ASTRO 2021: Can We Cure Oligorecurrent Prostate Cancer? You May Be Surprised!

(UroToday.com) The 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting included a Prostate Cancer Oligometastases session and a presentation by Dr. Angela Jia discussing whether we can cure oligorecurrent prostate cancer.

Dr. Jia started her presentation with a case presentation of a 65-year-old male who presented with a rising PSA: 5.3 (September 2016), 7.0 (September 2017), and 7.2 (February 2018). His digital rectal exam was negative and his MRI did not have evidence of extraprostatic extension or seminal vesical involvement. An MRI guided prostate biopsy noted Gleason 4+4=8 in 6 out of 12 cores, with 3/3 MRI targeted cores positive. In April 2018, he underwent a radical prostatectomy and bilateral pelvic lymph node dissection, pathology revealing Gleason 3+4=7 (tertiary pattern 5), pT3a, pN0 (0/5 lymph nodes), cM0, R1 (bladder neck margin >10 mm in length). In June 2018, his PSA was 0.77 ng/mL (his first post-op PSA), and in July 2018 it was confirmed at 0.9 ng/mL. At that point in time, he had one injection of Lupron and in August 2018 he underwent salvage radiotherapy with 45 Gy to the whole pelvis followed by 25 Gy cone down to the prostate bed. Although his PSA decreased post-salvage radiotherapy to 0.5 in January 2019, his PSA started to increase thereafter: 1.4 (July 2020), 2.3 (November 2020), 3.1 (February 2021), and 3.8 (April 2021). In March 2021, he underwent an Axumin PET-CT scan, which showed no suspicious radiotracer activity in the prostate bed or distant metastasis, however, two para-aortic lymph nodes demonstrated a low degree of radiotracer activity, suspicious for metastatic involvement. This was deemed oligorecurrent metastatic prostate cancer:

Currently, there are several questions that remain to be answered in this disease space, as emphasized by Dr. Jia:

1. How is oligorecurrent disease defined?
2. Does the site of recurrent disease matter?
3. What is the benefit of metastasis-directed therapy using radiotherapy?
4. What is the field size?
5. What about the addition of ADT?
6. Can we cure oligorecurrent disease?

In 2020, Guckenberger et al.¹ provided a European Society for Radiotherapy and Oncology (ESRO) and European Organization for Research and Treatment of Cancer (EORTC) consensus recommendation for the characterization and classification of oligometastatic disease. The following is a decision tree for classification of oligometastatic disease:¹

Based on this decision tree, there are several important questions (as highlighted in the above figure):

Q1: Does the patient have a history of polymetastatic disease before the current diagnosis of oligometastatic disease?

Q2: Does the patient have a history of oligometastatic disease before the current diagnosis of oligometastatic disease?

Q3: Has oligometastatic disease been first diagnosed more than 6 months after the primary cancer diagnosis?

Q4: Is the patient under active systemic therapy at the time of oligometastatic disease diagnosis?

Q5: Are any oligometastatic lesions progressive on current imaging? 

Questions 1 and 2 differentiate between the upper-level oligometastatic states of de-novo (red), repeat (blue), and induced oligometastatic disease (green). Question 3 differentiates de-novo oligometastatic disease into synchronous and metachronous oligometastatic disease. Questions 4 and 5 subclassify into oligorecurrence, oligoprogression, and oligopersistence.

Work from the SEER-Medicare database highlights that sites of metastases are prognostic. Gandaglia and colleagues² assessed 3,857 patients with metastatic prostate cancer, stratified by site of metastasis. They found a median OS of 43 months for those with nodal disease, 24 months for those with bone only disease, 16 months for those with visceral only disease, and 14 months for those with bone plus visceral disease: 

The current phase II data supporting the use of metastasis-directed therapy, are small studies including STOMP (n=62), ORIOLE (n=54), OLIGOPELVIS (n=67), and PSMA MRgRT (n=37). Based on the ORIOLE³ and PSMA MRgRT studies, there is some data predicting progression after metastasis-directed therapy. In ORIOLE, progression at 6 months was 38% for untreated PSMA-PET avid lesions compared to 5% for no untreated lesions. In PSMA MRgRT, 14 of 37 patients achieved complete metabolic response and 7 of 8 biochemical NED patients had complete metabolic response.

Work from De Bleser et al.⁴ has assessed metastasis-directed therapy in treating nodal oligorecurrent prostate cancer, comparing the outcome and toxicity of stereotactic body radiotherapy and elective nodal radiotherapy. This study was a retrospective analysis of 506 patients of which 309 underwent stereotactic body radiotherapy and 197 elective nodal radiotherapies. For patients presenting with only one node at recurrence, elective nodal radiotherapy resulted in longer adjusted metastasis-free survival than stereotactic body radiotherapy (HR 0.50, 95% CI 0.30-0.85), and there was no difference for patients presenting with more than one lymph node (HR 0.92, 95% CI 0.54-1.59):

With regards to the addition of ADT to radiotherapy in oligorecurrent disease, there are no published RCTs in this setting, however, there are several current trials investigating this question including NRG GU011, I-STOP (NCT04619069), DART (NCT04641078), and RADIOSA (NCT03940235). Work from Deek et al.⁵ shows that the addition of ADT does not significantly reduce polyprogression (class III):

Referring back to several of the questions presented by Dr. Jia at the beginning of the presentation, she highlighted these with the following answers:

1. How is oligorecurrent disease defined? <=5 lesions (not biological, but practical)
2. Does the site of recurrent disease matter? Prognosis is best for nodal > bone > visceral disease
3. What is the benefit of metastasis-directed therapy using radiotherapy? Overall survival benefit in SABR-COMET, ADT-free survival in STOMP and ORIOLE
4. Can we improve quality of life by delaying ADT? Yes, in STOMP and ORIOLE
5. Can we cure oligorecurrent disease? Yes, but only in a minority of patients

With regards to the case presentation, this patient was started on the GnRH antagonist Relugolix and was re-irradiated with proton therapy, receiving 46.8 Gy in 26 fractions from L2 to L5 with cone down to 16.2 Gy boost to the involved nodes, to minimize the area of overlap with the previous pelvis radiotherapy:

Dr. Jia highlighted that there are several treatment options for oligorecurrent prostate cancer, identified via conventional imaging:

1. Continued surveillance (considering comorbidities and life expectancy)
2. Local therapy, with or without ADT. This may include SBRT to the involved node (STOMP, ORIOLE, PSMA MRgRT), or external beam radiotherapy with dose escalation to the involved node (OLIGOPELVIS)
3. ADT alone
4. ADT with another systemic agent

Dr. Jia concludes her presentation about oligorecurrent prostate cancer with the following take home messages:

• Treatment of all sites of metastatic disease (up to 5) may be feasible, well tolerated, and prolong ADT-free survival
• The optimal duration and sequencing of ADT with local therapy is unknown. The following ongoing trials will provide additional data: NRG GU011, I-STOP (NCT04619069), DART (NCT04641078), and RADIOSA (NCT03940235)
• Elective nodal irradiation in the setting of nodal recurrence is feasible with acceptable toxicity. This is being evaluated in the STORM trial (NCT03569241)
• The “first time” oligorecurrent disease is an optimal window to treat, where disease eradication is still possible. Currently, 30-40% of patients treated with metastasis-directed therapy have long-term disease-free intervals
• Oligorecurrent disease is a heterogeneous population, currently defined by imaging sensitivity, and molecular stratification is needed to determine who will benefit from metastasis-directed therapy +/- ADT

Presented by: Angela Jia, MD, PhD, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.

References:

1. Guckenberger M, Lievens Y, Bouma AB, et al. Characterization and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organization for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21:e18-e28.
2. Gandaglia G, Karakiewicz PI, Briganti A, et al. Impact of the site of metastases on survival in patients with metastatic prostate cancer. Eur Urol. Impact of the metastatic site of metastases on survival in patients with metastatic prostate cancer. Eur Urol. 2015;68:325-334.
3. Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020 Mar 26;6(5):650-659.
4. De Bleser E, Jereczek-Fossa BA, Pasquier D, et al. Metastasis-directed therapy in treating nodal oligorecurrent prostate cancer: A Multi-institutional analysis comparing the outcome and toxicity of stereotactic body radiotherapy and elective nodal radiotherapy. Eur Urol. 2019;76(6):732-739.
5. Deek MP, Taparra K, Dao D, et al. Patterns of recurrence and modes of progression after metastasis-directed therapy in oligometastatic castration-sensitive prostate cancer. Int J Radiation Oncol Biol Phys. 2021;109:387-395.