Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Microtubule Antagonists

  • Taxanes:

    • Docetaxel (Docefrez, Taxotere)

      • Overview:³

        • Docetaxel is derived from the European yew and is classified as a semisynthetic taxane.

          • Taxus bacca (European Yew)^10,3

            Attribution:  Muséum de Toulouse [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)] Descouens D Aril of the European yew 10 August 2012 https://commons.wikimedia.org/wiki/File:Taxus_baccata_MHNT.jpg

        • Docetaxel is very comparable to paclitaxel in terms of:

          • Mechanism of action

          • Metabolism and

          • Elimination.

        • 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

            • Gastric cancer

            • Platinum-refractory advanced ovarian cancer

            • Bladder cancer.³

            • Prostate Cancer

      • Pharmacokinetics and Metabolism:⁹

        • 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 (V_d) 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:

                • α₁-acid glycoprotein,

                • Lipoproteins, and

                • Albumin.

        • 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.

          • 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.

               

              • "Genetic Rearrangements in the tyrosine kinase receptor ROS1 lead to the development of fusion proteins."^16,17

                 

              • "ROS1 Rearrangements and pathway activation."^16,17,18,19

                AKT =v-akt murine thymoma viral oncogene homolog; ERK = extracellular signal-regulated kinase;JAK = Janus kinase; MEK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer;PI3K = phosphotidylinositol-4, 5 bisphosphate 3-kinase; RAF = rapidly accelerated fibrosarcoma kinase; Ras = rat sarcoma kinase; ROS1-ROS proto-oncogene 1; STAT = signal transducer and activator of transcription.16

                 

              • 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

          • Non-Small Cell Lung Cancer:  Docetaxel in the context of maintenance therapy and in adjuvant treatment:¹²

            • 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:

                  • Docetaxel

                  • 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 for 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),

                        • Docetaxel

                        • Etoposide and

                        • Gemcitabine.¹²

                • "Current Status of Adjuvant Therapy for NSCLC"²¹

                  Attribution: Vansteenkiste J Current status of adjuvant therapy for NSCLC 17th Perspectives (3/2016) ImedexCME, published March 23, 2016 https://www.youtube.com/watch?v=E3zoO3KHF-M ImedexCME Youtube Channel:  https://www.youtube.com/channel/UChzdRqqisBHL_DgHGq0COFg

      • Toxicity:⁹

        • 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:

              • Flushing,

              • Rash

              • Back pain

              • 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.