The Royal Marsden

Cryotherapy as an intervention for High Dose Melphalan- induced Mucositis in Myeloma patients.

By Jessica Nicol-Smith and Janet Baker

Multiple Myeloma (MM) accounts for around 10% of all haematological cancers (Harouseau and Moreau, 2009) and despite many ground-breaking therapies being introduced over the last 30 years, high dose therapy accompanied with autologous stem cell transplant (ASCT) remains the standard for treating eligible MM patients (Hamed et al, 2019).

A major complication of this process is mucositis - inflammation of the mucosa induced by Melphalan chemotherapy. This can lead to toxicities in the form of loss of mucosal integrity and severe diarrhoea (Marcussan et al, 2017). The prolonged period of neutropenia as a result of high dose (HD) Melphalan, alongside multiple myeloma related immunodeficiency involving B-cell dysfunction, makes patients more vulnerable to mucositis related infections (Blimark et al, 2015). This results in longer hospital stays,  more febrile episodes, pain, malnutrition and nausea, compared to patients who experience no mucositis (Eilers and Million, 2011). In addition, qualitative studies have shown melphalan ASCT patients found oral mucositis to be the most debilitating side effect of their treatment (Elting Keefe and Sonis, 2008). The characteristics of many multiple myeloma patients add complicating factors that can make them more vulnerable to these side effects. Many patients are treated with multiple lines of treatment over a long time prior to a transplant, reducing their general fitness and therefore increasing vulnerability to infection, malnutrition and general deterioration (Maiese et al, 2015). 

It has been shown that mucositis can have a debilitating effect on multiple myeloma patient outcomes and experience. Oral Cryotherapy (OC) has been suggested as a possible prophylactic prevention of mucositis in Melphalan ASCT (Rajesh et al, 2014). It is hypothesized that patients sucking on ice chips before, during and after chemotherapy with a short half-life reduces incidences of mucositis by causing local vasoconstriction and reduced blood flow so reducing the amount of chemotherapy delivered to the oral mucosa (Perry, Doll and Freter, 2012). 

Salvador, Azusano, Wang and Howell et al (2012) and Batlle et al (2014) looked at the effectiveness of OC in patients receiving HD Melphalan with ASCT. Both studies observed that patients receiving OC had an overall smaller incidence of oral mucositis. Salvador, Azusano Wang and Howell et al (2012) also found a statistically significant reduction in use of opioid analgesics and a difference in length of stay of 1 day in their OC patients. Batlle et al (2014) had similar findings in that less mucositis related pain was reported and a decreased length of stay was observed in those patients receiving oral OC. 

These studies were similar in that participants were randomized into two groups; oral care alone and oral care with OC. They also both used the World Health Organization (WHO) oral mucositis grading scale, allowing for stronger comparison in results. The use of the WHO grading scale was conducted by nurses in both studies, however Batlle et al 2014 used the ‘nursing team’ whereas Salvador Azusano Wang and Howell (2012) used one trained haematology nurse acting as a research assistant. Using one nurse increases the reliability and validity of the WHO results within their study by reducing the chance of inconsistency in assessments. Marchesi et al (2017) investigated the effectiveness of OC in HD Melphalan ASCT patients using a prospective randomized study of an oral care alone and oral care with OC group. Using a sample size of 72 patients like Batlle et al (2014) found a statistically significant difference in grades 3-4 mucositis within their OC group. Marchesi et al (2017) also used the ‘nursing team’ as opposed to one nurse and acknowledged the nurses were not blinded to the study increasing the chance of unconscious bias. 

Salvador, Azusano, Wang and Howell (2012) conducted a pilot randomized controlled trial as opposed to Batlle et al (2014) whose study was retrospective, meaning they had less control over potential interfering variables (Price and Harrington, 2016). However, in doing this Batlle et al (2014) had a much larger sample size of 134 patients, compared to 46 in Salvador, Azusano, Wang and Howell (2012). Aside from the retrospective nature of Batlle et al (2014) allowing for a larger sample size, their inclusion criteria were also less strict. Although all patients were receiving HD Melphalan, a large proportion of their cohort were having this as part of BEAM conditioning for lymphoma which is shown to cause greater incidences of mucositis compared to HD Melphalan alone. They also did not take into account previous treatment or co-morbidities that could have an unfavourable prognostic factor on the results. 

Marchesi et al (2017) found similar results but excluded patients who had received previous exposure to anthracyclines alongside exposure to head and neck radiotherapy; their study only included MM patients undergoing their first ASCT after induction with VTD (Velcade, Thalidomide and Dexamethasone). Similarly to Salvador, Azusano, Wang and Howell (2012), a randomized controlled design was used, increasing the strength of the study (Aveyard, Sharp and Wooliams, 2011). Comparably, Marchesi et al (2017) split their sample size into two groups; OC and just oral care. They found the OC group experienced a significantly lower occurrence of grades 3-4 oral mucositis and multivariate analysis showed use of OC was the only factor significantly correlating grades 3-4 mucositis between the two groups. 

Another randomized trial looking at the efficacy of OC versus super saturated calcium phosphate rinses (SSCPR) versus saline rinses in MM patients undergoing HD Melphalan ASCT found that OC was so superior in preventing oral mucositis that the trial was stopped early (Toro et al, 2014). Using 117 patients split into 3 groups; OC plus oral rinses, SSCPR plus oral care and saline rinses, they found 90% of the OC group did not experience any oral mucositis and none had grade 3-4. When evaluating on this point further, Svanberg, Ohrnand Birgegard (2012) found in a randomised controlled study of 40 patients in Sweden scheduled for allogeneic transplant no significant difference was observed between patients using OC alone and using OC plus SSCPR, further highlighting the need for a review of contemporary practice. Toro et al (2014) assessed oral mucositis using the WHO scale, allowing for better comparison across studies using the same tool. 

An inconsistency observed is the length of time OC is instigated for. Eduardo et al (2014) acknowledges this in a prospective study of 71 patients. Using 3 groups, they investigated if laser therapy only was superior over OC and laser therapy. They found grades 3-4 mucositis was absent in patients receiving OC and cryotherapy compared to that of the control groups who had only received laser therapy. Eduardo et al (2014) uses an evidence-based decision to determine how long OC is administered for. They acknowledged the half-life of Melphalan during the infusion and elimination phases, therefore administering OC 5 minutes before, 30 minutes during and 30 minutes after to account for the half life. In comparison to other studies, Salvador, Azusano, Wang and Howell (2012) administered OC for a similar time period.  The others administered for longer periods and have observed similar results in terms of mucositis, which suggests Eduardo et al (2014) used OC for the minimum amount of time to be beneficial. This is important to consider when looking at patient compliance as.OC can be uncomfortable, causing headaches, chills and tooth pain (Perry, Doll and Freter, 2012). Marchesi et al (2017) observed a number of patients who were unable to tolerate OC administered over a longer time period. This highlights the importance of further research into the minimum effective time for administration of OC. There also appears to be a lack of qualitative research into patient experience of cryotherapy.

The secondary factors investigated in the studies are also of note when looking at the efficacy of OC. All studies have found a smaller incidence of oral mucositis in the OC group, therefore naturally one could assume patients experience less pain. However it is important to investigate this factor as perceptions of pain are shown to be the most memorable and debilitating factor from the  patient perspective of experiencing  mucositis (Ozturk et al, 2009),  and the most common assessment tool used amongst studies (WHO) does not include pain. Salvador, Azusano, Wang and Howell found patients in the OC group reported less pain. This was assessed using a 1-10 assessment scale which is entirely dependent on patient perception. It is noted that the OC group was significantly higher in age and levels of education which could both play a part in altering perceptions of pain (Lanitis et al, 2015). They also found less IV analgesics were used in the OC group. However, this could also be dependent on physician preferences on analgesic use. No difference was found in nutritional intake, which is shown to be largely affected by pain in mucositis patients (Lalla, Sonis and Peterson, 2008). Marchesi et al (2017) also found a significant lower occurrence of IV opioid use in the OC group, however they did not comment of the patients’ perceptions of pain. The use of total parenteral nutrition (TPN) was however significantly lower in the OC group which indicates patients in the OC group experienced less pain. Similarly, Batlle et al (2016) found that significantly less pain and a decrease in the use of IV analgesics was reported amongst the OC group. Eduardo et al (2014) did not investigate pain, analgesic use or nutritional intake. Other secondary outcomes include food and fluid intake, febrile episodes of an unknown origin (FUO) and length of stay (LOS). All noticed a reduction within the OC group, although the majority of these observations were not statistically significant (Salvador, Azusano, Wang and Howell, 2012 Marchesi et al, 2017 Batlle et al 2014). 

Research has suggested that the application of evidence based practice within nursing is often inconsistent due to lack of knowledge (Zelenikova, Beach and Ren (2014). Chifelle et al (2014) looked at evidence-based practice in OC. They found once nurses were educated about the evidence of OC, practice change was observed in that many more patients were being offered the treatment. However, owing to the financial strain the NHS is now under, posts such as nurse educators are shown to be reduced  (Safarani, Ravaghi, Raeissi and Maleki, 2018). Despite initial funding pressures on education, introducing its standardised use would be in keeping with the NHS’ 10 point efficiency plan by reducing avoidable demand and unwarranted variation in clinical quality (NHS England, 2018).

The logistics of implementing OC seem relatively simple. It is a very cost-effective treatment with minimal side effects. In terms of long term follow up no safety concerns have been identified (Svanberg, Ohrn, and Birgegard, 2012). Given the short expiry of Melphalan, nurses are often under pressure to administer it in a timely manner and a lack of readily available ice could impact how patients receive the treatment. It is shown that the use of ice machines can increase the risk of infection in transplant patients (Guspiel et al, 2017), however a freezer may offer an alternative solution. 

In conclusion, mucositis is a hugely debilitating side effect of treatment, with specific characteristics of multiple myeloma patients increasing their vulnerability. There is significant evidence to suggest the use of OC reduces mucositis in MM patients post HD Melphalan ASCT.  Some evidence also observes a consequent reduction in FUO, use of TPN and IV opioids, intestinal mucositis, length of stay and pain. There is a lack of evidence regarding how long OC should be administered for and it is unclear when examining the benefit of OC in patients with previous treatment and co-morbidities. However OC is shown to be a low cost and generally well tolerated and effective  treatment,  relatively easy to implement, and appears to have no long-term negative implications for patients. 

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