Late, Persistent, Substantial, Treatment-Related Symptoms After Radiation Therapy (LAPERS): A New Method for Longitudinal Analysis of Late Morbidity—Applied in the EMBRACE Study

Current incidence methods for reporting mild or moderate symptoms capture the (first) occurrence of an event and do not allow distinguishing between patients who suffer from long-lasting versus transient morbidity. This paper introduces a new methodological approach that identifies cancer survivors who have clinically relevant, long-lasting symptoms (patients with late, persistent, substantial and treatment-related symptoms, [LAPERS]). LAPERS can be evaluated in patients with baseline information and at least 3 late follow-up assessments after treatment. LAPERS identifies individual patients with a given symptom that is substantial (above a predefined clinically relevant threshold) and must be present in at least half of the follow-ups. Baseline morbidity is accounted for by requiring the median of the late symptom score to be worse than the baseline condition. The LAPERS approach was applied to 4 relevant patient-reported genito-urinary/gastrointestinal symptoms within the prospective, longitudinal EMBRACE study (An intErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer, www.embracestudy.dk). LAPERS was compared with crude incidence and prevalence rates. Within the EMBRACE cohort, 651/1044 patients (62%) had baseline and long-term follow-up available (median follow-up: 42 months). There was a considerable gap between LAPERS, crude incidence, and prevalence rates. The proportion of patients with LAPERS events was 3.8-4.8 times lower than crude incidences. The highest prevalence rates across follow-up times were 1.8-2.6 times lower than crude incidences. These findings indicate limitations of incidence methods for reporting substantial patient-reported symptoms because a considerable proportion of patients with symptoms do not experience them persistently over time, as they may fluctuate or get successfully treated. In contrast, the LAPERS method for longitudinal analysis identifies patients with clinically relevant, long-lasting symptoms.