Cytotoxic Chemotherapy and Cell Cycle - Essay Example

Introduction to Cytotoxic Chemotherapy: A Reflective Essay Introduction: This is a reflective essay about a patient whose identity is has been intentionally kept undisclosed for ethical reasons and for reasons of confidentiality. The patient is a 40-year-old single female who was taken care of in the clinical practice. This patient had stage 1 carcinoma of the breast with no lymph node involvement at presentation. The patient underwent FEC chemotherapy for this. The chemotherapy was uneventful except for some nausea that was managed well with antiemetic medications. This reflective essay is a journey through the cytotoxic chemotherapy of this particular patient from the perspectives of a practitioner with the aim and purpose to revisit the competencies and knowledge that are necessary to manage such a patient undergoing cytotoxic chemotherapy. While reflecting, this would enable the practitioner to improve the understanding of the cytotoxic drugs and their roles in management of carcinoma breast, and while undergoing such therapy, the impact of that on the overall physiology and psychology of our patient. Cell Cycle: The cell cycle is a series of events that regulate the life of the cell. Two main events characterize the cell cycle. The S-phase in which the cell duplicates its genome, and M phase, in which the cell splits into two daughter cells. It is necessary that these two crucial events are regulated and coordinated to occur in an ordered fashion at precisely the right time. The cell cycle has a central role in controlling cell growth and proliferation. This frequently becomes the target of genetic alteration. The accumulation of the genetic alteration may lead to deregulation of these ordered events and may be related to the onset of cancer. Neoplastic transformation is a multi-step process involving the clonal accumulation of genetic lesions that affect proto-oncogenes or tumor suppressor genes. The mechanism of cell division assures that the cell accurately duplicates its contents, especially its chromosomes. The cell cycle is divided into 4 (Molassiotis, A, Gibson, F. and Kelly, D. et al., 2006) phases. During M phase, the replicated chromosomes are separated and packaged into two new nuclei by mitosis, and the cytoplasm is divided into the two daughter cells by cytokinesis. The other three phases of the cell cycle are called interphase, G1 (gap 1), a period of growth during which the cell determines its readiness to commit to DNA synthesis; S during which the genetic material is replicated, and no replication is permitted; and G2 during which the fidelity of DNA replication is determined and errors are corrected. The transition between the G1 and S and between the G2 and M are tightly regulated to minimize errors in the replication process. Check points in G1 and G2 that determine whether to enter are regulated by protein kinases, cyclin-dependent kinase or cdk and kinase-associated proteins called cyclins. The cdk family of compounds associate with a distinct cyclin with characteristic substrate specifications, and these are expressed in different phases of the cell cycle. The check point regulating transition from G1 to S is frequently disrupted in cancer. For a cancer to arise, mutations must occur that affect a variety of pathways. Often the G1 cell cycle check point is affected. The expression of telomerase is a common feature in cancer. Overexpression of growth factors and their receptors is commonly detected. Activation of the ras protooncogene or other changes leading to a constitutively active MAP kinase cascade is common. Changes in cytoskeleton and responsiveness to contact-mediated growth inhibition are frequent in cancer cells. Usually when a mutation occurs in one component of a signaling pathway, other mutations are seen in the other pathways rather than in another component of the same pathway (Smith, T.J. et al., 2006). The high level of mutability of cancer cells facilitates adaptation to the environment including the development of resistance to anticancer drugs. As tumor progresses, they acquire the ability to secrete proteases that aid in the escape from local barriers so that they may metastasize. Discrete steps in tumor progression lead to the production of factors by the tumor cells that permit neovascularization by immature vessels in order to supply nutrients to the growing tumor. In short, the wide range of changes that must occur in a single cell to permit the behaviour associated with a malignant neoplasm makes it clear as to why carcinogenesis is a multistep process and why human cancers may have 10 or more genetic lesions that account for the biology. The etiology of breast cancer involves a complex interplay of genetic, hormonal, and probably dietary factors. Clustering of breast and ovarian cancers in families suggests an inherited susceptibility to these cancers. Genetic linkage analysis of cancer pedigrees with families having a history of both breast and ovarian cancer led to the localization of the first breast cancer susceptibility gene on chromosome 17q21.3. This is the position of BRCA1 gene, but subsequent analysis of families with a history of breast cancer not linked to BRCA1 led to the discovery of another breast cancer susceptibility gene, BRCA2, on chromosome 13q12-13. Each gene product interacts with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure (LoBiondo-Wood, G. and Haber, J. (1998). In this patient, it was decided as guided by existing practice and in conjunction with the patient's wishes of preserving the breast that the treatment would be curative in intent. In this case chemotherapy is the best course. Since it is best to have a standard treatment protocol, it was decided that a standard protocol would be followed. Because cancer therapies are toxic, patient management involves addressing complications of both the disease and its treatment as well as the complex psychosocial problems associated with cancer. In the short term during a course of curative therapy, the patient's functional status may decline, but treatment-induced toxicity is acceptable in this case since it is a curative regimen. As aptly it is termed cytotoxic chemotherapy, there were several adverse effects of the regimen given to her was evident during the chemotherapy. She was given the regimen of CEF. This consists of the following 5-Fluorouracil 500 mg/m2 iv on days 1 and 8, Epirubicin 60 mg/m2 iv on days 1 and 8, Cyclophosphamide 75 mg/m2 po on days 1-14, repeated every 28 days, for 6 cycles. 5-FU is an antimetabolite that indirectly affects DNA function. A broad definition of antimetabolites would include compounds with structural similarity to precursors of purines or pyrimidines or that interfere with purine or pyrimidine synthesis. Antimetabolites can cause DNA damage indirectly, through misincorporation into DNA, abnormal timing or progression through DNA synthesis, or altered function of pyrimidine and purine biosynthetic enzymes. They tend to convey greatest toxicity to cells in S-phase, and the degree of toxicity increases with duration of exposure. Common toxic manifestations include stomatitis, diarrhea, and myelosuppression. Second malignancies are not associated with their use. 5-Fluorouracil (5FU) represents an early example of "rational" drug design in that it originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells, especially gut. 5FU is metabolized in cells to 5FdUMP, which inhibits thymidylate synthetase (TS). In addition, misincorporation can lead to single strand breaks, and RNA can aberrantly incorporate FUMP. Epirubicin is an antitumor antibiotic. As a class they bind to DNA directly and can frequently undergo electron transfer reactions to generate free radicals in close proximity to DNA, leading to DNA damage in the form of single strand breaks or cross-links. Topoisomerase poisons include natural products or semi-synthetic species derived ultimately from plants, and they modify enzymes that regulate the capacity of DNA to unwind to allow normal replication or transcription (Parfitt, K. (ed), 2005). DNA damage from these agents can occur in any cell cycle phase, but cells tend to arrest in S-phase or G 2 of the cell cycle in cells with p53 and Rb pathway lesions as the result of defective checkpoint mechanisms in cancer cells. It can intercalate into DNA, thereby altering DNA structure, replication, and topoisomerase function. It can also undergo redox cycling by accepting electrons into its quinone ring system. It causes predictable myelosuppression, alopecia, nausea, and mucositis. In addition, it causes acute cardiotoxicity in the form of atrial and ventricular dysrhythmias. Cyclophosphamide is inactive unless metabolized by the liver to 4-hydroxy-cyclophosphamide, which decomposes into alkylating species, as well as to chloroacetaldehyde and acrolein. Alkylating agents as a class break down, either spontaneously or after normal organ or tumor cell metabolism, to reactive intermediates that covalently modify bases in DNA. This leads to cross-linkage of DNA strands or the appearance of breaks in DNA as a result of repair efforts. "Broken" or cross-linked DNA is intrinsically unable to complete normal replication or cell division; in addition, it is a potent activator of cell cycle checkpoints and signaling pathways that can activate apoptosis. As a class, alkylating agents share similar toxicities: myelosuppression, alopecia, gonadal dysfunction, mucositis, and pulmonary fibrosis. They differ greatly in a spectrum of normal organ toxicities. As a class they share the capacity to cause "second" neoplasms, particularly leukemia, many years after use, particularly when used in low doses for protracted periods (Rang, H.P., Dale, M.M., Ritter, J.M. and Moore, P.K., 2003). Exploring the possibility as to whether different regimens can be used in a single patient or not, it can be said that utilizing the principles of chemotherapy, research with cytotoxic chemotherapeutic agents, and clinical experience many chemotherapy regimens can be advocated. Therefore, there is little agreement about optimal chemotherapy regimens. The other regimens that can be prescribed are CMF, AC, CAF, AC plus Paclitaxel. In general doxorubicin-containing regimens have demonstrable therapeutic benefits. The anthracyclines and taxols are the most active cytotoxic agents. Chemotherapeutic agents demonstrate a dose-response effect. At sufficiently low concentrations, I have seen no cytotoxicity. At increasing concentrations, the cell kill will be higher than drug exposure. At high concentrations, the effect reaches a plateau. Normal healthy cells also are susceptible to the cytotoxic effects of chemotherapeutic drugs and exhibit a dose-response effect. Most chemotherapeutic agents are inducers of programmed cell death. Drugs, such as, alkylating agents, the purine/pyrimidine analogues, and the topoisomerase inhibitors result in DNA damage. In response to genotoxic damage, the cells can arrest at two identified check points, the G1/S and G2/M boundaries. At other levels the other chemotherapeutic agents may work, thus making the synergy between the components of the regimen possible leading to total death of cell with malignant potential and at the same time reducing the effects of toxicity towards normal cells (Rang, H.P., Dale, M.M., Ritter, J.M. and Moore, P.K., 2003). This patient was treated with FEC regimen. I will give an account of a chemotherapy cycle in this patient and shall discuss the routes of administration of the components. Cyclophosphamide is injected intravenously in a running infusion. For this, intravenous saline is initiated, and the fluid goes into the system through an 18-gauge intravenous catheter with a stop-cock to control the flow rate. The Cyclophosphamide is dissolved in 20 -50 mL of 5% dextrose and the injectant is drawn in a 50 mL syringe and either given in the bottle or injected slowly through the side channel of the intravenous line. Doxorubicin or epirubicin is an anthracycline. These are known as severe vesicants, and extravasation during administration may lead to local tissue necrosis. For this reason, this drug is administered through a long intravenous catheter inserted, and usually a fresh and wide-bore vein is selected, and the drug is injected very slowly being sure that at any point in time, the drug is injected within the vein. A long intravenous catheter would ensure that the drug is not extravasated. This drug should not be diluted at the time of administration. The 5-FU administration does not need any special instrument (Parahoo, K., 1997). Prior to administration of any chemotherapy, some laboratory investigations are very important. This patient was also subjected to several tests that we call cancer workup. This workup is necessary to plan the management. The histologic diagnosis of the cancer and the proper categorization of the tumor type are pivotal in planning further workup and in deciding among treatment options. This should be mentioned here that histologic subtyping with biochemical and immunologic tissue characterization has resulted in a level of distinction that was not previously possible. The staging investigations that were done in this patient did identify the extent of the malignant disease, and that is extremely important in planning appropriate therapy. No routine set of tests is important for all patients. In this patient, for chemotherapeutic suitability and for prevention of complications of chemotherapy, few investigations were done. The most important of them is a routine complete blood tests with haemoglobin, total count, differential count, an erythrocyte sedimentation rate, a chest x-ray, CT scan of the abdomen, chest, head were done. A urinalysis was done to rule out any existent infections. If there is anaemia, it is likely that the chemotherapy-induced bone marrow depression would make the anaemia more explicit, and the patient would suffer from symptoms. Anaemia would have a generalized effect on different organ system functions, and to prevent that supplementation would be necessary. Chest x-ray would reveal any prominent infection and differential count would indicate that. Coexistent infective process in the patient would worsen further after chemotherapy due to chemotherapy-induced leucopenia and immune suppression, specifically in relation to fluorouracil. Although 5-FU toxicity is schedule dependant, bone marrow suppression, gastrointestinal toxicity, and myocardial ischaemic syndrome are not infrequent. Therefore, an electrocardiogram was done in this patient to know the baseline status. The electrocardiogram was within normal limits. In this context, this patient would be particularly prone to develop a cardiac event following cycles of chemotherapy. Epirubicin is known to cause myelosuppression making the rationale of differential count as a screening examination more significant. Epirubicin and 5-FU both are metabolized by the liver. Metastatic disease in the liver and other problems may lead to hyperbilirubinaemia. Therefore, at a baseline, these patients need to be investigated by serum bilirubin, and dose adjustment is necessary is serum bilirubin is high. This medication can potentially precipitate cardiotoxicity in the form of cumulative-dose dependent one and irreversible cardiotoxicity may as well precipitate when concomitant Cyclophosphamide is used in the regimen. The rationale of electrocardiogram becomes meaningful to establish baseline status of the heart, so as to prevent any adverse events. High dose Cyclophosphamide may lead to myocardial necrosis. The most important investigation that is pertinent in this patient is ruling out any bladder or urinary tract infection. Cyclophosphamide is a potent immunosuppressive agent, and it can potentially lead to infections. Infection in the urinary tract of urinary bladder may further accentuate acrolein induced haemorrhagic cystitis that needs mesna and adequate hydration (O'Mahony, M., 2001). The patient and her relatives were explained about the regimen, the components of the regimen, the potential side effects and cytotoxicity, and the measures to prevent such. It was also stressed that it is important to complete the 6 cycles as advised, and how completion of these cycles are significant in destroying malignant cells in different cell cycles. This was exactly in accordance with law and medical ethics. This follows the ethical principle that every human being has a right to determine what shall be done with his own body. This requires disclosure of the patient's diagnosis, the nature of the proposed intervention, intended benefits, associated risks and side effects, and the medically reasonable alternatives and the corresponding risks. The toxic nature of chemotherapy introduces numerous risks and potential side effects. Although package inserts provide reliable and complete information on chemotherapeutic agents. The moral issue surrounds the uncertainties inherent in chemotherapy. Even if the staff believes strongly that chemotherapy can be the best suitable alternative almost tending to ignore the cytotoxicity, it is important to recognize the fact that the relatives, significant others, and the patient view cytotoxicity in a different manner. So the healthcare professionals need to disclose and explain the potential harm that may cause serious psychological trauma from apprehension for the patient and the closer ones. It has always been a debate as to how much information is adequate for the patient to be able to sign the informed consent. To be truly ethical, the extent of information should be determined by the patient, not the physician. It would be ethically wrong to require patients to handle a complicated form at a difficult time of his life. The information given at a particular time influences consent of the patient. Thus it can be argued that if the patients can make an informed choice, they can rescind them (Nursing Midwifery Council, 2006). The common short term side effects of chemotherapy are nausea, vomiting, diarrhea, mucositis, respiratory tract infection, alopecia, and weakness and loss of weight. The protocols for treating such problems include adequate hydration, maintenance of oral hygiene, treatment with vitamins and minerals, altering food habits, and ensuring detection of complications. In any way, malignancy and its therapy affects the body image of an individual. They describe their body image as "not looking normal", "a theme that comprises two dimensions", "ugly", or as "looking sick." They have a feeling of being vulnerably exposed. This psychological and physical change hints to need for a social change in the patient. Several coping mechanisms can be used for a social change induction that would be perceived as an improvement in the image. Management of physical appearance and social interaction can be done by avoiding, maintaining normality, testing the waters, and peer shield themes. These coping mechanisms would alter the altered body image, and as expected, these would restore the body image of the patients and would go a long way to re-establish their normal lives (NCI, 2005). Contemporary cancer treatments require a multidisciplinary approach in order to ensure safe prescribing and administration practices in administration of chemotherapy. The potential problems may arise in the areas that are reconstitution, spillage, contamination, storage, transportation, and disposal. The reconstitution may contain inappropriate concentration of the constituents, there is always a chance that higher or lower concentration as appropriate for the body surface area of the patient is applied. The increasing complexity of the drug regimens and the introduction of the new cytotoxic agents combined with the inexperience of the medical staff in this area. For Cyclophosphamide therapy, vigorous hydration with oral or intravenous fluids more than 3 L per day to maintain adequate urine output is necessary in order to decrease the risk of hemorrhagic cystitis. This medication is discontinued if dysuria or hematuria develops. Nurse should be vigilant about potentiation of cardiotoxic effects precipitated by epirubucin. Nausea and vomiting is a frequent accompaniment, and the nurses must take special note of the patient's diet. The rate of the infusion must be slow because otherwise adverse effects like dizziness, nasal congestion, watery eyes, rhinorrhea, or sneezing may occur. While preparing epirubicin, special care was taken so that there would be no mucosal or skin contacts for the risk of vesicant reaction. Precautions against possible hypersensitivity reaction was taken, and while administration, absolute guard against leakage was taken in all possible ways. Since this is an irritant the dose was administered for a 30-minute period. There was no hepatic dysfunction as indicated by serum bilirubin level, otherwise, dose adjustment would have been necessary. Establishment of an intravenous line, choosing a wide-bore needle, choosing the locations of the vein through which the chemotherapy would be given, all were important considerations along with I had to wear mask, cap, eye gear while preparing the medications. I used a computerized chart to prepare the medications, and it was double checked with the doctor's instruction whether all specifications were met or not (NCAB Working Group on Biomedical Technology, 2005). Making a nursing diagnosis is the process of collecting information through assessment and using this information through to make judgment about the patient's need of care. In the practice of oncology, nurses work intimately with physicians and the drugs they prescribe. The care of patients receiving chemotherapy provides fertile grounds for innovative clinical nursing practice, and this practice evolves from accurate patient assessment that leads to identification of an appropriate nursing diagnosis. Basic data should be collected from the patients. A detailed physiologic assessment can be adapted for acute, critical, and outpatient care. The goal of assessment is maintenance of current data base on the patient so that the plan of care and interventions are appropriate. Building on an initial assessment, rather than re-assessing patients as they move from setting to setting should be the goal. Patients are often overwhelmed by information and need time and professional help to consider the impact of the diagnosis and prognosis and to make decisions about definitive therapy. It is important to assess what level of participation in the decision making process is desired by the patient because that will help direct the nurse's informational interventions and can reduce anxiety and psychological distress. The assessment tools are designed in such a way that the potential side effects can be recognized, and also one can recognize the probability of a potential side effect in a given patient (Murphy, A. and Cowman, S., 2006). Most patients receive chemotherapy in an ambulatory setting, and this was the case with this patient also. There would be time constraints for patient-nurse interactions. This exactly happened with this patient, and managing time was difficult. The administration of the chemotherapy involves knowledge of drug pharmacology and tumor kinetics, patient assessment parameters, and techniques of physical assessment. My technical expertise is mainly based on the principles of intravenous therapy and use of venous access devices, drug administration and safe handling of antineoplastic agents, and adult learning. I administered the chemotherapy after evaluating the patient's tolerance to past chemotherapy. The patient has a little nausea, and it was controlled with ondasetron 16 mg, 8 mg before and 8 mg after the injection. There was no recommendation for change of antiemetic therapy made since this effectively controlled her symptoms. Recommendations for changes in antiemetic therapy are made to prevent or optimize control of nausea or vomiting. I also took responsibility for educating the patient to enhance self-care measures so adverse effects like constipation, mucositis, dental infection, and anorexia would not happen. The self-care measures like oral hygiene, dental care, fiber intake, water intake, and food adjustments were highlighted to the family in such a way that tolerance to chemotherapy is optimized. The patient and the family are also instructed on early symptoms and signs of other adverse effects, so that they waste no time to inform us or the clinic. These included specially jaundice, heart rhythm disturbances, hematuria, weakness, extreme fatigue, loss of appetite, and weight loss (National Institute for Clinical Excellence (NICE), 2003). The government has taken initiatives to improve cancer prevention as a prophylactic measure to reduce the burden of cancer patients in the state. Those who are patients affected with cancer, speeding up the diagnosis and treatment of cancer because these provide only chance of increasing life expectancy and reducing costs. There is a cancer reform strategy in place that aims to reduce inequalities and to improve the experience of people living with a beyond cancer. These policies make a guideline where it is ensured that care is delivered in the most appropriately equipped setting, and access to this care becomes free in that effective new treatments are implemented rapidly (Department of Health Cancer Reform Strategy, 2007).. The NHS has a cancer plan, and the cancer reform strategy guidance applied in the healthcare setting has encompassed all aspects of the chemotherapy for the cancer patients. Word Count 3847 References Department of Health Cancer Reform Strategy, (2007). Accessed from http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_081006 on January 1, 2008Khatcheressian, J.L., Wolff, A.C., LoBiondo-Wood, G. and Haber, J. (1998) Nursing Research: Methods, Critical Appraisal, and Utilization, 4th edn, Mosby, London. Molassiotis, A, Gibson, F. and Kelly, D. et al. (2006) A systematic review of worldwide cancer nursing research. Cancer Nursing, 29(6), 43140. Murphy, A. and Cowman, S. (2006) Research priorites of oncology nurses in the Republic of Ireland. Cancer Nursing, 29(4), 28390. National Institute for Clinical Excellence (NICE) (2003) Improving Supportive and Palliative Care for Adults with Cancer. NICE, London. NCAB Working Group on Biomedical Technology (2005) Report to National Cancer Advisory Borad. http://deainfo.nci.nih.gov/advisory/ncab/sub-bt/NCABReport_Feb05.pdf (Accesed April 2007). NCI (2005) Report to National Cancer Advisory Board. NCAB Working Group on Biomedical Technology. Nursing Midwifery Council (2006) Research and Audit A-Z advice sheet. NMC, London. O'Mahony, M. (2001) Women's lived experience of breast biopsy: A phenomenological study. Journal of Clinical Nursing, 10, 51220. Parahoo, K. (1997) Nursing Research: Principles, Process and Issues. Macmillan Press Ltd,London. Parfitt, K. (ed) (2005) Martindale. The Complete Drug Reference, 34th edn, Pharmaceutical Press, London. Rang, H.P., Dale, M.M., Ritter, J.M. and Moore, P.K., (2003). Pharmacology, 5th edn, Churchill Livingstone, Edinburgh. Smith, T.J. et al. (2006). ASCO 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. Journal of Clinical Oncology, 24, 50917. Read More