CTD and Peripheral neuropathy

In this essay I will describe a specific chemotherapy regimen used to treat patients with multiple myeloma. First, I shall identify and describe the chemotherapy agents in the regimen and also analyse the principles and mode of action by which these drugs act on the cell. I will then discuss a specific side effect associated with this treatment and how this affects the patient. This regimen is the administration of Cyclophosphamide, Thalidomide and Dexamethasone (CTD).

Authors:

David Casalduero Cidón

Asunción Cuenca Sánchez

Maria Dolores Cuenca Sánchez

‘Multiple myeloma is a malignant disease characterised by a clonal population of plasma cells in the bone marrow’ (Maddams and Hall, 2010, p. 295). Myeloma is an incurable disease and the efficacy of the treatment varies among patients due to the high heterogeneity of the disease. Suzuki (2013) Myeloma is the 17th most common cancer and the incidence is 9 new cases per 100,000 males and 7 for every 100,000 females in the UK, being related to age with the highest rate in older men and women (Cancer Research UK 2011).

CTD is a combination regimen, the principle of combination regimes are that every drug is active singly, but together they can have an increased effect; every drug has a different mode of action, attacking cancer cells in different ways (Perry, 2008). Besides, the toxicity and adverse effects may be decreased by selecting agents with dissimilar toxicity profiles (Airley, 2009). CTD has high response rates and can be indicated as an induction therapy for newly diagnosed myeloma (Morgan et al., 2012). On the other hand, some researchers have investigated the efficacy of this therapy and it may also be considered as a palliative treatment option in refractory myeloma patients due to the achievement of good results in disease control, low toxicity, well tolerated and a response rate of 89% (García-Sanz et al., 2004).

Cells carry out a division process known as cell cycle and involve cell division (mitosis) and the period between two divisions, called interphase (Blows, 2005).

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Cytotoxic drugs are more effective on actively dividing cells; these drugs are classified in two principle groups, cell cycle-specific which act on specific phases of the cycle and cell cycle-nonspecific which act in any phase of the cell cycle (Tadman, 2007). In addition, It is important to understand the mechanisms that take place in the cell cycle and how cytotoxic drugs act on the cell cycle to develop specific therapies to treat cancer (Gabriel, 2007).

Cyclophosphamide belongs to the alkylating agents similar to nitrogen mustard type. Its mode of action is based on DNA synthesis inhibition by forming cross-links. It is a cell cycle-nonspecific drug, acting in any stage of the cell cycle (Perry, 2008). According to Priestman (2008) the main action of cytotoxic alkylating agents is to act on DNA and RNA by attacking the nitrogen atom on the purine base guanine. Cyclophosphamide is excreted by the kidneys so special considerations are needed when patients who have renal insufficiency are treated (Perry, 2008). Cyclophosphamide side effects are showed in the table below (Dougherty et al., 2014).

Thalidomide has multiple modes of action (Suzuki, 2013) and is commonly classified as an immunomodulatory and antiangiogenic agent. According to Airley (2009) some of these mechanisms are mediated by the suppression of the angiogenic growth factor (VEGF) and basic fibroblast growth factor (bFGF); others include inhibition of tumor necrosis factor-α (TNF-α), induction of apoptosis, expansion of natural killer (NK) cells and costimulation of T-helper cells (Skeel, 2007). The figure 1 shows some of the Thalidomide’s mechanisms of action.

Thalidomide was approved by the Food and Drug Association for the treatment of multiple myeloma in 2006 and began to be seen as a potential drug against bone marrow syndromes (Airley 2009). According to Marliese et al. (2010) thalidomide has been shown to be very effective causing high response rates and augment survival, this response rate has been found to be increased when it is given with dexamethasone and chemotherapy (Cavallo et al., 2007). Bakanay and Beksac (2013) note that Thalidomide can provoke apoptosis in Myeloma cells and enhance the response of refractory patients to conventional therapies.

Thalidomide is effective in elderly patients with newly diagnosed myeloma, especially when combined with other agents such as dexamethasone (Morgan et al., 2011). Attal et al. (2006) shows that thalidomide is also a good option to administer as a maintenance therapy because it is able to extend response and survival by inhibiting proliferation and inducing apoptosis of remaining cells after chemotherapy. It is given orally as it is slowly absorbed within the gastrointestinal tract. A starting dose of 50 mg or 100 mg is given once daily in the evening (Skeel, 2007, p. 157). Table 2 shows the side effects of Thalidomide (Dougherty et al., 2014).

Dexamethasone has been shown to be very active as a single agent in Multiple Myeloma (Laubach and Richardson, 2010) and produce a high response in newly diagnosed, refractory and relapsed myeloma patients (Doss, 2006). It has an anti- inflammatory effect and is an adjunctive antiemetic and can treat allergic reactions (Kelvin and Tyson 2011). It can induce apoptosis of the cancer cell; enhance the activity of other anti-myeloma drugs and help to relieve pain by reducing the inflammation in areas affected by myeloma (Myeloma UK, 2014). However it has a high incidence of side effects (55%) as table 3 shows, so is used as a pulse, four days on four days off (Doss 2006, p. 515).

Peripheral neuropathy

The existence of side effects after administering anticancer therapies is caused due to the incapacity of the cytotoxic drugs to distinguish between normal and cancer cells and there are cells particularly affected such as rapidly proliferating cells of the bone marrow, gastrointestinal tract, reproductive system and hair follicles (Tadman, 2007,

p. 214). Nursing management of myeloma is challenging, that is why, nurses must keep up to date with the current evidence and be responsive to patient’s needs; they also need to be continually assessing and educating patients about side effects and how to manage these (Dowling et al., 2013). The most common side effects from the administration of CTD are constipation, infection, neuropathy and DVT (Palumbo and Cerrato, 2013).

The National Cancer Institute Common Toxicity Criteria (CTCAE, 2009) defines peripheral neuropathy as a disorder characterized by inflammation or degeneration of the peripheral motor or sensory nerves. It usually begins in the hands or feet and gets worse over time (National Cancer Institute, 2014). This disorder can be one of the disease manifestations or caused by treatment appearing after damage produced in sensory, motor or autonomic nerve fibers (Corthals, 2011, p. 15). The main symptoms experienced are numbness, tingling, increased sensitivity, pain, discomfort and altered coordination and weakness (Palumbo et al., 2010). It is graded from 1 to 5; these grades refer to the severity of the adverse events and show clinical descriptions (Table

4. CTCAE, 2009). Snowden et al. (2011) mention the importance of grading the degree of neuropathy by using recognized scales such as CTCAE, the Leeds assessment of neuropathic symptoms and signs (LANSS) or the Total Neuropathy Score.

There are several mechanisms that may explain it such as angiogenesis or toxicity and factors that can increase the risk of developing this disorder such as previous neuropathy, age, previous chemotherapy and deficiency of vitamin B12 or folate (Corthals, 2011). Corthals (2011) concludes that there is a genetic predisposition or risk mediated by genes influencing the repair mechanisms and inflammation of the peripheral nervous system and that a further research of this theory could lead to a development of neuro-protective strategies.

Peripheral neuropathy may principally appear due to the administration of the drug thalidomide being cumulative and dose-dependent but is also prevalent at diagnosis and related to the paraprotein or comorbidities such as diabetes mellitus (Wildes et al., 2012). Others researchers recommend that the administration of thalidomide should not overtake a six months period as the risk of thalidomide-induced peripheral neuropathy is unacceptably high (Snowden et al., 2011). According to Ludwig et al. (2013) Thalidomide should be avoided in patients with polyneuropathy and use less myelotoxic drugs in patients with compromised bone marrow function.

Morgan et al. (2011) compare the peripheral neuropathy incidence rate between CTD and MP (melphalan and prednisolone), it is increased with CTD. They found this disorder was frequently reported as mild or moderate and the incidence of grade 3-4 neuropathy was low. Dimopoulos et al. (2004) compared the side effect when using standard CTD or when administering thalidome as a pulse. The incidence is lower when given as a pulse. Sidra et al. (2006) treated 62 patients with CTD finding that was highly effective with a response rate of 83.8% but thalidomide had to be stopped in two patients and dose reduction was carried out in five patients because of peripheral neuropathy.

Attal et al. (2006) found that peripheral neuropathy was the main symptom that led to the interruption of the treatment and was more frequent in the thalidomide group (68%). They also found that the presence of severe neuropathy (grade 3-4) was acceptable (7%).

The evidence for prevention shows that the symptoms may improve in 3-4 months after dose reduction or withdrawal (Bakanay and Beksac, 2013) and symptoms may resolve in 16 weeks but occasionally may be irreversible (Corthals, 2011). Prevention may be to pay attention to the onset of symptoms, numbness or tingling and any changes in the sensation in hands or feet, this should be reported. The best way to do this may be maintain a record of signs and symptoms (Myeloma UK, 2014). However, there is no agreement on the best method of assessing peripheral neuropathy because of the subjective nature of the symptoms (Dowling et al., 2013).

Peripheral neuropathy has a big impact on quality of life and may be a challenge especially in older patients due to the effect of this disorder on mobility, functional independence, pain and the increased risk of falls (Wildes et al., 2012). The family play an essential role providing physical and emotional support and occasionally additional care may be required (Tadman, 2007). The national cancer institute (2009) provide information to the patients about nerve changes that can help them to identify early symptoms of peripheral neuropathy and also recommend some tips from other patients about symptoms management related to the daily life activities; such as wearing sturdy shoes and putting up rails in the bathroom to prevent falls, taking extra care in the kitchen and shower by asking somebody to make sure the temperature of the water is not too high and protecting hands by wearing gloves when working or in the kitchen.

Doss (2006) proposes some nursing interventions which range from health educational measures to assessment and treatment strategies (table 5). Additional therapies may help relieve symptoms such as massage, taking warm baths, using cold/heat packs with caution due to reduced sensation and the prescription of analgesics as gabapentin or pregabalin (Myeloma, 2014).

CONCLUSION

Knowledge about SACT and their side effects provides nurses a greater understanding about the cancer treatment process and the influence and impact on the patient’s life and should improve patient care.

Through the study of this regimen I can learn to identify and classify this and other types of anti cancer therapies and understand the way they act on the cell cycle and other physiological process. The study of peripheral neuropathy will help nurses to educate patient about vigilance and detect this side effect early, providing support and treatment to manage.

Figure 1. Thalidomide`s probable mechanisms of action.

thalidomide-mechanisms-of-action

Table 1. Side effects of Cyclophosphamide (Dougherty, McWhirter and Jones, 2014, p. 60).

Table 2. Side effects of Thalidomide (Dougherty, McWhirter and Jones, 2014, p. 134).

Table 3. Side effects of Dexamethasone (Cancer Research UK, 2015).

Table 4. Grades refer to the severity of adverse events (CTCAE, 2009).

Table 5. Nursing interventions for peripheral neuropathy.

Tables – CTD and Peripheral neuropathy

Tables – CTD and Peripheral neuropathy.pdf

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