What is EBRT prostate cancer

Prostate cancer: radiation therapy as a curative option

The technical evolution enables conformal dose coverage of the prostate and seminal vesicles with maximum protection of the organs at risk.

An overview of the therapies against the background of current clinical data.

According to the current version of the S3 guideline (1), the primary therapy options for locally limited prostate cancer with low risk are percutaneous radiation therapy (EBRT, "external beam radiotherapy"), low-dose-rate brachytherapy (LDR-BT), and radical prostatectomy (RPE) and active surveillance (AS, "active surveillance").

For medium risk, EBRT and RPE as well as the combination of EBRT and high-dose-rate brachytherapy (HDR-BT) are recommended. However, a multicentre prospective randomized study (2) and retrospective data (3) indicate the potential and equivalence of both the combination of EBRT with LDR-BT and LDR-BT alone with low acute and late side effects as alternatives to EBRT or RPE.

The latest studies in the updated S3 guideline have not yet received full attention for the high risk and cross-organ tumors. According to the guideline, EBRT with androgen suppression and RPE with lymph node dissection are named as the primary treatment options. The combination of EBRT and high-dose-rate brachytherapy (HDR-BT, no prospective randomized data!) With Iridium-192 is cited as an alternative for cT3 tumors.

However, the multicenter prospective randomized Ascende-RT study published in 2017 on 398 men (2, 4) shows a highly significant superiority of the combination of EBRT with LDR-BT and a total of 12 months of androgen suppression over EBRT for PSA-free survival with androgen suppression (PSA-free survival according to the Phoenix classification after 9 years 83.3% in the combination group versus 62.4% in the EBRT group; compared to this, stratified according to the surgical standard, PSA> 0.2 ng / ml: PSA-free survival at 9 years 82.2% in the combination group compared to 31.5% in the EBRT group). However, there was no difference in overall survival.

In this study, the combination of EBRT and LDR-BT led to more grade 3 side effects, which were mainly reflected in urethral strictures (cumulative incidence after 5 years 18.4%, the prevalence after 5 years at 8.6% because half of the cases could be treated with dilation or TUR-P) (4).

With regard to a comparison of the therapy methods recommended in the S3 guideline, there are only long-term data from the British Protect Trial, which was published in the NEJM in 2016, after the termination of the German Prefere study (insufficient recruitment figures) (5). Here, EBRT with 3 to 6 months of androgen suppression, RPE with and without lymphadenectomy and monitoring by PSA controls (active monitoring) were compared with one another.

After 10 years, all procedures showed equivalence for overall survival. However, monitoring led to metastases in twice the number of cases (n = 33/545), a highly significant difference compared to RPE and EBRT (RPE n = 13/553, EBRT n = 16/545 metastases; p = 0.004) . 56% of the monitored patients ultimately received active therapy. In this study, compared to RPE, EBRT led to statistically significantly less incontinence with an equally low frequency of intestinal side effects and a discreet but significantly lower reduction in potency (6).

Primary radiotherapy procedures

In this summary, the primary radiotherapy methods for the treatment of prostate cancer in all risk stages are to be examined, as they are currently offered in therapy centers in Germany.

According to D'Amico, newly diagnosed prostate cancer with a Gleason score ≤ 6, PSA ≤ 10 ng / ml and maximally unilateral involvement (T1c-T2b) is assigned to the low risk with regard to disease-specific survival (7). Here, the patient should always be advised on radiation therapy with regard to an EBRT of the extended prostate region or a sole LDR-BT.

To plan the EBRT, the patient with a completely empty rectum and a half-filled urinary bladder (usually in the supine position, less often in the prone position to protect the intestine) is examined by computer tomography and the prostate is virtually set as the isocenter. The isocenter is projected onto the patient using adjusted lasers and the laser lines are traced on the skin.

The preparation of the urinary bladder and rectum has a decisive influence both on the rate of genitourethral and gastrointestinal side effects and on oncological success (8–10). Therefore, compliance with the described filling states of the rectum and urinary bladder is also given special attention in the course of the fractional EBRT.

The EBRT is intensity-modulated almost everywhere in Germany (“intensity-modulated radiotherapy”, IMRT) (Figure 1). This enables the target volume to be conformally adapted to the anatomy while respecting the oncological safety margins. During planning, both prostate and seminal vesicles as well as organs at risk ("organs at risk", OAR: urinary bladder, rectum, sigmoid colon, small intestine, penile bulb, urethra, femoral heads) are contoured in the planning CT and prescribed with appropriate radiation doses. The aim is a homogeneous and conformal radiation dose in the prostate and seminal vesicles with a maximum reduction in radiation in the OAR, in accordance with the empirically defined tolerance doses (11).

IMRT plan of a target volume of the enlarged prostate and seminal vesicle region with integrated dose saturation on the prostate.

Two developments have contributed to the improvement of organ protection and oncological success of the EBRT in the last few years (12).

  • Image-guided radiotherapy (IGRT, Figure 2) enables using 4-dimensional stereotactic ultrasound (4D-US), implanted gold markers (“fiducial markers”, FM) or radio frequency transponders (“radio frequency markers”, RFM) ) as well as on-board-cone-beam-CT (CBCT) the precise positioning of the prostate in the central ray (13, 14) and beyond - as in the case of the 4D-US or RFM - the continuous tracking (tracking) of the prostate position during irradiation (15) (Figure 3). This enables an almost stereotactically precise positioning of the target region and, in the event of deviation, immediate interruption of the irradiation (gating).
  • In addition to IGRT, the introduction of volumetric modulated arc therapy (VMAT) has replaced the initially very slow multi-field IMRT (≥ 15 min / 2 Gy). This results in irradiation times per fraction of < 2 minuten="" möglich.="" durch="" weitere="" technische="" entwicklungen="" (ausgleichsfilterfreie="" bestrahlung,="" „flattening-filter="" free“,="" fff)="" lassen="" sich="" jetzt="" schon="" dosisraten="" von="" 25 gy/minute="" und="" bestrahlungszeiten="">< 1 min gy="" im="" regelhaften="" patientenbetrieb="">
Image-guided radiotherapy. Coronal, sagittal and transverse sections of the adapted planning CT and the cone-beam CT are shown.

Experimental techniques for further acceleration have long been established at centers and are currently being tested for daily applicability. Daily IGRT and accelerated irradiation allow the reduction of so-called safety margins to a few millimeters (16) and thus lead to the minimization of irradiated normal tissue (anterior rectal wall and bladder floor) despite the prostate position in the pelvis, which is directly dependent on bladder and rectal filling. This enables both acute and late side effects of the EBRT (6), which are already well tolerated, to be significantly reduced even further.

Typical side effects

Typical side effects of EBRT in the acute radiation phase are dysuria, nocturia and pollakiuria as well as proctitic complaints and discreet stool irregularities, which can also manifest in diarrhea when the iliac lymphatic drainage pathways are irradiated. All the symptoms described are usually marked on the CTC scale (RTOG / EORTC “common toxicity criteria” [17]) grade 1–2 and can be controlled symptomatically with medication.

Late side effects include fibrosis (extremely rarely genetic in the entire pelvic area), telangieectasias in the anterior rectal wall and the bladder floor, persistent stool irregularities and, very rarely, rectal fistulas as serious complications (< 1:1 000) auftreten.="" harnwegsinfekte="" sollten="" jederzeit="" kalkuliert="" antibiotisch="" behandelt="" werden,="" um="" in="" der="" nachsorgephase="" die="" urethrale="" toxizität="" möglichst="" gering="" zu="" halten.="" teleangieektasien="" sollten="" bei="" hämatologischer="" stabilität="" und="" gelegentlichem="" intestinalem="" oder="" urethralem="" blutabgang="" toleriert="" und="" nicht="" sofort="" prokto-="" oder="" zystoskopisch="" diagnostiziert="" und="" therapiert="" werden,="" um="" iatrogene="" hohlorganperforationen="" durch="" elektroevaporationen="" im="" bestrahlten="" gewebe="" zu="" vermeiden.="" die="" potenz="" ist="" in="" der="" regel="" unmittelbar="" nach="" abschluss="" einer="" volldosierten="" ebrt="" erhalten,="" kann="" aber="" nach="" 6="" jahren="" bei="" 70 %="" der="" patienten="" eingeschränkt="" sein="" (80 %="" impotenz="" 6="" jahre="" nach="" rpe)="">

Co-treatment of the iliac lymphatic drainage pathways ("whole pelvic radiotherapy", WPRT) in the case of intermediate or high risk without direct evidence of lymph node metastases, but calculated increased risk - according to Roach: 2/3 x PSA + ([Gleason score - 6] x 10) ; (18) - continues to be controversial. Several phase III studies could not show a clear connection between overall survival, PSA-free survival and radiation of the lymphatic drainage pathways carried out solely on the basis of the calculated risk (19). As an example, RTOG 94–13 compared the WPRT against radiation of the prostate and seminal vesicles (“prostate only radiotherapy”, PORT) as well as the neoadjuvant, accompanying and after completion of the RT continued anti-hormone therapy (AHT) in a 2x2-factorial design. WPRT showed an improvement in overall survival only for the subgroup of neoadjuvant treated patients (20, 21). The question of the superiority of the WPRT is currently being re-examined in the PIVOTAL (NCT01685190) and RTOG 09–24 (NCT01368588) studies.

If there is an intermediate (Gleason 7, PSA 10–20 ng / ml) risk, short-term anti-hormone therapy (AHT) for 6 months can be carried out in addition to percutaneous radiation to improve disease-free survival in the absence of cardiac risk factors (22). On the other hand, there is the clear recommendation for 2–3 years long AHT at high risk, which is also reflected in the current national guideline (1).

Follow-up care after primary radiation therapy includes, in addition to the structured recording of acute and late toxicities, the PSA values ​​that are initially collected every 3 months and later at longer intervals. Depending on the form of the definitive primary radiation therapy treatment, a low-normal PSA of < 2 ng l="" einstellen,="" der="" mitunter="" erst=""> 6 months after completion of treatment is reached. According to the recommendation of the RTOG-ASTRO Phoenix Consensus Conference, PSA recurrence should only be excluded from a PSA> 2 ng / ml above the nadir (23). On the other hand, there is the almost ablative effect of the extreme dose increase through the combination of EBRT with LDR brachytherapy, in which 45 Gy percutaneously and then 110–120 Gy through the implantation of J125 seeds. The Ascende RT trial, in combination with a 12-month androgen deprivation, recorded PSA remissions comparable to RPE (PSA < 0,2 ng l)="">

Brachytherapy is a special case in the PSA progression after completion of therapy (Figure 4), where a temporary PSA increase (PSA bounce,> 0.2 ng / ml above the nadir in up to 50% of patients around 18 Months after therapy over a period of 6 to 22 months) (24, 25).

Low-dose-rate brachytherapy plan for the implantation of J125 seeds using a 3-dimensional transrectal ultrasound with a biplanar probe.

Experience has shown that the PSA bounce can be assessed as a predictor of a subsequent stable remission and thus of successful healing (24).

Conclusion

  • The radiotherapy options are primary therapies that have been verified in prospective randomized studies for every stage of prostate cancer.
  • The technical evolution (IMRT, VMAT, IGRT, stereotactic procedures) enables conformal dose coverage of the prostate and seminal vesicles with maximum protection of the organs at risk. In this way, the radiation dose can be increased to areas that are necessary to eradicate the tumor cell clones (12, 16, 26, 27).
  • The patient selection comes first. The earlier dogma of the old man at the end of his life has developed further towards patients of all ages who are informed about all forms of therapy with risk-adapted therapy.
  • A new aspect is the shortening of the total treatment time by increasing the individual fraction dose (2.4–6 Gy) and reducing the total dose (hypofractionation). This is currently being tested in studies.
  • The elective irradiation of the lymphatic drainage pathways depending on a calculated theoretical risk of lymph node involvement should be viewed critically and reserved for currently controlled studies.
  • The (neo) adjuvant anti-hormone therapy is a relevant pillar in addition to the dose escalation in the case of high risk, provided there are no cardiac risk factors. ▄

DOI: 10.3238 / PersOnko / 2017.06.16.02

Dr. med. Benjamin Gauter-Fleckenstein

Dr. sc. hum. Martin Polednik

Prof. Dr. med. Frederik Wenz

Clinic for Radiation Therapy and Radiation Oncology,
University Medicine Mannheim, Medical Faculty Mannheim
of the Ruprecht-Karls-Universität Heidelberg

Conflict of Interest: Prof. Wenz gives congress fees, reimbursement of travel expenses, lecture fees and research grants, among other things. for clinical studies from Elekta. Dr. Gauter-Fleckenstein and Dr. Polednik declare that there is no conflict of interest.

Literature on the Internet:
www.aerzteblatt.de/lit2417

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