Discussion
The impact of the disease on patients’ QoL, has become an important consideration in health care and a weighty factor in clinical management of cancer patients22. In recent years, the investigation whether baseline QoL-assessment, in addition to clinic-pathological factors, may improve prognostic stratification, has aroused a growing interest, and focused the attention on the development of reliable QoL-assessment questionnaires, designed to capture information directly from the respondent. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), is considered to be a valid self-completion questionnaire to reliably and accurately assess QoL in cancer patients and is to date one of the most widely adopted instruments in cancer research and clinical practice23. In several studies among patients with different cancer histologies, the EORTC QLQ-C30, often associated with disease-specific questionnaires, has proved to be a valid and reliable tool for the assessment of the correlation between QoL and OS. In a quality of life study among patients with gastro-esophageal cancer, the appetite-loss item of the EORTC QLQ-C30, resulted to be a significant independent predictor of survival, highlighting the significant prognostic role of QoL measures in this patient population24. A study involving patients with Platinum-resistant Ovarian Cancer (PROC) reported a median OS extension of 6.3 months and 6.0 months, in patients with better physical function score and lower abdominal/gastrointestinal symptom scores respectively25. The reported significant correlation of the abdominal/gastrointestinal domain of the ovarian specific questionnaire (OV28)26 with OS, confirmed the importance of using a disease-specific instrument in the assessment of QoL, in order to better evaluate QoL aspects more strictly correlated with each particular type of cancer, exceeding the limits of a general questionnaire for all cancer patients. Similar findings are reported in a recent study among patients with nasopharyngeal carcinoma treated with intensity modulated radiation therapy. In this study QoL was assessed by asking patients to answer the EORTC QLQ Head and Neck Cancer-Specific Module (H&N35)27 in addition to the EORTC QLQ-C30 (version 3.0). A high pretreatment cognitive functioning score in QLQ-C30 was associated with longer local recurrence-free survival, while H&N35 pretreatment teeth-ill and felt-ill were significantly correlated with progression-free survival and distant-free survival respectively28. For patients with bone metastases, particularly occurring in advanced breast, prostate, lung and renal cell cancers29, pain represents a heavy burden, often responsible for a significant worsening of QoL. The pain-centered questionnaire EORTC Bone Metastases Module (EORTC QLQ-BM22) was specifically designed as a supplement to the EORTC QLQ-C30 to evaluate the specific aspects of QoL impairment associated with bone metastases30.  The present study is the first analysis of the prognostic value of baseline QoL measures in mCRPC patients with symptomatic bone metastases treated with 223Ra and was performed by submitting to patients both the EORTC QLQ-C30 and the EORTC QLQ-BM22. In accordance with the above studies among patients with different advanced cancers, baseline QoL showed a significant correlation with OS in our patient population. The resulting model of the multivariate analysis performed after PCA, showed that among patients with the same clinical condition in terms of baseline Hb and tALP values, those with better self-reported QoL, are more suitable to obtain a greater survival benefit from 223Ra. In particular, as shown in the OS analysis stratified by score of baseline QoL, the median OS is significantly longer in patients with higher baseline QoL scores as compared to patients with lower scores, specifically 16 and 8 months of median OS respectively. A recent paper proposed a three-variable predictive score as a reliable and helpful tool for stratifying the expected OS of mCRPC patients treated with 223Ra, by taking into account the baseline arrangement of ECOG-PS, PSA and Hb13. Our analysis, underlining the significant correlation between baseline QoL and OS, suggest as including the baseline QoL assessment in a multi-variable model of baseline clinicopathological factors, may add prognostic potential, thus improving mCRPC patients’ stratification about prognosis. Considering that the effect of 223Ra on OS is known to be obtained only after at least five cycles, stratifying patients’ expected OS is of fundamental importance31. The EORTC QLQ-C30, represents a valid and complete instrument, provides significant results, as reported in previous systematic reviews and allows QoL assessment at a minimal cost32,33. In a previous paper, the QLQ-BM22 demonstrated to be a sensitive instrument for assessing palliative-radiotherapy benefits in patients with symptomatic bone metastases, by evaluating responders’ QoL, before treatment and two months after treatment34. The pain domain of the QLQ-C30 and three out four domains of the QLQ-BM22, specifically painful sites, pain characteristics and functional interference, showed a significant improvement after treatment. This study confirmed the importance of using QLQ-BM22 as a bone metastases-specific tool when assessing QoL and evaluating response to palliative treatments in patients with symptomatic bone metastases. Our evaluation of QoL trend during 223Ra-therapy and follow-up period, performed through both the QLQ-C30 and the QLQ-BM22 questionnaire showed a global deterioration of QoL. These findings might be partially attributed to the inclusion of both responders and non-responders to 223Ra in terms of bone-pain relief, in the statistical analysis. Moreover, as we included all patients who had received at least one cycle of 223Ra, patients still in treatment were also evaluated, as well as patients with ”flare phenomenon” in pain35,36, meaning that potential responders to treatment were included in the study before they obtained a significant benefit from all the 6 scheduled cycles of therapy. A patient-reported QoL analysis from the ALSYMPCA study, performed with the general EuroQoL 5D (EQ-5D) questionnaire37 and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire38,39, demonstrated that in patients undergoing 223Ra-therapy, improved survival is associated with a slower decline in QoL over time as compared to placebo40. Despite our study showed similar results and confirmed QoL deterioration over time in mCRPC patients treated with 223Ra from baseline during both therapy and follow-up period, different instruments have been employed for QoL evaluation. These considerations might put the attention on the development of a standardized method to be applied in QoL assessment, in order to optimize the sharing of comparable data on patients’ QoL outcomes between different centers, thus improving both research and clinical practice. A possible limitation of the present study is the analysis conducted only in a single center among a limited sample of patients.