Targeted Radiotherapy for Recurrent Prostate Cancer

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.

In the case of a clinically relevant PSA relapse, the presence of metastases and the progression of the disease are commonly assessed with an abdominopelvic computer tomography (CT) as well as a skeletal scintigraphy. Advanced prostate cancer metastasizes primarily in the local pelvic lymph nodes and axial skeleton. Studies suggest, however, that only 11-14% of patients with a PSA-relapse show a positive CT-scan. Furthermore, the probability of a positive bone scan after radical prostatectomy is below 5% if the PSA-level is under 7 ng/ml. This indicates that conventional imaging techniques are not sensitive enough to detect metastases at early stages and low PSA levels.

Promising detection rates of metastases at low PSA-levels have been shown by the prostate-specific membrane antigen (PSMA) PET-CT imaging. PSMA is a glycoprotein overexpressed on the cell surface of prostate cancer cells which can be bound by radiolabeled small molecules, enabling whole-body tumor specific imaging with PET-CT. PSMA PET-CT is thus a state-of-the-art imaging method capable of detecting lesions of prostate cancer more accurately than any other clinically available imaging method. A number of recent studies show that PSMA PET-CT is particularly effective in detecting cases of recurrent cancer. Further research is required, however, to determine whether the increased sensitivity of the PSMA PET-CT in localizing metastases could improve the clinical outcome. It is currently unclear to which extent PSMA PET imaging results should influence the choice of treatment modality.

Disease recurrence after primary curative-intent treatment is commonly managed with salvage radiation therapy. To achieve the best results from salvage radiotherapy, research suggests that the PSA-level should be below 0.5 ng/ml, or preferably even lower at the start of treatment. Early salvage radiotherapy before a PSA-relapse > 0.5 ng/ml leads to an undetectable PSA-level in more than 60% of men. Furthermore, the treatment delays the need for androgen deprivation therapy by 12-14 months. Salvage therapy is usually directed to the prostate bed as well as the iliac and obturator lymph nodes. Due to the poor sensitivity of conventional imaging techniques, salvage radiation therapy is commonly delivered with a uniform dose without histological proof of the local recurrence. The optimal salvage radiotherapy dose has not been clearly defined. The USA Guideline Panel regards 64-65 Gy as the minimum dose, whereas the European Association of Urology recommends at least 66 Gy for salvage radiotherapy. A dose escalation beyond 72-76 Gy significantly increases the risk of severe side effects, even with newer treatment techniques. Despite the possibility of a cure for patients with prostate cancer relapse, notable side-effects of the treatment include increased irritative symptoms of the lower urinary tract and rectum. Additionally, for men primarily managed with prostatectomy, the risk of urinary incontinence rises.

Stereotactic ablative radiotherapy (SABR) is a highly focused radiation treatment that concentrates an intense dose of radiation on the recurrent tumorous lesion while limiting the dose to healthy surrounding tissues. A recent study by Phillips et al (2020) concluded that SABR improves progression-free survival, induces a systemic immune response and delays the initiation of androgen deprivation therapy. Thus, it is a promising treatment approach for men with recurrent hormone-sensitive oligometastatic prostate cancer. PSMA PET-CT may prove to be a promising standard imaging technique, allowing targeted treatment of recurring lesions with SABR.

Objective

The TASTEPRO pilot trial evaluates the feasibility of PSMA PET-CT targeted SABR radiation therapy in management of lymph node positive disease recurrence after radical prostatectomy. The investigators expect targeted SABR to be of equal or better oncological outcome compared to the template-based conventional salvage therapy. Furthermore, the trial seeks to evaluate whether the targeted SABR radiation would reduce treatment toxicity and adverse side effects, leading to improved quality of life. Results of the pilot trial will be used when designing larger trials on oncological efficacy and safety of PSMA PET-CT targeted SABR.