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. With this activity, the goal is to teach the reader about the basics of various chemotherapy drugs available. It highlights the role of the interprofessional team in the use of these agents.

Objectives:

• Describe the history of chemotherapeutic agents now available.
• 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 a 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 Historical documents suggest the use of arsenicals started in the 1900s.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 chemotherapy of cancer, including oral derivatives like chlorambucil and ultimately cyclophosphamide.[2] The discovery of actinomycin D pioneered the search for more antitumor antibiotics, including anthracyclines, chromomycins, 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 been approved by the U.S. Food and Drug Administration (FDA) in the last decade.

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 effect or 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 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 either 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 as a result of a given treatment. So, the treatment may require repeating to achieve a response. The toxicity of cytotoxic drugs is greatest 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 effective responses as well. They appear to prevent the development of resistant clones by promoting cytotoxicity in resting and dividing cells.[11] Cellular mechanisms that promote or suppress cell proliferation and cell 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.[12] Researchers are designing molecular targeted therapy on these pathways, selectively inhibiting growth, e.g., targeting cell signaling or angiogenesis, blocking protein degradation, etc.

Chemotherapeutic agents can classify according to the mechanism of action:

1. Alkylating agents (nitrogen mustard, chlormethine, chlorambucil, mechlorethamine, cyclophosphamide, melphalan): yield an unstable alkyl group, R-CH2+, which reacts with nucleophilic centers on proteins and nucleic acids.
2. Antimetabolites: [methotrexate, pemetrexed, 6-mercaptopurine, 5-fluorouracil, capecitabine, cytosine arabinoside, gemcitabine, cytarabine]: affect various cellular pathways required for DNA, RNA synthesis, e.g., methotrexate inhibits dihydrofolate reductase, 5-fluorouracil inhibits thymidylate synthetase, cytarabine inhibits DNA polymerase.
3. Mitotic inhibitors: [vinblastine, vincristine, paclitaxel, docetaxel], vinblastine and vincristine interferes with spindle assembly in mitosis
4. Antibiotics: [actinomycin D, bleomycin, daunomycin]: inhibit RNA and DNA synthesis
5. Anthracyclines [doxorubicin, daunorubicin, idarubicin, mitoxantrone] inhibit RNA and DNA synthesis
6. Topoisomerase II inhibitors: etoposide
7. Nitrosoureas: carmustine, lomustine
8. Antibodies: trastuzumab, bevacizumab, cetuximab, rituximab, cetuximab targets EGFR, trastuzumab is an antibody against Her2 receptors, bevacizumab is a recombinant humanized antibody to vascular endothelial growth factor (VEGF), rituximab is an anti-CD20 antibody.
9. Enzyme: asparaginase
10. Agents that inhibit DNA synthesis (hydroxyurea or damage DNA: cisplatin, carboplatin, oxaliplatin)
11. Signal transduction inhibitor: [imatinib, dasatinib, sorafenib, regorafenib, vismodegib] inhibit specific cell signals, e.g., imatinib: inhibits tyrosine kinase coded by the abl gene. It has many specific indications, such as gastrointestinal stromal tumors (GIST) and chronic myelogenous leukemia.[13]
12. Differentiation agents: all-trans retinoic acid, HDAC inhibitors
13. Hormones and hormone antagonists: [prednisone, tamoxifen, aromatase inhibitors, abiraterone] - aromatase inhibitors inhibit androgen estrogen conversion. Abiraterone is an inhibitor of cytochrome P450 17A1 a 17a hydroxylase, and C17,20 lyase and thereby inhibits testosterone synthesis.
14. Proteasome inhibitors: bortezomib 
15. DNA topoisomerase I inhibitors: camptothecin, irinotecan, and topotecan
16. Agents that inhibit DNA repair: PARP inhibitors[14]
17. Arsenic trioxide: increasing the degradation of the PML-RARa oncoprotein
18. Inhibitors of DNA methylation: zebularine, azacitidine, and 5-aza-2′deoxycytidine.
19. Chimeric toxic protein: denileukin diftitox (IL2 + diphtheria toxin)

Issues of Concern

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. 

Selective toxicities associated with specific chemotherapy agents are as follows.

• Anthracyclines: cardiomyopathy - sodium thiosulfate has been demonstrated to reduce doxorubicin-induced cardiomyopathy in mice.[15]
• Bleomycin and busulphan: pulmonary fibrosis
• Cisplatin: nephrotoxicity, neurotoxicity, ototoxicity.[16]
• Capecitabine, 5-FU: hand and foot syndrome
• Cyclophosphamide: hemorrhagic cystitis. Mesna (2-mercaptoethane sulfonate sodium) neutralizes cyclophosphamide's hemorrhagic cystitis inducing metabolite, acrolein. It does so by binding to its sulfhydryl group.[17]
• Ifosfamide: Fanconi syndrome, hemorrhagic cystitis, and central nervous system toxicity
• Mitomycin: hemolytic-uremic syndrome
• Vinca alkaloids: neurotoxicity
• Paclitaxel: neurotoxicity
• Trastuzumab: cardiomyopathy
• Vascular endothelial growth factor inhibitors: gastrointestinal perforation

Secondary malignancies from chemotherapeutic agents have been reported often from alkylating agents and topoisomerase inhibitors. These patients usually present 5 to 7 years after the drug exposure and have a poor prognosis. Many side effects, such as cisplatin-induced ototoxicity, result from reactive oxygen species and inflammatory cytokines. 

Clinical Significance

The side effects of cancer chemotherapy can be acute or prolonged, may need monitoring. It would require multi-disciplinary monitoring as certain 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, netupitant. palonosetron has a longer half-life, better efficacy, and higher binding affinity than granisetron.[18]
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, anticonvulsants (like gabapentin, pregabalin, or carbamazepine), or tricyclic antidepressants (amitriptyline).

Other Issues

1. Log kill hypothesis: refers to the property of chemotherapy that kills a constant fraction of tumor cells irrespective of the tumor's size. This drug activity falls under first-order kinetics, whereby a chemotherapy drug kills a constant proportion, rather than a constant number of cells, in a given tumor. 

2. Chemotherapy resistance: there are several mechanisms by which chemotherapy drug resistance, also referred to as "tachyphylaxis," occurs (see below). Tumor cells can exhibit primary resistance (having resistance before prior to 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 of that is directly proportional to the tumor size. 

3. 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). 

4. 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 the 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.[19] 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.[20] 

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 important to understand and equip themselves with the infusion protocols parameters and alert the treating clinicians if they notice any 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.