Clinical outcome of PSMA-guided radiotherapy for patients with oligorecurrent prostate cancer

In 1995, Hellman and Weichselbaum coined the phrase “oligometastases” to describe a state of cancer with a limited number of metastases in only one or a few sites [1]. From that time, numerous studies advocated for a local, aggressive treatment approach of patients with oligometastatic disease. An open-label phase 2 study randomized a cohort of 99 patients with a controlled primary tumor and 1–5 metastatic lesions to either palliative standard treatment or standard of care plus local treatment of metastases using stereotactic body radiation therapy (SBRT). After a median follow-up of 25 months, SBRT was associated with an improved overall survival compared with the control group [2]. Metastasis-directed therapy is even integrated in clinical guidelines for several tumor types. However, there is a lack of data regarding treatment of oligometastatic prostate carcinoma. The prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) enables detection of small metastases hitherto undetectable by conventional imaging [3‐7]. Recently, Ost et al. reported a significantly longer androgen deprivation therapy (ADT)-free survival for a cohort of 62 patients with oligorecurrent prostate cancer undergoing metastasis-directed therapy (MDR) compared with surveillance alone. Although the study was planned as a prospective, multicenter phase 2 trial, the number of patients was limited and no data were available on overall survival (OS) [8]. To this end, we aimed to evaluate the clinical outcome after local SBRT for patients with oligorecurrent prostate carcinoma detected by PSMA-PET/CT imaging.

The clinical outcome of patients with metastatic prostate cancer improved with intensified systemic therapy. Several large, prospective trials reported enhanced overall survival with docetaxel or abiraterone acetate plus prednisone in men with newly diagnosed, metastatic disease [13‐16]. However, all these trials were done before PSMA-PET/CT was widely available. Due to its high sensitivity, PSMA imaging is often performed in patients with PSA relapse after primary treatment leading to an increased number of patients diagnosed with oligorecurrent disease. Such lesions are invariably invisible on conventional CT or bone scan. While it would be logical that patients with oligometastatic disease might have better outcomes than patients with widespread metastases and might be more responsive to therapy, this hypothesis has not yet been proven.

For men with oligorecurrent prostate cancer, MDR may offer a new treatment approach delaying disease progression and the toxicities of systemic therapy. While several studies report on clinical outcome of local irradiation based on “conventional” imaging like MRI or choline PET (Table 4), only few studies of PSMA-guided MDR are available. In the current trial, a PSA response occurred in 83.1% after local irradiation of oligorecurrent prostate cancer patients who underwent PSMA-PET/CT. This is comparable with the finding of a study of 83 patients with biochemical recurrence after surgery wherein PET-guided, fractionated radiotherapy of nodal relapses decreased PSA in 82.9% of patients [22]. Interestingly, the excellent local control rates after irradiation were strongly correlated with a decrease of SUVmax in those patients undergoing PSMA imaging during follow-up. For all patients in our cohort, a statistically significant decrease of tracer uptake after irradiation was observed confirming that PSMA-PET/CT imaging may also aid in the assessment of treatment response. Even though we detected a PSA rise for a certain number of patients during follow-up, bPFS was quite high in our cohort. In contrast, 43.5% biochemical progression was reported in a study of 108 men with recurrent prostate carcinoma and PSMA-guided, normo-, or moderate hypofractionated radiotherapy after a median follow-up of 18 months [23]. Furthermore, a prospective trial of 33 oligorecurrent patients undergoing stereotactic ablative body radiotherapy demonstrated a 1- and 2-year disease PFS of 58% and 39%, respectively [24]. These differences may relate to differences in radiation planning and the location of metastases.

Even though several outcome data are available with regard to MDR based on conventional imaging (Table 4), a direct comparison with the current results should be done with caution. Due to the higher detection rate of PSMA-PET/CT, a clinical benefit of PSMA-guided irradiation might be expected; however, a final evaluation is very difficult considering the great heterogeneity of the different trials with regard to, e.g., treatment technique, fractionation, imaging technique, and the use of ADT. Moreover, it remains an open question whether there is a clinical benefit for ENI in comparison with local, small-volume SBRT for patients with nodal relapse. The current trial included a relatively large number of patients with nodal relapse (63.1%), and ENI was performed for 51.2%. In a multicenter analysis comparing outcome and toxicity of SBRT and ENI in a cohort of 506 patients with nodal oligorecurrent prostate cancer, fewer nodal recurrences were recorded after normofractionated, elective nodal irradiation. The authors concluded that ENI is preferred to SBRT in the treatment of nodal oligorecurrences [25]. Our study also demonstrated that patients obtaining more than 24 fractions—a subgroup which includes all men receiving ENI—had a lower risk for death or relapse. Similarly, we observed this clinical benefit for all patients receiving concurrent ADT. A recently published study by Kroeze et al. reported similar results with significantly improved biochemical recurrence-free survival rates after MDR due to the addition of ADT [26]. There is an urgent need for further studies assessing different strategies in radiation oncology for PSMA-guided radiotherapy.

Our study confirmed that PSMA-guided MDR is safe and well tolerated. While only a low rate of grade 3 GU toxicity was observed 3 months after radiotherapy, no grade 3 GI toxicity occurred nor did edema or fatigue. Lépinoy et al. reported on a similar grade 3 acute GU toxicity rate of 6.5% in a cohort of 62 patients with PET-positive nodal recurrence treated with either salvage-extended field radiotherapy or involved field radiotherapy. Similarly, no acute grade 3 or higher GI side effects were found. However, the rate of severe GU late toxicity in the French cohort was significantly below the rate in our trial (3.2 vs. 23.3%), even though one grade 4 event was recorded [27]. Overall, the rate of late toxicity was relatively high in the current study. The large proportion of men with symptoms and comorbidities before MDR as well as new therapies with potential side effects due to progressive disease in the follow-up period likely explains this difference. Furthermore, GU late toxicity in our cohort includes a large number of patients with sexual side effects (especially impotence and erectile dysfunction) which often occur in older men.

Although the current study is one of the largest evaluating the clinical role of PSMA-guided radiotherapy, it has several limitations. It is retrospective; the cohort there is a relatively short follow-up for patients with prostate carcinoma. Moreover, the number of men included in the current trial was relatively low which reduces the validity of subgroup analyses. The use of two different ligands may lead to some heterogeneity in the current trial. Even though the number of patients who underwent ¹⁸F-PSMA-1007-PET/CT was very low expecting no significant impact on the results of the current study, ¹⁸F-PSMA ligands may lead to improved detection rates within the urinary tract due to the low urinary clearance rate compared with ⁶⁸Ga-PSMA [28]. However, our study demonstrated promising results of PSMA-guided MDR even though further research is required to identify optimal treatment regimens and specific patient’s characteristics leading to an oncological benefit.