This observational study provides, for the first time, an overview of the clinical, social-health, and quality of life characteristics of frail patients with cancer, chronic pain and BTP together with their management in real life in Spain. It also evaluated the analgesic treatment received by patients for chronic pain and BTP and whether their choice was conditioned by the patients’ own frailty status.
Characteristics of BTP in frail cancer patients have not been described previously. However, Mercadante et al. recently published a large study in 4,016 patients with cancer and BTP . A comparison between our study and the latest encountered interesting results. Frail patients reported significantly greater mean number of BTP episodes per day than those in the reference study, 3.8 (95% CI 3.3-4.3) versus 2.4 (SD 1.4). The duration of BTP episodes reported by frail patients was shorter, 34.6 minutes (95% CI 28.8-40.3) versus 43.3 minutes (SD 36.9). The onset of BTP was sudden (short onset) in 43.2% of our frail patients, while this type of onset was seen in 68.9% of patients in the reference study. Even though the assessment of the BTP intensity was measured differently in both studies, we observed severe or unbearable BTP in 17.1% of our frail patients, and Mercadante et al. reported a mean intensity of 7.5 over 10 points . Furthermore, in another study conducted in 1,000 cancer patients, Davies et al reported severe BTP in 62.4% of patients. Similar results were observed among frail patients (62.6%) in our study .
Predictable BTP was found in 35.1% of our frail patients, alike data (30.5%) described by Mercadante et al.30 Difference on BTP mechanism was observed in both populations. Neuropathic pain was more frequently observed among our frail patients (16.7% vs 8.1%), while mixed pain was more common in those cancer patients of the referred study (71.8%, vs 31.1%) .
The higher the number of BTP episodes, the shorter the duration and the more gradual onset seen in frail patients. A pathophysiological process related to frailty status might underly these observations since a greater frequency of BTP episodes has been reported in patients with worse performance status . Interestingly, the performance status of patients observed in both studies was similar, 63.2 (95% CI 61-65.4) versus 61.8 (SD 18.73) .
Among our frail patients, 79.7% of them were in active treatment for cancer, likewise 78% of patients in the reference study. This situation should be considered, since receiving this type of treatment could condition the administration of other treatments, such as, for example, for background pain and BTP .
Drugs for the treatment of chronic pain and BTP administrated to frail patients did not substantially differ on their doses and the frequency of administration (Tables 3 and 4), to the standard treatment for chronic pain. Regarding BTP treatment, in our study, 83.8% of frail patients with cancer received opioid treatment for BTP control, just as patients with cancer included in other studies [26,27]. Transmucosal immediate release fentanyl was administered to 68.5% of frail patients with cancer, the treatment of choice for BTP in cancer patients . The doses of the treatments were within the range recommended in their prescribing information. On the other hand, our attention was caught by the fact that 10 patients used drugs that are not usually indicated for BTP but for basal pain therapy in standard practice, such as dexketoprofen, ibuprofen, metamizole or paracetamol, frequently complementary to the opioids administrated for the background chronic pain. In the Table 4 the number of administrations for such treatments were 28, but only 6 patients received only these drugs.
We observed BTP interference with daily activities in 93.7% of frail patients (Figure 1) while Mercadante et al reported that in 86% of their patients . Furthermore, they found that age, Karnofsky, BTP severity, short onset, and longer duration of BTP significantly interfered with daily activities of cancer patients. In our study, we were able to relate a poorer quality of life score (EQ-VAS) to a worse Karnofsky score in frail patients, already described in different studies [26,28,29]. In addition, our study found a significant association between quality of life and social exclusion in frail patients with cancer but due to the cross-sectional design we cannot know which one was the first event.
The EuroQoL-5D-5L questionnaire conducted in healthy Spanish population revealed that the 65–74-year-old age group reported problems with mobility (29.3%), self-care (10.4%), daily activities (19.1%), pain (43%), and anxiety or depression (20%) . According to our study, frail cancer patients with BTP seem to be more impaired, as 93.2% of frail patients experienced greater mobility problems, 74.2% self-care problems, 93.7% problems with activities of daily living, 98.2% pain, and 81.4% anxiety or depression (Figure 1). Meanwhile, data observed in a review of 32 studies in patients with cancer shows impairment rates for mobility ranging from 2-60%, self-care 2-50%, daily activities 15-100%, pain 12-80%, and anxiety or depression 13-100%, i.e., there is greater deterioration in frail patients in our study in three of the five dimensions .
The mean EQ-VAS score, as a measure of patient-perceived quality of life, was 51.3 mm (95% CI 48.5-54) in frail patients with BTP in our study, values well below those seen in the general Spanish population of the same age group, 69 mm (Figure 2) . In addition, this value is much more affected than in cancer patients, analysed in a review of 32 studies, who presented a value of 68.6 mm .
It is known that the occurrence of BTP has a significant impact on patient quality of life . In the case of patients in our study, the low quality of life levels observed could be due to both BTP and frailty status, or to the interaction of both factors.
In Spain, the prevalence of frailty has been studied in six cohort studies, ranging from 2.4% to 27.3% in patients over 65 years of age . However, in the setting of our study, conducted mainly in medical oncology units and in some pain and geriatric units, the prevalence of frailty is much higher [7,10,13], so the results of this study are relevant to standard clinical practice in these units.
This study has several limitations inherent to the cross-sectional observational design, which prevents causal relationships from being established. Patients were classified as frail using the Frail scale , following national recommendations , so frail patients could be classified differently from other classification scales not based on the Fried criteria . As this is a cross-sectional study, patients were included at different follow-up times after the onset of BTP. For this reason, we could not analyse which were the first treatments for BTP in frail patients or their doses, which could differ at the start, and then be adjusted. Other treatments for patients with cancer such radiotherapy and brachytherapy play an important role in this setting of patients for the treatment of pain with many advantages in elderly and frail patients, but not collected in our study that was focused on pharmacological treatment [11,12]