disease: 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle; give six cycles.
• Advanced gastric cancer - 75 mg.m^2 IV for a single dose on day 1 of a 21-day cycle as part of a multi-drug regimen.
• Locally advanced squamous cell head/neck cancer - 75 mg/m^2 IV for a single dose on day 1 of a 21-day cycle; give 3 or 4 cycles as part of a multi-drug chemotherapy regimen.

Renal dosing adjustment is undefined. Hepatic dose adjustments include avoiding the use of docetaxel when bilirubin is above the upper normal limit. Docetaxel use should also be avoided if AST and/or ALT are greater than 1.5 times the upper normal limit and alkaline phosphatase exceeding 2.5 times the upper normal limit.

Adverse Effects

Common adverse effects seen in patients treated with docetaxel include infusion reactions, myelosuppression, febrile neutropenia, fatigue, diarrhea, and fluid retention. Infusion reactions can range from standard flushing, itching, dyspnea, and fever to potentially life-threatening anaphylactic shock and cardiorespiratory arrest.[7] Myelosuppression is common with the use of cytotoxic drugs. With docetaxel, anemia, neutropenia, leukopenia, and thrombocytopenia are all reported.[1][3] Systematic review and meta-analysis of docetaxel use in patients with non-small cell lung cancer showed a significantly increased risk of severe infections, defined as grade 3 or higher, which is a potentially life-threatening adverse effect, thought to be related to the cytotoxicity exerted on the immune system.[1] Febrile neutropenia is also among the more serious adverse effects, as it is associated with significant morbidity and mortality when not properly managed.[7]

Patients often experience skin toxicities with docetaxel use. Namely, acral erythema, characterized by tingling in the palms and soles followed by edema and tenderness, and erythrodysesthesia, where fixed solitary plaques develop on the skin adjacent to the infusion site, are the most commonly seen. Peripheral neuropathy, both sensory and motor, is arguably the most common long-term side effect of docetaxel. This neuropathy, along with fatigue and neutropenia, is often the dose-limiting factor that causes patients to defer further treatment.[7][5][2] And finally, myalgias and arthralgias are known adverse effects of docetaxel and other drugs in the taxane family; there are cases reports of myositis associated with docetaxel, though this is rare.[10]

Docetaxel is known to confer resistance in multiple types of solid tumors. Through the alteration of blood vessels impairing drug distribution, efflux pumps decreasing intracellular drug concentration, alterations in microtubule structure or function evading stabilization by the drug, or the upregulation of anti-apoptotic pathways, tumors eventually adapt to survive the once-lethal environment created by docetaxel. These adaptations are another treatment-limiting factor that comes into play with long-term chemotherapy administration.[2]

Contraindications

Treatment with taxanes is relatively contraindicated in patients with pre-existing lung conditions, such as COPD.[7] A common complication accompanying taxane treatment is pulmonary toxicity. Pulmonary complications can be life-threatening, especially in predisposed patients with compromised lung function, so, for this reason, avoidance is necessary if possible. Additionally, before administering therapy, patients are screened for renal, hepatic, and bone marrow function to establish potential drug tolerability and that the side effects of treatment will be manageable.[7]

Monitoring

Following docetaxel infusion, patients receive monitoring for infusion reactions, skin toxicities, fever, other signs of infection, and signs of pneumonitis. Additionally, severe diarrhea or new-onset abdominal pain should warrant further evaluation and a possible surgical consultation, as these patients are at an increased risk for bowel perforation.[7] Patients are also advised to monitor for signs of increased fluid accumulations, such as swelling in the fingers, ankles, and mid-abdominal areas. Increased permeability of the capillaries purportedly causes fluid retention.[7] Swelling can be an indication for the administration of dexamethasone or diuretics to limit progression to more severe conditions of fluid retention, such as pleural or pericardial effusion.

Toxicity

Dose-dependent pulmonary toxicity has correlations with the administration of docetaxel.[7] Acute bilateral interstitial pneumonitis has been demonstrated to occur during, immediately following, and even long after the initial administration of the drug. Symptoms include dyspnea on exertion, a dry cough, fever, and malaise. The mechanism of action underlying this pulmonary toxicity is poorly understood, but the belief is that it is an immune-mediated reaction to the drug.[7] In treating this toxicity, supportive care usually is sufficient to bring patients back to their baseline lung function. However, in patients showing clinical signs of either oxygen desaturation or possible respiratory failure, an empiric trial of glucocorticoids has proven effective in relieving pneumonitis.

Enhancing Healthcare Team Outcomes

A broad range of clinical expertise plays a role in the treatment of cancer. Medical oncologists, radiation oncologists, specialists of involved systems (i.e., urologists in prostate cancer), and supporting staff all play a role in optimizing treatments and outcomes based on patients’ needs and wishes. Proper monitoring, managing adverse events and acquired comorbidities, counseling, and education on the various treatment options and all they entail can all be considered interprofessional responsibilities. An oncology-specialized pharmacist should be part of the treatment team to verify dosing and potential drug interactions, along with oncology-trained nursing staff trained in the administration of chemotherapy agents and awareness of possible adverse effects. The delivery of patient-centered care requires active coordination and regular correspondence between multiple disciplines of care.[11] [Level 5]