Clinical endpoints, such as overall survival, directly measure relevant outcomes. Surrogate endpoints, in contrast, are intermediate, stand-in measures of various tumour-related metrics and include tumour growth, tumour shrinkage, blood results, etc. Surrogates may be a time point measurement, that is, tumour shrinkage at some point (eg, response rate) or biomarker-assessed disease status, measured at given time points (eg, circulating tumour DNA, ctDNA). They can also be measured over time, as with progression-free survival, which is the time until a patient presents with either disease progression or death. Surrogates are increasingly used in trials supporting the marketing authorisation of novel oncology drugs. Yet, the trial-level correlation between surrogates and clinical endpoints—meaning to which extent an improvement in the surrogate predicts an improvement in the direct endpoint—is often moderate to low. Here, we provide a comprehensive classification of surrogate endpoints: time point measurements and time-to-event endpoints in solid and haematological malignancies. Also, we discuss an overlooked aspect of the use of surrogates: the limitations of surrogates outside trial settings, at the bedside. Surrogates can result in the inappropriate stopping or switching of therapy. Surrogates can be used to usher in new strategies (eg, ctDNA in adjuvant treatment of colon cancer), which may erode patient outcomes. In liquid malignancies, surrogates can mislead us to use novel drugs and replace proven standards of care with costly medications. Surrogates can lead one to intensify treatment without clear improvement and possibly worsening quality of life. Clinicians should be aware of the role of surrogates in the development and regulation of drugs and how their use can carry real-world, bedside implications.

Mature almond trees bear fruit mainly on short shoots called spurs, with only a small percentage of fruit produced laterally on long 1-year-old shoots. As a result, maintenance of large numbers of healthy spurs per tree is critical for fruit production. However, spurs that bear fruit have lower leaf area, leaf nitrogen content, and CO2 assimilation rate than non-fruiting spurs. This has been correlated with reduced percentages of spur survival and return bloom the following season. Thus, we hypothesized that spur leaf area, and ultimately spur health could be enhanced through application of foliar sprays and soil nitrogen treatments that would enhance leaf nitrogen content and spur leaf area. To test our hypothesis, we selected almond trees exhibiting significant yield differences as a consequence of differential soil rates of nitrogen fertilization (N rate) for three prior years (140, 224, and 392 kg/ha). In each tree, three spur types [non-fruiting spurs (F0); spurs with one fruit (F1); spurs with two fruit (F2)] were selected on the east side of the canopy and tracked for one complete season (2011–2012). Four foliar treatments (nutrient replacement, nutrient replacement with biostimulant, nitrogen, and non-spray) were directly applied to individual spurs in each N rate in the spring of 2011 and characteristic such as leaf nitrogen, and fruit quality were recorded throughout the season. In winter of 2012, spur survival and return bloom were addressed through individual visual inspection of the tagged spurs. In this experiment, soil and foliar N treatments effectively increased spur leaf area, fruit, and leaf nitrogen concentration. In the high N treatment, the leaf nitrogen values exceeded the critical nitrogen concentration established for almond trees and the critical leaf area for spur survival and blooming thresholds established by past research in this area. However, none of these positive changes in leaf N or leaf area improved spur survival and/or return boom of any spur type. Indeed, survival and hull + shell weight tended to be lower in the population of fruiting spurs with the highest leaf area and leaf nitrogen concentration and the return bloom probabilities were always lower in fruiting spurs than in non-fruiting spurs, independent of the nitrogen rate. These results and the relationship between nitrogen rate and spur survival are discussed.