Prognostic value of 99mTc-HYNIC-Octreotide scan in metastatic castrate resistant prostate cancer patients candidate for 177Lu-PSMA radioligand therapy

Introduction: 177Lutetium-Prostate Specific Membrane Antigen-617 (177Lu-PSMA) radioligand therapy (RLT) is an emerging treatment option for patients with metastatic castrate resistant prostate cancer (mCRPC). However, overall and biochemical response rates have been reported about 30% and 50%, respectively; emphasizing the importance of identifying response to treatment prognosticators. It is known that neuroendocrine differentiation may occur during progression of mCRPC, causing suppression of the PSMA gene, resulting in Somatostatin receptor-positive cells deprived of PSMA receptor. This subgroup is correlated with more aggressive clinical behavior of prostate cancer and unfavorable prognosis. This study aimed to evaluate the prognostic value of 99mTc-HYNIC-Octreotide scan in predicting response to treatment in mCRPC patients candidate for 177Lu-PSMA RLT.

Methods: <h4>36 consecutive mCRPC patients who were candidate for 177Lu-PSMA RLT had their background and laboratory data documented. All patients underwent 99mTc-HYNIC-Octreotide scan before RLT. Somatostatin-avidity of tumoral lesions was categorized in comparison to the liver, including no uptake, mild uptake (lower than the liver), moderate uptake (comparable to the liver) and severe uptake (higher than liver). Subsequently, patients underwent at least two cycles of 177Lu-PSMA RLT at 8 week intervals. Patient follow-up was performed with complete blood count (CBC), renal and liver function tests acquired every 4 weeks and prostate specific antigen (PSA) at 8 weeks after each cycle. Biochemical response to treatment was assessed 2 months after the second cycle based on PSA levels. Patients who did not meet progressive disease criteria, including those with any amount of PSA decline, stable PSA or < 25% rise in PSA were categorized as responder and those with at least 25% rise in PSA as non-responder.</h4>

Results: <h4>Out of 36 patients, 8 had to be excluded from the study as they died during the initial 2 month follow-up after receiving only one cycle of RLT; mainly due to other complications such as COVID-19 infection. Out of the remaining 28 mCRPC patients with the mean age of 69.3 ± 8.1 years, 67.9% (n = 19) responded to RLT while 32.1% (n = 9) were non-responders. 28.5% (n = 8) patients had Octreotide-negative metastatic disease while 71.5% (n = 20) had only mild uptake. 13 out of the 19 responders (68.4%) and 7 out of the 9 non-responders (77.8%) had metastatic lesions with mild Octreotide uptake, revealing no significant correlation (P value > 0.05). Gleason score (P value = 0.042) and presence of visceral metastasis other than lymph nodes (P value = 0.026) were significantly correlated with outcome. Baseline PSA and alkaline phosphatase (ALP) levels, presence of skeletal and lymph node metastases, history of prior prostatectomy or external beam radiation therapy were not significantly correlated with outcome (P value > 0.05).</h4><h4>Limitations: The severe drop of patients referred for RLT during the COVID-19 pandemic, interfering effects of lock downs on patient follow-up and loss of patients during follow-up due to COVID-19-related causes prohibited us from acquiring a larger sample size, better categorizing the patients and evaluating overall survival with a longer follow-up.</h4>

Conclusions: <h4>Neuroendocrine differentiation of prostate cancer cells with Somatostatin-analogue avidity less than the liver is not significantly correlated with response to 177Lu-PSMA radioligand therapy in mCRPC patients. However, further studies are required to see whether the same is true for highly Somatostatin receptor-positive metastases and to evaluate the effect of neuroendocrine differentiation of prostate cancer cells on long term prognosis, recurrence rate and overall survival of mCRPC patients.</h4><h4>Keywords: Neuroendocrine differentiation, prostate cancer, 177Lu-PSMA, radioligand therapy, 99mTc-HYNIC-Octreotide, prognostic factor</h4>