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).
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 Historical documents suggest the use of arsenicals started in the 1900s.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.
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. The discovery of actinomycin D pioneered the search for more antitumor antibiotics, including anthracyclines, chromomycins, mitomycin, and bleomycin. 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.
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.
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). Charles Huggins won a Nobel Prize in 1966 for investigations on hormone therapy in prostate cancer. This work was a stepping stone to a new era of hormone therapy, with the introduction of drugs like tamoxifen and anastrozole, etc.
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. 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.
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. 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. 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:
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.
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.
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. 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).
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
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. 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.
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.
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.
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