The prediction of the treatment response in diseases like mCRPCa with resistance to other treatments and increased likelihood of progression is of great importance in terms of guiding the treatment course. One of the most important milestones in determining whether PSMA imaging can be used to evaluate the efficacy of hormone therapy is to clarify the relation between PSMA expression and hormone therapy (NAD). In our study, we evaluated the PSA response predictability of
68Ga-PSMA PET/CT-based parameters such as SUVmax, SUVmean, Highest Peak, PSMA–TV, TL-PSMA, biochemical markers such as ALP and LDH, and the Gleason score, which is a pathological marker, in patients with mCRPCa before abiraterone/enzalutamide treatment.
Unfortunately, it is still difficult to accurately predict treatment response in prostate cancer even with use of recommended screening methods including imaging tools 9. Serum PSA measurement is the most appropriate biomarker for treatment response. Many physicians use the change in PSA levels to evaluate the efficacy of treatment in patients with mCRPCa. In previous studies, a PSA reduction of more than 50% confirmed 4 weeks after the initiation of treatment is considered as the gold standard for an effective response 14,15. The PSMA uptake in the tumor has been demonstrated to reliably reflect the number of viable tumor cells in preclinical studies 16. Total tumor volume obtained by 68Ga-PSMA PET/CT in mCRPCa may be superior to total tumor volume derived from bone scintigraphy as it detects both bone and soft tissue metastases 17. In a study by Gupta et al. 18 in mCRPCa patients treated with 177Lu-PSMA radio ligand, the authors reported the association of molecular vs. morphological criteria with a better performance in assessing the response via 68Ga-PSMA 11-PET/CT.
Karyağar et al. showed that the PSMA-TV value on pre-treatment 68Ga-PSMA PET/CT imaging and the post-treatment 12th week PSA value were able to predict the PSA response in 34 mCRPCa patients initiating enzalutamide treatment after docetaxel failure. Patients with a PSA response had significantly lower PSMA-TV values than the non-responders (78.37±80.99 cm3 vs. 451.58±734.61 cm3; p=0.028). At the 12th week of treatment, the mean serum PSA value was 9.35±17.54 ng/mL (0.53-61.4) in the responding group and 503.09±1028.16 ng/mL (8.60–4572) in the non-responder group (p<0.001) 19. In our study, the median Hpeak, PSMA-TV, TL-PSMA, 3rd month PSA value, delta PSA value and pre-treatment ALP values were significantly higher and able to predict the PSA response (p values were p=0.021, p<0.001, p<0.001, p<0.001, p<0.001 and p=0.027, respectively).
Plouznikoff et al. demonstrated that after a mean follow-up of 3 months, PSMA PET/CT is strongly associated with response to treatment in mCRPCa patients under NAD (enzalutamide or abiraterone) treatment. This strengthens the role of PSMA PET/CT in the follow-up of patients under NAD and confirms its usefulness as a modern PCa imaging technique. The authors also emphasized that while they did not find a PSMA-expressed flare phenomenon in their study, the likelihood of an early and limited flare phenomenon within the first 3 months of NAD cannot be excluded (20). In our study, we considered the 3rd month PSA values to determine the PSA response under treatment 8. The phenomenon of PSA flare during abiraterone therapy may occur up to 3 months after initiation of therapy in patients with mCRPCa 21. Although the emergence of the flare phenomenon does not affect PFS and OS, it may adversely affect the clinical decisions 22.
Karyağar et al. 19 found the cut-off value for PSMA-TV as >88.04 cm3 (area under the curve 0.731, p=0.028) in predicting the PSA response, and the sensitivity and specificity of PSMA-TV were 68.2% and 83.3%. Has Şimşek et al. 13 reported the cut-off values in predicting the PSA response to be >107 cm3 (p<0.001) for PSMA-TV and >1013 (p=0.001) for TL-PSMA, while the sensitivity and specificity values of PSMA-TV and TL-PSMA were reported as 75% and 80%. In our study, the cut-off value in predicting the response to PSA was ≥112.53 cm3 (p<0.001) for PSMA-TV, ≥857.1 (p<0.001) for TL-PSMA, and ≥16.36 g/ml for Highest peak (p=0.075). The sensitivity and specificity values were 84.6% and 84.4% for PSMA-TV, 92.3% and 90.6% for TL-PSMA and 69.2% and 68.7% for Highest peak. This showed that PSMA-TV, TL-PSMA and highest peak were important predictive parameters in estimating the response to PSA. The PSMA-TV and TL-PSMA values were significantly higher in progressive patients. Has Şimşek et al. 13 showed that using PSMA-based tumor burden in mCRPCa patients can be a useful method in selecting the patients who will benefit from docetaxel therapy and that this therapy may fail in patients with high TV-PSMA.
Bone ALP changes, rather than PSA, may play a role in predicting tumor response when PSA levels cannot provide accurate information about the effect of treatment on the degree of metastatic skeletal involvement or bone disease progression 9. In the study of Has Şimşek et al. 13 in predicting the PSA response after docetaxel treatment in patients with prostate cancer reported that high ALP (>64 U/L) level before treatment was statistically insignificant, while high LDH level (>234) U/L was significant and it was one of the independent prognostic factors in predicting PSA response. In contrast we found that pre-treatment median ALP values were significantly higher in patients with PSA progression, however there was no statistically significant difference between LDH levels.
Bernhardh et al. 23, considering the potential applications of volumetric PSMA PET/CT imaging, demonstrated that intratumoral PSMA expression may be an option to predict treatment response, and the success of radionuclide therapy in patients with metastatic prostate cancer is dependent on tumor size and intratumoral activity concentration. Schmuck et al. 12 concluded that PSMA-TV and TL-PSMA could better assess tumor burden of metastatic lesions than SUVmax in patients with biochemical recurrence after radical prostatectomy. They also stated that treatment response and failure were parallel to the coherent changes in both whole body PSMA-TV and whole-body TL-PSMA. Grubmüller et al. 24 proposed that parameters such as PSMA TTV, SUVmean, SUVmax and SUV-peak in PSMA 11-PET/CT may be appropriate to evaluate the treatment response in mCRPCa patients receiving systemic therapy. TL-PSMA may be a parameter that considers both lesion size and PSMA expression within the lesion in the prediction of metastatic disease. In the treatment of metastatic prostate cancer, treatment planning according to the size of the tumor burden has also gained importance 25,26. In our study, PSMA-TV (p<0.001) and TL-PSMA (p<0.001) values were found to be statistically significant in prediction of the progression in univariate logistic regression analysis, while TL-PSMA (p=0.005) value in multivariate analysis was found to be an independent prognostic factor in predicting progression.
Limitations of our study; the retrospective design, lack of post-treatment images, short follow-up period, and small number of patients are considered to be limitations of our study, however most of the studies in the literature are retrospective and the number of patients is similar.
In conclusion, our findings revealed the likelihood of two 68Ga-PSMA PET/CT parameters including PSMA–TV and TL-PSMA to predict the disease progression earlier than the PSA levels measured after treatment. Further prospective studies are needed to determine whether the combined use of 68Ga-PSMA PET/CT imaging and other biomarkers can potentially contribute to the prediction of treatment response in mCRPCa patients.
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