Limitations in pre-operative assessment Peak V′O2 is still widely used in practice for risk estimation at pre-operative assessment (as discussed in a chapter on pre-surgical evaluation later in this Monograph [66]). However, this is an effort-dependent variable that is influenced by peripheral factors (detraining, muscle weakness), particularly in lung cancer patients (who frequently present with associated COPD). In this context, it remains largely unknown whether a given peak V′O2 carries similar prognostic information in a patient limited by “lung factors” (i.e. mechanical-ventilatory and gas exchange) compared with another primarily limited by peripheral abnormalities. Due to the effects of obesity in increasing V′O2 for a given WR (as discussed in a chapter by NEDER et al. [14] in this Monograph), peak V′O 2 might be within the “low risk” range in a patient with severely reduced peak WR moreover, peak V′O2 correction by total body weight may penalise obese subjects exercising in a cycle ergometer [98]. Submaximal variables are not free from controversies: the θL is not always identified, particularly in ventilatory-limited patients with COPD [99]. In addition, the V′E–V′CO2 slope decreases as critical mechanical constraints progress with COPD severity [100] thus, a relatively preserved (or even reduced) V′E–V′CO 2 slope might give false reassurance of low risk despite the presence of end-stage COPD. Effects of interventions The interpretation of changes in tolerance to constant WR testing The magnitude of improvement in endurance exercise tolerance (time to intolerance (Tlim)) is influenced by the baseline Tlim [101]. This largely stems from the fact that tolerance to a given WR decreases hyperbolically above an individual’s highest sustainable WR. i.e. critical power (CP) [102]. Thus, Tlim is expected to vary greatly among subjects depending on where the selected WR lies in the individual’s power–duration relationship [103]. For instance, if the pre-intervention WR is substantially above the CP, Tlim might be excessively short. Conversely, a sub-CP test can be sustained for prolonged periods of time. If the intervention increases CP, a test performed just above this parameter is biased to “respond” to a greater extent than the other tests, i.e. regardless of the magnitude of the true physiological effect. Under these circumstances, the meaning of a given absolute (s) or relative (%) change in Tlim after an intervention might be difficult to interpret across subjects [103]. The MCID for the constant WR test Despite some valuable attempts in defining the MCID for Tlim in COPD (e.g. a 100-s or 33% increase from baseline) [104], these thresholds have not been prospectively validated in COPD or other clinical populations. In fact, it is conceivable that the MCID varies according to patient’s baseline Tlim, a complex issue that also complicates the interpretation of changes in lung function over time [105]. What are the key gaps in the knowledge that need to be addressed in the next 10 years to expand CPET application in the clinical arena? CPET in the investigation of exercise intolerance: the key unmet clinical needs Table 1 presents a list of research areas that should be considered in the future investigation of exercise intolerance. https://doi.org/10.1183/2312508X.10015318 xvii