Factors influencing outcome post Radium 223 dichloride in castrate resistant prostate cancer- A review of some real world challenges

Introduction: Radium-223dichloride has been the first approved targeted Alpha therapy, shown to prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively assessed the different factors influencing the OS and patient management. Method: A total of 32 mCRPC patients with failure of previous treatment were considered for inclusion. Different haematological parameters, no of cycles, performance status, disease grade and toxicities during treatment were considered for evaluation of the OS. Radium-223dichloride (55MBq/kg) was administered every 4 weeks for a maximum of 6 cycles. Primary end points were OS and progression free survival, while secondary end points were therapy toxicities, change in performance status, biochemical response and skeletal related events.

Results: Of the 32 patients, 2 patients with limited biochemical investigation were excluded from final biochemical analysis. Median age of patients was 77 years (range 57- 90 yrs), median follow up was 399 days (range 5- 1761 days). 28 patients (88%) had Gleason of > 8 and 4 patients (12%) had Gleason of ≤7. Patients with stage IV disease were 25 patients (78%) while ≤stage III disease were 7 patients (22%). Functional imaging was done in all patients with 18F Fluoride PET (n=28) (88%) and bone scan (n=4) (12 %). 30 patients had follow up data. Flare response was seen in 1 patient. No statistical significance was seen between S.PSA, ALP or other biochemical parameters with OS, only haemoglobin statistically correlated with OS (p value 0.028) and while differentiating between number of cycles (<4, 5 & 6 cycles) (p value 0.037). Total of 151 cycles were given in 32 patients, with < 4 cycles in 8 patients (25%), and 5 or more cycles in 24 patients (75%) of which 3 patients had 5 cycles and 21 patients had 6 cycles. Among 8 patients with < 4 cycles; 3 patients died, of which 1 patient died of unknown cause after 1st cycle, while another 2 patients (6%) died due to neutropenic sepsis. The number of cycles ( <4 cycles and > 4 cycles) were correlated with Kaplan Meier overall survival (p value 0.038). In the subgroup analysis ( <4 cycles, 5 cycles and 6 cycles) the cycles correlated with p value of 0.019. The OS in patients with 1-4 cycles was 230 days, in 5 cycles with 313 days and in 6 cycles was 613 days. Adverse effects in form of myelosuppression leading to stopping of full 6 cycles was seen in 7 patients of 32 patients ( 22%) and significantly correlated to OS ( p value 0.048). No statistical significance was seen between any of the co-morbidities, prior therapy or baseline or change in ECOG, pain scoring, or any biochemical parameters as albumin, platelets, ALP, WBC, WBC/WCC ratio, neutrophils, lymphocytes and N/L ratio. Grade 1/2 thrombocytopenia was noted in 13 patients (41%) but did not require hospitalisation or influenced any change in cycles. Conclusion: Higher numbers of cycles of Ra223 dichloride are seen to be associated with better OS. Myelosupression was associated with poor OS. Patients with better haematological profile as Hb ≥ 10 mg/dl at first presentation were seen to complete maximum number of the cycles. Thus better patient selection with good haematological profile can lead to maximum chances of completion of maximum cycles with better OS. Perhaps this information is useful to consider Ra223 dichloride at an earlier state in the patient journey.Acknowledgements: Support for this work includes UICC-TF/18/602556