Medical Pharmacology Chapter 33-34: Anticancer Drugs
Natural Products: Microtubule Antagonists
Docetaxel (Docefrez, Taxotere)
Docetaxel is derived from the European yew and is classified as a semisynthetic taxane.
Docetaxel is very comparable to paclitaxel in terms of:
Mechanism of action
Docetaxel is widely used to treat cancers including:3
Advanced breast cancer (second-line treatment)11
Non-small cell lung cancer (second-line treatment).
Docetaxel exhibits notable anticancer activity in:
Head and neck cancer
Small cell lung cancer
Platinum-refractory advanced ovarian cancer
Pharmacokinetics of docetaxel reflect, depending on dose, either a triexponential or linear elimination curve. 9
Terminal half-life appears to range from about 12 h to about 19h..
Docetaxel exhibits a large volume of distribution (Vd) as a result of its lipophilic character.8
Docetaxel clearance appears most sensitive to:
Body surface area,
Liver function, and
Plasma α1-acid glycoprotein levels.
Docetaxel binds avidly to plasma proteins (>80%).
Proteins mainly implicated in binding include:
Docetaxel depends on the liver microsomal drug metabolizing system (hepatic cytochrome P450 mixed-function oxidases) for metabolism.9
The cytochrome P450 isoforms particularly implicated in metabolism are CYP3A4 and CYP3A5.9
These isoforms act by oxidizing and cyclizing a site on the side chain, not the taxane ring.8
Clinical Uses (Examples):
Docetaxel exibits anticancer activity suitable for administration to treat a variety of cancers (see above).
As example, we will consider docetaxel uses in advanced non-small cell lung cancer (NSCLC).12
Targeted therapy has generally not been available for most patients with lung cancer, although some anti-ALK targets are being identified.13
Therefore, for patients in general as well as in patients with the EGFR mutation or ALK fusions or ROS1 fusions, cytotoxic chemotherapy is standard of care.
ALK (Anaplastic Lymphoma Kinase Gene) gene rearrangements represent primary disease drivers in ALK + non-small cell lung cancer (NSCLC).
In ALK + NSCLC, the ALK gene undergoes a translocation (rearrangement) within the chromosome resulting in effusion between ALK and another gene.
The most common ALK fusion involves EML4-ALK;.
ALK gene translocations are found in about 5% of non-small cell lung cancer patients.
ALK fusions, being constitutively active, result in promotion of proliferative downstream signaling and also enhance tumor cell survival.
ROS1 fusions: The ROS1 gene codes for a receptor tyrosine kinase which exhibits similar structure to the ALK protein.
Gene translocations involving ROS1 have been noted in lung cancer as well as some other cancers, e.g. glioblastoma.15
ROS1 has been described as a driver of NSCLC oncogenesis as result of genetic translocations (both inter-and intra-chromosomal) resulting in constitutive ROS1 kinase activation.
ROS1 fusion proteins both activate and drive downstream signaling sequences, such as AKT (v-akt murine thymoma viral oncogene homolog) or MEK (mitogen-activated protein kinase).
Activation of such signaling pathways promote tumorigenesis and cellular proliferation.
ROS1 is found in about 1-2% of patients with NSCLC, typically with adenocarcinoma histology.16
12 In maintenance treatment for non-small cell lung cancer (NSCLC), some patients ,whose disease does not progress following 4-6 therapeutic cycles using a platinum drug in combination with another agent may
(1) continue maintenance using this protocol or
(2) switch maintenance using a non-cross-resistance non-platinum agent.
Some patients initially receiving pemetrexed or bevacizumab for initial treatment continue using this agent until either progression occurs or they are no longer reasonably tolerated.12
If the patient was initially treated with another frontline protocol, maintenance treatment may involve switching to either pemetrexed (nonsquamous NSCLC) or docetaxel as these agents have a demonstrated benefit in progression free survival (PFS) time.12
Following disease progression: Adjuvant Treatment12
Some patients exhibit disease progression in the context of platinum-based treatment and although now refractory to platinum chemotherapy, some individuals ("good performance status" patients) may be suitable candidates for second-line treatment.
Single-agent second line treatment include:
Pemetrexed (nonsquamous NSCLC only)
Ramucirumab + Docetaxel.
Given the high recurrence rate of NCSLC, adjuvant chemotherapy is often employed.12
One aim of adjuvant chemotherapy in this case is elimination of macrometastatic disease.12
Adjuvant platinum-based protocols have been reported to be beneficial ifor patients who exhibit good performance status.
The combination of cisplatin and vinorelbine represents the most studied adjuvant combination in this setting.
Cisplatin may also be used in combination with other second, non-platinum-based drugs, including::
Pemetrexed (for nonsquamous NSCLC),
A number of toxicities are associated with docetaxel administration.9
The principal toxicity is neutropenia with an onset beginning on day 8.
Resolution may be expected in 2-3 weeks.
Absent premedication, hypersensitivity reactions may occur in up to about one-third of patients.
Hypersensitivity reaction presentations include:
Fever et al.
Major hypersensitivity reactions are more likely to occur during the first two courses of treatment and typically just after starting treatment.
Following cessation of docetaxel administration, hypersensitivity symptoms resolve rapidly, usually within about 15 minutes.
At this point treatment with diphenhydramine along with an H2-receptor blocker allows re-initiation of therapy.
Docetaxel administration is also associated with fluid retention caused by increased capillary permeability.
Corticosteroids given before docetaxel decreases the likelihood of fluid retention.
The fluid retention itself may be effectively managed with early and aggressive diuretic administration.
Many patients (50%-75%) exhibit skin toxicity.
Docetaxel administration may also result in neurotoxicity generally similar to that observed following paclitaxel administration.
With docetaxel neurosensory and neuromuscular effects appear both less likely and less severe compared to that observed with paclitaxel administration.9
Additional side effects have also been noted with docetaxel and the reader is directed to reference 9 for a more complete discussion.