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By Heather Gilmore, Clinical Specialist Physiotherapist in Haematology and Blood and Marrow Transplant at the University Hospital of Wales, Cardiff and Vale University Health Board and Janet Baker, Apheresis Nurse Specialist BFAC at The Royal Marsden in Sutton and Lecturer Practitioner at The Royal Marsden School.
Haematopoietic Stem Cell transplant (HSCT) is recognised as an intensive treatment for several haematological and non-haematological malignancies (Passweg et al, 2020). It can result in considerable mortality and morbidity causing both acute and late complications. These can be detrimental to patients’ quality of life (QoL), but HSCT can provide potentially longer life expectancy and for some, a curative option (Morishita et al, 2012).The advancement in HSCT practice (Limbach et al, 2020), in addition to enhanced supportive holistic care, has a positive impact on the constantly improving outcomes and overall survival (Ishikawa et al, 2019).
Equipping patients with the necessary skills and information, and encouraging them to lead healthier lifestyles, reduces the consequences of treatment, including the known late effects of HSCT (Faithful et al, 2019). This becomes key, both from a patient perspective, as they are able to lead a more independent life, and also from a health economic perspective, with less burden on carers and supportive care services on the finite resources available in the NHS (NHS, 2019).
Prehabilitation, as defined in current guidelines (Macmillan, 2019) can deliver this enhanced holistic care, by maximising patients’ resilience: physically, psychologically, and practically for any upcoming treatment. Within the context of HSCT this could be extended not only to the conditioning regimen’s toxicities, but also to post-transplant complications such as Graft versus Host Disease (GvHD), thus enhancing patients’ outcomes and experiences and ultimately their QoL.
A key theme of the prehabilitation guidelines is prevention; prevention of avoidable post-treatment complications and prevention of declining cardiovascular fitness and nutritional status due to poor health behaviours (Macmillan, 2019). Prehabilitation aims to empower patients to become stronger and fitter to help them tolerate treatment with reduced complications, both short and longer-term, as well as possibly improving long-term health behaviours. They align closely with The NHS Long-Term Plan (2019), which explores maximising value and personalised care, as well as with public health drivers encouraging enhanced physical activity and healthier eating for the whole population.
Whilst one of the strengths of the prehabilitation guidelines is that the recommendations come from a comprehensive evidence synthesis of up-to-date literature and are supported by experts, the majority of the available evidence is from the surgical oncology field, which could limit the guidelines’ applicability to the HSCT setting, and is perhaps reflective of practice where prehabilitation as a concept is more embedded into surgical services.
However, the guidelines propose that the principles discussed can also be applicable to those undergoing other forms of cancer treatments. HSCT patients and surgical oncology patients have several comparable characteristics: they undergo high-risk procedures with possible intensive care needs, experience reduced appetite, and increased fatigue following treatment. These, as well as pain or mucositis, and the additional protective isolation requirements for HSCT patients, can all result in decreased physical activity and in turn, muscle atrophy and greater risk of chest complications (Galgano and Hutt, 2018).
Likewise, surgical and HSCT patients share increased vulnerability to infections as a consequence of their treatment. For HSCT patients this is not only during the acute neutropenic stage, but can be long-lasting as a result of immunosuppressive therapy (Mackall et al, 2009).
Surgical literature supporting the prehabilitation guidelines demonstrates that prehabilitation, by improving fitness and nutritional status, can reduce post-treatment complications, improve QoL, and reduce length of hospital stay (ACS, 2020). Comparatively, studies exploring prehabilitation within HSCT are limited but evolving. It should be noted that most research has so far focused on allogeneic HSCT, which carries a higher risk of mortality and morbidity than autologous HSCT due to greater infection risk and acute and chronic GvHD (Jessop et al, 2019).
Limbach et al (2020), Kelsey et al (2014), Wood et al (2013) and Ishikawa et al (2019) all identify that allogeneic HSCT patients have reduced physiological function, in particular cardiopulmonary fitness (CPF), pre-transplant. Both Kelsey et al (2014) and Limbach et al (2020) observe that patients’ mean peak oxygen consumption (VO2peak – a measure of CPF (Kelsey et al, 2014)) is 29% and 27.5% lower respectively, compared with age- and sex-matched healthy controls. Although the small sample size (n = 21) limits the applicability of Kelsey et al (2014), their findings are reflected in Limbach et al’s (2020) study of 194 patients. While both papers demonstrate selection bias, accepting only participants with good performance status (such as a Karnofsky performance score of > 90%) and excluding those with pre-existing conditions, one can surmise that the VO2peak would be even lower than those reported if those patients were not excluded.
It is well-established that HSCT has high treatment related mortality (TRM) risks, ranging from 5-40% (Jessop et al, 2019). Pulmonary complications are an important cause of TRM and morbidity and are observed in 40-60% of HSCT (Bargi et al, 2016). Kelsey et al’s (2014) feasibility study analysis identified that VO2peak levels predicted pulmonary toxicities and overall survival within their sample of 21 heterogenous participants where 43% had pulmonary toxicities, with 14% dying and a further 14% requiring intensive care support. Although the sample size is small, the correlation between lower VO2peak levels and higher symptom burden, as well as greater mortality risk, is reinforced by Wood et al’s (2013) findings, (though they too have a small sample size). Wood et al (2013) additionally found that lower VO2peak volumes are correlated with increased hospitalised days, medium of 15 to 25 days during initial inpatient stay.
In their 2020 paper, Limbach et al discerned lower physical activity levels, advancing age and higher BMI as significant predictors of low CPF and thus reduced VO2peak. Given the positive association between higher VO2peak levels, survival and overall outcomes – plus the comparatively low levels prior to transplant among HSCT patients – one can surmise that a treatment which can positively modify VO2peak levels, and as such CPF, will be of clinical relevance. It is encouraging, therefore, that the guidelines identify improved fitness as a key benefit of prehabilitation and propose tailored physical activity programmes.
Wiskemann et al (2011) completed a multi-centre randomised controlled trial (RCT) of partly-supervised exercise throughout the allogeneic patients’ journey, starting prior to transplant, ranging from 1-4 weeks, and ending 6-8 weeks after discharge. 40 patients per arm completed the trial, which revealed significantly improved endurance capacity in the exercise group, albeit to a lesser extent than those identified by Baumann et al (2010) whose participants followed a more structured programme.
Faithful et al (2019) support offering intervention throughout the patient’s journey. Their systematic review of 16 RCTs identified greater benefits in physical functioning when prehabilitation is combined with rehabilitation, rather than standing alone. Admittedly none of the included RCTs involved HSCT patients, but we can apply these findings to an HSCT setting.
Van Haren et al ‘s (2013) systematic review explores physical exercise within the HSCT cohort further. It adds to the body of evidence suggesting HSCT patients benefit from exercise interventions. Furthermore, it highlighted that the later interventions start, the less of an impact they may have overall. This is promising in terms of instigating prehabilitation into the HSCT patient’s pathway. As with analysis of exercise studies, its overall findings are limited due to the heterogeneity of methodology, samples, follow-up times and outcome measures used. Interestingly, the prehabilitation guidelines offer advice on standardising outcome measures to improve comparison of relevant data in the future. Nevertheless, its recommendation of commencing rehabilitation earlier, ideally before HSCT, termed prehabilitation phase, is echoed in several other articles including Ishikawa et al (2019), which observes benefits in respect of lower limb strengthening, especially with older more co-morbid patients.
A key consideration when appraising the guidelines is age. Through natural ageing, people from their fifth decade onwards already lose approximately 3% of muscle strength per year (Bell et al, 2016). When compared to younger people, it takes longer for the more elderly to recover during periods of immobility, such as protective isolation during HSCT, despite their fitness declining at a comparable rate (Hvid et al, 2010). Furthermore, the dawn of Reduced Intensity Conditioning now sees older people having transplants, and, with VO2peak pre-transplant being one of the indicators of post-transplant general fitness and strength levels, we again are faced with an ethical consideration to support patients through prehabilitation, especially the more elderly.
Some argue that for high-risk transplant patients, prehabilitation is not feasible on account of insufficient time, as the longer spent between donor search and transplant, the more opportunity there is for the patient and their disease to worsen (Hatzimichael and Tuthill, as cited in Kenyon and Babic, 2018). Delaying transplant admission to facilitate prehabilitation would theoretically conflict with healthcare professionals’ duty not to cause harm (NMC, 2018). While most evidenced prehabilitation programmes last approximately six weeks, the prehabilitation guidelines assert, supported by Faithful et al (2019), that the benefits of prehabilitation can be seen within just two weeks. Van Haren et al (2018) explored the feasibility of exercise prior to HSCT in a non-randomised controlled trial, comparing supervised exercise sessions twice weekly for four to six weeks versus no exercise. The mean number of exercise sessions completed was six, rather than their predicted eight to-twelve sessions. Despite this, the fourteen patients in the intervention group demonstrated improvements in VO2peak, leg, arm and hand strength from baseline to admission for transplant. The small number or participants and a lack of satisfactory control group comparison due to their non-compliance, plus the lack of randomisation leading to diverse groups at baseline, weakens the findings somewhat. Nevertheless, the study demonstrates that supervised exercise programmes are feasible prior to HSCT without any adverse events.
Physical activity, as part of a multi-modal prehabilitation approach, as suggested by the Prehabilitation guidelines (Macmillan, 2019), merits serious consideration for inputting into the HSCT patient’s pathway. Many patients scheduled for HSCT are already heavily treated with resultant reduced CPF and muscle strength, both of which impact on the patient’s overall QoL. These lower levels have a negative impact on their mortality and overall morbidity. Exercise can have a positive influence on these deficits. Gaining optimal health, through the provision of prehabilitation, prior to the physiological stresses that HSCT brings, with its high risk of mortality and morbidity, will minimise the impact of treatment and maximise outcomes and thus QoL. It does not seem ethical or professional, in light of the above, not to consider introducing some of the principles and guidelines of prehabilitation, as stipulated by the Prehabilitation for people with Cancer guidelines (Macmillan, 2019).
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