Docetaxel and its Side Effects

The drug Docetaxel belongs to the taxane family of chemotherapeutic agents. These drugs are derived from plant alkaloids- from the bark of the pacific yew tree.

Image result for pacific yew tree
The pacific yew tree

Mechanism of Action

Normally, Cells divide when a cell structure called microtubules within the cell pulls the cell apart into two cells.

Docetaxel has high affinity to microtubules and leads to polymerisation of tubulin, hence preventing cells from dividing, and ultimately cell proliferation is stopped or slowed down.

This agent has activity in the mitotic phase or the M phase of the cell cycle (the phase in which microtubules split the cell) .

Image result for M itotic spindles
Microtubules pulling the cell apart, causing cell division

Route of Administration and Pharmacokinetics

This drug is administered IV.

It distributes widely and more than 90% is bound to blood proteins. It is then metabolized in the liver (P450 enzymes) and more than half of this drug is excreted in faeces.  Less than 10 % of drug is excreted renally.

When is Docetaxel given?

  1. Breast cancer
    Docetaxel is used in adjuvant or neoadjuvant settings. It is also used in metastatic cases.

3 weekly dose- 100 mg/m2 of body surface area

Weekly dose- 40 mg/m2

  1. Metastatic prostate cancer.

3 weekly-75 mg/m2

  1. Non squamous cell carcinoma when platinum therapy fails.
    It can also be given as first line in combination with cisplatin in those who have not received chemotherapy.

3 weekly- 75 mg/m2

  1. Can be used in non-responsive ovarian cancer and bladder cancer.
  1. Used in combination with cisplatin, 5-FU in the treatment of advance gastric adenocarcinoma and inoperable head and neck cancers.

3 weekly-75 mg/m2

The chemotherapy regimens which include docetaxel will be discussed in the articles explaining the treatment of various malignancies.

Drug Interactions

Since Docetaxel is mainly metabolized by CYP3A4 enzyme, inducers and inhibitors of this enzyme can lower or increase plasma levels of this drug, respectively.

Docetaxel also acts as a radio sensitising agent during radiotherapy.

Adverse Drug Reactions and how to manage them

  1. Bone marrow suppression
    This drug can cause neutropenia, mostly seen 1 week after therapy after which it resolves. Thrombocytopenia and anemia may also be seen.

Neutropenia is treated using Granulocyte stimulating factors, which increases the counts of WBCs.

  1. Hypersensitivity reaction
    Can occur mostly during the first 2 cycles of therapy and more often during the first 2 hours of infusion.

This could be due to polysorbate 80 which is used in the formulation that can act as  sensitising agent.

It presents as a skin rash, itching, fall in BP and in severe cases may present as bronchospasm and dyspnoea.

This reaction is controlled using IV steroids- Inj.Hydrocortione and an antihistaminic Inj. Diphenhydramine.

  1. Rash (mostly in forearms) and brownish discolouration of nails maybe seen in 50% patients mostly during the first week of therapy.
  1. Fluid Retention Syndrome
    Half the patients who have received docetaxel in excess of 400 mg/m2 present with fluid retention syndrome-weight gain, edema, ascites and pleural effusion.

Fluid retention syndrome can be prevented by a single dose of dexamethasone (a steroid) before chemotherapy. Dexamethasone significantly reduces the risk of Fluid retention syndrome.

  1. Alopecia(hair loss), mucositis(redness, pain and inflammation of gums), generalised fatigue and diarrhoea are seen in more than half the patients.
    These are reversible conditions and will resolve after completion of the course of chemotherapy.
  1. Peripheral neuropathy is seen but is not that common.
    In this condition there is a feeling of numbness or pricking type of pain in the hands and feet. These symptoms can be reduced by gabapentin tablets.
  1. Elevation in liver enzymes may be seen.
    The rise in liver enzymes is usually transient and will resolve on its own.
    Liver function tests have to be performed before every chemotherapy and should be avoided in case of raised bilirubin (usually cutoff is taken as 3-4 mg/dl.
  1. It is a vesicant drug and can cause phlebitis(inflammation and tenderness of the vein) and necrosis at site of injection.

To prevent phlebitis and necrosis at the site care must be taken that the IV cannula/chemo port needle are placed appropriately. The patient must be explained about potential extravasation of the drug and to inform the caregiver in case of such an event.

Even though Docetaxel can cause a wide range of adverse effects, most of them are treatable with supportive care and by stopping the drug and choosing another alternative.

The long term side effects of docetaxel such as skin changes resolve after 6-12 months after completion of therapy.

Precautions

  1. Liver function must be normal before starting the drug, since this drug is hepatotoxic.
  2. Absolute neutrophil count should be greater than 1500 cells/cubic mm. Complete bood count should be done prior to therapy.
  3. Signs for hypersensitivity must be looked for. BP must be monitored at regular intervals during infusion. Appropriate measures must be kept in place so that prompt action can be taken in case a hypersensitivity reaction occurs.
  4. Use only glass bottles and polyethylene lined IV set to administer the drug.
  5. It is a pregnancy Category D drug. Breastfeeding must be avoided.

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