This pre-specified analysis from the CORE study is, to the best of our knowledge, the first RCT to compare a contemporary CR program framework with a CBET in cancer survivors, assessing feasibility, safety and satisfaction parameters. Overall, the main results suggest that both programs are feasible, as indicated by recruitment, adherence, and safety outcomes. In several key parameters, including patient satisfaction, the CBCR was superior to the CBET.
Exercise-based programs for cancer survivors are a topic of contemporary interest [19,31-33]. However, several studies have focused on specific cancer subtypes (mostly breast cancer), with small samples, different endpoints and usually comprising CR versus usual care (no rehabilitation/ no exercise intervention) [19,31-33]. In the CORE trial, high CV risk survivors of various types of cancer, previously undergoing several treatments options (regarding cardiotoxicity), and/or with different CV comorbidities were eligible, reproducing the clinical practice heterogeneity, without depriving any cancer patient from a guided exercise intervention, as to attempt to reproduce real-word settings. Given the data supporting the potential benefits of exercise as a relevant non-pharmacological approach for people living with an oncologic disease, the cancer survivor support care must consider ET as supportive therapy (besides PA recommendations) which makes tailoring of this intervention an area of major interest [10,12-14,17]. As such, data pertaining to optimal program designs and components in terms of feasibility, acceptability and safety, are of paramount importance.
In this study, 72.4% of 116 potentially eligible patients initially screened accepted to participate and performed baseline assessments, suggesting that patients were motivated to engage in an exercise-based intervention. This value represents a higher rate compared to other reports that included a CR program aimed at cancer survivors [21,22]. Interestingly, recent reviews, focusing on barriers and facilitators for PA engagement reported that perceived health benefits, wellbeing and healthcare professionals’ guidance in a tailored exercise intervention could be important facilitators [33,34]. When assessing the reasons for not participating, work obligations accounted for around half of cases when declining to participate. Of note, this may be related to the fact that the exercise sessions took place during working hours. It should also be noted that, to avoid possible confusion in terms of consent rate and adherence, the timetables of exercise sessions were the same in both the CBCR and CBET groups. These data are informative, as future studies should attempt to address scheduling issues as potential means to increase overall participation in these programs, thus reaching a larger population.
The high retention and completion rates in both groups should be noted. Importantly, the fact that in both trial arms an intervention was delivered should be considered, when assessing these data. Indeed, in trials where participants are allocated to a control group, with no intervention besides usual care, more dropouts could be present, influencing completion rate. As such, our results in these feasibility outcomes are higher than those reported in other trials, which might be related to study design (namely the presence of an ET intervention in both groups) [21,22,29,32].
In terms of adherence, there were significant differences between groups, favoring the CBCR. Notably, absences were more frequent in CBET, with a relevant number of cases (14.2%) of missing sessions without any specific reason attributed to by participants. Several potential factors may be related to these findings. In this regard, the multidisciplinary nature of CR, encompassing close counselling and education, motivational sessions, and peer group support, could potentially help in explaining these data [24]. Moreover, the hospital setting of the CR unit may also have contributed to compliance with the schedule sessions. Finally, it has been suggested that lifestyle behavioral interventions and the encouragement for exercise beyond the supervised sessions, as recommended in CR programs, may increase adherence rates [35]. Furthermore, sessions delivered by the program’s psychologist addressing self-efficacy and behavioral skills could also have reinforced participant’s motivation [36,37]. Literature has shown that cancer survivors and people with CVD may share common problems, regardless the primary diagnosis, namely disturbances related to sleep disorders, fatigue, sexual problems, anxiety and depression, suggesting that a common comprehensive rehabilitation program can be just as suitable, so these motivational and educational group sessions may also have contributed to improving adherence rates in CBCR [36-38].
We should mention the difficulties encountered due to the pandemic situation experienced along the study period, with some patients missing exercise sessions due to covid-19 infection or isolation rules, which may have negatively affected feasibility rates.
The feasibility assessment of the CORE trial, provides detailed information concerning some of the hindrances to program application in cancer survivors’ population, undertaking special importance. Given the lack of data on this topic, the findings derived from this study can be of great value, by presenting an overview of some of the challenges to program implementation, and thus providing a potentially useful framework for further studies on this field.
Safety considerations, especially in high-risk CV patients, constitute a particular concern, in order to determine the appropriate level of medical supervision advised, according to clinical determinants [24]. The knowledge of the safety intervention profiles is pivotal for the healthcare providers to consider the implementation of specific therapies as a part of the standard of care. Exercised-based interventions addressing patients living with and beyond cancer, have been systematically recognized as safe strategies [39-41]. However, many studies do not present a comprehensive analysis of AEs related or unrelated to exercise during the ET intervention. Recent data examining safety profiles in exercise-based interventions in oncologic settings indicate that several studies contain no mention of AEs, suggesting an incomplete report [39,42]. Thus, there is a need for more data concerning possible AEs over the course of exercise-based interventions. The results of the CORE trial, suggest that exercise can be a safe strategy, with no serious AEs related to ET having been reported in either group. Nonetheless, all patients underwent a CPET before starting the program, making it possible to obtain important information in terms of risk stratification associated with exercise practice [16]. It should be highlighted that two patients were excluded after baseline assessment due to abnormalities during CPET, in need of further investigation. The recent AHA statement illustrates the potential role of the CPET prior to beginning a structured cardio-oncology rehabilitation intervention in high-risk patients, a concept reinforced by the present data [16]. Interestingly, in a previous study comprising a CR program for cancer patients without prior CVD, 2 patients (out of 25 enrolled) were withdrawn due to serious cardiac AEs (arrhythmias) [32].
As detailed in Tables 3 and 4, most of AEs were musculoskeletal. This finding underscores the need for an integrative approach, as a multidisciplinary team able to both address these as well as other potential needs specific to cancer patient can be pivotal in this type of programs [35]. These skills proved to be particularly important in addressing musculoskeletal disorders.
Regarding patient’s satisfaction, the questionnaire revealed a high level of satisfaction with both interventions, although with higher scores in the CBCR group (Table 5). Satisfaction scores regarding program location as well as monitoring by professionals throughout the intervention were also high. In this background, the fact that 84.2% patients in CBCR indicated that the intervention met initial expectations (“very satisfied”) should be highlighted. This contrasts with 51.3% of patients in CBET, suggesting that patients prefer an intervention that takes place in a clinical setting with a multidisciplinary outlook. Given the major role of these programs in terms of morbidity and quality of life in CVD in general, and the expanding interest in oncologic setting, current data from these analyses could be highly informative in helping improve future trial designs (namely in comparison to other modalities, such as those incorporating telemedicine), to enhance overall access and allow for optimization of tailoring to the needs of different patient groups [18,27,43,44].
Limitations
Some limitations should be considered when analyzing the present data. Firstly, patients were derived from a single center, on a limited number of individuals [26]. As such, generalization of these findings to other settings should be cautious. Secondly, due to the impossibility of blinding patients and those who delivered the intervention, the open design of this study may have influenced retention rates in both groups. Thirdly, as described in the results, both the COVID-19 pandemic as well as timing of the interventions (with possible limitations in terms of access to sessions during work hours) should also be considered. Finally, it should be noted that the primary endpoint in the CORE trial was CRF. Albeit the present study derives from a pre-specified analysis, this point should be considered when interpreting the data. While these points should be acknowledged, we believe that the current data derived from a contemporary RCT, provide a useful and pragmatic framework for future larger studies on this topic of major clinical importance.