Therapeutic efficacy, prognostic variables and clinical outcome of 177Lu-PSMA-617 PRLT in progressive mCRPC following multiple lines of treatment: prognostic implications of high FDG uptake on dual tracer PET-CT vis-à-vis Gleason score in such cohort

Abstract

Objective: To evaluate the therapeutic response, progression free survival (PFS), overall survival (OS) and clinical toxicity of 177Lu-PSMA-617 PSMA targeted radioligand therapy (PRLT) in the setting of heavily pre-treated metastatic castrate-resistant prostate cancer (mCPRC) patients and also examine the association of prognostic variables with therapeutic outcome in such patient cohort. Methods: We examined the medical records of mCRPC patients who had undergone 177Lu-PSMA-617 PRLT from March 2017 to February 2019 in our institute. Patients receiving equal to or more than two cycles were included and analyzed in this retroprospective study.The 68Ga-PSMA-11 PET-CT and 18-fludeoxyglucose positron emission tomography (18FDG PET)-CT scan findings, serum prostate-specific antigen (PSA) change, health-related quality of life (HRQoL) scales (Eastern Cooperative Oncology Group/Karnofsky score) and Gleason score were assessed for their implications on the outcome of therapy. The treatment response was evaluated under three categories: (a) symptomatic (b) biochemical and (c) imaging response.The PFS and OS following first PRLT were determined and the association of various variables with PSA doubling time (DT) and FDG uptake in the lesions were analyzed. Toxicity assessment was undertaken objectively by National Cancer Institute-Common Terminology Criteria for Adverse Events scale v. 5.0 for haematological and nephrotoxicity, and salivary gland toxicity assessed by xerostomia inventory score. Results: A total of 40 mCRPC patients (age range: 46–84 years; median 63 years), who had undergone 177Lu-PSMA-617 PRLT, of at least two cycles was identified and selected for the analysis. FDG uptake was noted in 87.5% of patients (n = 35). Out of 40 cases, 21 were responders (CR, PR and SD) and 19 were non-responders (PD) on symptomatic and biochemical scales while on molecular imaging response, 16 (43%) were responders and remaining 21 (57%) were non-responders. Lesion-wise, 68Ga-PSMA-11 avid metastatic nodal disease responded well with 177Lu PSMA-617 PRLT, as compared to hepatic and skeletal lesions. The median OS and PFS was 12 and 7 months respectively following first PRLT. Patients with negative serum PSA-DT demonstrated superior 1 year PFS as compared to those with positive serum PSA-DT (52.5 vs 47.5%) (p = 0.029). Patients receiving greater than two cycles PRLT demonstrated a higher negative PSA-DT as compared to those receiving two cycles (p-value = 0.03). Grade 1 xerostomia was observed in two patients (5%) (mean xerostomia score of 23), haematotoxicity in seven patients [Grade I (n = 2, 5%) and Grade II (n = 5, 14%)]. Conclusion: 177Lu-PSMA-617 PRLT was well-tolerated and able to produce disease control with good symptomatic and biochemical responses in the context of heavily pre-treated mCRPC with progressive disease, with low toxicity profile. Evident association of high FDG uptake was observed with aggressive disease biology coupled with increasing Gleason score and poorer 12 months PFS. Negative PSA-DT following therapy demonstrated longer PFS. The results demonstrate important future role of 177Lu-PSMA-617 PRLT in the treatment of mCRPC. Advances in knowledge: The present work explored in a large teriary cancer care setting, the efficacy of 177Lu-PSMA-617 PRLT, in an aggressive and unselected subset of mCRPC. The response and outcome was correlated with a number of prognostic variables, including molecular imaging findings (FDG uptake in the metastatic lesions), PSA DT and Gleason score.

Lutetium-177 prostate-specific membrane antigen-617 theranostics: New therapeutic hope in metastatic castrate-resistant prostate cancer?

“…[ 4 ] In a retrospective study of forty patients of mCRPC who failed on first-line treatment and received at least two cycles of 177 LuPSMA radioligand therapy, 21 (52.5%) had a symptomatic and biochemical response and 16 (43%) responded on molecular imaging, without any Grade 3 or 4 toxicity. [ 5 ] The most recent Phase II long-term outcome data on 90 patients in mCRPC with a median follow-up time of 28 months was published in January 2020[ 6 ] and showed median OS of 14 months and PFS of 11.8 months, similar to the index study[ 1 ] and with low toxicity.…”

Improving quality of life in patients with metastatic prostate cancer following one cycle of 177Lu-PSMA-617 radioligand therapy: a pilot study

“…The adverse side effects of chemotherapy such as myelosuppression, gastrointestinal and cardiac toxicity, neuropathy as well as alopecia have also to be weighed against the favorable side effects profile of PSMA treatment [1]. Despite its relevance, to date only fewer studies analyzed the influence of PSMA therapy on QoL [2,[17][18][19][20] and none of these studies closely examined the association between improvements in health-related QoL and changes in PSA. Our patient cohort consisted of 30 PSMA-treated patients, all of them were affected by bone metastases.…”

“…The mean ECOG performance status improved from 2.5 to 1.8. Suman et al [18] reported findings in a total of 40 mCRPC patients who had undergone at least 2 cycles of PSMA. QoL was assessed by the ECOG score and Karnofsky index, no specific assessment of pain symptoms was performed.…”

“…Furthermore, our study wanted to shed light on the relationship between changes in PSA and QoL, which has not been thoroughly investigated in previous studies on QoL and PSMA therapy [2,[17][18][19][20]. A PSA reduction at 2-months follow up was observed in 73 % (22/30) of patients, which is in keeping with the above mentioned most recent meta-analysis on 681 patients showing any PSA decline in 75 % of patients [11] (1).…”

Towards personalizing treatment strategies in mCRPC: can dual-tracer PET-CT provide insights into tumor biology, guide the optimal treatment sequence, and individualize decision-making (between chemotherapy, second-generation anti-androgens and PSMA-directed radioligand therapy) early in the disease course?

“…1). In a recently published study [24] that critically examined in the setting of [ 177 Lu]Lu-PSMA PRLT the value of [ 18 F]FDG uptake in an unselected subset of highly pretreated patients of mCRPC, there was an evident association of high [ 18 F]FDG uptake with increasing Gleason score and poorer 12-month progression-free survival (PFS), indicative of aggressive disease biology. When these patients were sub-divided into groups (Gp) as per the [ 18 F]FDG uptake (SUVmax) in the lesions (SUVmax values 0-7, 7.1-15 and ≥ 15.1), with approximately equal distribution of cases in each, patients with Gleason score 8 and above showed higher [ 18 F]FDG uptake (SUVmax > 7.1).…”