Prostate Cancer: Primary Therapy

Therapy for prostate cancer is based on tumor stage-localized carcinoma or advanced disease, degree of differentiation-with both the patient’s general condition and his or her biological age-curative goal only if life expectancy > 10 years-being factors in the decision. If a cure cannot be achieved, then the therapy must not worsen the quality of life. The local tumor needs a local treatment, the disseminated tumor disease a systemic therapy. In terms of therapy, a distinction is made between:

  • Incidental carcinomas found during transurethral resection of the prostate (surgical removal of the prostate through the urethra) and found in less than 5% of the resection chips (T1a tumors)
  • Localized tumors (T1b – T2b, N0, M0).
  • Locally advanced tumors (T3, N0, M0).
  • Metastatic tumors (Tx, N1, M0/1)
  • Hormone refractory tumors (= prostate cancers in progression (progress) under antiandrogen therapy/drugs that inhibit the action of male sex hormones).

Localized prostate carcinoma is classified into risk groups with respect to the development of recurrence (recurrence):

  • Low risk: PSA ≤ 10 ng/ml and Gleason score 6 and cT category 1c (diagnosed by prostate punch biopsy), 2a ( tumor affects < 50% of a lateral lobe).
  • Intermediate (middle) risk: PSA > 10 – 20 ng/m l or Gleason score 7 or cT category 2b (tumor affects > 50% of a lateral lobe).
  • High risk: PSA > 20 ng/ml or Gleason score ≥ 8 or cT category 2c (tumor affects both lateral lobes).

In patients with a life expectancy of at least 10 years, local therapy is recommended due to the typically slow disease progression of localized prostate cancer. Established treatment options are:

  • Active surveillance (Active Surveillance).
  • Radical prostatectomy – primary treatment option for localized prostate cancer in all risk groups.
  • Brachytherapy
  • Percutaneous radiotherapy

Watchful Waiting versus Actice Surveillance

  • Watchful waiting is considered a symptom-based treatment strategy. This strategy is recommended for patients with a life expectancy of less than ten years.Conclusion “Watchful waiting” is a palliative treatment concept.
  • Active Surveillance aims to start therapy in a timely manner. This strategy is suitable for physically fit and younger men.

Active Surveillance (Active Surveillance)

The prerequisite for choosing a strategy of Active Surveillance should be the following parameters:

  • PSA level ≤ 10 ng/ml;
  • Gleason score ≤ 6 (“Gleason grade group” I, highly differentiated carcinoma).
  • Clinical tumor stage cT1 and cT2a.
  • Tumor in ≤ 2 punctures with guideline-guided collection of 10-12 diagnostic prostate biopsies.
  • ≤ 50% tumor per biopsy (specimen collection).

For Gleason 3+4 (7a), active surveillance should be considered in the context of studies. “Active surveillance” procedure according to current guidelines:

  • Tumor should be monitored by PSA determination and DRU (digital rectal examination) every three months for the first two years. If the PSA level remains stable, 6-monthly examination is to be performed.
  • Rebiopsy should be performed depending on the initial magnetic resonance imaging (MRI).
    • Patients with initial MRI and systematic plus targeted biopsy, if necessary, before inclusion in active surveillance: rebiopsy with repeat MRI and systematic biopsy after 12 months.
    • Patients without initial MRI before inclusion in active surveillance: MRI with systematic plus targeted biopsy within 6 months, if necessary.

Note: If the inclusion criteria are no longer met in any criterion, or if the PSA doubling time shortens to less than three years, termination of “Active Surveillance” should be advised. Further guidance

  • In low-risk prostate cancer patients on active surveillance, rebiopsy is advised after one year, according to the protocol. The results of one study show that it is irrelevant whether a biopsy is repeated one year later or only when PSA kinetics are appropriate.CONCLUSION: Orientation to PSA kinetics to detect progression allows unnecessary biopsies to be avoided.
  • For studies in terms of active surveillance (Active Surveillance), a Gleason score of 3 + 4 = 7a is allowed.
  • The indication for active surveillance has been expanded to include incisional prostate carcinomas (incidental carcinomas; stages cT1a and cT1b). Note: Incidental prostate carcinomas (after transurethral resection of the prostate, TURP) that were T1 and T2 tumors that did not metastasize showed a 30% lower relative risk of death from prostate cancer within 10 years, after adjusting for age, concomitant disease, and treatment.
  • Insignificant carcinomas are considered clinically insignificant, so active surveillance is also sufficient instead of therapy. These are defined according to Epstein criteria as follows: Tumor volume 0.5 ml, Gleason score ≤ 6, absence of grade 4 tumors, and a pathologic T2 stage.The key parameter in defining these carcinomas is tumor volume! In a retrospective study, no increase in biochemical recurrence rate was found instead of under 0.5 ml was between 0.5 and 2.5 ml.
  • In a cohort study, 469 men diagnosed with localized prostate cancer who had opted for a strategy of active surveillance were followed up over 10 years during follow-up. These men were on average about 68 years old at the time of diagnosis and were followed for a median of 4.8 years. The following situation was present:
    • 94% of patients had a PSA level at diagnosis that was <10 ng/mL (median 5.1 ng/mL)
    • 98.2% of patients had a Gleason score of ≤ 6 and in 1.7% of 3 + 4 = 7
    • 4% of patients were from staging, assigned to group T1c and the remaining 6% were assigned to group T2a

    Course of the monitoring phase:

    • 62% of patients were still therapy-free after 10 years.
    • 77% of patients were still not treated after five years of observation; after 10 years, the treatment-free rate was 62%.
    • 65.7% of men underwent at least one repeat biopsy after an average of 1.94 years
    • 24.7% of men required treatment during active surveillance. Reasons for initiating therapy were:
      • Worse classification at control (44.8%).
      • PSA progression (30.2%)
      • Patient request (12.1%)
      • Progression to digital-rectal examination/a finger (digitus) examination of the rectum (rectum) (5.2%)
      • Metastasis (daughter tumors; 4.3%).
    • Therapeutic measures were:
      • 50.1% received radiotherapy (radiation therapy)
      • 22.4% underwent radical prostatectomy (surgical removal of prostate with capsule, the end pieces of vas deferens, and seminal vesicles, and simultaneous removal of pelvic lymph nodes)
      • 14.7% received brachytherapy (“radiotherapy from the inside”).
      • 12.1% decided to antiandrogenic therapy/drugs that inhibit the action of male sex hormones.
    • Output:
      • None of the patients died within ten years of their prostate cancer
      • Metastasis-free survival was 99.3% at five years and 97.4% at ten years.
      • Overall survival was 95% at 5 years and 88% at 10 years.
  • ProtecT (Prostate Testing for Cancer and Treatment) trial: the first large randomized trial of patients with prostate cancer detected by PSA screening, which compared radical prostatectomy (surgical removal of prostate with capsule, the terminals of the vas deferens, and seminal vesicles, and simultaneous removal of pelvic lymph nodes) and radiotherapy (radiotherapy) with active surveillance (“active surveillance”), reached the following results after an observation period of 10 years: There were
    • No benefits on disease-free survival (surgery and radiotherapy were equally effective).
    • Significant differences in side effects:
      • Radical prostatectomy: greatest negative effect on urinary continence (ability to hold urine) at 6 months, and although there was some recovery, urinary incontinence remained worse in the prostatectomy group than in the radiotherapy group and active-monitoring group at all time points (p < 0.001 for each measure)
      • Erectile function: was reduced from baseline to 6 months in all men, with significant differences between treatment groups (p < 0.001).At baseline, 67% of men reported that erections were hard enough for intercourse, but within 6 months, this rate dropped to 52% in the active-surveillance group, 22% in the radiotherapy group, and 12% in the prostatectomy group.
      • Bowel function and bowel habits were unchanged in the prostatectomy group and active-surveillance group but were worse in the radiotherapy group, especially at 6 months.
  • In another study, patients (2,500 men) over a follow-up of three years:
    • Actively monitored (n = 429)
    • Underwent radical prostatectomy (n = 1523):
      • Was associated with more severe urinary incontinence than external radiotherapy (irradiation) or active surveillance
      • Sexual function, assessed in the context of the EPIC-26 quality of life questionnaire, decreased significantly more within three years than after external radiatio
    • Received external radiatio (n = 598).
  • “Prostate Cancer Intervention versus Observation Trial” (PIVOT): immediate radical prostatectomy versus wait-and-see approach; patients with tumors detected by PSA screening and who were in early stage (stage T1-T2NxM0); observation period 19 years. Results: 5.5 percentage point reduction in mortality; 4.0 percentage point reduction in prostate cancer mortality; benefit was most apparent at intermediate risk according to d’Amico: immediate surgery resulted in a 14.5 percentage point reduction in all-cause mortality.

Localized tumors

Radical prostatectomy is a primary treatment option for patients with clinically localized prostate cancer of all risk groups.In patients with prostate cancer and low risk (cT1c and PSA < 10 and Gleason ≤ 6), lymphadenectomy can be omitted. Stage T1a N0 M0 In this tumor stage, it is important to wait and observe the further course of the disease most closely for the time being. The probability that the disease will progress is 16% for 15 years. Therefore, it is decided on an individual basis whether removal of the prostate is necessary. Stage T1b – T2 N0 M0 For larger, organ-confined tumors, radical prostatectomy (surgical removal of the prostate with capsule, the end pieces of the vas deferens, and the seminal vesicles, and simultaneous removal of the pelvic lymph nodes) is considered the standard primary therapy. Adjuvant (supportive) radiation or hormone therapy is sometimes used. Further notes

  • Lymphadenectomy may not be necessary if the risk is low (cT1c and PSA < 10 and Gleason ≤ 6).
  • Androgen deprivation (chemical castration), a primary therapy for localized prostate cancer commonly used in older patients, is of dubious benefit. The known risks of the therapy were not matched by a gain in lifetime.
  • Hyperthermia (superheating/heat therapy) alone should not be used in the primary therapy of localized prostate carcinoma.
  • The French Society of Urology has endorsed treatment with high-intensity focused ultrasound (HIFU) for primary therapy of prostate carcinoma in elderly patients (>70 years) with locally limited prostate carcinoma (T1-T2, Gleason score ≤ 7, PSA ≤ 15 ng/mL) (as of February 2009). For more on HIFU, see the article of the same name. According to the S3 guideline, HIFU therapy for localized prostate cancer is an experimental procedure.
  • Cryotherapy (cold therapy) is not an adequate treatment alternative in the primary therapy of localized prostate carcinoma. There are no study data to justify the use of this procedure in the primary therapy of localized PCa.
  • In a meta-analysis with patients who had a PSA < 10 ng/ml and a Gleason score ≤ 7 (3 plus 4) (localized low-risk disease), after focal therapy with the photosensitizer padeliporfin at a dose of 4 mg/kg body weight in combination with an applied light energy of 200 J/cm at a wavelength of 753 nm, no tumor was bioptically detectable after 6 monthsIn a phase 3 trial with the photosensitizer padeliporfin in patients with localized low-risk prostate cancer, the incidence of local recurrence was reduced. The collective consisted of 413 patients with localized prostate carcinoma (stage T2a) and favorable histologic findings (Gleason score 3). It was randomized to “Active Surveillance” or to photodynamic therapy with the photosensitizer padeliporfin.Ergenbis: Only 58 of 206 patients (28%) experienced tumor progression under photodynamic therapy. Under “active surveillance”, on the other hand, this occurred in 120 of 207 patients (58 %). Two years after photodynamic therapy, 101 patients (49%) had a negative prostate biopsy versus 28 patients (14%) in the “Active Surveillance” group.
  • The PREFERE trial, a four-arm randomized controlled trial, is currently investigating which of the four procedures mentioned in the S3 guideline (radical prostatectomy, percutaneous radiation/radiation, low-dose-rate brachytherapy, active surveillance) is more appropriate for locally limited prostate cancer with low or early intermediate tumor cell malignancy.
  • Comparison of patients with radical surgery or radiotherapy (Prostate Cancer Outcomes Study (PCOS)) for localized prostate cancer shows that in the short to medium term (after 2 and 5 years of follow-up), radiation is superior for bladder and sexual function. Bowel urgency, however, was more common in the group that received radiation.
  • Men with high-risk localized prostate cancer (T stage 3 or higher, with a pre-therapy PSA above 20 ng/dl or a Gleason score between 8 and 10 on biopsy) do not live longer after radical prostatectomy than after external beam radiation with brachytherapy.
Complaints After 2 years After 5 years
Urinary incontinence Six times more frequent after surgery five times more often after OP
Erectile dysfunction (ED) Three and a half times more frequent after surgery two times more often after OP
Urge to defecate Two and a half times more frequent after radiotherapy two times more often after radiatio (radiotherapy)

After 15 years, the differences in both groups had disappeared for all symptoms.

Locally advanced tumors

Subsequent recommendations are based on S3 guidelines:

  • Radical prostatectomy is a primary treatment option for patients with locally advanced prostate cancer.
  • Patients with locally advanced prostate cancer and planned local therapy should be informed about the advantages and disadvantages of both radical prostatectomy with lymphadenectomy (lymph node removal) and radiation therapy with additional time-limited hormone ablative therapy (hormone therapy), if necessary.
  • Patients with a prostate carcinoma of the high risk profile, who want a radical prostatectomy, should be informed about the increased risk of positive resection margins and for disease recurrence, as well as the resulting often additional necessary measures (eg, hormone ablative therapy, radiotherapy).
  • Patients with locally advanced prostate cancer who opt for radiotherapy should receive hormone ablative therapy in addition to percutaneous radiotherapy.

Stage T3 N0 M0 Treatment options at this tumor stage include radical prostatectomy, adjuvant radiotherapy, and hormone therapy. Stage T3 N1 M0 If lymph nodes are already affected, a radical prostatectomy (surgical removal of the prostate with capsule, the end pieces of the vas deferens and the seminal vesicles and simultaneous removal of the pelvic lymph nodes) and hormone therapy are performed. Sometimes hormone therapy alone is used. See also below under “Further notes”.

Metastatic hormone-sensitive tumors

Stage T4 N0-3 M0-1 If the tumor has already spread to adjacent structures, hormone therapy is used as the treatment of choice. Stage T1-4 N1-3 M0-1 Hormone therapy may be used for all tumors that have involved lymph nodes, whether or not metastases are present. Further notes

  • In patients with locally advanced or metastatic prostate cancer, adding early chemotherapy with docetaxel to hormone-ablative therapy may prolong survival.
  • Advanced Prostate Cancer Consensus Conference (APCCC) in St. Gallen on therapy for advanced prostate cancer [indicated in round brackets: % of experts]:
    • Castration-naive metastatic tumors:
      • The term “castration-naive” should be replaced by “hormone-sensitive “or “castration-sensitive”.
      • Decreasing PSA levels (< 4 ng/ml after approximately 6 months): intermittent rather than continuous androgen deprivation (71%).
      • Combination therapy for complete androgen blockade (approximately 50%):
        • Combination therapy with docetaxel for high tumor volume (about 50%).
        • No need for docetaxel in low-volume disease (approximately 75%).
    • Nonmetastatic castration-resistant tumors:
      • Diagnosis of M0 tumor is considered confirmed if computed tomography (chest CT/chest organs, abdominal CT/abdominal organs, pelvic CT/pelvic organs) and bone scintigraphy are negative (77%)
      • Also use androgen modulators (abiraterone, enzalutamide) when PSA levels are rising, although there is little evidence on the benefit (overall survival) in this situation (84%)
    • Metastatic castration-resistant tumors, first-line therapy:
      • Healthy, asymptomatic or minimally symptomatic patients: First-line therapy with abiraterone or enzalutamide in the majority of patients (88%).
      • Chemotherapy in these patients in a selected minority (approximately 50%):
        • Sipuleucel-T in this situation (56%).
      • In symptomatic patients without visceral metastases (daughter tumors in the intestines):
        • Treatment with radium-223 in a minority (approximately 66%).
        • Chemotherapy (usually taxane-based) as first-line option (91%); recommended in majority of symptomatic patients (41%)
    • Metastatic castration-resistant tumors, second-line therapy:
      • After first-line therapy with docetaxel: therapy with cabazitaxel (approximately 66%), but only in selected patients (57%).
      • After first-line therapy with abiraterone or enzalutamide, no second-line therapy with either of these drugs if primary resistance to therapy (no PSA decline, no radiologic and clinical improvement) is observed (53%)
      • If patients initially respond to first-line therapy with abiraterone or enzalutamide and then progression (“disease progression”) occurs, only 23% of experts ruled out further use of either agent.