Chemotherapeutic agents

Chemotherapeutic agents, also referred to as antineoplastic agents, are used to directly or indirectly inhibit the uncontrolled growth and proliferation of cancer cells. They are classified according to their mechanism of action and include alkylating agents, antimetabolites, topoisomerase inhibitors, antibiotics, mitotic inhibitors, and protein kinase inhibitors. Chemotherapy is associated with a range of adverse effects (e.g., nausea, vomiting, immunosuppression, and impaired growth of healthy cells), and some agents increase the risk of secondary neoplasm development. For some chemotherapeutic agents, specific detoxifying agents can be administered to avert preventable side effects (e.g., leucovorin after application of methotrexate, mesna after cyclophosphamide application).

For further information of management chemotherapy-related complications, see “Principles of cancer care.”

Basics of chemotherapeutic agents action ^[1][2]

• Kinetics
  • Chemotherapeutic agents are most active on cells with a high growth fraction, i.e., cells actively undergoing division (including normal cells, such as epithelial or bone marrow cells, as well as cancer cells)
  • The log-kill hypothesis is a mathematical model of chemotherapeutic agent action, according to which a given dose of a certain chemotherapeutic agent eliminates a constant fraction of cancer cells regardless of tumor size. ^[3]
• Cell cycle specificity
  • Cell cycle-specific antineoplastic agents act on proliferating cells only during a specific phase of the cell cycle. There is no cell-cycle specific antineoplastic agent that acts during the resting (G0) phase.
  • Cell cycle-nonspecific antineoplastic agents act on cells at any phase of the cell cycle, including the resting (G0) phase.
• Resistance mechanisms: cancer cells can develop resistance to chemotherapeutic agents via the following mechanisms
  • Mutations or altered expression of target cells (e.g., increased expression of dihydrofolate reductase can result in resistance of cancer cells to methotrexate)
  • Increased rate of DNA repair (e.g., this mechanism can cause resistance to alkylating agents)
  • Drug inactivation (e.g., some cancer cells can increase the synthesis of glutathione and other antioxidants, thus counteracting anthracyclines, which act through the generation of reactive oxygen species)
  • Alteration of apoptotic pathways (e.g., leukemic cells can increase the expression of antiapoptotic molecules such as Bcl-2 to escape chemotherapy-induced apoptosis)
  • Drug efflux (e.g., cancer cells can increase the expression of the MDR1 gene coding for P-glycoprotein which acts as the efflux transporter)

Basics of chemotherapy

For more information, see “Antineoplastic therapy” in “General oncology.”

Combination therapy

Chemotherapeutic agents are usually used in combination (combined chemotherapy regimens).

• Advantages
  • Increased log-kill
  • Prevention and counteraction of cancer drug resistance
  • Targeting both dividing and resting cells (in combination of cell cycle-specific and cell cycle-nonspecific agents)
  • Synergistic effects allow for lower doses and, subsequently, less toxicity
• Examples
  • CHOP (or R-CHOP) for the treatment of non-Hodgkin lymphomas
  • ABVD for the treatment of Hodgkin lymphomas
  • FOLFOX, FOLFIRI, or XELOX for the treatment of colorectal cancer.

Routes of administration

The most common route of administration for chemotherapy is intravenous; other important methods of delivery include oral, intrathecal, and topical application.

• Topical
  • Used in the treatment of cancerous or precancerous skin lesions
  • Chemotherapeutic agents that can be administered topically include 5-FU and mitomycin.
• Intrathecal administration
  • The aim of intrathecal administration is to prevent the need for cerebral radiation therapy and to treat meningeal disseminated diseases (e.g., meningeal leukemia/lymphoma)
  • Chemotherapeutic agents that can be injected intrathecally include methotrexate and cytarabine.
• Oral administration
  • Allows for ambulatory treatment, e.g., maintenance therapy, palliative treatment
  • Chemotherapeutic agents that can be administered orally include idarubicin, capecitabine, temozolomide, etoposide, methotrexate, 6-MP.

Efficacy of treatment

• Individual influencing factors
  • Patient factors (e.g., overall health, bone marrow capacity, liver and kidney function, age, compliance)
  • Cancer factors (e.g., growth fraction, cancer doubling time, type and stage of cancer, resistance)
• Blood-brain barrier
  • Many chemotherapeutic agents cannot cross the blood-brain barrier, which reduces their effectiveness in the treatment of malignant CNS diseases
  • Fat-soluble agents (e.g., carmustine, lomustine), however, can be transported across the blood-brain barrier via diffusion and are, therefore, used in the treatment of brain tumors.

Common adverse effects of chemotherapy

Chemotherapeutic agents damage actively dividing cells, but can also affect tissues with a low mitotic potential (e.g., neurons).

Gastrointestinal tract

• Chemotherapy-induced nausea and vomiting
• Chemotherapy-induced diarrhea
• Mucositis (soft tissue erythema of the buccal mucosa, gingival bleeding, multiple shallow ulcerations, and dysphagia)
• Constipation
• Intestinal perforation
• Causative agents include:
  • Alkylating agents (e.g., chlorambucil)
  • Antifolates (e.g., methotrexate)
  • Pyrimidine antagonists (e.g., 5-FU, cytarabine)
  • Antibiotics (e.g., dactinomycin)
  • Anthracyclines (e.g., doxorubicin, daunorubicin)

Blood

• Myelosuppression
  • Granulocytopenia and lymphocytopenia (increased risk of infection)
  • Thrombocytopenia (increased risk of bleeding)
  • Anemia (fatigue)
• Most chemotherapeutic agents induce some extent of dose-dependent myelosuppression.
• Severe suppression of the hematopoietic system can be caused by:
  • Alkylating agents (e.g., cyclophosphamide, busulfan)
  • Antifolates (e.g., methotrexate)
  • Pyrimidine antagonists (e.g., 5-FU, cytarabine)
  • Purine antagonists (e.g., 6-MP), taxanes (e.g., paclitaxel)
  • Anthracyclines (e.g., doxorubicin, daunorubicin)

Skin

• Hair loss
• Causative agents include:
  • Pyrimidine antagonists (e.g., 5-FU)
  • Antibiotics (e.g., dactinomycin
  • Anthracyclines (e.g., doxorubicin, daunorubicin)

CNS

• Centrally induced vomiting
  • Mediated by substance-P and neurokinin-1 receptors in the brain
  • Associated with delayed emesis after chemotherapy
  • Causative agents include e.g., nitrogen mustards (e.g., chlorambucil), nitrosoureas (e.g., carmustine)
• Chemotherapy-induced peripheral neuropathy
  • Pain, burning, tingling, and loss of sensation in the distal extremities that spread from the hands and feet (stocking-glove pattern).
  • Causative agents include:
    • Platinum-based medications (e.g., cisplatin)
    • Taxanes (e.g., paclitaxel)
    • Vinca alkaloids (e.g., vincristine)

Sexual organs

• Gonadal damage that may lead to temporary azoospermia, premature ovarian failure, and infertility

• Causative agents include alkylating agents (e.g., cyclophosphamide, chlorambucil, procarbazine)

Overview of chemotherapeutic drugs classes

Cytarabine causes myelosuppression with pancytopenia.

Cyclophosphamide can cause hemorrhagic cystitis.

Busulfan and Bleomycin Block your Breath: busulfan and bleomycin cause pulmonary fibrosis.

The tax rates are stable: taxanes stabilize microtubules.

Assemblies are not permitted in the vineyard: vinca alkaloids prevent microtubule assembly.

Vincristine crisps the nerves and vinblastine blasts the bone marrow.

Busulfan and bleomycin block your breath: Busulfan and bleomycin cause pulmonary fibrosis.

Except for bleomycin, all antitumor antibiotics are cell cycle nonspecific agents. Bleomycin is effective against cells in the G2 and M phase.

VemuRAFenib and daBRAFenib are BRAF inhibitors.

Detoxifying agents for antineoplastic treatment

The toxicity of certain chemotherapeutic agents can be prevented by the administration of particular detoxifying agents.

Management of complications

• See “Oncologic emergencies” and “Principles of cancer care.”