headerphoto

Introduction – Systemic Therapy (Chemotherapy and Targeted Therapy)

    Medical Oncology is a sub-specialty which deals with systemic therapy of cancer. The goal is optimal management of cancer with minimal short and long term toxicity. Cancer treatments are multimodal (i.e. surgery, radiation and chemotherapy, biologics and targeted therapy) and patients need to be supported and triaged through this complex system.

Chemotherapy

    Chemotherapy is the use of chemicals/drugs to treat cancer. It includes cytotoxic agents that target rapidly dividing cancer cells. Chemotherapy agents are commonly classified by their mechanism of action or source.

Alkylating Agents

    Alkylating agents cause DNA strand breaks in cells by covalent bonding of the alkyl group to cellular nucleophilic sites. Their actions are not selective for cancer cells and may cause acute and delayed toxicities to other tissues.

    Nonclassical alkylating agents act through a similar mechanism of action as alkylating agents but they do not have the classic alkylating chloroethyl group.

Antimetabolites

    Antimetabolites are structurally related to naturally occurring compounds involved in cellular production. There are pyrimidine and purine analogues.

Folate Antagonists

    Folate antagonists inhibit the availability of cellular folate, which is an essential cofactor in many DNA synthesis reactions.

Anti-tumour Antibiotics

    Anti-tumour antibiotics cause direct DNA damage or cell apoptosis by DNA transcription and duplication.

Antimicrotubule Agents

    Antimicrotubule agents target microtubules which play an important role in mitosis and in the maintenance of cell shape, scaffolding, and function. There are two types: vinca alkaloids and taxanes. Vinca alkaloids interact with tubulin and disrupt microtubule assembly, ultimately inducing metaphase phase arrest in dividing cells. Taxanes stabilize microtubules against depolymerisation which prevents disassembly and ultimately inhibits the dynamic reorganization of the microtubule network.

Topoisomerase Inhibitors

    Topoisomerase inhibitors act against DNA topoisomerases, which are key enzymes required for DNA replication. They relax the torsional stress that occurs during the unwinding of DNA double helix during cell division, relax supercoiled DNA, and decatenate intertwined DNA strands.

Classification of Cytotoxic Agents

    Chemotherapy is calculated according to the body surface, refer to: www.halls.md/body-surface-area/bsa.htm

Common Chemotherapy Regiments Used in Clinics

Abbreviations:
CMF: Cyclophosphamide, methotrexate,5- fluorouracil
AC: Doxorubicin (adriamycin), cyclophosphamide
TC: Docetaxel (taxotere),cyclophosphamide
FAC: 5-Fluorouracil,doxorubicin , cyclophosphamide
TAC: Docetaxel, doxorubicin, cyclophosphamide
FEC-D: 5-Fluorouracil, epirubicin, cyclophosphamide, followed by docetaxel
Folfox: Folinic Acid (Leucovorin), 5-fluorouracil, oxaliplatin
Xelox: Capecitabine (Xeloda,) oxaliplatin
Folfiri: Folinic Acid (Leucovorin), 5-fluorouracil, irinotecan
GemCis: Gemcitibine, cisplatin
VinoCis: Navelbine(Vinorelbine), cisplatin
BEP: Bleomycin, etoposide, cisplatin (Platinum)
ABVD: Doxorubicin, Bleomycin, Vinblastine and Dacarbazine
R-CHOP: Rituxamab, cyclophosphamide, doxorubicin, vincristine, prednisone
TaxolCarbo: Paclitaxel, carboplatin

For information on chemotherapy regimens for cancer type refer to: www.cancercareontario.com

Toxicity of Chemotherapy

    Chemotherapy agents are cytotoxic and target rapidly dividing cells. These include cancer as well as other cells that are naturally dividing in the body, such as hair, nails, mucosa, etc. The goal is to alleviate short and long-term toxicity.

    Most chemotherapy agents cause myelosuppression. The lowest or the nadir counts are on day 10, and counts recover within 3-4 weeks. However, some chemotherapy agents have long lasting myelosuppression and the nadir counts are at 2-4 weeks and recovery takes almost 6 weeks. The most common complication of myelosuppression is neutropenia leading to febrile neutropenia for which antibiotic treatment is required. Growth factor support is used to prevent life threatening febrile neutropenia. ASCO guidelines support primary prophylaxsis for regimens with at least a 20% risk of febrile neutropenia. Other hematologic complications are anemia and thrombocytopenia. Chemotherapy can cause: alopecia, mucositis, nausea, vomiting, diarrhea etc. Rare side effects of chemotherapy are pulmonary fibrosis, cardiotoxicity, renal dysfunction, neuropathy, myalgia, and phelebitis.

    Growth factor support is used to prevent life threatening febrile neutropenia. ASCO guidelines support primary prophylaxsis for regimens with at least a 20% risk of febrile neutropenia. Other hematologic complications are anemia and thrombocytopenia. Chemotherapy can cause: alopecia, mucositis, nausea, vomiting, diarrhea etc. Rare side effects of chemotherapy are pulmonary fibrosis, cardiotoxicity, renal dysfunction, neuropathy, myalgia, and phelebitis.

Targeted Therapy

    Targeted cancer therapies are drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy and radiotherapy, and less harmful to normal cells. Activation of growth factor receptors such as epidermal growth factor receptor, either by ligand stimulation or receptor overexpression/mutation, is one of the major mechanisms responsible for the upregulation of signal transduction pathways leading to growth and proliferation of cancer cells.

    Targeted cancer therapies interfere with cancer cell division (proliferation) and spread in different ways. Many of these therapies focus on proteins that are involved in cell signalling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, how a cell responds to specific external stimuli, and even cell death. By blocking signals that direct cancer cells to grow and divide uncontrollably, targeted cancer therapies can help stop cancer progression and may induce cancer cell death through a process known as apoptosis.

    Targeted therapy is being used in many cancers in combination with chemotherapy to block these pathways. These targeted therapy drugs are either large molecule monoclonal antibodies (MAB), or small molecule tyrosine kinase inhibitors (IB) as shown in the table below.

    Toxicity of targeted therapy is different from chemotherapy. Common side effects are allergic/anaphylactic reactions and usually prevented with dexamethasone; skin rashes; and increased risk of cardiotoxicity as in trastuzumab and bevacizumab.