Nuklearmedizin
DOI: 10.1055/a-2365-8113
Original Article

Prognostic Significance of Baseline Clinical and [68Ga]Ga-PSMA PET Derived Parameters on Biochemical Response, Overall Survival, and PSA Progression-Free Survival in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Undergoing [177Lu]Lu-PSMA Therapy

Esmail Jafari
1   The Persian Gulf Nuclear Medicine Research Center, Department of Nuclear Medicine, Molecular Imaging, and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
,
Reyhaneh Manafi-Farid
2   Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
Hojjat Ahmadzadehfar
3   Department of Nuclear Medicine, Klinikum Westfalen, Dortmund, Germany (Ringgold ID: RIN301634)
,
Fatemeh Salek
1   The Persian Gulf Nuclear Medicine Research Center, Department of Nuclear Medicine, Molecular Imaging, and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
,
Narges Jokar
1   The Persian Gulf Nuclear Medicine Research Center, Department of Nuclear Medicine, Molecular Imaging, and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
,
Ahmad Keshavarz
4   IoT and Signal Processing Research Group, ICT Research Institute, Faculty of Intelligent Systems Engineering and Data Science, Persian Gulf University, Bushehr, Iran (Ringgold ID: RIN199786)
,
GhasemAli Divband
5   Department of Nuclear Medicine, Jam Hospital, Tehran, Iran
,
Habibollah Dadgar
6   Cancer Research Center, RAZAVI Hospital, Imam Reza International University, Mashhad, Iran (Ringgold ID: RIN113387)
,
Farshad Zohrabi
7   Department of Urology, Bushehr Medical University Hospital, Bushehr University of Medical Sciences, Bushehr, Iran
,
Majid Assadi
1   The Persian Gulf Nuclear Medicine Research Center, Department of Nuclear Medicine, Molecular Imaging, and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
› Author Affiliations

Abstract

Background In this study, we sought to identify the clinical baseline characteristics and pre-therapy 68Ga-PSMA PET derived parameters that can have impact on PSA (biochemical) response, OS and PSA PFS in patients with metastatic castration-resistant prostate cancer (mCRPC) who undergo RLT with [177Lu]Lu-PSMA-617.

Methods Various pre-treatment clinical and PSMA PET derived parameters were gathered and computed. We used PSA response as the criteria for more than a 50% decrease in PSA level, and OS and PSA PFS as endpoints. We assessed the collected parameters in relation to PSA response. Additionally, we employed univariable Cox regression and Kaplan-Meier analysis with log rank to evaluate the influence of the parameters on OS and PFS.

Results A total of 125 mCRPC patients were included in this study. The median age was 68 years (range: 49–89). Among the cases, 77 patients (62%) showed PSARS, while 48 patients (38%) did not show PSA response. The median OS was 14 months (range: 1–60), and the median PSA-PFS was 10 months (range: 1–56). Age, prior history of chemotherapy, and SUVmax had a significant impact on PSA response (p<0.05). PSA response, RBC count, hemoglobin, hematocrit, neutrophil to lymphocyte ratio (NLR), alkaline phosphatase (ALP), number of metastases, wbPSMA-TV, and wbTL-PSMA significantly affected OS. GS, platelet count, NLR, and number of metastases were found to have a significant impact on PSA PFS.

Conclusion We have identified several baseline clinical and PSMA PET derived parameters that can serve as prognostic factors for predicting PSA response, OS, and PSA PFS after RLT. Based on the findings, we believe that these clinical baseline characteristics can assist nuclear medicine specialists in identifying RLT responders who have long-term survival and PFS.



Publication History

Received: 18 April 2024

Accepted after revision: 12 July 2024

Article published online:
03 September 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Rawla P. Epidemiology of prostate cancer. World journal of oncology 2019; 10 (02) 63 DOI: 10.14740/wjon1191. (PMID: 31068988)
  • 2 Schaeffer E, Srinivas S, Antonarakis ES. et al. Prostate cancer, version 1.2021: Featured updates to the nccn guidelines. JNCCN Journal of the National Comprehensive Cancer Network 2021; 19 (02) 134-143
  • 3 Parker C, Nilsson S, Heinrich D. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. New England Journal of Medicine 2013; 369 (03) 213-223 DOI: 10.1056/NEJMoa1213755. (PMID: 23863050)
  • 4 Dadgar H, Seyedi Vafaee M, Norouzbeigi N. et al. Dual-phase 68Ga-PSMA-11 PET/CT may increase the rate of detected lesions in prostate cancer patients. Urologia Journal 2021; 88 (04) 355-361
  • 5 Dadgar H, Emami F, Norouzbeigi N. et al. Application of [68 Ga] PSMA PET/CT in Diagnosis and Management of Prostate Cancer Patients. Molecular Imaging and Biology 2020; 22: 1062-1069 DOI: 10.1007/s11307-019-01445-z. (PMID: 31758511)
  • 6 Assadi M, Manafi-Farid R, Jafari E. et al. Predictive and prognostic potential of pretreatment 68Ga-PSMA PET tumor heterogeneity index in patients with metastatic castration-resistant prostate cancer treated with 177Lu-PSMA. Frontiers in Oncology 2022; 12: 6956
  • 7 Shiri I, Salimi Y, Maghsudi M. et al. Differential privacy preserved federated transfer learning for multi-institutional 68Ga-PET image artefact detection and disentanglement. European journal of nuclear medicine and molecular imaging 2023; 1-14
  • 8 Maffey-Steffan J, Scarpa L, Svirydenka A. et al. The (68)Ga/(177)Lu-theragnostic concept in PSMA-targeting of metastatic castration-resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up. Eur J Nucl Med Mol Imaging 2020; 47 (03) 695-712
  • 9 Assadi M, Pirayesh E, Rekabpour SJ. et al. 177Lu-PSMA and 177Lu-DOTATATE therapy in a patient with metastatic castration-resistant prostate cancer and neuroendocrine differentiation. Clinical nuclear medicine 2019; 44 (12) 978-980
  • 10 Assadi M, Rezaei S, Jafari E. et al. Potential application of lutetium-177-labeled prostate-specific membrane antigen-617 radioligand therapy for metastatic castration-resistant prostate cancer in a limited resource environment: Initial clinical experience after 2 years. World Journal of Nuclear Medicine 2020; 19 (01) 15-20 DOI: 10.4103/wjnm.WJNM_20_19. (PMID: 32190017)
  • 11 Jafari E, Ahmadzadehfar H, Dadgar H. et al. An overview on prostate-specific membrane antigen uptake in malignancies other than prostate cancer: a pictorial essay. World Journal of Nuclear Medicine 2020; 19 (03) 260-265
  • 12 Ahmadzadehfar H, Eppard E, Kürpig S. et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget 2016; 7 (11) 12477
  • 13 Ahmadzadehfar H, Schlolaut S, Fimmers R. et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177 Lu]Lu-PSMA-617 radioligand therapy. Oncotarget: Impact Journals 2017; 8 (61) 103108-103116
  • 14 Ahmadzadehfar H, Wegen S, Yordanova A. et al. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [177 Lu] Lu-PSMA-617. European journal of nuclear medicine and molecular imaging 2017; 44: 1448-1454
  • 15 Karimzadeh A, Heck M, Tauber R. et al. 177Lu-PSMA-I&T for treatment of metastatic castration-resistant prostate cancer: prognostic value of scintigraphic and clinical biomarkers. Journal of Nuclear Medicine 2023; 64 (03) 402-409
  • 16 Jafari E, Amini AL, Ahmadzadehfar H. et al. Cardiotoxicity and cardiac monitoring following the use of radiotheranostics agents including 177Lu-PSMA for prostate cancer and 177Lu-DOTATATE for neuroendocrine tumors. Nuklearmedizin-NuclearMedicine 2021; 60 (02) 99-105 DOI: 10.1055/a-1332-8230. (PMID: 33461224)
  • 17 Jafari E, Ahmadzadehfar H, Bagheri D. et al. Assessment of early oxidative stress following the use of radiotheranostics agents 177Lu-PSMA for prostate cancer and 177Lu-DOTATATE for neuroendocrine tumors; radioprotective effect of vitamin C. Nuclear Medicine Communications 2021; 42 (03) 325-331 DOI: 10.1097/MNM.0000000000001327. (PMID: 33306634)
  • 18 Jafari E, Ahmadzadehfar H, Dadgar H. et al. An overview on prostate-specific membrane antigen uptake in malignancies other than prostate cancer: A pictorial essay. World Journal of Nuclear Medicine 2020; 19: 260
  • 19 Jokar N, Moradhaseli F, Ahmadzadehfar H. et al. Theranostic approach in liver cancer: an emerging paradigm to optimize personalized medicine. Clinical and Translational Imaging 2023; 11 (01) 51-70
  • 20 Jokar N, Velikyan I, Ahmadzadehfar H. et al. Theranostic Approach in Breast Cancer: A Treasured Tailor for Future Oncology. Clin Nucl Med 2021; 46 (08) e410-e420 DOI: 10.1097/RLU.0000000000003678. (PMID: 34152118)
  • 21 Shooli H, Nemati R, Ahmadzadehfar H. et al. Theranostics in brain tumors. PET clinics 2021; 16 (03) 397-418 DOI: 10.1016/j.cpet.2021.03.005. (PMID: 34053584)
  • 22 Stangl-Kremser J, Sun M, Ho B. et al. Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic castration-resistant prostate cancer receiving prostate-specific membrane antigen targeted radionuclide therapy. The Prostate 2023; 83 (14) 1351-1357
  • 23 Kafka M, Horninger A, di Santo G. et al. Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study. European Urology Oncology 2024; 7 (03) 421-429 DOI: 10.1016/j.euo.2023.07.018. (PMID: 37604763)
  • 24 Fedorov A, Beichel R, Kalpathy-Cramer J. et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging 2012; 30 (09) 1323-1341 DOI: 10.1016/j.mri.2012.05.001. (PMID: 22770690)
  • 25 Nioche C, Orlhac F, Boughdad S. et al. LIFEx: a freeware for radiomic feature calculation in multimodality imaging to accelerate advances in the characterization of tumor heterogeneity. Cancer research 2018; 78 (16) 4786-9 DOI: 10.1158/0008-5472.CAN-18-0125. (PMID: 29959149)
  • 26 Eiber M, Herrmann K, Calais J. et al. Prostate cancer molecular imaging standardized evaluation (PROMISE): proposed miTNM classification for the interpretation of PSMA-ligand PET/CT. Journal of Nuclear Medicine 2018; 59 (03) 469-478 DOI: 10.2967/jnumed.117.198119. (PMID: 29123012)
  • 27 Scher HI, Morris MJ, Stadler WM. et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. Journal of Clinical Oncology 2016; 34 (12) 1402
  • 28 Ferdinandus J, Eppard E, Gaertner FC. et al. Predictors of response to radioligand therapy of metastatic castrate-resistant prostate cancer with 177Lu-PSMA-617. Journal of Nuclear Medicine 2017; 58 (02) 312-319
  • 29 Ahmadzadehfar H, Rahbar K, Baum RP. et al. Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177 Lu] Lu-PSMA-617. A WARMTH multicenter study (the 617 trial). European Journal of Nuclear Medicine and Molecular Imaging 2021; 48: 113-122
  • 30 Barber TW, Singh A, Kulkarni HR. et al. Clinical Outcomes of (177)Lu-PSMA Radioligand Therapy in Earlier and Later Phases of Metastatic Castration-Resistant Prostate Cancer Grouped by Previous Taxane Chemotherapy. J Nucl Med 2019; 60 (07) 955-962 DOI: 10.2967/jnumed.118.216820. (PMID: 30683770)
  • 31 Emmett L, Crumbaker M, Ho B. et al. Results of a prospective phase 2 pilot trial of 177Lu–PSMA-617 therapy for metastatic castration-resistant prostate cancer including imaging predictors of treatment response and patterns of progression. Clinical genitourinary cancer 2019; 17 (01) 15-22
  • 32 Pathmanandavel S, Crumbaker M, Yam AO. et al. 177)Lu-PSMA-617 and Idronoxil in Men with End-Stage Metastatic Castration-Resistant Prostate Cancer (LuPIN. J Nucl Med 2022; 63 (04) 560-566
  • 33 Manafi-Farid R, Harsini S, Saidi B. et al. Factors predicting biochemical response and survival benefits following radioligand therapy with [177 Lu] Lu-PSMA in metastatic castrate-resistant prostate cancer: a review. European Journal of Nuclear Medicine and Molecular Imaging 2021; 1-14
  • 34 Heidegger I, Kesch C, Kretschmer A. et al. Biomarkers to personalize treatment with 177Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer-a state of the art review. Therapeutic Advances in Medical Oncology 2022; 14: 17588359221081922
  • 35 Heck MM, Tauber R, Schwaiger S. et al. Treatment outcome, toxicity, and predictive factors for radioligand therapy with 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. European urology 2019; 75 (06) 920-926
  • 36 Hofman MS, Violet J, Hicks RJ. et al. 177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial. The Lancet Oncology 2018; 19 (06) 825-833
  • 37 Yadav MP, Ballal S, Bal C. et al. Efficacy and safety of 177Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer patients. Clinical nuclear medicine 2020; 45 (01) 19-31 DOI: 10.1097/RLU.0000000000002833. (PMID: 31789908)
  • 38 Yadav MP, Ballal S, Sahoo RK. et al. Radioligand Therapy With 177Lu-PSMA for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. American Journal of Roentgenology 2019; 213 (02) 275-285
  • 39 Vlachostergios PJ, Geyer JT, Miller J. et al. Exceptional response to pembrolizumab in a patient with castration-resistant prostate cancer with pancytopenia from myelophthisis. Journal of Oncology Practice 2019; 15 (06) 343-345
  • 40 Vlachostergios PJ, Zachos I, Tzortzis V. Biomarkers in prostate-specific membrane antigen theranostics. Diagnostics 2021; 11 (06) 1108 DOI: 10.3390/diagnostics11061108. (PMID: 34207069)
  • 41 Hartrampf PE, Seitz AK, Weinzierl FX. et al. Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [177Lu]Lu-PSMA I&T during long-term follow-up. European Journal of Nuclear Medicine and Molecular Imaging: Springer Science and Business Media Deutschland GmbH 2022; 1-9
  • 42 Rasul S, Hartenbach M, Wollenweber T. et al. Prediction of response and survival after standardized treatment with 7400 MBq 177Lu-PSMA-617 every 4 weeks in patients with metastatic castration-resistant prostate cancer. European Journal of Nuclear Medicine and Molecular Imaging 2021; 48 (05) 1650-1657
  • 43 Barber TW, Singh A, Kulkarni HR. et al. Clinical outcomes of 177Lu-PSMA radioligand therapy in earlier and later phases of metastatic castration-resistant prostate cancer grouped by previous taxane chemotherapy. Journal of Nuclear Medicine 2019; 60 (07) 955-962
  • 44 Ahmadzadehfar H, Schlolaut S, Fimmers R. et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu] Lu-PSMA-617 radioligand therapy. Oncotarget 2017; 8 (61) 103108
  • 45 Gafita A, Calais J, Hui W. et al. Predictive factors and prediction nomograms for LuPSMA radioligand therapy in patients with metastatic castration-resistant prostate cancer: an international multicentre retrospective study. Soc Nuclear Med. 2020
  • 46 Hartrampf PE, Hüttmann T, Seitz AK. et al. SUVmean on baseline [18F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [177Lu]Lu-PSMA I&T. European Journal of Nuclear Medicine and Molecular Imaging 2023; 50 (11) 3465-3474
  • 47 Grubmüller B, Senn D, Kramer G. et al. Response assessment using 68 Ga-PSMA ligand PET in patients undergoing 177 Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer. European journal of nuclear medicine and molecular imaging 2019; 46: 1063-1072 DOI: 10.1007/s00259-018-4236-4. (PMID: 30569186)
  • 48 Tian S, Lei Z, Gong Z. et al. Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review. Cancer Cell International 2020; 20 (01) 409 DOI: 10.1186/s12935-020-01508-0. (PMID: 32863768)
  • 49 Kumano Y, Hasegawa Y, Kawahara T. et al. Pretreatment Neutrophil to Lymphocyte Ratio (NLR) Predicts Prognosis for Castration Resistant Prostate Cancer Patients Underwent Enzalutamide. BioMed Research International 2019; 2019: 9450838 DOI: 10.1155/2019/9450838. (PMID: 30800682)
  • 50 Tatenuma T, Kawahara T, Hayashi N. et al. The Pretherapeutic Neutrophil-to-Lymphocyte Ratio for Docetaxel-Based Chemotherapy Is Useful for Predicting the Prognosis of Japanese Patients with Castration-Resistant Prostate Cancer. Biomed Res Int 2019; 2019: 2535270
  • 51 Wrenger R, Jüptner M, Marx M. et al. Pre- and intratherapeutic predictors of overall survival in patients with advanced metastasized castration-resistant prostate cancer receiving Lu-177-PSMA-617 radioligand therapy. BMC Urology 2022; 22 (01) 96
  • 52 Yordanova A, Linden P, Hauser S. et al. The value of tumor markers in men with metastatic prostate cancer undergoing [(177) Lu]Lu-PSMA therapy. Prostate 2020; 80 (01) 17-27
  • 53 Kessel K, Seifert R, Weckesser M. et al. Molecular analysis of circulating tumor cells of metastatic castration-resistant Prostate Cancer Patients receiving 177Lu-PSMA-617 Radioligand Therapy. Theranostics 2020; 10 (17) 7645
  • 54 Gafita A, Calais J, Grogan TR. et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. The Lancet Oncology 2021; 22 (08) 1115-1125
  • 55 Robert S, Ken H, Jens K. et al. Semiautomatically Quantified Tumor Volume Using 68Ga-PSMA-11 PET as a Biomarker for Survival in Patients with Advanced Prostate Cancer. Journal of Nuclear Medicine 2020; 61 (12) 1786
  • 56 van der Sar ECA, Kühr AJS, Ebbers SC. et al. Baseline Imaging derived predictive factors of response following [177Lu] Lu-PSMA-617 therapy in salvage metastatic castration-resistant prostate cancer: a lesion-and patient-based analysis. Biomedicines 2022; 10 (07) 1575 DOI: 10.3390/biomedicines10071575. (PMID: 35884878)
  • 57 Grubmüller B, Rasul S, Baltzer P. et al. Response assessment using [68Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer. The Prostate 2020; 80 (01) 74-82
  • 58 Gafita A, Heck MM, Rauscher I. et al. Early prostate-specific antigen changes and clinical outcome after 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer. Journal of Nuclear Medicine 2020; 61 (10) 1476-1483
  • 59 Suman S, Parghane RV, Joshi A. et al. 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. The British Journal of Radiology 2019; 92: 20190380
  • 60 Ferdinandus J, Eppard E, Gaertner FC. et al. Predictors of Response to Radioligand Therapy of Metastatic Castrate-Resistant Prostate Cancer with 177Lu-PSMA-617. Journal of Nuclear Medicine: Society of Nuclear Medicine 2017; 58 (02) 312-319
  • 61 Onal C, Sedef AM, Kose F. et al. The hematologic parameters in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate. Future Oncology 2018; 15 (13) 1469-1479
  • 62 Koo KC, Lee JS, Ha JS. et al. Optimal sequencing strategy using docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant prostate cancer: utilization of neutrophil-to-lymphocyte ratio. World journal of urology 2019; 37: 2375-2384