Chemotherapy (Chemo): Mechanisms, Types

Introduction

The term “chemotherapy”, also called chemo, came from two words: chemical & therapy, which mean “drug treatment.” Chemotherapy refers to treatment with a cell-killing (cytotoxic) medication. It uses medications (antineoplastic drugs) to either kill cancer cells or prevent them from growing and dividing by interfering with cellular function and reproduction.

It is used to treat systemic disease rather than localized lesions that are amenable to surgery or radiation. Depending on the type of cancer, the stage of cancer, and the patient’s overall condition, the drugs will be given and it may be paired with surgery or radiation therapy. Neoadjuvant therapy is treatment administered before surgery. Adjuvant therapy is treatment given after surgery.

It can be used as a primary treatment to shrink or remove tumors, as a palliative treatment to relieve symptoms and enhance the quality of life, or as a palliative treatment to destroy any remaining cancer cells.

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Purposes of Chemotherapy

• To treat cancer as the primary treatment (curative chemotherapy)
• To shrink malignant cells before surgery or radiation to make the therapy more effective (neo-adjuvant chemotherapy)
• To destroy any remaining malignant cells after surgery or radiation (adjuvant chemotherapy)
• To control tumor cells growth when a cure isn’t possible
• To increase the lifespan and quality of life of a cancer patient
• To ease signs and symptoms by killing some of the cancer cells i.e. palliative chemotherapy

Indications of Chemotherapy

• Breast cancer
• Lung cancer
• Colorectal cancer
• Leukemia
• Lymphoma
• Multiple myeloma
• Ovarian cancer
• Pancreatic cancer
• Prostate cancer
• Sarcomas
• Bone marrow diseases
• Immune system disorders

Contraindications of Chemotherapy

• Poor overall health
• Advanced age
• Previous exposure to chemotherapy or radiation therapy
• Severe liver or kidney dysfunction
• Pregnancy or breastfeeding
• Some cancer types may not respond well to chemotherapy or may require alternative treatments.

Mechanism of Chemotherapy

There is a process by which a new cell matures into a fully functioning cell and involves a series of phases called the cell cycle. Cancer arises when cells grow, divide, and proliferate uncontrollably. Cancer cells frequently divide more quickly than healthy ones.

Chemotherapy is a systemic drug because it permeates the bloodstream and is distributed throughout the entire body. Chemotherapy drugs target cells at different phases of the cell cycle. Drugs used in chemotherapy prevent cancer cells from mitosis (cell division) and growth. As chemo is distributed throughout the body, it may also have an impact on some rapidly dividing healthy cells, including those in the bone marrow, skin, hair, and intestines.

Depending on the type of drugs used in chemotherapy, the mechanism of action varies. The following are a couple of well-known mechanisms by which chemotherapy drugs work:

• Chemotherapy drugs may disrupt the cell cycle preventing cancer cells from multiplying and ultimately leading to their death.
• Some chemotherapy drugs may damage the DNA of cancer cells preventing the cells from replicating and leading to their demise. 
• Certain chemotherapy drugs can inhibit the production of proteins necessary for the survival of cancer cells disrupting vital cellular processes and inducing cell death.
• Angiogenesis, the formation of new blood vessels that supply the tumor with nutrients, can be inhibited by some medications, effectively starving the cancer cells.
• It can also suppress or stimulate the immune system. Immunomodulatory drugs help boost the body’s immune response against cancer cells or counteract the immune system’s response to tumors.

Types of Chemotherapy Drugs

Alkylating agents

This class of drugs works directly on DNA to prevent cells from replicating. These medications are capable of killing cells at any stage of the cell cycle. These are used to treat different types of cancers, including lung, and ovary, and breast cancer as well as sarcoma, multiple myeloma, lymphoma, leukemia, and Hodgkin disease.

Some examples of alkylating agents are:

• Nitrogen mustard: chlorambucil, melphalan, cyclophosphamide, ifosfamide, bendamustine
• Nitrosoureas: streptozotocine, fotemustine, carmustine, lomustine
• Platinum analogs: cisplatin, carboplatin, oxaliplatin
• Triazenes- Dacarbazine, procarbazine, mitozolomide, temozolamide
• Alkyl sulfonate- Busulfan
• Ethyleneimine (aziridine): thiotepa, diaziquone, mytomycin

Nitrosoureas is useful in certain types of brain cancer because it can travel into the brain crossing the blood-brain barrier (a special area that keeps most drugs out of the brain).

Antimetabolites

Antimetabolites disrupt DNA and RNA synthesis by acting as substitutes for the normal building blocks of RNA and DNA.

These are commonly recommended to treat breast, ovary, and intestinal tract cancer, and leukemias.

Some examples of antimetabolites include:

• Cytidine analogs: gemcitabine, azacitidine, cytarabine, decitabine
• Folate antagonists – pemetrexed, methotrexate, pralatrexate
• Purine analogs – cladribine, thioguanine, pentostatin, clofarabine, nelarabine, fludarabine, 6-mercaptopurine (6-MP)
• Pyrimidine analogs: capecitabine, 5-fluorouracil (5-FU)

Topoisomerase inhibitors (Plant alkaloids)

This group of drugs inhibits an enzyme called topoisomerase and also called plant alkaloids. They aid in the separation of DNA strands so that they can be copied. Some leukemias and ovarian, gastrointestinal, ovarian, colorectal, pancreatic, and lung cancers are treated with topoisomerase inhibitors.

• Topoisomerase I inhibitors: irinotecan, liposomal, irinotecan, topotecan
• Topoisomerase II inhibitors: etoposide (VP-16), teniposide, mitoxantrone (also acts as an anti-tumor antibiotic)

Mitotic inhibitors (Plant alkaloids)

It is made from natural products and is also called plant alkaloids. 

They can block cell replication. Different types of cancer including lymphomas, leukemias, myelomas, breast cancer, and lung cancer can be treated by mitotic inhibitors.

Some examples of mitotic inhibitors include

• Taxanes: cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel
• Vinca alkaloids: vinblastine, vincristine, vincristine liposomal, vinorelbine

Antitumor antibiotics

Antitumor antibiotics do not act like the antibiotics used to treat other types of infections. They either break up DNA strands or stop DNA synthesis needed by cells to grow. They are frequently used to treat many cancers.

Some examples are:

• Anthracyclines: daunorubicin, doxorubicin (Adriamycin), doxorubicin liposomal, epirubicin, idarubicin, valrubicin
• Non-anthracyclines: Bleomycin, dactinomycin, mitomycin-C, and Mitoxantrone.

Hormonal agents

Two types of hormonal agents are usually used as chemotherapy drugs

• Corticosteroids can treat leukemia, multiple myeloma, and lymphoma and reduce swelling around tumors of the brain and spinal cord. Ex: Prednisone and Dexamethasone.
• Sex hormones help control the growth of breast, uterine, and prostate cancers. They cut off the nutrition supply to destroy the cancer cells. Ex: Tamoxifen and Leuprolide.

Biological response modifiers

These drugs boost the body’s immune system to fight the growth of cancer.

Some examples are: 

• Herceptin and Avastin
• Erbitux and Rituxan.

Miscellaneous

These drugs do not belong to the particular group as they act differently.

• Hydroxyurea
• Tretinoin
• All-trans-retinoic acid
• Mitotane
• Arsenic trioxide
• Omacetaxine
• Asparaginase
• Eribulin
• Proteasome inhibitors
• Ixabepilone

Route of Chemotherapy

• Intravenous (IV): by injecting intravenously in the form of infusion. It has a 100% absorption rate. The drugs can be given by inserting an IV cannula in the arm or into a central venous catheter.
• Per oral (PO): by taking orally in pill, liquid, or capsule form
• Intramuscular (IM): by injecting into a muscle
• Intradermal (ID): by injecting under the skin
• Intrathecal (IT): by injecting into the cerebrospinal fluid (CSF), space around the brain and spinal cord
• Intraperitoneal (IP): by delivering into the peritoneal cavity through a tube
• Intraarterial (IA): by injecting into the artery through a needle or catheter
• Tropical: Drugs contain creams or gels and can be rubbed on the cancer-affected skin directly.

Chemotherapy Cycles

The number of chemotherapy cycles is based on the features of cancer and how well the body heals after each treatment. The cancer doctor decides how many cycles a patient need. The cycle of the treatment is made up of the chemotherapy session and the rest period. The body can recover from the side effects during the rest period. Additionally, it permits the affected healthy cells to go back to normal.

Procedure

Before Procedure

Explain the procedure and take consent. Inform about adverse effects and instruct to notify if any side effects occur.

• Do any supportive care, including pre-medications, antiemetics, and hydration.
• Review medication history.
• Check Lab values: liver function test, renal function test, and complete blood count. Drugs may be held in severe neutropenia, thrombocytopenia, or impaired liver and kidney functions.
• Perform imaging (X-ray and scans) to check the size of the cancer tissue.
• Make a plan before treatment starts like type, number of sessions, and route of administration depending on the type, location, and stage of the cancer.
• Calculate the correct dose according to the measurement of the height and weight of the patient.
• Insert IV line, needle, port, or tube according to route choice. Assess the site for erythema and pain.

During Procedure

• Administer the chemotherapy drugs.
• Observe for extravasation (leakage of blood, lymph, or other fluid, such as an anticancer drug, from a blood vessel or tube into the tissue around it). If extravasation is suspected, stop the infusion.
• Monitor the patient for the first 15 mins for signs of hypersensitivity or anaphylaxis.

After Procedure

• Document drug dose and any occurrence of extravasation
• Monitor the vital signs.
• Monitor for other adverse effects of infusion
• Remove the IV line, needle, etc. Normally, the port will be taken out after finishing all of the chemotherapy cycles.
• Advise the patient to avoid contact with sick people and drink lots of fluid for the first 48 hours after chemotherapy.

Side Effects of Chemotherapy

Chemotherapy works by targeting the DNA or RNA of cancer cells, which prevents them from dividing and growing. However, it can also affect normal, healthy cells that divide rapidly, such as those in the bone marrow, hair follicles, and digestive system. This is why chemotherapy can cause some side effects like

• Nausea and vomiting
• Hair loss
• Fatigue
• Infection
• Bleeding and bruising
• Neuropathy
• Skin changes
• Mouth sores
• Cardiotoxicity
• Bone marrow suppression:
• Neutropenia
• Anemia
• Thrombocytopenia

Some chemotherapy drugs can cause long-term side effects, such as

• Infertility
• Cognitive changes
• An increased risk of secondary cancers

Management of Common Side Effects

The side effects can be acute or prolonged and may need multi-disciplinary monitoring.

• Infusion reactions, from hypersensitivity reactions: use pre-medications like  methylprednisolone, epinephrine
• Nausea and vomiting: use metoclopramide, dexamethasone, ondansetron, and granisetron.
• Mucositis: use mouthwash.
• Fatigue: do exercise, optimize sleep quality and behavioral therapies such as relaxation.
• Chemotherapy-induced diarrhea: use agents like loperamide, diphenoxylate, atropine, and octreotide.
• Neurotoxicity: use agents like vitamin B6, pregabalin, carbamazepine, and amitriptyline.

Precautions

• The liver and kidney metabolize and eliminate the majority of chemotherapy agents. If the patient has liver or kidney disease, dose adjustment of some chemotherapy drugs is necessary, as they are toxic, leading to organ failure. 
• Similarly, the cytochrome P450 (CYP) enzyme metabolizes several chemotherapy medicines. If inhibitors of CYP enzyme such as ketoconazole and grapefruit juice and some common drugs like phenytoin and phenobarbital are in use, these drugs can change the chemotherapy drug levels which may result in decreased efficacy or increased toxicity. It is due to drug-drug interaction.
• As there is an increased risk of infection due to immunosuppression, the patient should be informed and aware of infection control measures like personal hygiene and avoiding contact with sick individuals.
• Patients should be educated and counseled regarding the side effects and managing these side effects.
• Even if their partner is taking contraception, chemotherapy patients should use condoms the whole time they are receiving treatment.

Summary

• Chemotherapy treats cancer cells or prevents them from growing by using antineoplastic drugs.
• It can be given based on the type of cancer, its stage, and the patient’s condition.
• It can be continuous or alternated between periods of treatment and rest to allow recovery.
• It can also affect normal, healthy cells that divide rapidly and shows some side effects. So, practice hand hygiene, educate patients, and watch for side effects.
• There are several types of drugs depending on the mechanisms of action. Patients receive those medicine via different routes such as oral, intravenous, intramuscular, intrathecal, etc.

References

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