Effects of physiotherapy in the management of cancer-related pain and fatigue: A systematic review of randomized controlled trials.

Background: Cancer is ranked as the 2 nd common deadliest disorder worldwide, and the growing incidence demands updating and optimizing the treatment strategies for cancer survivors. However, evidence regarding this area is scarce; therefore, this systematic review aimed to evaluate the effects of Physiotherapy (PT) in managing cancer-related pain and fatigue. Methodology: Electronic search conducted utilizing Google Scholar, Embase.com, Cochrane CENTRAL via Wiley, Web of Science Core Collection, MEDLINE via Ovid, PEDro, and PubMed. Randomized controlled trials published from 2014 to April 2021 analyzing the effects of PT approaches for cancer-related pain and/or fatigue management in adult cancer patients were included in the review. Sixteen eligible trials were evaluated, of which eight trials addressed Cancer-Related Pain (CRP) while others addressed Cancer-Related Fatigue (CRF). The risks of bias and trials credibility were analyzed via the Cochrane tool to assess bias risk. Results: Strong evidence favors the effectiveness of various PT approaches mainly, aerobic and resistance exercises for CRF and CRP management. However, endurance exercises, high-intensity interval training, and myofascial release were effective in CRF management. In contrast, Xbox Kinect-based games, stretching, lymphatic drainage, and passive mobilization effectively reduced CRF. Conclusion: Large body of evidence supports the effectiveness of PT exercises mainly, aerobic and resistance exercises, in cancer-associated pain and fatigue management. Hence exercises prescriptions should be implemented in the treatment plan of cancer patients. sample size of the eight trials related to the effects of PT on CRF The study Most of the trials use the Multidimensional Fatigue Inventory (MFI) as an outcome follow-up duration of the studies from point five six Several PT like Proprioceptive Neuromuscular Facilitation (PNF), Training (RT), aerobics, High-intensity Interval Training (HIIT), myofascial release, at high and low-to-moderate CRF compared to usual


Introduction
Cancer ranks as the 2 nd common deadliest disorder around the globe, and its global incidence is suspected to rise to 21 million by 2030 1 . The latest study conducted by McTiernan in 2019 reported that physical activity decreases the risk and improves the survival of several types of cancer 2 .
Although traditional treatments for cancer such as hormone therapy, surgery, chemotherapy, and radiotherapy have favorable effects, they also result in various adverse effects mainly, fatigue, pain, anxiety, depression, nausea, and a high risk of developing a tumor 3 . The clinical oncological society of Australia outlined exercise as an integral part of standard treatment to upgrade the overall health and the life expectancy of cancer patients 4 .
A growing body of evidence indicates that Physiotherapy (PT) is effective and safe for patients undergoing cancer treatment 5 . PT approaches can reduce the intensity of symptoms associated with cancer. However, the relief is associated with the amount of work done 6 . Recent literature also shows that exercise helps improve anxiety, depression, psychological needs satisfaction, and the quality of life also have a vital role in the recovery of cancer adverse effects 7,8 . A study by So WK et al. found that pain and fatigue often occur together with depression and are referred to as symptom clusters in cancer survivors 9 . It is clear from the evidence that cancer-related pain (CRP) is multidimensional and complex hence highlights the need for innovative multidisciplinary treatment strategies 10 .
Fatigue is found to be the common symptom and treatment side effect of cancer 11,12 . According to National Comprehensive Cancer Network, Cancer-Related Fatigue (CRF) is a persistent and distressing feeling of tiredness associated with cancer or cancer therapy which is not proportional to recent activity 13 . A study shows that CRF cannot be relieved by taking rest or sleep 14 . The latest literature reported rational approaches for the treatment of CRF in which exercise is an integral component 15 . However, a recent evaluation claimed physiotherapists have foundational knowledge and skill in cancer care but, more clinical practices are recommended 16-17 . In the latest version of adult cancer patient recommendations, the optimal treatment strategy for pain management combines pharmacological and non-pharmacological therapies that mainly include exercise and psychotherapy 18 . Similarly, the latest systematic review (SR) also claimed exercise as a measure to reduce CRF 19 . The evidence regarding the incredible effects of PT in oncological rehabilitation is scarce; therefore, this SR aimed to critically analyze the effects of PT in cancer-relatedpain and fatigue management and provide a shred of up-to-date evidence. related pain) AND (cancer-related fatigue" OR "fatigue") AND (''exercise'' OR ''physiotherapy'' OR '' oncological rehabilitation'' OR "physical activity") AND (''randomized controlled trial' OR ''RCT'') AND ''custom date range (2014 to 2021)". Titles and/or abstracts were reviewed, and the articles not meeting inclusion criteria were excluded. However, the remaining articles were studied in full to evaluate suitability in consideration with the PRISMA guidelines.

Study Selection:
Initial screening was carried out based on titles, and/or abstracts were also analyzed against the eligibility criteria of the SR. The primary electronic search yielded a total of 300 records, of which 246 trials were excluded based on titles and/or abstracts, duplication, pain and /or fatigue not addressed as the outcome of interest, treatment protocol not defined, and/or not meeting the eligibility criteria. However, 18 studies were recruited to analyze in full, of which 16 relevant RCTs were included in this review, the remaining two articles were excluded based on poor quality and unclear methodology. Out of 16 included trials, eight studies evaluated the effects of PT on CRP, and the remaining eight addressed CRF. The full texts of the trials were found via online search engines and directly contacting authors. The field experts were also contacted to identify any ongoing or missing trials so that no relevant data is missed. All the authors worked together as a team in the screening and review process. The trials selection is outlined in a flow diagram in figure 1.

Extraction of Data:
The information, including trials publication year, location, research design, study population, sample size, treatment applied, duration of follow-up, outcome measures, and main findings, were extracted from the trials and organized via Microsoft Excel.

Risk of Bias:
The assessment of trials' quality was evaluated via the Cochrane tool for assessing the risk of bias 21 . It analyzes biases in seven different manners: random allocation, allocation concealment, blinding of participants, outcome assessment, incomplete outcome data, selective reporting, and other biases. All the authors worked together to analyze trials for the risk of biases.

Results
All 16 trials involved 1,386 cancer patients; the majority of the participants were females with breast cancer. However, lungs, pancreatic, testicular, and other cancer patients were also included.

Effects of physiotherapy in the management of cancer-related pain and fatigue
The sample size of the eight studies related to the effects of PT on CRP was 598, with few trials reported sample size calculation. Most of the RCTs addressed breast cancer patients. However, Visual Analogue Scale (VAS), Numeric Rating Scale (NRS), and Brief Pain Inventory (BPI) were used as outcome measures in most of the trials ( Table 1). The follow-up duration of the studies ranges from one to twelve months.
A great variety of PT approaches like passive mobilization, Xbox Kinect-based games, tissue massage, breathing Exs, pilates-based exercises, stretching, Range of Motion (ROM), aerobics, resistance, Manual Lymphatic Drainage (MLD), and teaching Self-administered Complex Decongestive Therapy (saCDT) were found effective in reducing CRP.   High-intensity Interval Training (HIIT), myofascial release, endurance exercises at high and low-to-moderate intensity were reported to be effective in reducing CRF compared to usual care (Table 2).

Risk of bias within trials and quality appraisal
Two reviewers assessed the quality of the trials, and the third independent senior reviewer took the suggestions regarding the disagreements. All the trials showed a low risk of bias in random allocation except Cho et al. 27 reported unclear. In most studies, a high risk of bias regarding participant blinding 22-25, 28-32, 34-36 was found. While in 50% of the trial's outcome assessment, blinding had a high risk of bias 22, 25, 28-30, 32, 34, 35 . The risk of bias could not be ensured from the method defined for other bias from some studies 27,33,35 .

Synthesis of results
All the trials favor the efficacy of various PT approaches mainly, aerobic and resistance exercises, in decreasing cancer-related fatigue and pain. One study suggested that generally prescribed physical activity levels are sufficient to relieve CRF.

Discussion
This SR has enlightened the effects of various PT approaches that reduce pain and fatigue related to cancer by critically analyzing the RCTs conducted over the past 08 years (January 2014 to April 2021  40 . Similarly, one more study by Brown et al. 41 concluded exercise to be effective in improving CRF.
Another important finding of this review is that exercise is safe; however, this study supports the idea to prescribe exercise for cancer patients, and principles of exercise training must be followed along with the consideration of individual's health goals, functional and fitness level 42 . In addition to that, continuous monitoring should be done so that effectiveness of interventions could be assured, also keeping in mind precautions, contraindications, and exercise safety 43 .
It is noteworthy that despite the scarcity of evidence regarding this important topic, the present review plays a vital role in reinforcing the incredible effects of PT in oncological rehabilitation. It demonstrates that PT results in clinically significant outcomes in cancer-associated symptoms management and extends patients' survival. Hence exercise prescriptions should be implemented worldwide in the management plan of cancer survivors.
This comprehensive review is the first to our knowledge to critically evaluate the effects of PT. Some of the limitations of this review were that few cancer types were addressed with the most prevalent breast cancer. Furthermore, some trials use a small sample size with a short follow-up duration. In addition, various PT techniques with different doses make it hard to generalize these outcomes to diversified cancer patients. However, despite these limitations, the findings of this review are still clinically significant.
As this particular area of research lies still in its infancy, it is recommended that further highquality trials addressing which PT intervention, what duration, frequency, and intensity is effective for which specific type of cancer is the need of time.

Conclusion
A large body of evidence favors the effectiveness of various PT approaches mainly, aerobic and resistance exercises, in managing both cancerassociated pain and fatigue. Endurance exercises, high-intensity interval training, and myofascial