Evidence-based exercises intervention in adults diagnosed with Lymphoma.

L ymphoma patients can suffer from poor quality of life (QOL) and reduced functional capacity because of the disease or treatment-related complications. Lymphoma, defined as malignant neoplasms of lymphoid origin, can be broadly classified into 2 main categories: Hodgkin Lymphoma (HL; prevalence-10%) and non-Hodgkin Lymphoma (NHL; prevalence-90%). 1 Hodgkin Lymphoma is an uncommon B-cell Lymphoma, which accounted for 83,087 new registered cases and 23,376 deaths, whereas 544,352 new cases of NHL were registered with 259,793 deaths globally in the year 2018. 2 The prevalence of HL has been reported to be higher in the age group of 20-39 years, whereas NHL is more prevalent in patients ≥60 years of age. 3 , 4 Lymphoma is believed to be more common among males than in females. In addition, male patients display increased mortality rates and the risk is 3.1-fold and 1.7-fold higher among individuals with a family history of HL and NHL. 3 - 5

Depending on the type of Lymphoma, the treatment protocol can involve active surveillance of the condition, chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplants. Patients diagnosed with Lymphoma who undergo therapeutic interventions for the management of HL and NHL are often imperilled to several systemic and non-systemic complications. Cardiac or pulmonary complications, and risk of infections are some of the common complications observed in patients diagnosed with Lymphoma. 6 - 9 Lymphoma survivors usually suffer from diminished physical capacity, cardiopulmonary compromise, reduced muscle power, and limited physical function during and after treatment and the survivorship related complications can last for up to 10 years. 10 - 12

Physical therapy (PT) intervention has been advocated as a part of the multidisciplinary approach to help improve QOL and physical function. However, the PT intervention mostly depends on the treatment regime, associated complications, and its impact on patients’ function, thereby making it challenging for the rehabilitation specialists. A recent systematic review reported positive outcomes from aerobic endurance training, sensorimotor, and strength training on patients fatigue, psychological symptoms, and QOL. 13 Mind-body exercises, such as yoga and Chan-Chuang qigong, have also been reported as having favorable effects on fatigue, general QOL, and sleep pattern. 13 However, there are concerns regarding the study design and quality of trials; and hence the current systematic review aim is to evaluate the overall effectiveness of PT intervention on QOL, fatigue, sleep, and psychological and physical function in adults diagnosed and treated for Lymphoma.

Methods

The current systematic review was carried out in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. 14 A literature search was carried out to cover the period between April to June 2020. Additionally, the literature search was regularly updated during the review and writing process (July to December 2020).

A comprehensive, electronic literature search was carried out using the following databases: PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro), and Cochrane Library. The search strategy involved the use of several keywords and Medical Subject Headings (MeSH) terms. The Boolean operators “and” and “or” were used to combine the search terms. Moreover, thesaurus terms and relevant truncation or wildcard symbols were used to retrieve all possible suffix variations of a root word. Initially, the search was carried out using every single keyword. In the second step, the keywords were combined in pairs and trios, and finally, a conclusive search was carried out using a combination of all the keywords. All the electronic searches were limited to full-text, peer-reviewed publications in English involving human adults. The electronic search was carried out to identify articles published from March 2010 to March 2020. Duplicate studies from separate databases were eliminated. The detailed list of keywords and search strategies employed to perform the literature search of electronic databases are presented in Table 1 . In addition, the electronic search was supplemented by the manual inspection of the reference lists pertaining to papers included in the present review, to identify other eligible studies.

Articles were included if they were full, peer-reviewed articles, written in English involving human adults, were randomized controlled trials, discussing any PT interventions, including participants >18 years of age, with a confirmed diagnosis of any type or stage of Lymphoma; and there were no demographic or ther restrictions, studies published during the time period from March 2010 to December 2020 date, owing to significant changes in the medical management of Lymphoma that would affect the incidence of adverse effects.

The exclusion criteria employed by the present review were abstracts, conference reports, unpublished studies, articles published in non-peer-reviewed journals, case study, case series, single case reports, qualitative studies, trials published in languages other than English, and studies involving subjects/patients <18 years of age.

Five authors (AJ, GJ, SS, HX, and JX) independently screened the titles, abstracts, and full texts of the articles (as needed) identified through the literature search against the selection criteria. The authors then agreed on and excluded the studies that failed to meet the inclusion/exclusion criteria. Full-text articles were reviewed by 3 independent reviewers (AJ, GJ, and SS). Any disagreements with regard to the selection of studies were resolved through discussions and the involvement of a fourth reviewer (SM). The process of selection and reasons for exclusion are illustrated in a PRISMA flow diagram ( Figure 1 ).

Three reviewers (AJ, GJ, and SS) independently completed the data extraction and tabulation of information including: authors, title, publication date, aims, participants, age, diagnoses, treatment, inclusion/exclusion criteria, study design, and level of evidence using the Sackett’s levels of evidence (type and duration of intervention, duration of follow-up, outcomes and quality assessment).

The extracted data are presented in Table 2 . All the entered data were manually cross-checked for discrepancies through a zoom meeting and disagreements were referred to a fourth reviewer (SM).

Quality assessment/appraisal

The methodological quality of the trials included in the present review was evaluated using the PEDro scale, 15 which is a 10-item scale designed to assess the internal validity (8 items) of a trial, including randomization, concealed allocation, blinding, baseline similarity, intention to treat, and 2 items, namely, measures of key outcomes from more than 85.0% of subjects and relevant reporting of the trial’s statistical comparisons. The score for each article ranged from 0 (lowest quality) to 8 (highest quality). Scores of 4-10 denote fair to high quality and 0-3 denote poor to low quality. The methodological quality of each study was independently assessed by 3 reviewers (AJ, GJ, and SS). Disagreements among the reviewers were resolved through consensus-based discussions and the assistance of a fourth reviewer (SM) was enlisted in case of persistent disagreements. The results of the quality assessment of studies are presented in Table 3 .

Evidence assessment

The current review employed the system developed by the Oxford Centre for Evidence-based Medicine to grade the levels of evidence, in order to determine the degree of confidence concerning the evidence regarding an intervention. 16 The mentioned scale has 5 levels, ranging from 1a (well-designed meta-analysis or high-quality RCTs) to 5 (no well-designed studies). Each study was independently assessed by 3 reviewers (AJ, GJ, and SS), in accordance with Sackett’s levels of evidence.

Results

The systematic literature search yielded 577 results (PubMed: 344; CINAHL: 27; Cochrane Library: 67; and PEDro: 19). Subsequently, duplicate publications were excluded and 408 articles were retained for review, among which, 12 articles met the inclusion criteria. The PRISMA flowchart of the search and selection procedure is shown in Figure 1 .

The current review included 12 randomized controlled trials that involved 1010 participants, among which, 824 were diagnosed with Lymphoma. The sample size ranged from 36-122 and age of the participants ranged from 19-90 years.

Out of the 577 articles identified from the initial search, a total of 12 randomised control trials were shortlistd for this systematic review. From the 12 articles, 9 studies included participants with Lymphoma who were at various stages of chemotherapy or had completed treatment and 3 studies included participants with various haematological malignancies and had stem cell transplantation. 17 - 28

Quality of the studies

Physiotherapy Evidence Database scale was used for assessing the quality of the studies and the mean PEDro score for the 12 RCTs was 6.3±0.89. Detailed information regarding the PEDro scores pertaining to the studies is presented in Table 3 .

The data presented in Table 3 shows that all the studies exhibited a baseline similarity, reported statistical comparisons, were randomly assigned, and provided both point measures and measures of variability. However, none of the trials complied with the items of blinding and was considered to have a high risk of bias with reference to blinding the subjects, therapists, and assessors, except for the study by Persoon et al, 28 which involved a low risk of bias associated with blinding the assessors alone. In addition, all the studies stated that the allocation was concealed, except 3 studies. 18 , 20 , 24 Additionally, 4 trials included in the present review did not comply with the item of intention to treat. 17 , 19 , 20 , 27

Furthermore, details regarding the grading of levels of evidence using the system developed by the Oxford Centre for Evidence-based Medicine 16 are presented in Table 3 . Most of the studies (10/12) were assigned with the grade of 1b (high-quality RCTs), whereas 2 studies were assigned with the grade of 2b (limited non-randomized trials). Overall, the studies displayed reliable methodological quality, indicating a low risk of bias.

Interventions

The primary PT intervention was exercise and included aerobic exercises, resistance exercises, balance exercises, education, and mind-body exercises. 17 - 24 , 26 , 28 Two studies used telephone consultations as the primary intervention. 25 , 27 The mean duration of the exercise interventions varied from 3-36 weeks, and majority of the studies used moderate-to high-intensity aerobic exercises with 50-85% of peak oxygen consumption or heart rate max. 18 , 20 , 21 , 23 , 24 , 26 , 28 The range of resistive exercise intensity was 50±80% of the indirectly determined one-repetition maximum. The mean frequency of exercise interventions varied from once to daily per week for 15-60 minutes.

Multiple outcomes measures

The studies included in the current review, evaluated subjective and patient-reported outcomes concerning several variables, including the QOL, fatigue, psychological wellbeing, monitored side-effects, sleep pattern, and lifestyle (physical activity and nutritional status). 17 - 19 , 23 - 28 Five trials assessed CV fitness whereas 3 other stuides assessed the muscle strength of the upper and lower limbs. 24 , 26 , 28 Streckmann et al 18 evaluated the balance and peripheral deep sensitivity.

Discussion

This systematic review, showed that PT treatment programs and individualized exercises for different Lymphoma stages significantly improved physical function and endurance. Studies showed various exercise programs and PT interventions have been tested for those patients to assess the improvement of patients’ outcomes.

The current review aimed to assess the available evidence regarding the effectiveness of PT or exercise intervention in adults diagnosed with Lymphoma with reference to the improvements in QOL, fatigue, sleep, and psychological and physical function. The literature review yielded 12 randomized controlled trials (RCTs) of varying methodological quality and sample sizes, which displayed considerable variation with regard to the inclusion criteria concerning diagnosis. Vallerand et al 25 included leukemia and Lymphoma patients, 5 studies 18 , 24 , 26 - 28 included Lymphoma and multiple myeloma patients and 6 studies included Lymphoma patients alone. Moreover, the baseline characteristics of the patients diagnosed with Lymphoma ranged from newly diagnosed cases to long-term survivors, which increased the likelihood of heterogeneity and made the interpretation and comparison of results difficult.

Furthermore, the studies displayed considerable variation with reference to the PT interventions, including aerobic training, strength training, sensorimotor training, strength training, home-based exercise, telephone counseling sessions, and other intervention with mind-body exercise. In addition, the current review observed variations in the frequency, intensity, and duration of interventions across the studies. Consequently, the determination of a standardized intervention protocol for clinical practice was challenging. An additional, significant constituent of the current objectives and practice of PT is the assessment of the carryover effect. The present review included only one longitudinal study that reported the results of a one-year follow-up. 26 Consequently, the long-term effects and the ability of Lymphoma patients to maintain the beneficial effects of the interventions remain ambiguous.

A majority of the studies did not comply with the criteria of blinding the patients, therapists, or assessors. In the current review, only Persoon et al 28 described the blinding methods employed. Although blinding the patients, therapists, or assessors is an effective method that can be employed to control the confounding variables in RCTs, the implementation may not always be possible. Although blinding may be initially possible in many studies, the maintenance of the same throughout a trial might become challenging.

A major cause of missing data in clinical trials is the dropout/withdrawal of subjects, which creates uncertainty in relation to the interpretation of results. Dropout of subjects is also an important outcome, as it may reflect the lack of tolerance to interventions, adverse effects, or lack of compliance. Among the 12 studies, 10 discussed the dropout/withdrawal status of their respective subjects. 17 , 19 , 20 , 22 - 28 Moreover, it is important to take note of the occurrence of any adverse events during the intervention. In the current review, 8 studies addressed the incidence of adverse events. 17 - 19 , 22 - 25 , 28

Several standardized tools have been used to evaluate the outcomes of PT interventions in persons diagnosed with Lymphoma. Eight studies used QOL to assess the outcomes of interventions. 17 , 18 , 22 , 24 - 28 Furthermore, 4 trials assessed CV fitness. 18 , 21 , 24 , 26 Two reported significant improvements in physical performance 18 , 24 and 3 trials assessed the muscle strength in the upper and lower limbs. 24 , 26 , 28

The current review used stringent inclusion criteria and a narrow population to reduce some of the inconsistencies that bulge the current body of literature. It provides high-quality evidence-based practice to determine whether the PT intervention is an effective and safe intervention for adult patients with Lymphoma.

Study limitations

First, the review may not offer a comprehensive picture of the available evidence, because of the fact that the review was limited to English articles. Consequently, there is a possibility that good-quality studies written in other languages, which might have supported the present recommendations, were excluded. The statistical heterogeneity among the studies included in the review was another limitation. Potential sources of heterogeneity include variations in the type, duration, and intensity of interventions. Moreover, the initiation of PT interventions varied across the studies. Hence, the results of the current review must be interpreted with caution, owing to the baseline differences and heterogeneity of the study population.

Future research warrants RCTs with larger samples and long-term follow-ups, in order to improve the understanding of the effects of PT interventions and exercise on Lymphoma patients.

In conclusion, there is moderate evidence strength suggesting that exercises therapy for persons diagnosed with Lymphoma can include aerobic or CV exercise, strength training, and mind-body exercise has beneficial effects on fatigue, physical performance, and QOL in persons diagnosed with Lymphoma patients. Future research should focus on more robust and well-defined exercises therapy intervention protocols, in order to establish the long-term benefit of exercises therapy intervention.

Acknowledgment

The authors gratefully acknowledge Dr. Deborah Doherty for her support in all process during the study period and the writing of this manuscript. The authors also would like to thank Wiley Editing Services for English language editing.

Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.

References

1. Swerdlow SH , Campo E , Harris NL , Jaffe ES , Pileri SA , Stein H , et al. WHO classification of tumours of haematopoietic and lymphoid tissues . [Updated 2017]. Available from: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017

2. Sung H , Ferlay J , Siegel RL , Laversanne M , Soerjomataram I , Jemal A , et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin 2021 ; 71 : 209 – 249 . 33538338 10.3322/caac.21660

3. Fitzmaurice C , Abate D , Abbasi N , Abbastabar H , Abd-Allah F , Abdel-Rahman O , et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the Global Burden of Disease Study . JAMA Oncol 2019 ; 5 : 1749 – 1768 . 31560378 10.1001/jamaoncol.2019.2996 PMC6777271

4. Zhang S , Gong TT , Liu FH , Jiang YT , Sun H , Ma XX , et al. Global, regional, and national burden of endometrial cancer, 1990-2017: results from the Global Burden of Disease Study, 2017 . Front Oncol 2019 ; 9 : 1440 . 31921687 10.3389/fonc.2019.01440 PMC6930915

5. Cerhan JR , Slager SL. Familial predisposition and genetic risk factors for Lymphoma . Blood 2015 ; 126 : 2265 – 2273 . 26405224 10.1182/blood-2015-04-537498 PMC4643002

6. Guner SI , Yanmaz MT , Selvi A , Usul C. Chemotherapy and radiation induced pulmonary dysfunction in Hodgkin Lymphoma patients . Indian J Hematol Blood Transfus 2016 ; 32 : 431 – 436 . 27812252 10.1007/s12288-015-0619-x PMC5074957

7. Keefer K , Bender R , Liao J , Sivik J , Van de Louw A. Characteristics of pulmonary complications in non-Hodgkin’s Lymphoma patients treated with rituximab-containing chemotherapy and impact on survival . Ann Hematol 2018 ; 97 : 2373 – 2380 . 30030570 10.1007/s00277-018-3448-9 PMC7102168

8. Meza-Meneses P , Cornejo-Juárez P , Vilar-Compte D , Volkow-Fernández P. Infectious complications as a predictor of mortality in patients with non-Hodgkin Lymphoma receiving rituximab-containing chemotherapy . Rev Invest Clin 2019 ; 71 : 275 – 282 . 31448779 10.24875/RIC.19002982

9. Rotz SJ , Ryan TD , Hlavaty J , George SA , El-Bietar J , Dandoy CE. Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant . Pediatr Blood Cancer 2017 ; 64 . 28453909 10.1002/pbc.26600

10. Husson O , Oerlemans S , Mols F , Schep G , Van De Poll-Franse LV. High levels of physical activity are associated with lower levels of fatigue among Lymphoma patients: results from the longitudinal PROFILES registry . Acta Oncol 2015 ; 54 : 678 – 684 . 25752967 10.3109/0284186X.2014.996664

11. Schoormans D , Jansen M , Mols F , Oerlemans S. Negative illness perceptions are related to more fatigue among haematological cancer survivors: a PROFILES study . Acta Oncol 2020 ; 59 : 959 – 966 . 32412348 10.1080/0284186X.2020.1759823

12. Vermaete N , Wolter P , Verhoef G , Gosselink R. Physical activity and physical fitness in Lymphoma patients before, during, and after chemotherapy: a prospective longitudinal study . Ann Hematol 2014 ; 93 : 411 – 424 . 23963412 10.1007/s00277-013-1881-3

13. Amatya B , Khan F , Lew TE , Dickinson M. Rehabilitation in patients with Lymphoma: an overview of systematic reviews . J Rehabil Med 2021 ; 53 : jrm00163 . 33710351 10.2340/16501977-2810 PMC8814843

14. Moher D , Shamseer L , Clarke M , Ghersi D , Liberati A , Petticrew M , et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement . Syst Rev 2015 ; 4 : 1 . 25554246 10.1186/2046-4053-4-1 PMC4320440

15. Moseley AM , Herbert RD , Sherrington C , Maher CG. Evidence for physiotherapy practice: a survey of the Physiotherapy Evidence Database (PEDro) . Aust J Physiother 2002 ; 48 : 43 – 49 . 11869164 10.1016/s0004-9514(14)60281-6

16. Sackett CA , Kielpinski D , King BE , Langer C , Meyer V V , Myatt CJ , et al. Experimental entanglement of 4 particles . Nature 2000 ; 404 : 256 – 259 . 10749201 10.1038/35005011

17. Chuang TY , Yeh ML , Chung YC. A nurse facilitated mind-body interactive exercise (Chan-Chuang qigong) improves the health status of non-Hodgkin Lymphoma patients receiving chemotherapy: Randomised controlled trial . Int J Nurs Stud 2017 ; 69 : 25 – 33 . 28122280 10.1016/j.ijnurstu.2017.01.004

18. Streckmann F , Kneis S , Leifert JA , Baumann FT , Kleber M , Ihorst G , et al. Exercise program improves therapy-related side-effects and quality of life in Lymphoma patients undergoing therapy . Ann Oncol 2014 ; 25 : 493 – 499 . 24478323 10.1093/annonc/mdt568

19. Yeh ML , Chung YC. A randomized controlled trial of qigong on fatigue and sleep quality for non-Hodgkin’s Lymphoma patients undergoing chemotherapy . Eur J Oncol Nurs 2016 ; 23 : 81 – 86 . 27456379 10.1016/j.ejon.2016.05.003

20. Zimmer P , Baumann FT , Bloch W , Schenk A , Koliamitra C , Jensen P , et al. Impact of exercise on pro inflammatory cytokine levels and epigenetic modulations of tumor-competitive lymphocytes in non-Hodgkin-Lymphoma patients-randomized controlled trial . Eur J Haematol 2014 ; 93 : 527 – 532 . 24913351 10.1111/ejh.12395

21. Courneya KS , Friedenreich CM , Franco-Villalobos C , Crawford JJ , Chua N , Basi S , et al. Effects of supervised exercise on progression-free survival in Lymphoma patients: an exploratory follow-up of the HELP trial . Cancer Causes Control 2015 ; 26 : 269 – 276 . 25491935 10.1007/s10552-014-0508-x

22. Courneya KS , Sellar CM , Trinh L , Forbes CC , Stevinson C , McNeely ML , et al. A randomized trial of aerobic exercise and sleep quality in Lymphoma patients receiving chemotherapy or no treatments . Cancer Epidemiol Biomarkers Prev 2012 ; 21 : 887 – 894 . 22523181 10.1158/1055-9965.EPI-12-0075

23. Courneya KS , Stevinson C , McNeely ML , Sellar CM , Friedenreich CM , Peddle-McIntyre CJ , et al. Predictors of follow-up exercise behavior 6 months after a randomized trial of supervised exercise training in Lymphoma patients . Psychooncology 2012 ; 21 : 1124 – 1131 . 21766483 10.1002/pon.2010

24. Furzer BJ , Ackland TR , Wallman KE , Petterson AS , Gordon SM , Wright KE , et al. A randomised controlled trial comparing the effects of a 12-week supervised exercise versus usual care on outcomes in haematological cancer patients . Support Care Cancer 2016 ; 24 : 1697 – 1707 . 26423617 10.1007/s00520-015-2955-7

25. Vallerand JR , Rhodes RE , Walker GJ , Courneya KS. Feasibility and preliminary efficacy of an exercise telephone counseling intervention for hematologic cancer survivors: a phase II randomized controlled trial . J Cancer Surviv 2018 ; 12 : 357 – 370 . 29411314 10.1007/s11764-018-0675-y

26. Van Dongen JM , Persoon S , Jongeneel G , Bosmans JE , Kersten MJ , Brug J , et al. Long-term effectiveness and cost-effectiveness of an 18-week supervised exercise program in patients treated with autologous stem cell transplantation: results from the EXIST study . J Cancer Surviv 2019 ; 13 : 558 – 569 . 31286387 10.1007/s11764-019-00775-9 PMC6677707

27. Hung YC , Bauer JD , Horsely P , Coll J , Bashford J , Isenring EA. Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot, randomised controlled trial . Bone Marrow Transplant 2014 ; 49 : 786 – 792 . 24710562 10.1038/bmt.2014.52

28. Persoon S , ChinAPaw MJM , Buffart LM , Liu RDK , Wijermans P , Koene HR , et al. Randomized controlled trial on the effects of a supervised high intensity exercise program in patients with a hematologic malignancy treated with autologous stem cell transplantation: results from the EXIST study . PLoS One 2017 ; 12 : e0181313 . 28727771 10.1371/journal.pone.0181313 PMC5519072