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World Journal of Oncology

Review

Volume 000, Number 000, April 2024, pages 000-000

Potential Therapeutic Role of Respiratory Muscle Training in Dyspnea Management of Cancer Survivors: A Narrative Review

Dyspnea or breathlessness is a common, debilitating symptom among cancer survivors, especially in those with advanced cancers [1, 2]. Dyspnea is defined as “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” [3]. Other terms such as “shortness of breath”, “difficulty breathing”, “chest tightness” and “air hunger” are also frequently used in the literature [1, 3]. The prevalence of dyspnea is ranging from 10% to 70% of patients with cancer according to systematic review of over 10,000 patients [4]. A recent systematic review reported an average dyspnea prevalence of 58% (range 10% to 90%) among patients with advanced all-type cancers, and 34.9% among patients with lung cancer, respectively [1]. In particular, 45.5% of cancer survivors experienced exertional dyspnea, a factor that negatively affects activities of daily living and exercise [1]. Despite this high prevalence and tremendous burden, dyspnea is often underestimated by clinicians [1, 5]. For example, while clinicians reported that less than 30% of patients with lung cancer experienced moderate to severe dyspnea, over 50% of their patients reported the occurrence of this symptom [1]. Dyspnea in patients with advanced cancers is clinically significant in particular when presented at rest, which indicates a poor prognosis (typically a survival less than a few months) [2, 6]. Studies in patients with lung, breast and other cancers reported a significantly lower survival rate in those who present dyspnea compared to those who did not [7, 8]. In addition to a high mortality risk, the distressing burden of dyspnea is frequently compounded by fatigue, anxiety and depression, resulting in functional limitations in activity of daily living, avoidance of physical activity and poor quality of life [2, 6].

The cause of dyspnea is multifactorial and many demographic and clinical characteristics have been shown to be associated with dyspnea. These include: age, gender, cancer type and stage, presence of metastatic disease, type of cancer treatments, smoking history, cardiopulmonary comorbidities, physical inactivity, low pulmonary function, body weight loss > 5%, obesity, anemia, anxiety, depression pain and fatigue [1]. While pharmacological therapies are part of dyspnea management in cancer [2], and opioids such as morphine remain the cornerstone for treating dyspnea [5], their efficacy in alleviating dyspnea is limited [2]. Literature review of 17 randomized controlled trials found that opioids and anxiolytics such as benzodiazepines were no more effective than placebo in improving breathlessness [2]. Although supervised exercise therapy/pulmonary rehabilitation has been shown to be effective in improving dyspnea in patients with lung cancer [9], this treatment modality has not been recommended by American Society of Clinical Oncology (ASCO) for dyspnea management in patients with advanced cancer [2]. This is possibly due to insufficient evidence, and the fact that supervised exercise therapy/pulmonary rehabilitation is not a standard of care for patients with cancer [2]. While preliminary findings of respiratory muscle training (RMT) are encouraging with potential benefits in alleviating dyspnea among cancer survivors [10-17], the evidence of RMT efficacy for reducing dyspnea is still premature and large randomized controlled trials of RMT in cancer survivors are warranted. Given the prevalence of dyspnea in cancer survivors, its detrimental effects on physical function and quality of life, its association with poor survival while effective treatments are limited [1, 2, 6], exploring other potentially effective therapies has important clinical implications for symptoms management in cancer survivorship. Herein, the current review paper aimed to explore the potential therapeutic role of RMT for dyspnea management in cancer survivors. The article outlines the evidence on the effectiveness of RMT on respiratory muscle function as potential mechanism to reduce dyspnea. The article summarizes the existing evidence on RMT in health and disease for dyspnea improvement, and systematically reviews the existing evidence of RMT on dyspnea in cancer survivors. Finally, the review proposes a scientific rationale for why and how RMT could potentially treat dyspnea in cancer, a principle that should be empirically tested in future large randomized controlled trials.

The respiratory muscles are responsible for the air flow in (inspiration) and out of (expiration) the lungs [18, 19]. The primary muscle of inspiration is the diaphragm and additional muscles include the external intercostals, as well as accessory muscles including the sternocleidomastoid and the scalene muscles [19]. The primary muscles of expiration are the abdominal muscles: rectus abdominis, internal and external obliques and transversus abdominis, and the internal intercostals as accessory muscles. At rest, inspiration is an active process of the diaphragm and external intercostals muscles contraction, while expiration occurring primarily passively via elastic recoil of the lung and chest wall [19]. Respiratory physiology during physical exercise is quite different from resting state, since both inspiratory and expiratory processes are energy demanding especially at higher exercise intensities. The metabolic cost of breathing at rest is approximately 2% of total body oxygen (VO₂) consumption, while during strenuous exercise it can rise up 10-15% of maximal VO₂ consumption (VO₂max) [19]. In normal healthy individuals, the respiratory system including the respiratory muscles has been traditionally viewed as well capable to meet the physiological demands of exercise even at high intensity, whereas the respiratory muscles are highly resilient to fatigue [19]. However, respiratory muscle function could be impaired due to cancer treatments and their associated toxicities, deconditioning, muscle atrophy, cardiopulmonary conditions, anemia and hypoxemia, conditions that are common in cancer survivors [20-23]. This can lead to reduced respiratory muscle strength and endurance, respiratory muscles fatigue during exercise and dyspnea on exertion [24, 25]. Studies that assessed direct physiological responses in cancer survivors supported this mechanism. Travers et al [26] measured the physiological responses at rest and during cardiopulmonary exercise testing (CPET) between cancer survivors with different cancer types. The study compared cancer survivors with and without dyspnea to normal, age-matched healthy controls. This study showed that at peak exercise and for a given ventilation and oxygen uptake levels, dyspnea intensity was greater in cancer survivors with dyspnea compared to those without and control groups. Peak oxygen uptake (a gold-standard measure of cardiorespiratory fitness (CRF)) was significantly lower among cancer survivors with dyspnea compared to cancer survivors without dyspnea and healthy controls [26], which is a strong predictor of reduced survival [27, 28]. Breathing pattern was more rapid and shallow, and dyspnea was the primary reason for exercise termination among cancer survivors with dyspnea compared to cancer survivors without dyspnea and healthy controls. The authors concluded that in the absence of obstructive and restrictive lung disease in cancer survivors, respiratory muscle weakness is a possible mechanism for dyspnea [26]. Similarly, O’Donnell et al [29] compared breast cancer survivors to healthy age-matched controls. This study demonstrates a 20% lower peak VO₂ and > 50% greater dyspnea intensity in the breast cancer group compared to controls. In addition, the results showed that breast cancer survivors had lower respiratory and limb muscle strength and more rapid and shallow breathing pattern. The study concluded that breast cancer survivors have dyspnea and exercise intolerance due to multifactorial reasons including limb and respiratory muscle weakness and deconditioning [29].

CRF plays an important role in dyspnea pathophysiology [30]. CRF reflects the integrated physiological capacity of the heart, lungs, and skeletal muscle to supply the required energy during maximal aerobic exercise, commonly termed maximal oxygen uptake (VO₂max) [27, 31]. Poor CRF is a strong predictor of morbidity and mortality in many patient populations including cancer survivors [27, 28], and has been demonstrated to be associated with dyspnea [30, 32, 33]. Unfortunately, cancer survivors typically present low CRF, which increases their risk for variety of adverse outcomes and high symptom burden [22, 34]. For instance, a systematic review of 27 studies involving a total of 1,856 breast cancer survivors showed that the weighted mean VO₂max in breast cancer survivors prior to adjuvant therapy was 24.6 mL/kg/min (17% lower than healthy sedentary women (29.7 mL/kg/min)). After completion of adjuvant therapy, weighted mean VO₂max was 22.2 mL/kg/min, which is a 25% lower than healthy sedentary women [22]. Another systematic review of 28 studies involving patients with breast cancer, lung cancer, lymphoma, hematological cancers, prostate cancer and mixed cancer types reported that VO₂max ranged between 16 and 25 mL/kg/min. These levels are 4% to 35% lower VO₂max when compared with normal healthy references [34]. The mechanism in which low CRF (VO₂max) can provoke dyspnea could be related to the reduced physiological reserves and increased relative intensity of any given physical task [27, 30, 31]. Most activities of daily living such as walking and household work require energy of 2 - 5 metabolic equivalent task (MET; 1 MET = 3.5 mL O₂/kg/min), corresponding to 7 to 17.5 mL O₂/kg/min [35]. For normal independent function in activities of daily living, a minimum of 18 mL/kg/min for men and 15 mL/kg/min for women of VO₂max is necessary [27, 36]. Given the above mentioned low VO₂max values among cancer survivors, it could be argued that many activities of daily living and leisure physical activity for these patients would be considered as high intensity effort relative to their low VO₂max, remaining them with low physiological reserves. A relative high intensity physical activity causes hyperventilation response including exponential increase in minute ventilation and breathing frequency, which in turn could be perceived as dyspnea [31, 35]. Additionally, due to a low CRF and mitochondrial dysfunction, at any given physical work rate, lactate concentration levels and blood acidity will be higher. As a consequence to this increased metabolic acidosis, an earlier buffering response by bicarbonate will be present, resulting in higher carbon dioxide (CO₂) levels, triggering a disproportional increase in ventilation and higher dyspnea perception [30, 31, 35, 37]. Although dyspnea was not assessed as an outcome, and causality should not be drawn, a meta-analysis of 48 randomized controlled studies, involving 3,632 patients with different cancers demonstrated an increased CRF (+2.13 mL O₂/kg/min) following supervised exercise training [38]. This powerful finding supports the potential of supervised exercise training for dyspnea improvement during activities of daily living, although interventional studies examining the effect on dyspnea as an outcome are needed.

An additional important factor that may contribute to dyspnea among cancer survivors is obesity [39, 40]. Obesity is commonly defined as body mass index ≥ 30 kg/m² [41], and its prevalence in the general adult population is approximately 40% [42], with projection of reaching half of the US population by 2030 [43]. Considerable body of literature indicates that obese individuals often present impaired respiratory muscle function and dyspnea at rest and during physical exertion [39, 44]. Reduced inspiratory and expiratory muscle strength and inspiratory muscle endurance are documented in subjects with obesity [39, 44]. There are several potential mechanisms that can explain the role of obesity in dyspnea. These include obesity-related alterations in breathing mechanics and obesity-related metabolic alterations of locomotion [31, 39, 40, 44]. Alterations in breathing mechanics could be related to excessive fat mass in the abdominal and chest wall. The extra fat weight in the abdominal and chest areas increases the respiratory muscles load and work of breathing at any given level of ventilation, while requires higher metabolic demand (oxygen cost of breathing) and respiratory muscles effort [39, 40, 44]. In addition, adipose tissue encasing the chest and the abdomen decreases chest wall compliance (more stiffness), while placing the diaphragm and intercoastal muscles at a mechanical disadvantage. These impaired biomechanics further increase the mechanical load by inefficient respiratory muscles contraction, resulting in ventilatory constraints, especially during exercise [31, 40, 44]. The elevated mechanical load on the respiratory muscles also increases a neural ventilatory drive, which can be perceived as dyspnea [40, 44]. Another potential mechanism that could contribute to dyspnea is obesity-related metabolic alterations of locomotion. Compared to people with normal weight, individuals with obesity have a metabolic disadvantage even in non-body weight bearing activities such as cycling on recumbent bicycle. During locomotion, the excessive fat weight in the body and the limbs place an additional metabolic load on the active muscles at any given work-rate, decreasing the mechanical efficiency (oxygen consumption/work rate). As a consequence, there is an earlier onset of metabolic acidosis and increased buffering by bicarbonate, which results in higher CO₂ levels, disproportionate increase in ventilation, higher dyspnea perception and early exercise termination [31, 40].

RMT is a form of repetitive breathing exercises performed during inspiration, expiration or both [19, 45]. There are two main types of RMT: 1) The voluntary isocapnic hyperpnea, an endurance type of RMT; and 2) The resistive flow-dependent or pressure threshold loading, a strength type of RMT [19, 24, 45, 46]. The voluntary isocapnic hyperpnea RMT typically involves performing relatively high level of ventilation at rest for up to 30 min, aiming to improve respiratory muscle endurance. This regimen is carried out for 3 - 5 times per week for 3 - 5 weeks at intensity of 50-90% of maximal voluntary ventilation (MVV) [19, 24]. The resistive flow-dependent or pressure threshold loading RMT typically involves breathing exercise performed at rest while using a custom-built or a commercially available device which provides resistance to inhalation (inspiratory muscle training (IMT)) or exhalation (expiratory muscle training (EMT)) or both, aiming to improve respiratory muscle strength [19, 45, 46]. The load is often set at 15% to 70% of maximal inspiratory pressure (MIP) for IMT or maximal expiratory pressure (MEP) for EMT measured at baseline. The training regimen performed for 5 to 20 min per session, 3 - 5 times per week for about 4 weeks [19, 45].

Respiratory muscles have the capacity to adapt to repetitive stimuli similarly to other skeletal muscle [19, 45, 46]. In healthy individuals, systematic reviews and meta-analyses have demonstrated that RMT improves respiratory muscle strength and endurance as well as maximal oxygen consumption primarily in less fit subjects [19, 46], providing the opportunity for the utilization among cancer survivors, as these patients present low fitness as well [22, 34]. The effect of RMT on physical performance is not different between endurance and strength type of RMT, while the combined IMT and EMT strength type of RMT showed 12.8% higher improvement than IMT alone [19, 46].

In patients with chronic obstructive pulmonary disease (COPD), a meta-analysis of 32 randomized controlled trials showed significant improvement in inspiratory muscle strength (MIP; +13 cm H₂O), endurance time (+261 s), 6-min walking distance (+32 m) and quality of life (+3.8 units), while dyspnea was significantly reduced (Borg score -0.9 point; Transitional Dyspnea Index +2.8 units) after IMT interventions compared to control [47]. More recent meta-analysis of 14 randomized controlled trials in patients with COPD showed that RMT improved both daily dyspnea level (Medical Research Council Dyspnea Scale -0.38 units) and dyspnea during exercise (Borg Dyspnea Score -0.72 point) [48].

In patients with asthma, a meta-analysis of 11 randomized controlled studies (total of 270 participants) reported that IMT significantly improved inspiratory muscle strength (MIP +21.95 cm H₂O, 95% confidence interval (CI): 15.05 - 28.85) [49]. While a quantitative meta-analysis for dyspnea outcomes was not possible, a qualitative analysis of five studies showed improvement in dyspnea based on Borg and Medical Research Council Scales. Three of the five studies showed significant association between increase in MIP and decrease in dyspnea, supporting the mechanism of increasing inspiratory muscles strength for reducing dyspnea as well as the potential role of IMT in dyspnea management. In addition, the analysis revealed a significant reduction in fatigue following the IMT intervention [49], a symptom that is most common among cancer survivors [50], and could be potentially improved with IMT.

A recent meta-analysis in patients with heart failure including 13 randomized controlled studies (n = 342) (10 IMT alone and three IMT combined with other interventions) demonstrated a significant improvement in inspiratory muscle strength (MIP +25.12 cm H₂O, 95% CI: 15.29 - 34.95) [51]. Although only few of these studies assessed the effect of IMT on dyspnea, one study of combined IMT and aerobic exercise has demonstrated a significant reduction in dyspnea after the intervention. Despite this limited evidence on the beneficial effect of IMT on dyspnea, this meta-analysis robustly demonstrated an improvement in CRF, functional capacity and quality of life, suggesting clinical improvement using IMT for this patient group [51].

In patients undergoing thoracic surgery, a network meta-analysis of 25 studies, involving 2,070 patients, compared RMT to aerobic exercise training on post-operation outcomes [52]. The study showed RMT resulted in lower odds ratio of post-operation complications (0.33), respiratory failure (0.22) and reduction in length of hospitalization (-1.69 days) compared to control. The effect of RMT was similar to aerobic exercise training for these outcomes [52], providing an opportunity for safe and effective low-cost, low resources intervention. Additionally, considering the fact that most patients diagnosed with solid tumors will undergo some surgical procedure [50], RMT could be integrated during the pre-operative waiting window to optimize post-operative outcome.

In patients with lung cancer undergoing curative lung resection surgery, a meta-analysis of 10 studies (eight included both IMT and aerobic exercise) showed that preoperative IMT compared with controls decreased the length of hospitalization (-3.44 days) and the effect was further enhanced when IMT was combined with aerobic exercise [53]. Preoperative IMT reduced the likelihood of developing pneumonia and post-operation complications by 63% and increased functional capacity in 6-min walking distance (+20.2 m) [53].

A systematic literature search of three electronic databases (MEDLINE/PubMed, Web of Science and EBSCO) was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines through February 4, 2024 [54]. The search strategy was created considering terms related to the effect of intervention (RMT) and the outcome of interest (dyspnea) in cancer survivors. Utilizing the following keywords: “respiratory muscle training” OR “inspiratory muscle training” OR “expiratory muscle training” AND “cancer” OR “cancer survivors” OR “patients with cancer” AND “dyspnea” OR “breathless” OR “shortness of breath”, relevant publications were extracted. Quality of the studies was assessed using the National Heart, Lung, and Blood Institute’s tailored quality assessment tools [55, 56]. A total of 76 articles were identified through initial literature search. After reviewing titles/abstracts and full-text studies, 66 articles were excluded due to not meeting the eligibility criteria. Ten studies (randomized controlled trials (n = 7), controlled but not randomized controlled trial (n = 1) and single arm studies (n = 2)) assessing the effect of RMT on dyspnea in patients with cancer were included in the current review (Fig. 1). Although dyspnea was a secondary outcome in these studies, a risk of bias was relatively low and most studies had a good quality (Supplementary Material 1, www.wjon.org).

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Figure 1. PRISMA flow diagram of literature search and studies selection.

While strong evidence for the beneficial effect of RMT on dyspnea in cancer survivors is scarce, preliminary data support its potential therapeutic value (Table 1) [10-17, 57, 58]. A small pilot, single group study has demonstrated a beneficial effect of 4-week RMT on dyspnea in cancer survivors (lung, n = 5 and breast, n = 5) [10]. Both Baseline Dyspnea Index (+1.2 units) and Transitional Dyspnea Index (+5.1 units) were significantly improved following the RMT intervention [10]. A small randomized controlled pilot study has shown that an addition of RMT to standard 12-week exercise training improved dyspnea in daily life (Transitional Dyspnea Index +2.9 points) among 19 breast cancer survivors [11]. A randomized controlled study of 40 patients with non-small-cell lung cancer undergoing lobectomy has shown significant improvement in dyspnea following 3 weeks of preoperative pulmonary rehabilitation combined with breathing exercises but not specifically RMT [12]. Patients in the rehabilitation group reduced their dyspnea after the intervention (Borg dyspnea -0.7 units) and remained with significantly lower post-operation scores compared to the usual care control group (Borg dyspnea 2 versus 3.1 points) [12]. A pilot randomized controlled trial of 46 patients with clinically stable lung cancer has shown dyspnea improvement after IMT intervention [13]. The experimental group performed five IMT sessions weekly for 12 weeks, while the control group continued with usual care. At 12-week time point, a significant difference (-0.8 points) was found between the groups in modified Borg Dyspnea Scale, suggesting the efficacy of IMT for reducing dyspnea [13].

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Table 1. Studies on Respiratory Muscle Training in Cancer Survivors

A pilot investigation (single group) evaluated the efficacy of 4 weeks EMT among six patients with head and neck cancers who underwent laryngectomy. This study showed 38% reduction in dyspnea (-2.3 units in dyspnea index) after the intervention [16]. Recent, large controlled (not randomized) study (66 hospitalized stable patients with lung cancer) demonstrated a significant reduction in dyspnea on exertion after 2 weeks intervention. The intervention group participated in IMT + exercise therapy (30 breathes twice daily at 30-40% of MIP + 20 - 40 min exercise therapy 5 days/week for 2 weeks), while the control group received exercise therapy alone. The mean difference between the groups following the intervention was -1 unit on modified Borg Dyspnea Scale, suggesting beneficial therapeutic effect of IMT [17]. However, a virtual telemedicine pilot randomized controlled study found no improvement in dyspnea among 22 patients with lung cancer. Patients randomly received either IMT + walking or educational intervention. The IMT + walking group participated in six video conferences (every 2 weeks for 12 weeks) instructing to perform 10 - 15 min of IMT twice daily for 5 days/week + to walk four times a week. The control group participated in video conferences with general education on the benefits of exercise. After both 6 and 12 weeks, no difference in dyspnea score was observed between the groups [57].

Three randomized controlled trials evaluated the effect of RMT on dyspnea in patients undergoing hematopoietic stem cell transplantation [14, 15, 58]. While two studies demonstrated positive effect of IMT + rehabilitation exercise versus exercise alone on dyspnea reduction [14, 15], one study found only a trend towards dyspnea reduction with IMT but did not reach statistically significant difference between the groups [58]. A possible explanation could be that in the latter study, patients were hospitalized with more severe acute condition, where complementary aerobic exercise was performed at lower volume and intensity [58].

Given the importance of dyspnea in cancer survivorship, ongoing studies including from our group are currently in the process. These include “Inspiratory muscle training and behavioral support to alleviate dyspnea and promote walking in lung cancer survivors: a pilot study” (NCT05059132), “Respiratory muscle training before surgery in preventing lung complications in patients with stage I-IIIB lung cancer” (NCT04067830) and “Inspiratory muscle training in obese breast cancer survivors” (NCT05193149) (ClinicalTrials.gov).

Taken together, the existing evidence from randomized controlled trials, controlled study and single arm interventional studies supports the potential efficacy of RMT on dyspnea reduction in cancer survivors. In particular, the efficacy was pronounced when RMT was combined with other modalities of rehabilitative exercise and delivered in a supervised, in-person fashion. However, given the variation and some inconsistency in the study outcomes, large randomized controlled trials assessing dyspnea as primary outcome in survivors with different cancer types are warranted to establish the therapeutic efficacy of RMT on dyspnea in cancer survivors.

As previously stated, dyspnea is highly prevalent among cancer survivors, it is associated with increased mortality risk, causing functional limitations, compromising mental health, and resulting in avoidance of physical activity and poor quality of life [1, 2, 4]. Effective therapeutic options are limited, and pharmacological interventions have unclear benefits [2]. There are multifactorial reasons for dyspnea in cancer survivors [2, 4, 6, 7]; however, physiological objective data indicate that weakness and fatigue of respiratory muscles could play a mechanistic role in dyspnea among cancer survivors [6, 24-26, 29]. Moreover, obesity, low CRF and physical inactivity are highly prevalent among cancer survivors [59], factors that further exacerbate dyspnea [6]. While only preliminary data exist on the efficacy of RMT among cancer survivors [10-13], robust evidence in healthy and diseased populations has demonstrated the efficacy of RMT to increase inspiratory muscle strength and reduce dyspnea [19, 45-47, 49, 51]. Achieving higher strength and endurance of respiratory muscles with RMT can improve the fatigability resilience of these muscles, decrease the relative mechanical effort of breathing and reduce the perception of dyspnea (Fig. 2) [19, 45-47, 49, 51]. Since RMT has an excellent safety profile along with a potential mechanism of reducing dyspnea by enhancing respiratory muscle function, integrating this training modality in cancer survivorship and cancer rehabilitation could be clinically valuable for patients with cancer and dyspnea complaints [19, 45-47, 49, 51]. In addition, most RMT devices are easy to use, have low costs and can be utilized in home-based/limited supervision interventions, which further support their feasibility, practical application and integration in clinical and research settings for cancer survivors.

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Figure 2. Mechanisms of dyspnea in cancer and the potential therapeutic role of respiratory muscles training for dyspnea management.

A comprehensive dyspnea evaluation is beneficial for RMT intervention efficacy assessment prior to integration in cancer survivorship [60, 61]. Dyspnea is a complexed multidimensional symptom that warrants evaluation of sensory-perceptual experience (subjective report of the breathing), affective distress (unpleasantness of breathing), and impact or burden on functional ability or activity of daily living and quality of life) as recommended by American Thoracic Society [1, 3]. Dyspnea is moderately linked to pain, and commonly co-occurs with fatigue, anxiety and depression, encompassing physiological, psychological and emotional factors, which further challenge its evaluation [1, 61]. Although many instruments and scales are available for dyspnea evaluation, only few have been studied in patients with cancer to comprehensively assess the sensory-perceptual experience, affective distress and impact [3, 60, 61]. An important consideration for utilizing any instrument is its ability to diagnose/characterize dyspnea versus its responsiveness of detecting change over time with intervention [60, 61]. While, Baseline Dyspnea Index, Transitional Dyspnea Index and Borg Dyspnea Scale showed responsiveness to RMT interventions [10-13], their validity in cancer survivor has yet to be established [60, 61].

Several dyspnea instruments have been validated for patients with cancer [61]: Cancer Dyspnea Scale (CDS), the Dyspnea-12 (D-12) and Total Dyspnea Scale for Cancer (TDSC) [61]. CDS is a 12-item patient-reported outcome measure of perceived breathlessness. The CDS was studied among lung cancer patients and was validated for other cancers as well. The scale is divided into three factors related to “sense of anxiety”, “sense of effort” and “sense of discomfort”. The scale was cross-culturally validated and showed good to excellent internal consistency and good test-rest reliability. The CDS showed moderate to high correlation with Visual Analogue Scale-Dyspnea (VAS-D) and modified Borg Dyspnea Scale, although responsiveness to interventions is yet to be appraised [61]. The D-12 is a 12-item patient-reported outcome scale, developed to assess dyspnea severity in cardiopulmonary and cancer diseases. D-12 is divided into two factors called “physical” and “affective” which describes physical and mental breathlessness components [61]. D-12 scale was cross-culturally validated, has demonstrated good to excellent internal consistency and moderately to strongly correlated with dyspnea severity (modified Borg Dyspnea Scale) and (modified Medical Research Council Dyspnea Scale). In addition, a moderate correlation was found between D-12 and measures related to physical status, psychological status, quality of life, and activities of daily living. However, responsiveness to interventions is very low [61]. TDSC is an 11-item patient-reported outcome for cancer patients. The scale is a comprehensive measure of dyspnea and its impact on activities of daily living. TDSC is composed of two factors (effects on activities of daily living and psychology, and effects on social activity). The scale has a good to excellent internal consistency, has a strong correlation with CDS and a moderate correlation with quality of life and psychological status. Responsiveness to interventions of TDSC is unknown [61]. The minimal clinically important difference (MCID) for interventions was established for the D-12 scale only and included patients with cardiorespiratory diseases but not with cancer. The MCID for D-12 is 2.8 points for interventions ranging from 2 to 6 months [62, 63].

CPET is a gold-standard tool for evaluation of unexplained exertional dyspnea and direct measure of CRF (VO₂max), a strong predictor of survival including in patients with cancer [27, 28, 30, 31, 64]. Directly measured variables from CPET enable to distinguish between cardiopulmonary and muscles limitations to exercise and assist to identify the cause of exertional dyspnea. Despite the overwhelming evidence on the utility of CPET in diagnosis, prognosis and treatment efficacy evaluation, CPET is underutilized in oncology and cancer survivorship settings and is not a standard of care [2, 30, 31, 64]. Thus, referring cancer survivors who complain on dyspnea to CPET combined with pulmonary function test and respiratory muscle strength testing (MIP and MEP) could be valuable for identifying the cause of dyspnea to inform and optimize the treatment [30, 31, 64].

In patients with cardiopulmonary diseases, the scientific clinical literature on the efficacy of RMT in reducing dyspnea is compelling [19, 45-47, 49, 51]. However, in patients with cancer, the evidence for RMT efficacy is preliminary, insufficient and with many gaps [10-13, 65]. Randomized controlled trials of RMT interventions are warranted in patients with different types of cancer and dyspnea. Evidence on the efficacy of RMT in reducing dyspnea in cancer survivors with and without respiratory muscle weakness seems to be an important topic for investigation, since RMT may be therapeutically beneficial for dyspnea even in patients with normal respiratory muscle function. While evaluation instruments of dyspnea have been developed and studied in patients with cancer, establishing MCID for these tools in cancer survivors is an important clinical research goal. In addition, studying different RMT protocols such as IMT vs. IMT + EMT, varying frequencies and intensities of RMT and combination of strength and endurance RMT could provide more insights for optimization of this intervention to reduce dyspnea. Finally, given the mechanisms of dyspnea, the robust evidence on the health benefits of supervised exercise training in patients with cancer [23, 66-68], the supportive evidence for superior outcomes in combining exercise with RMT [11, 12, 51], rigorously studying this combination in cancer survivors is an important future research direction for cancer care.

In summary, dyspnea is a prevalent and debilitating symptom among cancer survivors, associated with increased mortality risk, mental health compromises, functional limitations in activity of daily living and poor quality of life. Effective evidence-based, therapeutic options are limited. RMT is a well-established form of training having strong evidence for improving respiratory muscle function and alleviating dyspnea primarily in patients with pulmonary diseases. Physiological mechanistic studies and preliminary interventional evidence support the potential therapeutic effects of RMT in reducing dyspnea for cancer survivors. However, large randomized controlled trials examining the effect of RMT alone and in combination with supervised exercise training are necessary for evidence-based recommendations to integrate RMT in dyspnea management for cancer survivors.

Suppl 1. NHLBI Study Quality Assessment Tools 2021.

Acknowledgments

None to declare.

Financial Disclosure

The authors declare that they do not have a financial relationship with any commercial entity that has an interest in the subject of this manuscript. This study received no external funding.

Conflict of Interest

The authors declare that they do not have a conflict of interest.

Author Contributions

All authors participated in review. They were involved in writing and revising the article prior to submission. Baruch Vainshelboim contributed to conceptualization, methodology, visualization, drafting, writing and revising the submitted manuscript. Sagar D. Sardesai and Dharini Bhammar contributed to conceptualization, critical review and revision of the article for important intellectual content. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

Abbreviations

CDS: Cancer Dyspnea Scale; CPET: cardiopulmonary exercise testing; CRF: cardiorespiratory fitness; EMT: expiratory muscle training; IMT: inspiratory muscle training; MIP: maximum inspiratory pressure; MEP: maximum expiratory pressure; RMT: respiratory muscle training; TDSC: Total Dyspnea Scale for Cancer; VO₂max: maximal oxygen consumption

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