From the 1Department of Rehabilitation Medicine, Royal Melbourne Hospital, 2Department of Medicine (Royal Melbourne Hospital), University of Melbourne, 3Australian Rehabilitation Research Centre, Royal Melbourne Hospital and 4Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
Objective: To evaluate existing evidence from published systematic reviews for the effectiveness of rehabilitation interventions in patients with lymphoma.
Data sources: A comprehensive literature search was conducted using medical/health science databases up to 1 October 2020. Bibliographies of pertinent articles, journals and grey literature were searched.
Data extraction and synthesis: Two reviewers independently selected and reviewed potential reviews for methodological quality and graded the quality of evidence for outcomes using validated tools. Any discrepancies were resolved by final group consensus.
Results: Twelve systematic reviews (n = 101 studies, 87,132 patients with lymphoma) evaluated 3 broad categories of rehabilitation interventions (physical modalities, nutrition and complementary medicine). Most reviews were of moderate-to-low methodological quality. The findings suggest: moderate- quality evidence for exercise programmes for improved fatigue and sleep disturbance; low-quality evidence for exercise therapy alone and qigong/tai chi for improved symptoms and overall quality of life, and an inverse association between sunlight/ultraviolet radiation exposure and incidence of non-Hodgkin’s lymphoma; and very low-quality evidence for beneficial effects of yoga for sleep disturbances. Association between physical activity and lymphoma risk is indistinct.
Conclusion: Despite a range of rehabilitation modalities used for patients with lymphoma, high-quality evidence for many is sparse. Beneficial effects of exercise programmes were noted for fatigue, psychological symptoms and quality of life. More research with robust study design is required to determine the effective rehabilitation approaches.
Key words: lymphoma; rehabilitation; systematic review; critical appraisal.
Accepted Feb 16, 2021; Epub ahead of print Mar 12, 2021
J Rehabil Med 2021; 53: jrm00163
Correspondence address: Bhasker Amatya, Department of Rehabilitation Medicine, Royal Melbourne Hospital, Royal Park Campus, 34-54 Poplar Road, Parkville, Victoria 3050, Australia. E-mail: Bhasker.firstname.lastname@example.org
Lymphoma and its treatment cause significant disability and morbidity, often requiring comprehensive rehabilitation. Currently, a range of rehabilitation interventions are applied in patients with lymphoma. This review systematically evaluated evidence from published systematic reviews of clinical trials to determine the effectiveness of rehabilitation interventions in patients with lymphoma. The findings suggest that there is moderate-quality evidence for exercise programmes in improving fatigue and sleep disturbance. There was low-quality evidence for exercise therapy alone and qigong/tai chi for improved symptoms and overall quality of life, and very low-quality evidence for beneficial effects of yoga for sleep disturbances. The evidence for association of vitamin D or physical activity and lymphoma risk is limited.
Lymphomas are a heterogeneous group of malignant neoplasms of the haematopoietic system, characterized by the aberrant proliferation of mature lymphoid cells or their precursors (1). Traditionally lymphoma is classified broadly into 2 major groups: non-Hodgkin’s lymphoma (NHL, 90%) and Hodgkin’s lymphoma (HL) (1); however, lymphomas can also be stratified by cell of origin, as in the World Health Organization (WHO) classification (B-cell, T-cell/natural killer-cell (T/NK) and HL), or clinical behaviour (aggressive or indolent) (2, 3). An estimated 590,000 new cases of lymphoma (3.2% of all cancers) were diagnosed worldwide in 2018, the majority being NHLs (509,590 cases, 2.8% of all cancers) (4). NHL is a leading cause of death amongst the haematological malignancies globally, estimated to cause over 248,000 deaths (2.6% of all cancers) in 2018 (4). The incidence of lymphoma is increasing, with total worldwide incidence projected to reach approximately 919,000 by 2040 (5).
The total global economic burden of lymphoma is unknown; however, treatments and supportive care requirements are resource-intensive and associated with significant financial costs for patients/families and healthcare systems. Productivity losses arise from disease and treatment-associated morbidity and premature mortality (6). In 2018, the mean monthly healthcare and utilization costs per patient for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the USA were approximately US$11,890 and $10,460, respectively (6). In Spain, in 2017 lymphoma represented 45.4% of productivity losses due to haematological malignancies, resulting in €121 million in losses due to premature mortality (7).
Current therapeutic advances and cancer detection/diagnosis have improved survival rates for patients with lymphoma (PwL). The age-standardized 5-year net survival of lymphoid malignancies in adults ranges from 40% to 70% globally in 2010–14, with a 5–10% increase in trend for the period 2000–04 (8). The 5-year survival rate in the US in 2010–16 was estimated to be 72.7% for NHL and 87.4% for HL (9). As the incidence of NHL is strongly associated with increasing age, improved supportive care and availability of reduced intensity chemotherapy regimens (such as prednisone, etoposide, procarbazine, and cyclophosphamide – ‘PEP-C’; rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone – ‘R-miniCHOP’, rituximab, cyclophosphamide, vincristine, prednisolone – ‘R-CVP’) are critical to facilitate deliverable therapy to older patients. Despite these factors, certain lymphomas and their treatment are associated with short- and medium-term residual neurological deficits, leading to physical, cognitive, psychosocial and behavioural impairments, limiting activities of daily living (ADL) and participation (10–13). Treatment procedures can be extensive (e.g., radiotherapy, chemotherapy and/or surgery), and associated with a range of side-effects/complications, such as neuropathy, cardiotoxicity, cachexia, fatigue, deconditioning, myopathy, etc. (14–16). Furthermore, in the transitional period, various adjustment issues are reported, such as increased care needs, inability to drive and return to work, financial constraints, relationship stress, and limitation in societal participation (11, 14, 17, 18). Distressing symptoms, such as fatigue, is a major complaint, reported in 60–100% of patients during or after cancer treatment, which persists for several years after treatment (19–21). Therefore, patients require routine surveillance to monitor complications and relapse and integrated longer-term management, including rehabilitation (22–24).
Rehabilitation is an integral part of any cancer management, and there is evidence suggesting the beneficial effect of comprehensive rehabilitation (25–31). Furthermore, a major limitation of delivery of chemotherapy and predictor of inferior outcome is poor performance status (32). As the incidence of older patients treated for lymphoma requiring rehabilitation before or after anti-lymphoma therapy increases, effective evidence-based rehabilitation strategies are expected to play critical and expanding roles in best practice. Currently, a range of rehabilitation interventions are trialled in the management of lymphoma pre-treatment, during adjuvant therapies, and late phases of care, and, for the longer-term, care continuum in the community. The aim is to maximize patient function, promote independence and participation, and improve psychological well-being and quality of life (QoL) (28, 29). Reports suggest that patients with haematological malignancies, including lymphomas, can make functional gains in inpatient rehabilitation settings (31). Maximal exercise capacity seems to decrease before treatment in PwL, especially in patients with advanced disease, and tends to return to close to normal during and/or after treatment (33). Furthermore, comprehensive exercise programmes were found to be effective in reducing disability and symptoms (depression, anxiety, fatigue, pain, etc.), improving functional capacity, muscular strength and QoL (19, 31, 34, 35). One systematic review reported that NHL survivors who met public health exercise guidelines defined by the American College of Sports Medicine (i.e. engaging in >30 min/day of at least moderate physical activity (PA) on ≥ 5 days/week, or > 150 min a week) reported a clinically important better health-related quality of life (HRQoL) than their counterparts who did not meet exercise guidelines (11). Aerobic exercise training interventions were associated with positive effects on cardiorespiratory fitness, fatigue and self-reported physical functioning, and were feasible and safe in PwL (33). Other complementary and alternative therapies, such as mindfulness-based cognitive therapy, meditation, yoga, and tai chi, have shown improvement in cognitive function and QoL (36–38). Another recent systematic review reported that a combination of PA together with mental exercise may be more beneficial to PwL (39). There remains, however, an unmet need in the cancer population, and only a limited number of survivors receive the appropriate rehabilitation intervention that they need (40, 41). Furthermore, despite acknowledging rehabilitation as an integral component of the management of cancer patients, rehabilitation-specific guidelines for many cancer groups are limited, and many general cancer guidelines do not incorporate recommendations for specific rehabilitation interventions (42–44).
As mentioned above, various systematic reviews have evaluated the current evidence regarding the effectiveness and safety of different rehabilitation interventions in PwL. However, these published reviews vary in scope, methodology and quality, with diverse, and occasionally discordant, conclusions. The heterogeneity of the lymphoma rehabilitation literature warrants a comprehensive review, with a focus on the evidence for efficacy and potential harm of various rehabilitative strategies. A systematic review of systematic reviews is a new approach to synthesize current evidence across the same or similar interventions, to summarize treatment effect in a much broader concept (45). This approach allows comparison of results from multiple reviews, thereby providing a comprehensive evidence-based summary (45, 46). To our knowledge, systematic reviews of rehabilitation strategies for PwL have not been thoroughly and qualitatively appraised to date. Therefore, this review aimed to systematically evaluate existing evidence from published systematic reviews for the effectiveness of rehabilitation strategies for improved function, impairments and participation in PwL. Specific questions addressed include: Are rehabilitation interventions effective in minimizing impairment, activity limitation, participation restriction and treatment-related complications in PwL?, and: What specific types of rehabilitation interventions are effective in PwL, and in which setting?
A comprehensive review of the literature for published systematic reviews/meta-analyses evaluating the efficacy of rehabilitation interventions for PwL was undertaken, using a multipronged approach. A search of health science databases was conducted, including: Cochrane Library, PubMed, EMBASE, and CINAHL (from inception to 1 October 2020). The search strategy included combinations of multiple search terms (both MeSH and keyword text terms) for 3 themes: lymphoma; systematic review; and rehabilitation (Appendix I). A full description of the search strategy (with EMBASE as an example) is given in Appendix II. A manual search of bibliographies of pertinent articles and relevant journals for additional references was conducted. A grey literature search was performed using different internet search engines and websites: such as System for Information on Grey Literature in Europe; New York Academy of Medicine Grey Literature Collection and Google Scholar. Furthermore, websites of various healthcare institutions; and governmental and non-governmental organizations associated with haematological cancers were searched for any potential reviews. It was planned to contact authors and known experts in the field for information; however, this was not necessary, as any further data was not required for the analyses.
All systematic reviews that focused specifically on rehabilitation interventions conducted in any settings (inpatient, ambulatory, home-based or community rehabilitation settings) for the management of PwL were included. Systematic reviews involving other cancer groups/haematological malignancies, where data specifically provided for lymphoma sub-groups, were also included. Exclusion criteria were: reviews solely evaluating diagnostic, pharmacological and/or surgical interventions; those conducted in the paediatric population; non-English publications; narrative reviews; theses; health technology appraisal and reviews listed only in conference proceedings.
Study selection and data extraction
All studies identified through the search process and other sources were exported to an EndNote X9 (Clarivate, London, UK) database for the removal of duplicates. Two authors (BA, FK) independently screened and shortlisted all abstracts and titles of reviews identified by the search strategy for inclusion and appropriateness, based on the pre-specified inclusion/exclusion criteria described above. The study selection process was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Each study was independently evaluated, and the full-text article was obtained for assessment to determine the likelihood of inclusion. Any disagreement regarding the possible inclusion/exclusion of any individual study was resolved by consulting with other authors and by a final consensus. All relevant data were extracted using standard proforma, which included: publication and search date; objectives; characteristics of included studies and study subjects; intervention; findings/patient outcomes in the review; and limitations. Any discrepancies were resolved by discussion with other authors (TL, MD) and by re-reviewing the study.
Assessment of methodological quality of included reviews
Two reviewers (BA, FK) independently assessed the methodological quality of each included review, using the revised “A Measurement Tool to Assess Systematic Reviews” (AMSTAR-2) appraisal tool (Table I) (47). The AMSTAR-2 consists of 16 assessment items, with 7 being critical methodological items (items 2, 4, 7, 9, 11, 13, 15) and the rest outcome variables of items (1, 3, 5–6, and 10–16). Based on predefined criteria, each item was categorized as “Yes” (if the item was answered completely correct and well-documented, “Partial yes” (if the item was answered correctly with limited evidence), and “No” (if the item was not subject to relevant evaluation or improper evaluation) (47). Based on the judgment on the 16 individual appraisal items, overall methodological quality and confidence in the results of each systematic review were rated into 4 levels: “high” (no or 1 non-critical weakness), “moderate”’ (more than 1 non-critical weakness), “low” (1 critical flaw with or without non-critical weaknesses), or “critically low” (more than 1 critical flaw with or without non-critical weaknesses) (47). Any disagreements were resolved by consensus among all review authors.
The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) tool (48) was used to assess the quality of evidence for each outcome according to the following features:
Study limitations (risk of bias): internal validity of the evidence.
Inconsistency: heterogeneity or variability in the estimates of effect across studies.
Indirectness: degree of differences between population, intervention, comparator, for the intervention and outcome of interest.
Imprecision (random error): extent to which confidence in the effect estimate is adequate to support a particular decision.
Publication bias: degree of selective publication of studies.
The quality of evidence was classified as (48): “high-quality”: very confident that the true effect lies close to that of the estimate of the effect; “moderate-quality”: moderately confident in the effect estimate, such that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; “low-quality”: confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect, and “very low-quality”: very little confidence in the effect estimate and the true effect is likely to be substantially different from the estimate of the effect.
Any discrepancies were resolved by a final consensus amongst all reviewers.
Table I. Quality assessment (A Measurement Tool to Assess Systematic Reviews” (AMSTAR-2) appraisal tool; AMSTAR-2) of included systematic reviews
The search retrieved 901 published systematic reviews. Of these, 29 reviews evaluating rehabilitation interventions currently used in the management of PwL met the abstract inclusion criteria and were selected for closer scrutiny. Full texts of these articles were retrieved, and both reviewers performed the final selection. Two systematic reviews that met the inclusion criteria were identified from the manual search of bibliographies of relevant articles. Overall, a total of 12 reviews were included: 3 published in the Cochrane Library database (30, 38, 49) and 8 published in other academic journals (19, 33, 37, 39, 50–54). A PRISMA flow diagram of the study selection process is shown in Fig. 1. Lists of excluded reviews with reasons for exclusion are tabulated in Appendix III.
Fig. 1. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram showing a selection of reviews.
There was marked heterogeneity amongst the included reviews in terms of: included primary studies, lymphoma patients, intervention protocols, rehabilitation settings, and outcomes measured. The included reviews were published (or updated) between 2012 and 2019. The majority of reviews (8 reviews) limited the searches to only randomized controlled trial (RCT) or clinical controlled trial (CCT) designs, and 2 reviews (33, 52) included all study design, and another 2 (19, 54) included only cohort and case-control studies. Of the 12 reviews, 6 solely included lymphoma cohorts (19, 33, 38, 39, 52, 54), the rest involved different cancer groups and/or haematological malignancies and provided data on PwL. Overall, these 12 reviews included 23 RCTs and 78 other design (ODs) studies, with a total of 87,132 participants with lymphoma. Ten of the 12 included systematic reviews performed meta-analyses (19, 30, 37–39, 49, 50, 52–54), and the other 2 provided only a qualitative description of findings (33, 51).
Methodological quality of included reviews
The risk of bias of primary studies within included reviews was not re-assessed; instead, overall quality of the included reviews was critically assessed using the AMSTAR-2 tool (Table I). Only 2 reviews (both Cochrane reviews) were judged to be of “high quality” (30, 49), 4 reviews were of “moderate quality”’ (38, 39, 52, 53), 4 reviews were of “low quality” (19, 50, 51, 54), and 1 was judged to be of “critically low quality” (33) (see Table I). The majority of reviews (6 reviews) (30, 38, 39, 49–51) used the Patient Intervention Control Outcomes (PICO) description as an organizing framework in the research question and inclusion criteria, the remainder specifically failed to detail comparator groups. Only 3 reviews (all Cochrane reviews) (30, 38, 49) provided an explicit statement on registered information of the protocol before the review, and none reported any significant deviation from the prior protocol. All reviews searched within 24 months of completion of the review; however, a comprehensive literature search was performed only by Mishra et al. (30), whereas others either did not include a grey literature search or contacted the experts in the field. Five reviews did not provide details on study selection and data extraction in duplicate (19, 33, 37, 53, 54). Lists of excluded studies were described in only 4 reviews (30, 38, 39, 49). The majority of reviews adequately described details of the included studies in tables. All reviews, except 2 (19, 33), assessed the scientific quality of the included primary studies using the validated risk of bias (RoB) tools. There was heterogeneity amongst the included reviews in the RoB tools used: 7 reviews used core items of the Cochrane RoB tool, 1 each used the PEDro (50), Newcastle Ottawa Scale (52), and 2 adapted tools used previously by other authors (19, 54). Ten reviews applied appropriate methods for statistical synthesis (meta-analysis) (19, 30, 37–39, 49, 50, 52–54), of which 3 reviews (37, 52, 53) did not assess the potential impact of RoB in individual studies on the results of the synthesis. Eight reviews (30, 38, 39, 49, 50, 52–54) provided satisfactory explanations for any heterogeneity in the results, carried out an adequate investigation of publication bias and discussed its likely impact on the results of the review. The majority of reviews, except 2 (37, 51) provided their funding sources and declared their potential source of conflict of interest; however, surprisingly; the majority (all 9 non-Cochrane reviews) (19, 33, 37, 39, 50–54) did not address the potential competing interests and source of support of authors of the primary studies.
Evidence synthesis of rehabilitation interventions
The rehabilitation approach to patients with haematological malignancies including PwL included a range of interventions. Of the included systematic reviews evaluating various interventions, most (n = 8 reviews) addressed different PA, physical fitness status and exercise programmes in isolation or concomitant with other interventions; 3 reviews evaluated different complementary and alternative medicine (CAM) interventions (yoga, tai chi and qigong); and 1 review examined the efficacy of vitamin D. The findings indicate that, although a spectrum of interventions is used in PwL, the evidence for many of these is limited, unclear, or both, because of a paucity of methodologically robust studies. The existing best-evidence synthesis for rehabilitation interventions in PwL is summarized in Table II. The impact of the outcomes of these interventions, based on the type of intervention, is summarized below.
Table II. Characteristics of the included reviews
Table II. Cont.
Physical therapeutic modalities
Exercise programmes. Different exercise programmes, both during and after treatment, are increasingly being recognized as an important component of the rehabilitation modalities of cancer survivors, including PwL. Despite the variation in the evaluated exercise programmes, in terms of the types, intensity, duration, settings (institution, community, or home); the overall findings support the effectiveness of exercise programmes in PwL in improving functional capacity, muscular strength, functional mobility, fatigue, psychological well-being, treatment complications and QoL.
One systematic review (n = 6 RCTs, 429 participants) evaluated the effects of various exercise programmes (aerobic endurance training, sensorimotor and strength training) on QoL and other health outcomes, for adults with lymphoma (39). The findings indicated that exercise showed a significant positive effect, specifically on fatigue (effect size (z): 1.905, p = 0.05); however, despite showing some improvement, the magnitude of the effect size did not reach the statistically significant level for QoL, sleep quality and/or depression (p > 0.05 for all). A subgroup analysis according to different types of exercises showed that aerobic exercise exhibited little improvement in aspects of QoL and fatigue, but mind-body exercise (such as qigong, yoga) showed a beneficial effect in improving sleep (z=2.07, p = 0.04) and depression (z = 2.87, p = 0.004) (39). The authors, however, highlighted the need for further investigation due to a small number of included studies with marked heterogeneity.
In an updated Cochrane review (18 RCTs, 1,892 participants), Knips et al. evaluated the efficacy, safety and feasibility of aerobic physical exercise in patients with haematological malignancies, including lymphoma (3 RCTs, 292 participants) (49). The authors did not conduct a subgroup analysis for the PwL. The overall post-intervention findings showed significant improvement in fatigue (standard mean difference (SMD) 0.31; 95% CI 0.13–0.48) and some improvement in depression (SMD 0.19; 95% CI 0.0–0.38). There was no conclusive evidence for favourable effect of aerobic exercises on overall survival (relative risk (RR) = 0.67; p = 0.112), and improvement in QoL (SMD 0.11; 95% CI –0.03–0.24), physical functioning (SMD 0.15; 95% CI –0.01 to 0.32), and anxiety (SMD 0.03; 95% CI –0.30 to 0.36) (49).
Another Cochrane review (n = 38 RCTs and 2 CCTs, 3,694 participants) analysed the effect of various exercise interventions on HRQoL in adult cancer survivors after treatment, including lymphoma survivors (n = 4 RCTs, 192 participants) (30). There was marked heterogeneity amongst the included trials in terms of the patient population; mode/type, duration, and intensity of intervention. The authors did not perform any sub-group analysis according to cancer types. The overall results suggest exercise programmes showed a beneficial effect in improving global HRQoL at 12 weeks (SMD 0.48; 95% CI 0.16–0.81) and at 6 months (SMD 0.46; 95% CI 0.09–0.84). Exercise programmes also resulted in improvement in fatigue (SMD –0.82; 95% CI –1.50 to –0.14), anxiety (SMD –0.26; 95% CI –0.07 to –0.44) and pain (SMD –0.29; 95% CI –0.55 to –0.04) at 12 weeks follow-up (30). There was no conclusive evidence suggesting the beneficial effect of an exercise intervention on cognitive and/or physical functioning, general health perspective, role function, or spirituality (30).
In another systematic review (n = 16 RCTs, 9 non-RCTs, 1,188 participants) Heywood et al. evaluated the efficacy of exercise interventions (aerobic exercise and/or resistance training) in patients with advanced cancers, including lymphoma (n = 4 RCTs, 197 participants) (51). The authors did not conduct a subgroup analysis based on cancer types. The overall results suggest that exercise interventions were effective in significant improvements in physical function, and fatigue (p < 0.05 for all). Between- and within-group improvements were reported with exercise for psychological function, sleep quality and body composition (e.g., reduction in lean body mass) (51). There was inconclusive evidence for the advantageous effects of exercise in reducing pain and survival rates. Based on these findings, the authors recommend the inclusion of exercise interventions as an adjunct therapy for patients with advanced cancers, including lymphoma (51).
One systematic review (n = 37 RCTs, 2,929 participants) evaluated the efficacy of exercise in reducing depressive symptoms in cancer survivors, including lymphoma (n = 2 RCTs, 161 participants) (50). Exercise modalities evaluated included: walking, stationary cycling, weight machines, resistance bands and yoga, with a mean duration of 13.2±11.7 weeks and 3.0±2.5 sessions per week. The findings in all cancer survivors demonstrated that exercise interventions provided a small significant reduction in depressive symptoms (weighted mean effect size value (d+) –0.13, 95% CI –0.26 to –0.01, p < 0.001) (50). An increase in the weekly volume of aerobic exercise was found to reduce depressive symptoms in a dose-response fashion (p = 0.03), and most when exercise sessions were supervised (p = 0.01) in cancer survivors between ages 47 and 62 years (p = 0.01). Sub-group analyses in PwL showed no significant reduction in depressive symptoms (d+ = –0.30, 95% CI –0.89 to 0.29, p = 0.424) (50). The authors recommend treating clinicians should discuss the safety and feasibility of exercise to optimize depressive symptom management in all patients with advanced cancers (50).
Physical activity and fitness. There is consensus amongst treating clinicians that cancer survivors should be regularly engaged in PA. PA is considered an effective intervention for improving QoL and overall well-being in patients with cancers, including PwL (33).
In a systematic review, Vermaete et al. evaluated PA and physical fitness in PwL (n = 13 all design studies, 2,450 participants, PWL 2,399) before, during and after treatment. The authors reported that only 21–29% of lymphoma survivors met the public health guidelines for PA, as defined by the American College of Sports Medicine (i.e., engaging in >30 min/day of at least moderate PA on ≥ 5 days/week, or >150 min a week) (33). The maximal exercise capacity was decreased before treatment, especially in PwL with advanced disease, but was close to normal during and/or after treatment. Lower levels of PA and lower physical fitness were associated with more fatigue. Aerobic exercise training interventions were feasible and safe, with positive effects on cardiorespiratory fitness, fatigue and self-reported physical functioning (33).
One meta-analysis (n = 15 cohort and 8 case-control studies, 1,648,601 participants; including 15,173 PwL in 15 studies) evaluated the relationship of PA with subtype-specific haematological cancers. No associations were identified between PA and risks of lymphoma (HL or NHL), multiple myeloma, or leukaemia (54). Comparison of high vs low levels of PA revealed statistically non-significant associations with risk of NHL (RR 0.91, 95% CI 0.82–1.00), HL (RR 0.86, 95% CI 0.58–1.26), leukaemia (RR 0.97, 95% CI 0.84–1.13), or multiple myeloma (RR 0.86, 95% CI 0.68–1.09). Similar results were found for subtypes of NHL; i.e., for DLBCL (RR 0.95, 95% CI 0.80–1.14) and for follicular lymphoma (RR 1.01, 95% CI 0.83–1.22) (54). The authors indicated that these findings may not represent a true lack of associations given the variation in high vs low physical activity definitions, the quality of PA assessments, and the variability in haematological cancer classification schemes in primary studies.
In another meta-analysis (n = 7 case-control, 5 cohort studies, 1,278,469 participants, PwL 11,511) evaluated the association between PA and risk of lymphoma (19). The authors reported no significant effect of PA on the risk of developing lymphoma (pooled odds ratio (OR) = 0.90; 95% CI 0.79–1.02; p = 0.10). In a subgroup analysis the authors found some significant protective influence of PA on the risk of lymphoma in case control studies (pooled OR = 0.81; 95% CI 0.68–0.96; p = 0.02), but not in cohort studies (pooled OR = 1.02; 95% CI 0.88–1.19; p = 0.76) (19). There were no significant differences for HL and NHL subgroups (χ2 = 0.16; p = 0.69), and no significant difference between recreational and occupational activities (χ2 = 1.01; p = 0.31) (19).
The descriptive nature of the primary studies from which these analyses are derived precludes definitive conclusions regarding the relationship between PA and lymphoma risk, due to the possibility of unknown confounders. Nevertheless, based on these large cohorts, no clear association between PA and lymphoma risk was identified.
Nutritional intervention (vitamin D)
Healthy nutrition, weight management, and maintenance of a healthy lifestyle are important for vitality, functioning, and QoL for cancer patients, including PwL.
In a meta-analysis (n = 30 articles, 56,458 participants) Park et al. investigated the effect of various measures of vitamin D status (sunlight/ultraviolet radiation (UVR) exposure, dietary intake, and serum/plasma 25(OH) D levels) in NHL and its subtypes (52). The authors identified a significantly lower relative risk of NHL among subjects with high sunlight/UVR exposure compared with subjects with lower exposure (RR = 0.80; 95% CI 0.71–0.90). There were significant inverse associations between overall sunlight/UVR exposure and DLBCL (RR = 0.72, 95% CI 0.54–0.97), FL (RR = 0.81, 95% CI 0.73–0.90), and marginal zone lymphoma (MZL) (RR = 0.70, 95% CI 0.57–0.87), but not for chronic lymphocytic leukaemia and small lymphocytic lymphoma (CLL/SLL) (RR = 0.87, 95% CI 0.68–1.11), B-cell NHL (RR = 0.84, 95% CI 0.68–1.05), and T-cell NHL (RR = 0.70, 95% CI 0.48–1.01) (52). These associations were non-significant when the analyses were restricted to prospective studies only. Dietary vitamin D (> 200 IU/day) (RR = 1.03; 95% CI 0.90–1.19) and serum/plasma 25-(OH) D levels (RR = 0.97; 95% CI 0.82–1.15) were not associated with NHL incidence and its subtypes (52). All included studies were cohort or case-control studies, and a direct causal/protective relationship cannot be concluded, as unmeasured confounding variables may have resulted in the observed associations.
Complementary and alternative medicines
Many PwL uses CAM approaches as an adjunct to other mainstream therapies; however, few are reported as being effective in enhancing clinical outcomes (55).
Yoga. In a Cochrane review (n = 1 RCT with 20 PwL) Felbel et al. assessed the effects of yoga practice in addition to standard cancer treatment (38). The authors found no evidence that yoga improves distress (mean difference (MD) –0.30, 95% CI –5.55 to 4.95; p = 0.91), fatigue (MD 0.00, 95% CI –0.94 to 0.94; p = 1.00), anxiety (MD 0.30, 95% CI –5.01 to 5.61; p = 0.91) or depression (MD –0.70, 95% CI –3.21 to 1.81; p = 0.58) in PwL (38). There was very low-quality evidence that yoga improves the overall quality of sleep (MD –2.30, 95% CI –3.78 to –0.82; p = 0.002) (38). The influence of yoga on HRQoL and overall survival rate was not reported.
Tai chi and qigong. In an updated systematic review (n = 12 RCTs, 915 participants) Zeng et al. examined the effectiveness of qigong/tai chi on cancer survivors including lymphoma (n = 2 RCTs, 204 PwL). The authors did not perform a subgroup analysis for PwL (37). The overall results suggest significant positive effects of qigong/tai chi on reducing fatigue (SMD 2.05, p = 0.005, 95% CI 0.63–3.47) and sleep quality (p < 0.001). No beneficial effect was observed for improvement on anxiety, stress, depressive symptoms, and overall QoL (p > 0.05 for all) (37).
Wayne et al. in another systematic review (n = 15 RCTs, 1,283 participants; 1 RCT with 96 NHL patients) reported similar advantageous treatment effects of tai chi/qigong (53). The findings suggest significant improvement in fatigue (effect size (ES) = −0.53, p < 0.001), sleep difficulty (ES = −0.49, p = 0.018), depression (ES = −0.27, p = 0.001), and overall QoL (ES = 0.33, p = 0.004), but not in pain (ES = −0.38, p = 0.136) (53). The authors concluded that tai chi/qigong show promising results in addressing cancer-related symptoms and QoL in cancer survivors; however, more methodologically robust trials with longer follow-up periods and appropriate comparison groups are needed for definitive symptom-specific recommendations (53).
This review systematically analysed the evidence from published systematic reviews to date, for the effectiveness of various rehabilitation interventions on patient outcomes in PwL. The findings indicate that, although a wide range of rehabilitation approaches are commonly recommended and trialled in this population, there is still a lack of high-quality evidence for the effectiveness of many of these modalities. Furthermore, there is a paucity of studies evaluating other rehabilitation strategies that have an evidence base for patients with other oncological conditions, such as multi-disciplinary rehabilitation programmes, self-care and educational programmes, psychological programmes, etc. The overall findings of this review suggest, moderate-quality evidence for exercise programmes for improved fatigue, sleep disturbances, low-quality evidence for exercise therapy for improved pain, psychological wellbeing (depressive symptoms, anxiety) and overall QoL; and qigong/tai chi for improved fatigue, sleep disturbances, psychological symptoms (depression, anxiety) and overall QoL and an inverse association between sunlight/UVR exposure on lymphoma incidence based on descriptive studies. There was very-low quality evidence for yoga for improved sleep disturbances. The evidence suggesting associations of PA with risks of lymphoma is still uncertain.
Rehabilitation programmes have become an integral part of the management of people with various oncological conditions, including haematological malignancies (38, 54). The scope of contemporary oncological rehabilitation has shifted from physical therapeutic modalities alone, to more comprehensive management, including: secondary prevention for symptom and complication management; risk factor education; psychological support; and function and participation (56). Despite established guidelines, and standardized protocols for acute management of PwL (and other haematological malignancies) (57–59), specific guidelines on structured rehabilitation programmes are yet to be published. Furthermore, in PwL, due to diverse clinical presentations, varying levels of patient disability (and impairments), unpredictable prognosis and changing patient needs, a wide spectrum of individualized rehabilitation approaches may be required at different stages of the condition spectrum.
This review identifies different interventions employed for PwL; however, despite reported high prevalence of psychological impact in this population, there is limited relevant research. There is existing evidence indicating the effectiveness of psychological therapies (such as educational, cognitive-behavioural, or coping skills approaches) in facilitating physical and emotional function, immune function, and enhanced survival in other cancer populations (60–62). The review did not identify any studies evaluating the efficacy of rehabilitation interventions on survival length or relapse incidence in PwL. Furthermore, some lymphoma localizations and non-neoplastic complications, such as polyradiculoneuropathy and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy/oedema, monoclonal-protein and skin change), necessitate the involvement of a multidisciplinary rehabilitation team; however, these are yet to be evaluated. There is also a lack of reviews assessing vocational interventions for enhancing employment and/or education specifically targeting PwL.
This review found many of the evaluated interventions were too broadly described; specifically exercise interventions, without sufficient detail (optimal settings, type, intensity, and duration of therapy, and cost-effectiveness, etc.) to enable replication of the interventions. Furthermore, the structured and conceptual theory constructing these interventions was not adequately defined. The process surrounding the development of common outcome goals, which are achievable through the participation of the patient and the treating professional involved in the patient care (warranted in rehabilitation settings), was, surprisingly, not mentioned in any included reviews. The WHO International Classification of Functioning, Disability and Health (ICF) framework provides elements of a theory about rehabilitation and provides a taxonomic system of human functioning (63); however, none of the included reviews cited this widely used model. This ICF model can be used as a common framework to help prioritize personalized goals for PwL, to set rehabilitation criteria.
There was heterogeneity amongst the included reviews, even in those evaluating similar outcomes. The methodological quality of the included systematic reviews varied, with only 2 and 4 out of 12 rated as of “high” and “moderate” methodological quality, respectively (AMSTAR-2 score). Most of the reviews included a broad range of cancer populations and only a few focused specifically on lymphoma cohorts. This has reflected with marked heterogeneity of cancer types, clinical presentation, and goals for treatment in the primary trials within the included reviews. The participant characteristics were heterogeneous amongst the studies regarding characteristics of lymphoma (type, lesion location and area, time since lymphoma, other comorbidities, age, etc.), which may have resulted in variability in findings. The included reviews consistently remarked on the poor quality of the primary studies with relatively small numbers of patients. There was also marked heterogeneity in the primary trials regarding the description of control arms, assessment time-points and outcome measures used. Likewise, evidence for the use of rehabilitation approaches targeting different cancer-related outcomes in the included reviews was diverse. This is mainly due to the variation of interventions provided (duration, intensity, settings, timing, etc.), outcome measurement tools, control intervention protocols and length of follow-up. Furthermore, outcome measures used, and assessment time-points also differed. Therefore, pooling data for quantitative analyses were not possible, and a best-evidence synthesis was described using qualitative analyses. The overall evidence for some of the studies was downgraded from actual evidence reported by authors, due to imprecision and inconsistency of findings, use of different outcome measures and inclusion of non-RCTs with poor methodology quality, precluding meta-analysis. Therefore, the quality of evidence and the external validity of the findings should be interpreted with caution. The confounding effects of adjunct rehabilitation therapies coupled with acute treatment need further exploration.
Evidence for the benefits of rehabilitation programmes is well established in various cancer groups (28, 29, 56, 64). Specifically, physical activities are the most commonly trialled and shown to attenuate a range of conditions and/or treatment-related physical and psychological impairments (65). A cancer control framework examining the short-term and long-term effects of PA defines 2 distinctive periods: the rehabilitation period, which immediately follows primary treatment, and the disease prevention/health promotion period, which describes longer-term survival (66). These published reports recommend that the rehabilitation period is highly important and variable (67) and that PA (and other types of rehabilitation programmes) are relevant throughout this period, including the longer-term survival period (66, 67). The benefits of any rehabilitation programme will vary according to the type of cancer and treatment, the cancer stage, and the mode, intensity, and duration of the exercise programme; and the patients’ compliance (65, 67). Consistent with the findings of the current review, Spence et al. reported beneficial effects of exercise programmes in cancer patients in improving physical functioning, strength, PA levels, QoL, fatigue, immune function, haemoglobin concentrations, potential markers of recurrence, and body composition (65). The majority of studies included in this review were predominantly conducted in the breast cancer population, and none of the studies included PwL (65).
Close communication between the patient, the rehabilitation team and the treating haematologist is essential, since the goals of care for patients with haematological malignancies can change precipitously with the emergence of relapsed disease, disabling complications (e.g. critical sepsis) or patient frailty precluding further effective therapy. Consensus agreements between treating team and patient regarding the goals of rehabilitation are critical to its appropriate application and success, irrespective of modality. Patients with limited treatment options or persistent frailty despite rehabilitative attempts should be offered palliative care in combination with or, where appropriate, replacing restorative and curative approaches.
To our knowledge, this is the first review to systematically appraise published systematic reviews to evaluate the effectiveness of rehabilitation interventions for various cancer-related outcomes in PwL. This approach not only provides a comprehensive evidence-based summary of the effects of different interventions on various outcomes, but also provides reassurance as to whether the conclusions of individual reviews are consistent (45, 46). The aim was to provide an overview of available evidence for the rehabilitation interventions used in the lymphoma population, to assist and guide treating clinicians in choosing an appropriate treatment approach. Furthermore, it elaborates on the existing gaps in research and limitations in the included systematic reviews for future research and clinical implications.
It is not possible to rule out limitations in methodology and completeness of retrieved literature. Regardless of the comprehensive search employed, this review encompassed published literature written in English in specific health science databases, which may have introduced a selection and reference bias. However, an extensive comprehensive search using broad search terms in most prominent databases was usedand websites of prominent stroke-related organizations were explored to identify the relevant studies. Widely used validated tools to assess methodology (AMSTAR-2) and quality of evidence (GRADE) of included studies were used, despite the limitations of these global tools. The accuracy of the assessor’s assessments cannot be guaranteed; however, the selection of studies and quality assessments were independently done by 2 authors, and further group consensus was reached. Due to significant heterogeneity among the included reviews, with high variability in treatment protocols and the participants, the effect of the intervention was only categorized quantitatively. These issues limit the generalizability of the findings. Evaluation of safety related to evaluated rehabilitation interventions was not possible, as reports of adverse events in the included reviews were incomplete or missing. Associated costs and/or economic benefits of interventions were not reported in any review. Some included reviews specifically investigated the association of dietary (vitamin D intake, UV exposure) and physical activities, and risk of lymphoma. However, these interventions were not part of comprehensive rehabilitation programmes within the studies; these reviews were included as there is evidence to suggest that oncological rehabilitation should include risk factor education as a part of a comprehensive programme. Furthermore, the findings are important from the rehabilitation perspective and for the development of structured rehabilitation programmes. The effect of these interventions on patients’ disease trajectory requires investigation in future studies. Many included reviews were not up to date, as the last search dates were older than 3 years; hence many recent studies may have been missed. The findings of this review should therefore be interpreted with caution.
The management of patients following lymphoma is complex and challenging. Rehabilitation techniques can benefit PwL throughout the disease-continuum. However, there is still a lack of high-quality evidence for many rehabilitation interventions in lymphoma survivors. Positive effects of exercise programmes were noted for various outcomes (fatigue, psychological symptoms) and overall QoL. Some benefit of qigong/tai chi was found for improved symptoms and overall QoL, and yoga for sleep disturbances. There is a need for studies with robust methodology in larger cohorts, to evaluate the roles of various rehabilitation programmes and longer-term effects. Future studies should consider patient characteristics, outcome measures, timing, mode and intensity of rehabilitation interventions.
This review was supported by the internal resources of the Rehabilitation Department, Royal Melbourne Hospital, Royal Park Campus, Melbourne, Australia.
The authors have no conflicts of interest to declare.
Appendix I. Search terms used
Appendix II. EMBASE Search strategy (01 October 2020)
Appendix III. List of excluded systematic reviews