Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cell lung cancer. It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.
Common side effects include hair loss, cytopenia (low blood cell counts), numbness, shortness of breath, nausea, vomiting, and muscle pains. Other severe side effects include allergic reactions and future cancers. Docetaxel-induced pneumotoxicity is also a well recognized adverse effect which has to be identified timely and treated after withholding the drug. Side effects are more common in people with liver problems. Use during pregnancy may harm the fetus. Docetaxel is in the taxane family of medications. It works by disrupting the normal function of microtubules and thereby stopping cell division.
Docetaxel was patented in 1986 and approved for medical use in 1995. It is on the World Health Organization's List of Essential Medicines. Docetaxel is available as a generic medication.
Medical uses
Docetaxel is used in the treatment of various cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancer. Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, and head and neck cancers and melanoma. In hormone-refractory prostate cancer docetaxel improves life expectancy and overall life quality.
The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule. While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.
Outcomes Treatment with docetaxel increases survival time in people with certain types of cancer. While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large. Many people survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel. Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival. Conjunctive treatment of prednisone with docetaxel has been shown to lead to improved survival rate as well as improved quality of life and reduction of pain compared with treatments with mitoxantrone.
As well as inhibiting mitosis, the presence of docetaxel has been found to lead to the phosphorylation of the oncoprotein bcl-2, which leads to apoptosis of cancer cells that had previously blocked the apoptotic inducing mechanism, leading to tumour regression. Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice. Docetaxel has also been found to have greater cellular uptake and is retained longer intracellularly than paclitaxel allowing docetaxel treatment to be effective with a smaller dose, leading to fewer and less severe adverse effects.
Breast cancer
Docetaxel and paclitaxel have comparable efficacy metastatic breast cancer but paclitaxel has less severe side effects. Additionally, it has been noted that docetaxel is prone to cellular drug resistance via a variety of different mechanisms.
Monitoring and combination use Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles. Treatment is given under the supervision of an oncologist. Strict monitoring of blood cell counts, liver function, serum electrolytes, serum creatinine, heart function, oxygen saturation and fluid retention is required detect adverse reactions and toxicity so that treatment can be modified or terminated if necessary.
Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions. Other medications will often be given to aid pain management and other symptoms. The treatment of breast cancer with doxorubicin and cyclophosphamide is enhanced by adjuvant treatment with docetaxel. Docetaxel is also used in combination with capecitabine, a DNA synthesis inhibitor.
Side effects
Docetaxel is a cytotoxic chemotherapeutic agent. As with all chemotherapy, adverse effects are common, and many side effects have been documented. Because docetaxel is a cell-cycle-specific agent, it is cytotoxic to all dividing cells in the body. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as hair loss occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the 'common and frequent' classification.
Haematological adverse effects include neutropenia (95.5%), anaemia (90.4%), febrile neutropenia (11.0%) and thrombocytopenia (8.0%). Deaths due to toxicity accounted for 1.7% of the 2045 patients, and incidence was increased (9.8%) in patients with elevated baseline liver function tests (liver dysfunction).
The use of docetaxel during chemotherapy, especially when given weekly, may lead to complications with the lacrimal drainage system. The mechanism for this problem seems to be secretion of docetaxel by the lacrimal gland which can then cause stenosis, or narrowing, of the punctum and canalicular outflow system. In most cases the primary symptoms is epiphora or tearing. When treated early most patients can avoid the need for surgery, but some cases the only cure is a conjunctivodacryocystorhinostomy in which a glass tube is placed to bypass the tear duct.
Taxane-induced pneumotoxicity is rare. However, 1–5% of patients taking docetaxel may develop severe pneumotoxicity. Patients may develop exertional breathlessness and desaturation which needs to be detected early. Chest X-Ray may show bilateral opacities and High Resolution CT chest may reveal Organizing Pneumonia (OP) pattern or Non-Specific Organizing Pneumonia (NSIP) pattern or a combination. Docetaxel-induced DPLD is a fatal adverse effect, which can be managed by the cessation of the drug and starting on steroids in adequate doses.
Observations of severe side effects in the above 40 phase II and phase III studies were also recorded.
Many more side effects have been reported for conjunctive and adjuvant treatment with docetaxel as well as rare post-marketing events.
Contraindications and patient factors Docetaxel is contraindicated for use with patients with a baseline neutrophil count less than 1500 cells/μL, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.
Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased. Kidney failure is thought not to be a significant factor for docetaxel dosage adjustment. Patients with hepatic insufficiency resulting in serum bilirubin greater than the upper limit of normal (ULN) should not be administered docetaxel, though this is not a stated contraindication. Dosage should be reduced by 20% in people who develop grade 3 or 4 diarrhea following exposure to docetaxel, hepatotoxicity defined by liver enzymes at levels greater than five times the ULN, and grade 2 palmer-planter toxicity.
Paediatric trials of docetaxel have been limited, and so safety of use in patients under 16 years has not been established.
Pregnancy Based on the limited data available, docetaxel appears to be safe in pregnancy if administered during the second and third trimesters; however, maternal and fetal risks should be weighed against benefits to determine the appropriate course of action. As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred.Gideon Koren, Nathalie Carey, Robert Gagnon, et al. Cancer Chemotherapy and Pregnancy, "Journal of Obstetrics and Gynecology Canada", March 2013 Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent. Further studies are needed to better assess the safety of docetaxel in pregnancy and determine appropriate dosing in pregnant women.
Drug interactions Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved. Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies. Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants.
+ Common and/or likely drug-drug combinations and known side effects from drug interactions Drug interacting with docetaxel Adverse effects from interaction Cisplatin Increased risk of delayed neuropathy Cyclosporine, dalfopristin, erythromycin, itraconazole, ketoconazole, quinupristin, terfenadine, troleandomycin Increased risk of docetaxel toxicity including some or all of the following: anaemia, leucopoenia, thrombocytopenia, fever, diarrhoea Doxorubicin hydrochloride Cholestatic jaundice and pseudomembranous colitis Doxorubicin hydrochloride liposome Increased doxorubicin exposure Vaccinations for Bacillus of Calmette and Guerin, measles, mumps, poliovirus, rotavirus, rubella, smallpox, typhoid, varicella, yellow fever Increased risk of infection by live vaccine Thalidomide Increased risk of venous thromboembolism
Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel. When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.
Pre-treatment with corticosteroids has been used to decrease hypersensitivity reactions and oedema in response to docetaxel and has shown no effect on the pharmacokinetics of docetaxel. The efficacy of docetaxel was improved by treatment with oral capecitabine, and after more than 27 months follow-up the survival benefit has been confirmed. Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an increased AUC of docetaxel by 50 to 70%, indicating doxorubicin may affect the disposition of docetaxel. Etoposide has also been shown to decrease docetaxel clearance, though patient numbers for this observation have been low.
Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.
Chemistry