Docetaxel

Article Author:
Nicole Farha
Article Editor:
Anup Kasi
Updated:
2/6/2019 10:43:09 AM
PubMed Link:
Docetaxel

Indications

Docetaxel, in combination with cisplatin, is approved 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 non-small cell lung cancer patients with metastatic disease, as it has a good tolerability profile. Docetaxel serves as a standard adjunct agent in the treatment of breast cancer, demonstrating significant improvements in survival in high-risk patients regardless of prognostic factors such as the expression of estrogen receptor, 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,[2] docetaxel’s primary mechanism of action is to bind beta-tubulin, enhancing its proliferation and stabilizing its conformation. 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 over-expressed 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. It can be administered as a one-time single dose or as regular doses given at increments varying from once weekly to once every five weeks. Dosing regimen depends on the cancer type and level of treatment aggressiveness.[1][5][6][3] Weekly administration is generally restricted mostly to 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 loaded onto liposomes or micelles enhances the selective uptake by cancer cells expressing certain cellular markers, optimizing intracellular concentration.[8]

Adverse Effects

Common adverse effects seen in patients treated with docetaxel include infusion reactions, myelosuppression, febrile neutropenia, fatigue, diarrhea, and fluid retention.[7] 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 non-small cell lung cancer patients 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.[7] Peripheral neuropathy, both sensory and motor, is arguably the most common long-term side effect of docetaxel,[7] and this neuropathy, along with fatigue and neutropenia, is often the dose-limiting factor that causes patients to defer further treatment.[5][2] And finally, myalgias and arthralgias are a known adverse effect of docetaxel and other drugs in the taxane family; cases reports exist 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, prior to administration of therapy, patients are screened for renal, hepatic, and bone marrow function to establish potential drug tolerability, and that side effects of treatment will be manageable.[7]

Monitoring

Following infusion of docetaxel, patients receive monitoring for infusion reactions, skin toxicities, fever and 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 is purported to cause 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 been associated 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 it is believed to be 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 the optimization of treatments and outcomes, based on patients’ needs and wishes. Proper monitoring, managing adverse events and acquired comorbidities, and counseling and education on the various treatment options and all that they entail can all be considered multidisciplinary responsibilities. The delivery of patient-centered care requires active coordination and regular correspondence between multiple disciplines of care.[11] [Level V]


References

[1] Du Q,Jiang G,Li S,Liu Y,Huang Z, Docetaxel increases the risk of severe infections in the treatment of non-small cell lung cancer: a meta-analysis. Oncoscience. 2018 Jul     [PubMed PMID: 30234144]
[2] Antonarakis ES,Armstrong AJ, Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer. Prostate cancer and prostatic diseases. 2011 Sep     [PubMed PMID: 21577234]
[3] Kim SB,Sayeed A,Villalon AH,Shen ZZ,Shah MA,Hou MF,Nguyen Ba D, Docetaxel-based adjuvant therapy for breast cancer patients in Asia-Pacific region: Results from 5 years follow-up on Asia-Pacific Breast Initiative-I. Asia-Pacific journal of clinical oncology. 2016 Jun     [PubMed PMID: 26891467]
[4] Ostwal V,Bose S,Sirohi B,Poladia B,Sahu A,Bhargava P,Doshi V,Dusane R,Nashikkar C,Shrikhande SV,Ramaswamy A, Docetaxel/Oxaliplatin/Capecitabine (TEX) triplet followed by continuation monotherapy in advanced gastric cancer. Indian journal of cancer. 2018 Jan-Mar     [PubMed PMID: 30147101]
[5] Parikh M,Pan CX,Beckett LA,Li Y,Robles DA,Aujla PK,Lara PN Jr, Pembrolizumab Combined With Either Docetaxel or Gemcitabine in Patients With Advanced or Metastatic Platinum-Refractory Urothelial Cancer: Results From a Phase I Study. Clinical genitourinary cancer. 2018 Jul 12     [PubMed PMID: 30166228]
[6] Sakaguchi M,Maebayashi T,Aizawa T,Ishibashi N, Docetaxel-induced radiation recall dermatitis with atypical features: A case report. Medicine. 2018 Sep     [PubMed PMID: 30200132]
[7] Ho MY,Mackey JR, Presentation and management of docetaxel-related adverse effects in patients with breast cancer. Cancer management and research. 2014     [PubMed PMID: 24904223]
[8] Kushwah V,Jain DK,Agrawal AK,Jain S, Improved antitumor efficacy and reduced toxicity of docetaxel using anacardic acid functionalized stealth liposomes. Colloids and surfaces. B, Biointerfaces. 2018 Aug 23     [PubMed PMID: 30172202]
[9] Varshosaz J,Enteshari S,Hassanzadeh F,Hashemi-Beni B,Minaiyan M,Sadeghian-Rizi S, Synthesis And In Vitro/In Vivo Characterization Of Raloxifene Grafted Poly(Styrene Maleic Acid)-Poly (Amide-Ether-Ester-Imide¬¬) Micelles For Targeted Delivery Of Docetaxel In G Protein-Coupled Estrogen Receptor Breast Cancer. Anti-cancer agents in medicinal chemistry. 2018 Sep 5     [PubMed PMID: 30205803]
[10] Thomas J,Warrier A,Kachare N, Docetaxel-Induced Myositis. Journal of clinical rheumatology : practical reports on rheumatic     [PubMed PMID: 30148754]
[11] Bahl A,Bellmunt J,Oudard S, Practical aspects of metastatic castration-resistant prostate cancer management: patient case studies. BJU international. 2012 Mar     [PubMed PMID: 22257100]