Continuing Education Activity

Chemotherapy in cancer has merged the disease course from a terminal and catastrophic result in merely all cases to a treatable and sometimes curable illness through the right approach. This activity's goal is to teach the reader about the basics of various chemotherapy drugs available; it also highlights the role of the interprofessional team in the use of these agents.

Objectives:

• Describe the history of chemotherapeutic agents currently on the market.
• Review the mechanism of action of common chemotherapeutic classes and agents.
• Outline the most frequent adverse effects of the basic drug types, as well as some specific drug side effects.
• Identify interprofessional team strategies for improving care coordination and communication to advance cancer chemotherapy and improve outcomes.

Introduction

The three events that led to the development of cancer treatment began with three events in the last century: the discovery of X-rays by Wilhelm Konrad Roentgen, the use of transplantable animal-tumor models in cancer research, and the first surgical procedure developed by Halsted (radical mastectomy).[1] 

The term “chemotherapy” was coined by German chemist Paul Ehrlich who investigated the use of drugs to treat infectious diseases. He was also the first scientist to study animal models to screen a series of chemicals regarding their potential activity against diseases. Historical documents suggest the use of arsenicals started in the 1900s. Radiotherapy ad surgery were the mainstays of cancer management in the 1960s. As micrometastases and recurrence of cancer after surgery and radiation therapy became evident, combination chemotherapy started gaining significance.[2]

Publication of the Lindskog article suggesting the success of nitrogen mustard in the treatment of lymphoma had a considerable initial effect on the development of cancer chemotherapy, including oral derivatives like chlorambucil and ultimately cyclophosphamide.[2] The discovery of actinomycin D pioneered the search for more antitumor antibiotics, including anthracyclines, mitomycin, and bleomycin.[3] Farber et al., in 1947, showed success in the treatment of childhood leukemia by using antimetabolites with antifolate activity, called aminopterin, later be known as methotrexate.[4]

The successful management of choriocarcinoma and leukemias with methotrexate led to further investigations in cancer chemotherapy. And drugs like thiopurines (e.g., 6-mercaptopurine), 5-fluorouracil came into the forefront of cancer treatment.[5]

Nowell et al. studied the association of translocation of chromosomes 9 and 22 to several leukemias, which later led to developing the first molecular targeted treatments years later (imatinib).[6] Charles Huggins won a Nobel Prize in 1966 for investigations on hormone therapy in prostate cancer.[7] This work was a stepping stone to a new era of hormone therapy, with the introduction of drugs like tamoxifen and anastrozole, etc.[8][9]

With an increased understanding of the biology of cancer, there are now several therapeutic monoclonal antibodies available. rituximab and trastuzumab were approved during the late 1990s to treat lymphoma and breast cancer, respectively.[10] Molecular targeted therapy is a new approach to cancer treatment. Several agents have received approval from the U.S. Food and Drug Administration (FDA) in the last decade.  

Researchers are designing molecular targeted therapy on these pathways, selectively inhibiting growth, e.g., targeting cell signaling or angiogenesis, blocking protein degradation, etc. Targeted therapies are discussed as a separate topic[11]. Immune checkpoint inhibitors PD1, PDL1, CTLA 4, which cause immune activation against cancer cells, are widely used in various cancers. Immunotherapy is discussed in a separate topic.

Function

The goal of chemotherapy is to inhibit cell proliferation and tumor multiplication, thus avoiding invasion and metastasis. But this results in toxic effects of chemotherapy due to the effect on normal cells as well. Inhibition of tumor growth can take place at several levels within the cell and its environment.

Traditional chemotherapy agents primarily affect either macromolecular synthesis and function of neoplastic cells by interfering with DNA, RNA, or proteins synthesis or affecting the appropriate functioning of the preformed molecule. When interference in macromolecular synthesis or function is sufficient, it leads to cell death due to the chemotherapeutic agent's direct effect or by triggering apoptosis. With traditional agents, cell death may be delayed as a proportion of the cells die due to a given treatment. So, the medicine may require repeating to achieve a response. The toxicity of cytotoxic drugs is most significant during the S phase, as it is the DNA synthetic phase of the cell cycle. Vinca alkaloids and Taxanes act in the M phase and block mitotic spindle formation.

Combination chemotherapy is a common choice to produce adequate responses as well. They appear to prevent the development of resistant clones by promoting cytotoxicity in resting and dividing cells.[12] Cellular mechanisms that promote or suppress cell proliferation and differentiation are intricate, involving several genes, receptors, and signal transduction. Investigations in cancer cell biology have led to significant insight into mechanisms of apoptosis, angiogenesis, metastasis, cell signal transduction, differentiation, and growth factor modulation.[13] Researchers are designing molecular targeted therapy on these pathways, selectively inhibiting growth, e.g., targeting cell signaling or angiogenesis, blocking protein degradation, etc.

Chemotherapy can be administered in neoadjuvant, adjuvant, combined, and metastatic settings. Neoadjuvant therapy is a treatment given before the primary treatment. Adjuvant therapy is the treatment given in addition to the initial therapy, which can suppress or eliminate the growth of occult cancer cells. Adjuvant therapy is now the standard for breast, lung, colorectal, and ovarian cancers. Combined modalities like chemotherapy and radiation are used to shrink the tumor before the surgery or curative intent in cancers like head and neck, lung, anal.

The combination of chemotherapeutic agents is delivered cyclically based on the three basic principles.

1. Fraction kill hypothesis: A uniform drug dose kills a constant fraction of tumor cells rather than a constant number regardless of tumor burden.
2. Neoplastic tumor cells have a linear response between the dose administered and the efficacy.
3. Goldie-Coldman hypothesis: Cancer cells acquire spontaneous mutations that cause drug resistance.

Henceforth, multitargeted therapy or combination therapy is more superior to single-agent therapy in most cancer treatments. Additionally, combination chemotherapy agents with different mechanisms of action and also nonoverlapping toxicities can be chosen to decrease the resistance and toxicities. Curative regimen like bleomycin/vinblastine/cisplatin for testicular cancers is an example of combination chemotherapy. Combination chemotherapy is a common choice to produce adequate responses as well. They appear to prevent the development of resistant clones by promoting cytotoxicity in resting and dividing cells.

Chemotherapeutic agents can classify according to the mechanism of action:

Alkylating Agents 

Examples of alkylating agents are as follows:

• Nitrogen mustard- bendamustine, cyclophosphamide, ifosfamide
• Nitrosoureas – carmustine, lomustine
• Platinum analogs – carboplatin, cisplatin, oxaliplatin
• Triazenes- Dacarbazine, procarbazine, temozolamide
• Alkyl sulfonate- Busulfan
• Ethyleneimine- Thiotepa

Mechanism of action (MOA): These drugs yield an unstable alkyl group, R-CH2+, reacting with nucleophilic centers on proteins and nucleic acids. Inhibit DNA replication and transcription.

Toxicity: Dose-limiting toxicity: myelosuppression (neutropenia nadir: 6 to 10 days with recovery in 14 to 21 days). Mucositis, nausea and vomiting, neurotoxicity, alopeciaLong-term toxicities: pulmonary fibrosis, infertility, secondary malignancies

Antimetabolites

Mechanism of Action: Inhibit the replication of DNA

Examples of antimetabolites are as follows

A) Cytidine analogs – azacitidine, decitabine, cytarabine, gemcitabine

• MOA: Directly incorporate into DNA and inhibit DNA methyltransferase (azacitidine, decitabine) or DNA polymerase (cytarabine, gemcitabine)
• Indications: Azacitidine and decitabine for MDS, AML, cytarabine for MDS, AML, and gemcitabine for breast, NSCLC, ovarian, pancreatic, bladder, sarcoma, HL, NHL
• Toxicity: Myelosuppression in general. Cytarabine high dose causes neurotoxicity, conjunctivitis. Gemcitabine causes liver enzyme elevations, interstitial pneumonitis.

B) Folate antagonists – methotrexate, pemetrexed

• MOA: reduces folate, which is essential in the synthesis of purine nucleotides and thymidylate
• Indications: Methotrexate for ALL, NHL, CNS, sarcoma, and pemetrexed for malignant pleural mesothelioma, NSCLC (non-squamous)
• Toxicity: Myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, cutaneous reactions
• Toxicity prevention: Hydration and alkalization of the urine, leucovorin rescue

C) Purine analogs – cladribine, clofarabine, nelarabine

• MOA: structural analogs of guanine and act as false metabolites
• Indications: Cladribine for hairy cell leukemia, AML, CLL, NHL. Clofarabine for ALL, AML. fludarabine for CLL, AML, NHL, BMT conditioning agent. Nelarabine for T-ALL, lymphoma. Pentostatin for hairy cell leukemia, CTCL, CLL.
• Toxicities: Myelosuppression, immunosuppression (suppress CD4+ cells) put patients at risk for opportunistic infections

D) Pyrimidine analogs – fluorouracil (5-FU), capecitabine (prodrug of 5-FU).

• MOA: Active metabolite (F-dUMP) forms a stable covalent complex with thymidine synthetase in the presence of reduced folate, therefore, interfering with DNA synthesis and repair.
• Indications: 5-FU for colorectal cancer, anal cancer, pancreatic cancer, gastric cancer. Capecitabine for colorectal cancer, breast cancer.
• Toxicity: Dose-limiting hand-foot, mucositis, diarrhea. Dose-limiting myelosuppression.[14] Toxic levels of 5FU can occur in patients with Dihydropyrimidine Dehydrogenase (DPD) deficiency or drug overdose. This can lead to cardiac dysfunction, colitis, neutropenia, and encephalopathy. Uridine triacetate is approved for the toxicity of these patients.
• Antimicrotubular Agents

Examples of antimicrotubular agents are as follows:

A) Topoisomerase II inhibitors: Anthracyclines [doxorubicin, daunorubicin, idarubicin, mitoxantrone inhibit RNA and DNA synthesis. In addition, it inhibits topoisomerase II, causing inhibition of DNA repair resulting in blockade of DNA and RNA synthesis.

• Indications: Daunorubicin for ALL, AML, APL. Doxorubicin is used for ALL, AML, Wilms tumor, neuroblastoma, sarcomas, breast, ovarian, bladder, thyroid, HL, and NHL. Liposomal doxorubicin has a longer half-life and is less cardiotoxic.
• Toxicity: Myelosuppression, cardiotoxicity (cumulative), mucositis. The lifetime cumulative dose of adriamycin is 550 mg/m^2. Secondary malignancies like treatment-related MDS/AML(t-MDS/t-AML) is a rare complication with poor prognosis have been reported often from alkylating agents and topoisomerase II inhibitors (-16. These patients usually present 5 to 7 years after the drug exposure.
• Epipodophyllotoxins (Etoposide and Teniposide). Indications: Testicular, SCLC, ALL, AML, Breast, CNS, Sarcoma, HL, NHL, Merkel cell, NSCLC, BMT conditioning agent. Dose-limiting myelosuppression – primary leukopenia

B) Topoisomerase I inhibitors: Irinotecan, Topotecan

• MOA: prevents relegation by blocking the release of Top I from the cleavable complex & forming a ternary complex
• Indications: Irinotecan for colorectal, cervical, esophageal, sarcoma, pancreatic, lung. topotecan for cervical, ovarian, SCLC
• Toxicity: Irinotecan causes dose-limiting diarrhea. Topotecan causes dose-limiting neutropenia, thrombocytopenia.

C) Taxanes – paclitaxel, docetaxel, cabazitaxel

• MOA: Disruption in the equilibrium of polymerization and depolymerization of microtubules causing abnormal cellular function and disruption of replication leading to apoptosis. Inhibit assembly of microtubules—M phase-specific.
• Indications: Docetaxel for breast, lung, prostate, ovarian, cervical, sarcoma. paclitaxel for breast, lung, and ovarian. Abraxane is protein bound paclitaxel. Cabazitaxel for prostate cancer.
• Toxicity: Hypersensitivity reactions, myelosuppression, peripheral neuropathy

D) Vinca alkaloids: vinblastine, vincristine, vinorelbine

• MOA: Bind to tubulin and inhibit microtubule formation arrests cell in metaphase. M-phase specific.
• Indication: Vincristine for ALL, HL, NHL, Neuroblastoma, SCLC
• Toxicity: Peripheral neuropathy (both motor and sensory function affected), myelosuppression

Antibiotics 

Examples of antibiotics used as chemotherapy agents are as follows: actinomycin D, bleomycin, daunomycin:

• MOA: inhibit RNA and DNA synthesis
• Bleomycin binds to DNA, producing single and double-strand DNA breaks.
• Indications: Testicular, HL, Head, and neck cancers
• Toxicity: Cumulative pulmonary toxicity, hyperpigmentation

Miscellaneous

A) Hydroxyurea: MOA: inhibits ribonucleoside diphosphate reductase; S-phase specific

• Indications: AML, CML, sickle cell disease
• Toxicity: Myelosuppression, dermatologic reactions

B) Tretinoin:

• MOA: vitamin A derivative; targets RAR-α promoting cell differentiation
• Indication: APL
• Toxicity: APL differentiation syndrome – fevers, cardiopulmonary symptoms

C) Arsenic trioxide

• MOA: Induces cell differentiation
• Indication: APL
• Toxicity:  QT prolongation – baseline and serial EKG monitoring, replace K, Mg. APL differentiation syndrome

D) Proteasome inhibitors:

• Indication: bortezomib used in multiple myeloma.
• Toxicity: Peripheral neuropathy

Issues of Concern

Chemotherapy agents can be given per oral (PO), intravenous (IV), subcutaneous (SC), intramuscular (IM), intrathecal (IT). Most of the chemotherapy agents are IV because of the 100% absorption rate. Some compounds like paclitaxel are poorly soluble, so they need to be mixed with solvents like cremophor for better absorption. Physicians should be aware of factors that influence absorption, like surgery and gastric motility, especially in cancer patients using opioids.

Most of the chemotherapy agents are metabolized and excreted by either liver or kidney. Some of the chemotherapy drugs are toxic to the liver or kidneys. In such cases, toxic levels can build up in these leading to organ dysfunction. Therefore, it is essential to consider dose adjustments in these organ failure patients. For example, capecitabine dose needs to be adjusted for patients with renal disease.

Chemotherapy agents are generally administered using body surface area (BSA) dosing. Drug-drug interactions are expected. The cytochrome P450 (CYP) enzyme is involved in the metabolism of various chemotherapeutic drugs. Drugs like bortezomib, docetaxel, etoposide, imatinib, sunitinib, sorafenib, vinca alkaloids are metabolized by CYP3A4/5. It is imperative to be aware of some of the common drugs with strong inducers like phenobarbital and phenytoin and inhibitors of CYP enzymes like grapefruit juice, ketoconazole since these drugs can alter the drug levels of the chemotherapy agents and can decrease efficacy or increase toxicity.

Chemotherapeutic agents are commonly associated with side effects. Usually, the side effects of chemotherapy are a reflection of their mechanism of action. Often cytotoxic chemotherapy targets DNA and proteins expression in both cancer cells and normal host cells. Hence, the therapeutic index leading to toxicity is very narrow. In addition, most chemotherapy drugs show activity in rapidly multiplying cells, so they quickly affect multiplying cells, e.g., bone marrow, GI tract, hair follicles. Common toxicities associated with such agents include myelosuppression, mucositis, nausea, vomiting, diarrhea, alopecia, fatigue, sterility, infertility, infusion reactions. Furthermore, there is an increased risk of infections due to immunosuppression. 

Chemotherapeutic agents are commonly associated with side effects. Usually, the side effects of chemotherapy are a reflection of their mechanism of action. Most chemotherapy drugs show activity in rapidly multiplying cells, so they tend to affect rapidly multiplying cells, e.g., bone marrow, GI tract, hair follicles. Common toxicities associated with such agents include myelosuppression, nausea, vomiting, GI side effects, mucositis, alopecia, sterility, infertility, infusion reactions. Furthermore, there is an increased risk of infections due to immunosuppression. 

Clinical Significance

The side effects of cancer chemotherapy can be acute or prolonged, may need monitoring. In addition, it would require multi-disciplinary monitoring as specific patient populations may be at higher risk for complications.

Management of common side effects of chemotherapy:

1. Infusion reactions, from hypersensitivity reactions: Management options include using pre-medications like diphenhydramine, methylprednisolone, epinephrine
2. Chemotherapy-induced nausea and vomiting: Treatment options include prochlorperazine, haloperidol, metoclopramide, lorazepam, dexamethasone, ondansetron, granisetron, dolasetron, palonosetron, dronabinol, aprepitant, fosaprepitant. Palonosetron has a longer half-life, better efficacy, and higher binding affinity than granisetron.[19]
3. Mucositis: Using magic mouthwash, avoidance commercial mouthwashes, and lemon glycerin swabs
4. Fatigue: Interventions like exercise, optimizing sleep quality, and behavioral therapies such as relaxation can help fatigue.
5. Chemotherapy-induced diarrhea: Using agents like loperamide, diphenoxylate, atropine, octreotide.
6. Chemotherapy-induced constipation: Using agents like docusate, senna, milk of magnesia, bisacodyl, lactulose, polyethylene glycol, enemas
7. Neurotoxicity: Using agents like vitamin B6, glutamine, gabapentin, pregabalin, carbamazepine, or tricyclic antidepressants (amitriptyline).

Toxic levels of 5FU can occur in patients with Dihydropyrimidine Dehydrogenase (DPD) deficiency or drug overdose. This can lead to cardiac dysfunction, colitis, neutropenia, and encephalopathy. Uridine triacetate is approved for the toxicity of these patients. 

Other Issues

Chemotherapy resistance: there are before drug exposure) or secondary resistance (resistance after exposure to a drug). 

Mechanisms: many chemotherapy drug resistance mechanisms include: efflux, inactivation of drug, alteration of drug targets, and cell death inhibition. 

• A particular efflux pathway involves the tumor producing a substance known as p-glycoprotein, which essentially removes the drug from the tumor cell.  
• Tumor cell heterogeneity is another mechanism that follows the Goldie-Coldman hypothesis in which every tumor cell has a variable degree that is directly proportional to the tumor size. 

Routes of administration of chemotherapy: include oral, intravenous, intrathecal (into the cerebrospinal fluid via spinal cord), injections (subcutaneous, intraperitoneal), or into the bladder (intravesicular instilling). 

Complications of Extravasation of Vesicants and Management 

A vesicant refers to a drug's ability to cause tissue necrosis if infiltrated from the vein into the subcutaneous tissue (extravasation) 

Complications include pain, burning, stinging, erythema, sudden onset edema, and tissue necrosis. Tissue necrosis occurs as a spectrum, from partial skin thickness (appearing as blisters) to full-thickness (skin appearing white)

Management: after confirming extravasation, vesicant administration should stop, residual medication or blood should be aspirated with a separate 10mL syringe, which is then disconnected and replaced by a new 10mL normal saline syringe. The IV cannula is then removed, the irritation site should be covered lightly (to avoid excess pressure) with a sterile dressing, and either cold or hot packs should be applied based on the drug (see below). The affected limb should be elevated for 48 hours (if applicable), and surgical consult and photographs should be taken. 

• Cold pack: dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mechlorethamine, mitomycin-C, streptozocin
• Hot pack: vincristine, vinblastine, vinorelbine 

Enhancing Healthcare Team Outcomes

Since the administration of most chemotherapy agents occurs at infusion centers, nursing and allied health professionals play a significant role in taking care of patients on such drugs. They are usually the first point of contact for the patients. All health professionals need to understand the type of drug in use and its associated side effects for the patient. Close monitoring and early recognition of side effects can help prevent significant morbidity and mortality. For example, patients with a history of anemia, thrombocytopenia should avoid the use of NSAIDs. Intra-muscular injections and rectal suppositories should be avoided in such patients.

Thorough buccal cavity assessments and avoidance of commercial mouthwashes in patients with mucositis can help decrease patient discomfort. Many chemotherapeutic agents have specific known side effects that are minimizable prophylactically. For instance, following folate inhibitors such as methotrexate with folate analogs such as leucovorin help reduce bone marrow suppression severity.[15] This concept applies to general chemotherapy side effects. For example, oral mucositis is a common chemotherapy side effect, which can be minimized by administering Palifermin, a keratinocyte growth factor that helps reduce mucosal endothelial cell damage.[16] 

Patients undergoing chemotherapy usually need strong emotional support, and they are going through anxiety, depression, and anticipatory grief from the expected side effects of the drugs. Multidisciplinary and interprofessional interventions at various stages of their treatment regimen can promote mental health.

Patients undergoing chemotherapy require a team-based approach for monitoring any adverse events. The role of nursing and allied health professionals includes providing supportive care, preventing infections, monitoring for adequate nutrition and hydration, and monitoring patient safety: handwashing and infection precautions like isolation protocols require strict adherence. Since patients require frequent laboratory monitoring, it is essential to understand and equip themselves with the infusion protocols parameters and alert the treating clinicians if they notice abnormal parameters. Early nursing interventions can revert worse outcomes in patients.

It is crucial to recognize the common causes and the magnitude of the impact of errors involving cancer chemotherapy. Improving communication, standardizing protocols, utilizing read back and verifying dosages, working with pharmacists are all interventions that can help reduce medical errors in a multidisciplinary setup.

Nursing, Allied Health, and Interprofessional Team Interventions

A nursing team for chemotherapy infusion and administration/monitoring is necessary. Also, patients that experience complications of extravasation of vesicants require nursing management as outlined in the 'other issues' section.