Dr. med. Dirk Manski

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Prostate Cancer: Treatment by Radical Prostatectomy

Guidelines and review literature: (EAU Guidelines Prostate Cancer) (S3-Leitlinie Prostatakarzinom) (Walsh-Campbell Urology 11th Edition).

Indications for Radical Prostatectomy

Radical prostatectomy (RPE) is indicated in patients with localized prostate cancer and a life expectancy of at least ten years. Prostatectomy is the gold standard of curative therapy. Radical prostatectomy is the only curative method that demonstrated in a randomized trial (compared to conservative treatment) a survival benefit (Bill-Axelson et al., 2005, 2008 and 2011). In retrospective analysis of large trials, radical prostatectomy shows especially for high-risk cancer oncological advantages over radiotherapy (Boorjian et al., 2012).

Possible Surgical Techniques of Radical Prostatectomy

Radical prostatectomy is possible with various surgical techniques, which differ primarily in the surgical access. The line of dissection is the same for all techniques. Comparative studies between the different surgical techniques are available, but they are of limited value due to the trial quality (usually non-randomized or retrospective). Tumor stage, patient age and health (fitness), and the surgeon's talent and experience are more important factors for an excellent postoperative outcome than the surgical approach.

Trials Comparing Different Prostatectomy Techniques:

The evaluation of the numerous trials is difficult, because experience and skill of the surgeon is probably the determining factor for postoperative outcome, rather than the surgical approach. Current therapeutic standards in \glqq centers of exellence\grqq are either RRP or RALP. RALP has advantages in terms of bleeding volume and, in some studies, shortens length of inpatient stay and catheterization time. In large comparative studies, no or no relevant differences were found with regard to potency, continence, or oncologic cure (Coughlin u.a., 2019) (Haese u.a., 2019) (Nyberg u.a., 2018) (Sooriakumaran u.a., 2018).

Clinical Value of Lymphadenectomy:

The standard of care is performing pelvic lymphadenectomy together with radical prostatectomy. In low-risk tumors (Gleason score <7 and PSA < 10 ng/ml), the probability of lymph node metastasis is very low (< 5%), and pelvic lymphadenectomy can be omitted. The dissection field of pelvic lymphadenectomy is debated (limited versus extended field). The boundaries for a limited (diagnostic) dissection are the external iliac artery (lateral boundary), superior ramus of the pubis (caudal boundary), bifurcation of the common iliac artery (cranial boundary), bladder and branches of the internal iliac artery (medial boundary) and obturator fossa (dorsal boundary). For extended lymphadenectomy, the dissection is extended to the aorta, in the area of the internal iliac artery, and presacrally. Randomized studies were unable to demonstrate an oncological advantage of extended lymphadenectomy (Lestingi et al., 2021) (Touijer et al., 2021), but many guidelines recommend it for high-risk prostate cancer patients.

Nerve-Sparing Radical Prostatectomy:

Cavernous nerve sparing can preserve erectile function after prostatectomy. Despite meticulous nerve sparing, patients suffer a dramatic loss of erectile function after surgery due to minor trauma of the cavernous nerves. Healing of the nerve fibers leads to a slow recovery, and erectile function improves up to two years after radical prostatectomy. The potency rates after surgery (for patients who were potent before surgery) are 30–60%.

Nerve-sparing is problematic from the oncologic viewpoint: the cavernous nerves are located within the fascial shell of the prostate. It is important to select patients with a low risk of a T3 tumor on the side of the planned nerve sparing. The following preoperative risk factors minimize the risk of R1 resection due to nerve-sparing: PSA below 10 ng/ml, no palpable tumor, and maximum one core with Gleason 4 pattern on the corresponding side.

Oncological Results of Radical Prostatectomy:

The probability of recurrence-free survival after radical prostatectomy is between 83–29% (follow-up 10 years), depending on the clinical risk. The cancer-specific 10-year survival rate is between 89–99%, see table D’Amico risk classification for prostate cancer.

Pathological prognostic factors: independent prognostic factors in the pathological specimen are the Gleason score, margin status, extraprostatic tumor growth, seminal vesicle infiltration, perineural invasion, and lymph node metastases.

D’Amico risk classification for prostate cancer: clinical risk (mortality) for localized prostate cancer before definitive treatment (D'Amico et al., 2003). (*) Figures represent cancer-specific mortality. EBRT: external beam radiotherapy. RPE: radical prostatectomy
Risk Criteria 10-year mortality after EBRT (*) 10-year risk of PSA Prgression after RPE 10-year mortality after RPE (*)
Low PSA <10 ng/ml and Gleason score ≤6 2% 17% 1%
Intermediate PSA 10–20 ng/ml or Gleason score 7 8% 54% 4%
High PSA >20 ng/ml or Gleason score >7 24% 71% 11%

Adjuvant Therapy After Prostatectomy

Neoadjuvant Hormone Treatment Before Prostatectomy:

Several randomized trials evaluated neoadjuvant hormone therapy before prostatectomy and found it to be ineffective. Although neoadjuvant therapy leads to better pathological results (less R1 and tumor volume), it does not correlate with improving recurrence-free survival. Neoadjuvant hormone therapy is not recommended before prostatectomy.

Neoadjuvant Chemotherapy:

Neoadjuvant chemotherapy for advanced prostate carcinomas is not an established treatment approach. However, the feasibility and an acceptable complication rate have been demonstrated in several series.

Adjuvant Therapy for Lymph Node Metastases:

Immediate permanent hormonal therapy is the standard of care for patients with lymph node metastases. The higher the tumor burden (number of positive lymph nodes), the more likely to benefit from immediate hormonal therapy. Patients with high tumor burden also benefit from adjuvant radiotherapy of the prostatic fossa and pelvic lymph nodes (Tilki et al., 2022). Depending on the risk profile and response, hormone therapy may be paused after 2–3 years.

It is debatable whether an immediate adjuvant hormone treatment is necessary for patients with minimal lymph node metastases. For example, patients with only one positive lymph node (after extended lymphadenectomy) will progress in only 39%. Follow-up of PSA and delaying hormone therapy until PSA level rises is, therefore, an option in patients with ≤2 involved lymph nodes after extended nodal dissection. An alternative to long-term hormone therapy is intermittent hormonal therapy depending on the PSA response, especially for minimal lymph node metastases.

Adjuvant Hormone Therapy Without Lymph Node Metastases (pN0):

Adjuvant hormone therapy is not indicated after radical prostatectomy without lymph node metastases and without PSA progress, even if there are relevant risk factors for recurrence present (e.g., Gleason ≥8, R1 or pT3b).

Adjuvant Radiation Therapy For Positive Margins (R1):

20–60% of patients with R1 resection (and with pN0 M0) will experience a PSA progression. If obvious incomplete resection is seen in the pathological specimen (T3, broad positive margins), immediate adjuvant (salvage) radiotherapy has been the standard of care. However, the validity of the studies used for this recommendation is limited, because the control groups were irradiated too late or not at all. The alternative is active surveillance and early adjuvant radiotherapy for PSA progression (PSA >0.2 ng/ml); this avoids urogenital toxicity for those patients who do not require radiotherapy. Recent studies demonstrate comparable progression-free survival for early salvage radiotherapy (Vale et al., 2020).

Biochemical Recurrence After Radical Prostatectomy

Biochemical recurrence after radical prostatectomy is defined by two consecutive rising PSA values greater than 0.2 ng/ml more than three months after prostatectomy. The reason for PSA progression is either local recurrence or distant metastases [table Probability of local or systemic recurrence for patients with rising PSA after radical prostatectomy]. If the patient rejects local recurrence therapy (usually radiation therapy) or if there is relevant comorbidity, imaging for low PSA recurrence is not indicated. Watchful waiting is offered, and management depends on PSA doubling time.

Probability of local or systemic recurrence for patients with rising PSA after radical prostatectomy (Heidenreich et al., 2008).
Risk factor Local recurrence (%) Systemic recurrence (%)
Time to PSA-progress
< 1 year 7 93
1–2 years 10 90
>2 years 61 39
> 3 years 74 26
PSA doubling time 11,7 Mo 4,3 Mo
Gleason score
5–6 55 45
7 39 61
8–10 11 89
local tumor stage
≤pT2b 40 60
pT3a, R0 54 46
pT3a, R1 48 52
pT3b 16 84
pN1 7 93

Diagnosis of Biochemical Recurrence After Radical Prostatectomy

A rising PSA level is very sensitive; imaging methods such as CT, bone scan, or TRUS cannot localize the cause of biochemical recurrence under PSA values of 10 ng/ml and are therefore not indicated. PSMA-PET is a promising option for patients with a PSA >0,5 ng/ml. Furthermore, the following factors speak in favor of a local recurrence (and against distant metastases): no evidence of lymph node metastases, Gleason score below 8, postoperative PSA nadir below the detection limit, PSA progress after more than one year after prostatectomy and PSA doubling time over ten months. For an accurate analysis of prognostic factors for a local or systemic recurrence, see table Probability of local or systemic recurrence for patients with rising PSA after radical prostatectomy.

Prognosis without therapy:

The formation of clinically visible metastases takes an average of eight years; the average time to death after metastasis formation is five years. Unfavorable prognostic factors are an early PSA progression, a short time to metastases, or a quick PSA doubling time. Patients with PSA recurrence more than two years after prostatectomy, a PSA doubling time of more than ten months, primary Gleason score <8, no seminal bladder infiltration, and no lymph node metastases have a good prognosis (Pound et al., 1999). This patient group (if age is appropriate) is well suited for watchful waiting.

Radiation Therapy for Suspected Local Recurrence:

A PSA response can be expected in 20–80% of the patients, depending on patient selection. Predictors of successful adjuvant radiotherapy are the consequent exclusion of patients with a high probability of distant metastases (see above), radiotherapy starting with a PSA under 0.5–1 ng/ml, and the administration of 66–70 Gy. Patients at high risk for further progression despite radiotherapy (PSA above 0.7 ng/ml, Gleason 8–10) benefit from combining radiotherapy with androgen deprivation therapy: options include 24 months of bicalutamide 150 mg/d (Shipley et al., 2017) or six months of GnRH analogs (Carrie et al., 2019).

Hormone Therapy for Suspected Systemic Progression

Hormone therapy is recommended for a PSA doubling time <3–6 months or symptomatic progression. Symptom-free patients with slower PSA progression should be observed until the criteria for hormonal therapy are appropriate. Adjuvant therapy with dutasteride is an option with few side effects and helps to slow down PSA progression. The influence on overall survival is, however, unclear (Schroeder et al., 2013).

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