Recurrent prostate adenocarcinoma after radical prostatectomy: Principles of multidisciplinary management across a spectrum of disease

Abstract

A man aged 76 years in good health presented for evaluation of a rising prostate-specific antigen (PSA) level after prior radical prostatectomy (Figure 1). Briefly, his prostate cancer had been diagnosed 5 years prior in the setting of a rising PSA. A standard biopsy had revealed International Society of Urological Pathology (ISUP) grade group 3 disease, and he underwent radical prostatectomy without pelvic nodal sampling. Pathologic examination demonstrated extracapsular extension and the presence of intraductal carcinoma; otherwise, at final pathology, the tumor was ISUP grade group 3, with negative surgical margins but evidence of perineural invasion. Postoperative PSA was undetectable for 3 years and then began to slowly rise, reaching 0.06 ng/dL 42 months after surgery. PSA then began to rise more rapidly, reaching 0.37 ng/dL 51 months after surgery. He underwent a prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan at that time, which showed an enhancing nodular soft tissue along the right prostate bed (1.1 × 0.5 cm) with intense PSMA uptake, as well as uptake in a 3-mm right internal iliac node, a 3-mm right common iliac node, and a 3-mm aortocaval node (Figure 2). Focal uptake in a left presacral area was thought to represent a ganglion, whereas uptake in the T11 vertebral body was equivocal; follow-up magnetic resonance imaging (MRI) of the thoracic spine confirmed that the T11 lesion was a hemangioma. MRI of the prostate bed showed a small focus of T2-hypointense soft tissue in the right pelvis lateral to the prostatectomy bed measuring 15 × 5 mm.

The patient was evaluated by a radiation oncologist, urologist, and medical oncologist, and decided to pursue a clinical trial of stereotactic body radiotherapy (SBRT; ClinicalTrials.gov identifier NCT03541850).¹ He received 40 grays (Gy) in five fractions to the prostate bed gross nodule and PSMA-positive nodes, 30 Gy in five fractions to the prostate bed, and 25 Gy in five fractions to the elective lymph node regions. In addition to SBRT, he started a planned short course of androgen-deprivation therapy (ADT; this was allowed on the protocol) but stopped after 1 month because of intolerance. PSA dropped to 0.18 ng/dL 6 months after SBRT, but then rose to 0.27 ng/dL 3months later and 0.99 ng/dL 6 months after that (now nearly 6 years after his prostatectomy). PSMA PET/CT imaging revealed a decrease in size and positivity of the right internal iliac node, with stable low uptake in the right CI node and prostate bed, and resolution of the aortocaval node. However, there was new uptake in two 4–6 mm left para-aortic nodes and a 5-mm node anterior to the aorta (Figure 3).

The patient enrolled on a trial of PSMA PET/CT–guided, metastasis-directed therapy (MDT) with 6 months of androgen-annihilation therapy (AAT; leuprolide, apalutamide, and abiraterone; ClinicalTrials.gov identifier NCT03902951).² The highest PSA before beginning AAT was 1.1 ng/dL. He received 1 month of AAT, then completed SBRT to the PSMA-positive para-aortic nodes (30 Gy in five fractions). His PSA decreased to 0.02 ng/dL after 6 months of AAT. Within 1 month of cessation, his testosterone had recovered to 312 ng/dL, and his PSA rose slightly, to 0.05 ng/dL. It remained <0.1 ng/dL for 9 months, then increased to 0.22 ng/dL nearly 12 months after testosterone recovery (92 months after prostatectomy).

A PSMA PET/CT was obtained, which showed two new PSMA-positive lesions in left para-aortic nodes as well as increasing uptake in the right prostatectomy bed (adjacent to his prior treatment area; Figure 4). MRI of the prostate bed showed a small, T2-hypointense, soft tissue, nodular focus in the right pelvis lateral to the prostatectomy bed measuring approximately 9 × 9 mm, with delayed enhancement. PSA rose to 0.45 ng/dL in 2 months, and he enrolled in a randomized clinical trial evaluating PFS using PSMA-guided SBRT with or without two cycles of the PSMA-radioligand 177LuPNT2002 (ClinicalTrials.gov identifier NCT05496959).³ The patient was assigned to the intervention arm; and, after treatment (including SBRT to the prostate bed recurrence and PSMA-positive para-aortic nodes), his PSA dropped to 0.02 ng/dL at 3 months and became undetectable after 6 months. Serial PET/CT scans obtained 12 and 24 months later remain negative, and his PSA remains undetectable through the present, now 10.5 years after his radical prostatectomy.

I first heard of PSA from my cardiologist. Ever since I had open-heart surgery for a mitral valve replacement, my cardiologist recommended checking blood often, and he made sure I had a PSA checked each year. My PSA eventually rose from a normal level 1 year to above 6.45 ng/mL the next. I was referred to a urologist who did a biopsy. It showed cancer in three spots. I then searched for a doctor that had experience in robotic prostate surgery. I ultimately decided on an experienced surgical team near my home. The day after the surgery, the urologist called me and told me that he didn’t think they got all of the cancer; and, in a few years when my PSA level starts to get higher, they would need to start me on hormone treatments. I didn’t feel like I got treated very well, and I started looking for alternatives. Meanwhile, my PSA unfortunately did start to rise, like predicted.

My cardiologist referred me to another urologist, who told me he was going to retire soon and that he had been reading about what he thought would be a breakthrough in prostate cancer treatment, the PSMA scan. He said the treatment has not been approved yet but thought I should check it out. He said they had a new scan machine at UCLA and a hospital in San Francisco. He said he would write a letter to UCLA to see if they would take me as a patient.

Soon, I was able to meet Dr Kishan and his team at UCLA. I learned that, unfortunately, the PSMA scan would not be covered by Medicare or my supplemental insurance because it was not approved. However, it was available on a clinical trial, which I decided to participate in. As it turns out, it saved my life. The scan showed something in the prostate bed and two lymph nodes. For me, a long course of radiation would have been logistically challenging. Dr Kishan enrolled me in his trial of a course of 5 days of radiation (SBRT) using advanced technology. I’ve always been interested in cutting-edge treatments, and the idea of a trial appealed to me.

My PSA went down initially after radiation, but unfortunately, by about 18 months later, my PSA was back up, now at 1.1 in October 2021. I had another PSMA scan and it showed two new nodes. I was offered the SATURN trial, which involved intense hormone therapy (Lupron plus two drugs) for 6 months along with radiation (SBRT) to each site. I was nervous because I hadn’t done well with just a little Lupron with the first radiation, but I was willing to try it if it could help.

While my PSAs did look good while I was on the hormone therapy and for a while after, my PSA started to rise after my testosterone levels recovered. I had another PSMA scan and an MRI. These showed two new lymph nodes and recurrence in my prostate bed. At that point, I was offered another trial, the LUNAR trial, which was designed with the hope that the new radioactive lutetium drug would kill disease we couldn’t see, and since hormone therapy (even the intense one) didn’t work, I was interested. I was nervous because it was a randomized trial, but after so many recurrences, I wanted to try it. I was randomized to the group that received the two cycles of the lutetium drug followed by SBRT. I had another PSMA scan after the two treatments to prepare for SBRT and this time, my PSA went down and stayed down. I had another PSMA scan 1 year later, and 2 years later, and both times they were clear. I’ve been disease-free for 2 and a half years now and continue to follow up with my team.

Today, I am very happy. I have been dealing with prostate cancer for over a decade. Ever since the call right after the surgery that it will come back, I have felt this has been a chronic process. I have felt fortunate to have access to so many trials, and, even though two of them didn’t work, I feel like I received cutting-edge care. And this last one seems to have done the trick.

Although localized prostate cancer can be cured with radical prostatectomy or definitive radiotherapy in many patients, recurrences unfortunately can be common. These recurrences range in spectrum from a localized recurrence, to a regional nodal recurrence, to true metastatic disease and can sometimes plague patients in succession. In the current case, the patient received guideline-concordant care after his first recurrence, with early salvage radiotherapy delivered upon a PSA rise to greater than 0.2 but less than 0.5 ng/mL. Advanced imaging was used to guide the design of his radiotherapy fields and revealed both a local recurrence and nodal disease. He was treated on a clinical trial of ultrahypofractionated radiotherapy, with a plan for 6 months of hormonal therapy; radiotherapy fields included the prostate fossa and elective nodes, encompassing all sites of gross disease on the PSMA PET/CT. Despite this approach, he developed a recurrence fairly quickly, highlighting the potential of occult disease even with a positive PSMA PET/CT to direct treatment.

This patient’s subsequent clinical course illustrates the benefits and pitfalls of an approach anchored on SBRT-based MDT with systemic intensification. His second recurrence, after PSMA-influenced salvage radiotherapy, reflected an out-of-field recurrence in M1a station lymph nodes. His PSA responded on the SATURN trial, but he was among the 50% of patients who had a detectable PSA level within 6 months of testosterone recovery (underscoring the importance of monitoring eugonadal progression-free survival, and not just progression-free survival). His third recurrence was successfully treated with the combination approach used on the investigational arm of the LUNAR trial, suggesting the potential benefit of that approach even in patients with multiple recurrences.

Every aspect of this patient’s care—from the refinement of salvage radiotherapy to the optimization of metastasis-directed SBRT—is currently being studied in large, randomized trials, highlighting the quickly shifting landscape of the management of recurrent prostate cancer. A multidisciplinary, evidence-based approach is essential to care. Somewhat uniquely, each of these patient’s three recurrences were treated on an institutional, investigator-initiated trial, with the last one tentatively holding the promise for a cure.

Amar Kishan reports grants/contract from Janssen Biotech Inc., Novartis, Point Biopharma, Varian Medical Systems Inc., and ViewRay Technologies Inc.; personal/consulting fees from Boston Scientific Corporation, Janssen Biotech, Lantheus, Novartis, and Varian Medical Systems Inc.; and stock options in MiraDx outside the submitted work. Adam E. Singer reports personal/consulting fees from AVEO Pharmaceuticals Inc., Bristol Myers Squibb Company, Eisai Company Ltd., and Exelixis Inc. outside the submitted work. Kekoa Taparra reports personal/consulting fees from Genentech outside the submitted work. Nicholas G. Nickols reports grants/contracts from Lantheus outside the submitted work. Johannes Czernin reports personal/consulting fees from Aktis Oncology, Coretag, and IsoRay Inc.; support for other professional activities from Trethera; and stock ownership in Sofie outside the submitted work. Jeremie Calais reports personal/consulting fees from Amgen, Astellas Pharma, Bayer, Blue Earth Diagnostics, Coretag, Curium US LLC, DS Pharma, FibroGen, GE Healthcare, IsoRay Inc., Janssen Pharmaceuticals, Lantheus, Lightpoint Medical, Novartis, Nucleus RadioPharma, Nucs AI, Pfizer, Point Biopharma, Radiopharm Theranostics, Sanofi, Siemens, Sofie, and Telix; and support for other professional activities from Curium US LLC, GE Healthcare, IBA RadioPharma Solutions, Lantheus, Monrol, Novartis, Point Biopharma, RadioMedix, Telix outside the submitted work. John K. Lee reports grants/contracts from PromiCell Therapeutics Inc.; personal/consulting fees from Hierax Therapeutics Inc., ImmunityBio Inc., Lyell Immunopharma, and PromiCell Therapeutics Inc.; a patent (applied for) licensed by PromiCell Therapeutics Inc.; stock options in PromiCell Therapeutics, Inc.; and service as a fiduciary officer of PromiCell Therapeutics Inc. outside the submitted work. Matthew B. Rettig reports grants/contracts from Johnson & Johnson Health Care Systems Inc., Lantheus, Merck, the US Department of Defense, and the US Department of Veterans Affairs; personal/consulting fees from AVEO Pharmaceuticals Inc., Immune Bio, Lantheus, and Novartis; and support for other professional activities from Bayer, F. Hoffmann-La Roche, FibroGen, Johnson & Johnson Health Care Systems Inc., ORIC, and PleXus Communications outside the submitted work. The remaining authors disclosed no conflicts of interest.