Summary (10 sec read)

Metastasis-directed Lu-177 PSMA therapy is a novel and effective treatment for oligometastatic prostate cancer (OMPC), which involves five or fewer metastatic sites. OMPC is a transitional state between localized and widespread metastatic prostate cancer, often diagnosed through advanced imaging techniques like PSMA PET-CT. This state is characterized by more indolent tumor biology, making it suitable for targeted focal ablative therapy.

Lu-177 PSMA therapy, recently approved by the FDA for metastatic castration-resistant prostate cancer (mCRPC), targets prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells. Administered intravenously, Lu-177 PSMA binds to PSMA receptors on tumor cells, emitting localized radiation to destroy malignant cells. This therapy is particularly effective in treating both visible and microscopic lesions identified through PSMA PET/CT scans.

Combining systemic therapy, such as Androgen Deprivation Therapy (ADT), with metastasis-directed therapies (MDT) like Lu-177 PSMA has shown improved patient outcomes and overall survival, as demonstrated in the STAMPEDE trial. Clinical studies indicate a positive correlation between the tumor radiation absorbed dose from Lu-177 PSMA therapy and treatment response, with minimal toxicity to organs like the kidneys and bone marrow.

A case at FMRI highlighted the therapy's success, with a 65-year-old patient showing significant PSA reduction and complete resolution of pelvic lymph nodes and prostatic lesions post-treatment, without significant side effects or bone marrow suppression, underscoring the efficacy and safety of Lu-177 PSMA therapy.

The number of prostate cancer cases around the world is very high and has been increasing over the years. In fact, it's the second most common cancer in men and the second leading cause of cancer deaths. Oligometastatic prostate cancer (OMPC) that has five or fewer sites of metastasis is considered a transitional state between localized and widespread metastatic tumors. With improvements in diagnostic modalities such as functional imaging / PSMA PET-CT, OMPC is being diagnosed with greater frequency than ever before.

OMPC is a unique clinical state with inherently more indolent tumor biology which is susceptible to metastasis-directed focal ablative therapy. However, the therapeutic approach for these groups of patients is not clear-cut, and validated systems to help doctors are still under development. Further prospective data is needed to best select patients with OMPC, which are most likely to benefit from a given therapeutic approach. Systemic therapy plays a crucial role in the treatment of these kinds of patients. That being said, the optimal type and duration are unknown. The addition of a second treatment to Androgen Deprivation Therapy (ADT) may also be helpful. Multiple recent studies have shown that systemic therapy and local, metastasis-directed therapies (MDT; like radiation or surgery) are effective when combined in the treatment of prostate cancer. MDT may also be used in select patients wishing to delay the initiation of systemic therapy. In addition, metastatic directed therapy in prostate cancer improves overall survival in prostate cancer as shown in the STAMPEDE trial.

Lutetium-177 labelled prostate-specific membrane antigen (177Lu-PSMA) is a promising new therapeutic approach to treat metastatic prostate cancer which has been approved recently by the FDA in the treatment of metastatic castration-resistant prostate cancer (mCRPC). This tumor-specific treatment is directed against PSMA, which is overexpressed in prostate cancer cells. So radioligand therapy using Lutetium-177 labelled PSMA molecule is able to deliver high dose targeted radiation directly to the tumor sites.

This therapeutic molecule is administered intravenously. It specifically seeks out and binds to the PSMA receptors on the tumor cells, and emits local radiation which leads to targeted irradiation of the malignant cells, leading to the cancer cell death. The very small lesions which are seen on PSMA PET/CT scans, may not be feasibly targeted with SBRT due to their small size or difficulty ascertaining their location without the radiotracer.

Treatment with PMSA-targeted radioligands had found to be beneficial in this setting, by treating all lesions (both those seen on PET imaging, and those too small to be seen). Given the decay characteristics of Lu-177, including the relatively short-range beta emissions and longer half-life, it is likely that Lu-177 can effectively target small metastatic lesions. Multiple studies by Von Eyben et al., Prive et al., Azad et al., Novartis, and Malik et. al. does showcase the potential promise of this agent in these settings. The earlier published data suggest that there is a linear relationship between tumor radiation absorbed dose from Lu-177 PSMA Therapy and treatment response. There is an increased likelihood of response with increasing dose to tumors. Moreover, the organ at risk from Lu-177 PSMA therapy (Kidney, bone marrow, etc.) does not overlap with EBRT-based treatment of the metastatic site. So overall the patient might get benefitted from both treatments without any significant side effects and may lead to improved patient outcomes.

Given below is an example of such a patient, treated at the Nuclear Medicine Therapy Center at FMRI Gurugram. He is a 65-year-old gentleman diagnosed with carcinoma prostate involving seminal vesicles with multiple pelvic lymphadenopathy. The initial PSA level was 28 ng/ml which was reduced to 0.3 ng/ml after a single dose of Lu-177 labelled PSMA therapy. The follow-up PSMA PET/CT scan demonstrates complete resolution of multiple pelvic lymph nodes and prostatic lesions. No evidence of any significant toxicity or bone marrow suppression was observed in the last six months of follow-up.

  1. Von Eyben, F.E.; Kiljunen, T.; Joensuu, T.; Kairemo, K.; Uprimny, C.; Virgolini, I. 177Lu-PSMA-617 radioligand therapy for a patient with lymph node metastatic prostate cancer. Oncotarget 2017, 8, 66112–66116.
  2. Privé, B.M.; Peters, S.M.B.; Muselaers, C.H.J.; van Oort, I.M.; Janssen, M.J.R.; Sedelaar, J.P.M.; Konijnenberg, M.W.; Zámecnik, P.; Uijen, M.J.M.; Schilham, M.G.M.; et al. Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study. Clin. Cancer Res. 2021, 27, 3595–3601.
  3. Malik D., Sen B., Thakral, P., Subha S., Manda, D., Virupakshappa. Upfront Use of 177Lu-Labeled PSMA Radioligand Therapy and Treatment Response Assessment in Treatment-Naive Prostate Cancer, Clinical Nuclear Medicine: 2022; 47 (2): e167-e169.