Literature Review:

How could adherence to exercise and lifestyle reprogramming be improved for all breast cancer survivors including women from disadvantaged backgrounds?

Cancer is developed when changes in the DNA occur and cause malfunction to normal cell replication and the process of healthy cell death (apoptosis) causing the development of tumour angiogenesis which creates its own blood and nutrient supply and spreads (metastasis) (Weinberg,1996) known as the Warburg effect (Vander et al.,2009).

2020 figures state that 2.3 million women have been diagnosed with breast cancer making it the most common type of cancer, attributing to 685,000 deaths worldwide (Lei et al,.2021). Current research suggests that not one factor is a determinate of cancer, but rather multiple factors over time (Ashley,1969). Factors contributing to cancer include 14 lifestyle and environmental risks including: smoking, alcohol, metabolic syndrome, and type 2 diabetes. Smoking was the leading risk factor, with 60,000 cases reported in 2010 (Parkin et al.2011). More recently type 2 diabetes, and obesity are leading causes, attributing to 40% of all cancers (Keum et al.,2015). Obesity promotes proinflammatory cytokines, which drives cancer growth by promoting tumour angiogenesis (Picon‐Ruiz et al.,2017). Less common factors include exposure to environmental radiation (Anand et al.,2008), or inherited abnormal genes effecting long-term stability of DNA (Tomasetti, & Vogelstein 2017). It is widely accepted that consuming a western diet, rich in red and processed meats using nitrates and nitrites for preserving, as opposed to a Mediterranean diet rich in fish, and vegetables, is a contributing factor to cancer growth (Key et al., 2004).

Treatment for breast cancer is decided based on the stage and development of the cancer (Charles et al.,1998). Treatment options include tumour removal, radiation therapy, chemotherapy, hormone therapy or adjuvant (combination) (Abner et al.,1993). Although survival rate has increased significantly, the quality of life for many breast cancer survivors cis often low and the side effects of the treatments can last for years, often permanently, reducing patients’ ability to lead fulfilling lives (Vacek et al.,2003; Reich et al.,2008: Patsou et al.,2017). Cancer survivors are known to experience varying degrees of fatigue, depression, and anxiety during and post treatment (Jacobsen et al.,1999: Berger & Higginbotham,2000), which is thought to be a combination of side effects and emotional turmoil (Lebel et al.,2009), symptoms include pain, tingling and restriction of the shoulder and arm, nausea, depression, and lethargy (Freitas-Silva, et al.,2010: Brackstone, 2016).

Prior to 1990, exercise was condemned, the advice was to rest during and post treatment (Jones, & Alfano 2013). In the late 1980’s a trial measured the impact of a 10-week interval aerobic and resistance program on the side effects, body composition and functional capacity of 45 patients during treatment. The study found significant improvements in all clinical markers as well as proving very safe (MacVicar et al.,1989). This paved the way for many trials confirming the now widely accepted evidence that exercise is a significant factor in easing side effects and decreases the risk of noncommunicable disease (Thompson et al.,2003: Ostman et al.,2017: Ploeger et al.,2009: de Jesus Leite et al.,2021), but there still exists gaps in evidence and applied clinical practice. Oncology teams interviewed have reported they do not feel best placed to advocate exercise and do not know the referral pathway (Schmitz et al.,2010).

The exercise referral Scheme (ERS) was initiated in the 1990’s in the UK to support non exercisers (Pavey et al.,2012). The recommended 150 moderate or 75 minutes vigorous weekly exercise is evidenced to prevent disease (Ding et al.,2016: Picon‐Ruiz et al.,2017). The standard 12-week ERS has some good outcomes for groups of women who have a good exercise history, a positive support network and few barriers to exercise (Campbell et al.,2005), but how can exercise adherence be improved for all breast cancer survivors including those from disadvantaged backgrounds?

What works and where are the gaps in Breast Cancer Exercise and lifestyle reprograming?

ERS has evolved over the years. Programmes are now including lifestyle reprogramming (LSR) nutrition, and a variety of adaptations to enhance outcomes (Kirkham et al.,2018). Kirkham et al.,(2018) did a randomized trial, to assess the effectiveness of ERS on health-related quality of life (HRQOL), they used questionnaires to assess retention, uptake and referral from oncologists, enjoyment, self-efficacy, and perceived barriers. They hypothesized the intensive 15-month program could increase long-term adherence to exercise and healthier eating (post one year follow up). As shown in a similar review (Eynon et al.,2019). The study was split into 3 phases to work with 62 cancer patients receiving adjuvant therapy. The programme was longer than the usual schemes offered with an unusually high staff ratio, which may be a factor of adherence due to needed social support (Husebo et al.,2015). Like other studies, longer ERS produced superior outcomes (Eynon et al.,2019). It was positioned next to the cancer treatment center, making it a familiar place to access, (nine still failed to adhere due to distance issues) which is a common barrier (Mina et al.,2017).  The staff were health specialists at degree level, possibly giving more trust and reassurance to participants (Mina et al.,2018), the centre was within the university and therefore access to high quality exercise testing and physiology monitoring equipment would be available and likely help overcome reported fears of causing further injury or illness through exertion (Schmitz et al.,2010). The trial incorporated a two-hour nutrition guidance and education session, it is well evidenced that exercise alone does not reduce bodyweight significantly (Swift et a;.2014) and that obesity and diet type is a contributing risk of cancer (Kanoski & Davidson,2011), furthermore adherence to wellness programs is reportedly low when no physical results are seen (Dalle et al.,2015), combining calorie reduction and exercise is more likely to give desired results (Caudwell et al.,2009), finally there is strong evidence which demonstrates implementing lifestyle changes without addressing the behaviour , through psychological intervention (Jeffery et al.,2000, Sarlio-Lahteenkorva, 1998); leads to short-term results and relapse patterns which cause further damage to the individuals self-esteem (Werrij et al.,2009). Although benefits have been recorded on a 12-week ERS without nutrition or behaviour science (Mutrie et al.,2007), good nutrition alongside exercise is advised to promote recovery, long-term good health and to reduce the risk of cancer reoccurrence (Friedenreich et al.,2017). Lifestyles which have led to comorbidity and cancer tend to be progressive, including addictive and habitual behaviours; recent research has highlighted the benefit of including behaviour change science (Jack, et al.,2010). The randomized trial prescribed 150 mins per week of moderate aerobic and resistance whole body exercise. Participants engaged in nutrition education, and possible psychological support, but no mention of behaviour change intervention, evidenced to be effective in other trials (Markland & Tobin, 2010; Edmunds et al., 2007). The participants reported feeling highly satisfied with the programme. Younger women were referred, indicating possible referral bias, which may account for the lack of increase in enjoyment, self-efficacy and HRQOL outcomes from baseline, likely due to the group already intrinsically enjoying exercise prior to the study (Brunet etal.,2013). Results showed activity levels increased and were sustained one year later, resistance exercise increased and then dropped off, possibly due to a lack of home equipment, or that adherence to homebased prescribed exercise is notoriously poor (Campbell et al.,2001), self-efficacy, fears and increased pain are some of the barriers highlighted (Kabak et al.,2020). Jack et al.,(2010) concluded in a systematic review that people who were at higher risk of non-adherence had low levels of social support and therefore more perceived barriers. Studies have found that benefits of aerobic exercise were superior in a group setting as opposed to home via written or pre-instructed exercise although high levels of self-efficacy may be a more important predictor for exercise adherence (Pinto et al.,2009).  For some women, who display high levels of self-efficacy, and are at the right stage of The Transtheoretical model (TTM), home exercise may be adequate (Pekmezi et al.,2011). Ritvo et al.,(2017) initiated a pilot randomized trial using a new phone app (IMOVE) to promote long-term adherence, the participants were given the app on completion of a 12-week, intensive ERS including behaviour change and nutrition education, they were given a pedometer linking 10 health coaching sessions. This trial is still running, it will be interesting to see who it was successful for and whether the outcome will be in line with the angel project study, set up for 18 weeks during Italy’s lockdown (Di Blasio et al.,2002), a very detrimental time for breast cancer survivors (Füzéki etal.,2020), the trial supplied live online exercise classes, sleep and nutrition support, mindfulness and 24 hr monitoring of sedentary behaviour. The intervention was successful in stopping the damaging spiral of inactivity and depressive states (Schwarzer, & Hamilton,2020), but did not find significant improvements in activity. However, if the study re-ran in a non-lockdown period, eliminating variables such as stress, fear and home constraint for COVID-19, the trail data may show a positive promotion of activity considering the likelihood of time allowed outside doing daily living chores and accessing social support (Kruk,2009: Sahu, 2020).

The Kirkham et al., (2018) 15-month study costed $1,273 per person which appeared excellent value for the staff ratio and facilities, however this level of staffing and equipment access would cost substantially more in the community, whilst intervention to reduce risk of reoccurrence of cancer is thought to be cost effective (Schmitz et al.,2019) Campbell et al.,(2015) indicated that ERS needs to reduce costs by 60%. A comparison of the cost of cancer medical intervention and lifestyle reprogramming is difficult to compare due to the heterogeneity of participants, medical intervention and ERS type (Pavey 2001). The study was long with a high staff ratio but no mention of behaviour change intervention to identify and address personal fears and barriers (Blaney et al.,2013), it may be beneficial to add more than two hours of nutrition intervention as implemented in this trial (Pinto et al.,2009), targeting women with low previous exercise history with identified needs to address dietary habits (Kushi et al.,2010: Ravasco, 2019),who are experiencing a lack of support, and women recorded as scoring high for neuroticism and therefore less likely to adhere (Courneya et al.,2002). Separating studies for women who need less support who are likely to adhere to homebased exercise prescription, could be assessed using the self-efficacy scale and stage of readiness (TTM) to predict adherence. This group of women could be supported utilizing one of the many emerging apps (Roberts et al.,2019) or via weekly telephone calls to save money (Pintoet al.,2009)

Exercise has been evidenced to reduce the symptoms experienced, however exercising with severe fatigue and low mood may feel counterproductive (Hayes et al.,2009).  Fatigue is one of the top dropout causes to ERS in cancer patients possibly due to delivery of chemotherapy infusion cycles (Schwartz et al.,2001). There are emerging trials testing periodisation exercise with cancer patients to run alongside the chemotherapy cycles (Fairman et al.,2017). Kirkham et al.,(2020) ran a 2-arm randomized controlled trial, Periodizing a breast cancer exercise programme with the goal of varying training specificity, volume, and frequency to avoid large gaps, due to post chemo infusion symptoms. They hypothesised that periodizing exercise could improve exercise adherence and outcomes, as seen in similar studies (Hoover et al.,2016: Issurin, 2016). The study included four groups, the usual care group, a delayed 6–8-week post operation group, a periodized group who exercised prior to chemo, and a linear group who started 2 weeks post treatment. Baseline markers were recorded prior to treatment and at week 3, avoiding week four’s anticipated worst week for symptoms (Sun et al,.2005). The fatigue mean measurements were taken from the piper fatigue scale (Piper et al.,1998). Statistics showed a blunted effect in VO2.  They progressively increased from (marginal mean ± standard error: 3.2 ± 0.4) (5.1 ± 0.4, P = 0.001), before reducing to lower levels (not baseline due to chemotherapy cumulative effect) before treatment four (4.3 ± 0.5, P = 0.021). Another small trial observed a 15% decrease in VO2 peak, showing exercise did not improve VO2 peak but did lessen (blunted effect) the overall decrease observed over four months (Howden et al.,2019). No significant changes in other baseline measurements were seen, like other findings in a 17-week study showing a blunted effect in the exercise group (Courneya et al.,2007). The study concluded that periodization made a significant difference to adherence and showed positive outcomes for participants to tolerate exercise by reducing the dose for the first 5 days post infusion but did not make a difference to short-term physiological markers as found in other limited studies (Howden et al,.2019: Courneya et al.,2007). The groups were small samples, with no indication of previous exercise history or behaviour towards exercise, types of support or lifestyles of the participants. The study appeared to cover three of the four principles outline for oncology exercise prescription (individualization, specificity, progressive overload, and rest/recovery), it did not make the programme individualised to the participants specific needs or address progressive overload as outlined in (Fairman et al.,2017). The two-arm study has highlighted the barriers, but due to the complexity of the comparable groups, further studies need to narrow down the barriers and exercise dose, amongst similar participants with specific support needs for clearer results and outlined benefits to periodize cancer exercise prescription. In a longitudinal study Courneya et al.,2005 found the top three barriers (accounting for 45% out of 37 reported, were not enough time (65 times), side effects (51 times) and fatigue (44 times) reported out of 353 reported barriers. Those who were unable to adhere 2-4 weeks reported one barrier and those who did not adhere for 12-16 weeks reported more than 4 barriers) and scored higher on neuroticism, also seen in these studies (Courneya, & Hellsten,1998: Kruisdijk et al.,2020).). and had lower levels of support at home, highlighting the need for further study into these barriers (Rogers, 2008). Due to the mixed readiness on the TTM chart, future studies choosing participants who were all in the preparation stage may give a clearer indication of the top barriers as well as selecting participants from disadvantaged backgrounds to access the intervention needed for this group would be advantageous.

Conclusion

Exercise for cancer patients has been suggested to reduce the risk of reoccurrence by 50% (Holmes et al.,2005). Breast cancer patients have a variety of treatments, stages of cancer, side effects and symptoms. ERS /LSR can therefore not be a generic prescription (Kirkham et al,.2018).  The Keogh, & MacLeod, (2012) review found prostate cancer patients who exercised for the recommended 3 hours per week including aerobic and resistance showed significantly improved physiological markers, function, and side effects in 12 studies, it was found that group exercise was superior to homebased and that counselling to overcome barriers was an important factor to adherence. Whilst there appears to be sufficient evidence that cancer ERSLSR improves perceived physical function, side effects of treatment and QOL (Campbell et al.,2019). Over or underdosing, not addressing barriers to exercise and nutrition may waste money in preventing cancer reoccurrence and future comorbidities, (Grimmett et al.,2019: Dean& Söderlund 2015).

Pavey et al.,(2011) highlighted the shortcomings of the ERS, could be due to a lack of specialist employees, a confusing referral process and may require longer studies to assess the long-term outcomes and adherence. The heterogeneity of the ERS programme dose, exercise and intervention type, length, contact hours, participant barriers and the outcomes measured does not allow evidence-based conclusions to be made. There are gaps in research needing further exploration into adherence and positive long-term clinical outcomes in order to create standardisation of  pathways, specialist lifestyle reprogramming, evidenced based number of optimum programme weeks using individualised exercise correct doses, periodized programs alongside chemotherapy cycles, behaviour change science, nutrition and studies on group live zoom classes to form part of the programme as a solution to physical and some social barriers, which may also address financial considerations (Wanga et al., 2020:Roberts et al.,2019).

Further gaps exist in specific research on groups who are hardest to reach with little social support and therefore more at risk of cancer / comorbidity diseases (Oliver et al.,2021). whilst 12-week basic ERS exercise is often adequate for groups who have previous exercise experience, social support, and less barriers to exercise (Courneya et al.,2002). Women from disadvantaged backgrounds may need more intensive and longer programme support, in the form of behaviour change intervention, nutrition and education (Stull etal.,2007), as well as considering group live zoom classes to form part of the programme for further support between sessions, for exercise, nutrition and counselling support (Byaruhanga et al.,2020). There is a gap in research for disadvantaged women, with support needs and a need to find solutions to engage, encourage adherence and make long-term lifestyle changes.

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