D E LOS M AS SOBERBIOS BEMOLES Y la península párase

Although chemotherapy strategies are intended to damage tumour cells, treatments also affect normal cells that result in systemic toxicity and side effects. Complications associated with chemotherapy treatment (i.e. treatment morbidity) may present as acute side effects such as nausea, hot flashes, and dry mouth. Chronic (long-term) conditions include cardiac and vascular toxicity (Meinardi et al., 2000). However, morbidities such as cardiac toxicity may also have an early onset but continues into chronic conditions in later life (Yeh and Bickford, 2009). The following section will describe common morbidities associated with chemotherapy treatment.

1.6.1 Cardiac Complications

Cardiac complications include heart failure, myocardial ischemia, hypertension, thromboembolism, and bradycardia, and have been identified during anthracycline use (Yeh and Bickford, 2009, Thorn et al., 2011). The mechanism for cardiac toxicity is poorly understood; although there is evidence to suggest that reactive oxygen species from anthracyclines form metabolites that interfere with cardiac fibrillation by disrupting iron and calcium regulation (Thorn et al., 2011). Another proposed mechanism for causing cardiotoxicity is the disruption of mitochondrial respiration that can initiate apoptosis in cardiac cells (Clementi et al., 2003). Other direct effects on cardiac cells have been linked to 5-fluorouracil, which has been shown to cause cell hypoxia and interfere with metabolic regulation (Meinardi et al., 2000). Targeted therapies such as Trastuzumab have been shown to cause congestive heart failure and compromised left-ventricle ejection fractions (Slamon et al., 2001). Due to these potential hazards, drugs are grouped separately to minimize the additive toxic effects; for example, Trastuzumab is not recommended in combination with anthracycline chemotherapy. A higher incidence of cardiotoxic effects were observed when anthracyclines were given with Trastuzumab (27%) compared to Trastuzumab alone (5%) (Hudis, 2007).

The incidence of heart failure was documented to be as high as 45% of patients who received anthracycline-based drugs (Yeh and Bickford, 2009). Other agents such as antimetabolites can induce myocardial ischemia in up to

68% of patients. Fluorouracil has been associated with cardiotoxicity and present as severe chest pain, and the death rate (mortality) for these episodes is estimated at 13% (Yeh and Bickford, 2009).

1.6.2 Haematopoietic Toxicity

Cytotoxic effects can occur in blood cells and lead to neutropenia, which is a condition associated with severe neutrophil depletion. Neutrophils are a type of white blood cell that are responsible for host immunity to infectious agents. The risk of developing neutropenia increases with age, and its onset is associated with anthracyclines and alkylating chemotherapy treatment

(Crawford et al., 2004). Consequences associated with hematopoietic toxicity include susceptibility to bacterial infections from Escherichia coli, Klebsiella

pneumoniae, Staphylococcus, Streptococcus, and Enterococcus, and are most

commonly observed in the digestive tract, lungs and skin (Crawford et al., 2004). Symptoms associated with neutropenia present as fevers and fatigue. Mortality from neutropenia-related infections have been reported around 8% (Crawford et al., 2004).

Other complications include neutropenic sepsis which affect specialized immune-producing cells in the bone marrow. Neutropenic sepsis can be fatal and mortality rates range between 2% - 21% (National Institute for Health and Clinical Excellence (NICE), 2012). Symptoms associated with neutropenic sepsis are similar to neutropenia and involve fever (pyrexia) and susceptibility to infections. Treatments for both conditions involve antibiotic therapy and a

temporary suspension of chemotherapy until blood tests indicate a recovery in

neutrophils (National Institute for Health and Clinical Excellence (NICE), 2012).

1.6.3 Gastrointestinal Toxicity

Damage to the gastrointestinal (GI) system will present as nausea, diarrhoea, esophagitis, stomatitis, and mucositis and are associated with many chemotherapeutic agents such as taxanes, platinum compounds,

(Boussios et al., 2012). The onset of symptoms is typically acute; for example, cisplatin doses given between 5-120 mg/m2 _{trigger vomiting (emesis) within 24} hours after dose administration. Similarly, alkylating agents cause nausea and vomiting as early as 1-2 hours after treatment administration (Boussios et al., 2012). The prevalence of symptoms is dependent on the type of

chemotherapy; alkylating agents and platinum based compounds showed the highest incidence of GI toxicity of up to 90% of patients (Boussios et al., 2012).

1.6.4 Alopecia

Chemotherapy-induced alopecia is characterized as hair loss on the scalp and other parts of the body, and is associated with high anxiety and distress in cancer patients (Trueb, 2009). Cells of the hair follicles are rapidly dividing and therefore are prone to injury from cytotoxic therapy (Trueb, 2009). The onset of alopecia often occurs one to three weeks after starting

chemotherapy and full hair-loss typically takes place between one to two

months (Trueb, 2009). Chemotherapy agents associated with high rates of hair loss include: anthracyclines, alkylating agents, and pyrimidine antimetabolites (Chon et al., 2012). In contrast, platinum-based drugs such as cisplatin rarely cause hair loss (Trueb, 2009).

1.6.5 Neurotoxicity

Neurotoxicity can present in 30-40% of patients as peripheral

neuropathy. This condition is described as extremely painful sensations in the toes, fingers, and extremities (Wolf et al., 2008). Peripheral neuropathy can be caused by platinum agents, taxanes, and alkylating agents that damage the neural cells of the peripheral nerves (Wolf et al., 2008). The onset of symptoms may occur spontaneously during treatment, and present as “tingling” in the toes and fingers. Some reports have indicated that full neuropathic recovery is rarely achieved; while others have indicated improvement or resolution within 3-6 months after completing chemotherapy (Kannarkat et al., 2007, Argyriou et al., 2005). Other neurotoxic effects include paclitaxel acute pain syndrome. This condition is characterized as arthralgia and myalgia and is experienced in approximately 58% of patients who have received paclitaxel drugs as part of

their treatment regimen (Wolf et al., 2008). Despite symptoms experienced in the muscle, the suspected mechanism is believed to be caused by

hypersensitization of neural fibres of the spinothalamic system (Wolf et al., 2008).

1.6.6 Anaphylaxis

Hypersensitivity to chemotherapy agents can lead to anaphylaxis reactions which involve the rapid activation of inflammatory signals such as histamine, cytokines, and chemokines that result in sudden respiratory contraction, and cardiovascular response (Castells et al., 2012). Taxane- hypersensitivity reactions are common; approximately 30% of patients develop some form of hypersensitivity, however improved pre-treatment protocols such as administering antihistamines and corticosteroids prior to taxane-infusion have reduced the rate to approximately 10% (Castells et al., 2012, Feldweg et al., 2005). The exact mechanism of chemotherapy-induced hypersensitivity is still under investigation, however at extremely high doses of paclitaxel (10-100 times the dose given clinically), human basophil cells were shown to