TArgeted STEreotactic Radiotherapy for Oligorecurrent PROstate Cancer (TASTEPRO) - a Randomized Controlled Pilot Trial

Introduction

Prostate cancer is the second most common cancer diagnosed in men and the second leading cause of cancer death after lung cancer. Out of an estimated 1.1 million cancers diagnosed worldwide in 2012, prostate cancer accounted for approximately 15% of all cancer cases. The incidence of prostate cancer around the globe varies widely, being the highest in North America and northwestern Europe.

The International Society of Urological Pathology (2014) divides prostate cancer into three risk groups, consisting of low-risk, intermediate-risk and high-risk prostate cancers. Determining factors include the PSA-level, Gleason Score, and the extent of the primary tumor according to the TNM classification. The treatment modality of choice for prostate cancer depends on the risk-group. Low-risk prostate cancers are primarily managed conservatively, and the aim is to reduce over-treatment. This so-called deferred treatment includes the concepts of active surveillance and watchful waiting. Active surveillance is suitable for patients diagnosed with a localized and well-differentiated prostate cancer with a low risk of progression. Patients remain under close surveillance and the treatment intent is curative, as active treatment is initiated if changes in biopsy results or a T-stage progression occur. Watchful waiting is a palliative approach for patients with an estimated life expectancy below 10 years. These patients are treated symptomatically in order to maintain the best possible quality of life. Intermediate-risk prostate cancers are commonly treated operatively or with radiotherapy. Patients with high-risk prostate cancer show an increased risk of metastatic progression and death from the disease. Consensus regarding optimal treatment of high-risk prostate cancer does not thus far exist. Treatment options for localized disease include operative radical prostatectomy with subsequent pelvic lymph node dissection. A further therapy option for high-risk localized prostate cancer is the external-beam radiation therapy in combination with long-term androgen deprivation treatment.

Developing PSA recurrence is common after primarily curative radical prostatectomy or radiotherapy, occurring in 27%-53% of all patients. A rising PSA-level after curative-intent therapy may precede metastatic progression. The threshold for a clinically relevant PSA relapse depends on the primary treatment. A PSA rise of > 0.4 ng/ml after radical prostatectomy is considered as the best threshold prediction for further metastases, although further studies suggest a cut point for a PSA-relapse at > 0.2 ng/ml. After primary radiotherapy, a PSA rise of ≥ 2 ng/mL higher than the nadir (absolute lowest PSA level) achieved through the therapy is considered a PSA relapse. A rapid PSA-doubling time of under three months or a PSA recurrence within the first three years indicates a high risk of metastasis. On the contrary, a PSA-relapse more than three years after surgery or a PSA doubling time of over 12 months correlates with a low risk of metastases. Therefore, it is evident that the speed of PSA relapse after treatment correlates with the aggressiveness of the disease.

Recent studies have suggested that the enzyme Thymidine kinase 1 (TK1) could be used as a tumor marker for prostate cancer. TK1 is an enzyme involved in the DNA synthesis and its expression correlates with active cellular proliferation. A study by Murtola et al (2020) found that serum TK1 levels were significantly elevated in metastatic prostate cancer compared to non-metastatic cases. High serum TK1 levels were also identified as a predictor of prostate cancer specific and overall mortality. Further research is required to determine whether TK1 could be included in the prostate cancer risk stratification and influence the planning of optimal treatment and surveillance. Circulating tumor DNA (ctDNA) is a further marker which has demonstrated potential in detecting disease recurrence. ctDNA originates from degenerate tumor cells and can be detected in plasma. ctDNA can be used to estimate disease burden and has prognostic value in metastatic prostate cancer. A study by Lau et al (2020) found that patients with positive tumor ctDNA experienced rapid disease recurrence and progression compared to patients without detectable ctDNA, suggesting that ctDNA could potentially predict patients at highest risk for relapse.