Dr. med. Dirk Manski



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Prostate Cancer: Radiation Therapy


Guidelines and review literature: (EAU Guidelines, Mottet et al, 2015) (S3-Leitlinie Prostatakarzinom der DGU) (Walsh-Campbell Urology 11th Edition).

External Beam Radiotherapy (EBRT) For Prostate Cancer

Indications for External Beam Radiotherapy for Prostate Cancer:

External beam radiotherapy (EBRT) is a therapeutic option for all risk groups of organ-limited or locally advanced prostate cancer without metastases. Life expectancy should be at least 10 years. Patients with severe micturition symptoms are not well suited for radiation therapy. In retrospective comparisons, radiation therapy shows comparable oncological results to radical prostatectomy in well-differentiated tumors. Radical prostatectomy has oncological advantages in poorly differentiated tumors [see table D’Amico risk classification for prostate cancer and Results of EBRT}]. Radiotherapy, however, has significant advantages for urinary continence compared to prostatectomy. Review literature: Morris et al (2005).

Technique of External Beam Radiation Therapy:

A clear dose-response relationship has been demonstrated for the outcome of radiation therapy. Unfortunately, radiation-induced side effects rise significantly if more than 70 Gy are applied with conventional radiation techniques. Technical modifications made dose escalation in the prostate safe and helped to avoid damage to vital structures such as the urethra, rectum and bladder. Dose escalation to 74–80 Gy is associated with an improvement in the oncological results, while the urogenital toxicity is not significantly increased (Viani et al, 2009).

3D Conformal Radiotherapy for Prostate Cancer:

The three-dimensional conformal radiation therapy is the current standard technology of external beam radiotherapy for prostate cancer. With the help of a CT, the target dose is virtually planned for the prostate. The planning program calculates the expected doses for sensible adjacent structures. The prostate is irradiated in several levels (e.g. four radiation fields), which possibly do not affect vital structures. With the help of individual apertures, so-called multileaf collimator (MLC), the radiation fields are limited to the target.

The recommended radiation dose of the prostate is 74–80 Gy. The basic prerequisite for a successful radiation therapy is the exact positioning of the patient with exact repositioning during the next irradiation. For the irradiation of the prostate, a full bladder very important. The full bladder keeps the bladder walls out of the radiation fields and avoids side effects. The total dose is fractionated (spread out over time), a typical fraction size may be 1.8–2 Gy per weekday, until the desired dose is reached.

Intensity Modulated Radiotherapy (IMRT) for Prostate Cancer:

In contrast to 3D conformal radiation therapy with homogeneous radiation fields, the cross section of the IMRT radiation field can be inhomogeneous modulated in intensity. Thus, the radiation may be modified not only by multileaf collimator, but also by the change in intensity in the radiation beam. IMRT can deliver a high-dose radiation to the prostate (90 Gy) with an acceptable side effect profile. Disadvantages are the high technical and human effort and therefore costs.

Proton Therapy for Prostate Cancer:

The irradiation with charged particles offers advantages with respect to dose application to the target with good protection of the neighboring organs. Since the main energy is released at the end of the linear beam of protons (Bragg peak), the radiation effect is minimal to the lateral and beyond the target. Proton therapy can be combined with photon irradiation. First studies show promising results (Coen et al, 2009), but clear advantages of proton therapy for prostate cancer are not proven yet.

Nerve Sparing Radiation Therapy:

Through accurate planning and radiation techniques, sensitive structures for erection such as base of the penis and apex of the seminal vesicles are protected.

Results of External Beam Radiation Therapy for Prostate Cancer

Prospectively-randomized trials could prove an significant dose-dependent effect of EBRT on recurrence-free survival. The standard dose is a radiation dose of at least 70 Gy. The long-term outcome after radiotherapy is presented in table oncological results of radiotherapy in prostate cancer.

Long-term results after EBRT for prostate cancer, meta-analysis of five randomized RTOG trials, n = 1557, no hormone therapy, follow-up 15 years, presented in five (5-YSR), ten (10-YSR) and fifteen (15-YSR) year survival rates (disease-specific) (Roach et al, 2000).
Tumor stage 5-YSR 10-YSR 15-YSR
Gleason 2–6 + T1–2 96 % 86 % 72 %
Gleason 2–6 + T3 94 % 75 % 61 %
Gleason 7 + T1–2 94 % 75 % 61 %
Gleason 7 + T3 83 % 62 % 39 %
Gleason 8–10+ T1–2 83 % 62 % 39 %
Gleason 8–10 + T3 64 % 34 % 27 %

Adjuvant Hormonal Therapy:

Several randomized studies demonstrated a survival benefit for adjuvant hormone therapy after radiotherapy for patients with high risk prostate cancer [see table D’Amico risk classification for prostate cancer]. The duration of the adjuvant hormonal therapy differs between 6–24 months and begins 2 months before radiation therapy. The duration of hormone therapy should to be determined individually considering comorbidity, age, life expectancy and tumor risk. Adjuvant hormone therapy is not indicated for patients with low risk prostate cancer. The situation for patients with intermediate risk prostate cancer is unclear. If adjuvant hormonal therapy is performed, the duration should be limited to 6 months (DGU, 2014).

Side effects of Radiation Therapy

The side effects after radiotherapy are divided into acute effects (within 90 days after therapy) and late effects (more than 3 months after therapy), see table classification of long-term complications after radiation therapy.

Urination Symptoms:

Overactive bladder symptoms, obstructive micturition symptoms, urinary retention, macrohematuria, urethral stricture, incontinence, urinary bladder fistula. The risk of RTOG/EORTC relevant urogenital toxicity >2 is approximately 30%. If pronounced obstructive voiding symptoms exists before EBRT, radical prostatectomy should be considered. Severe side effects are rare and include bladder fistulae, severe hemorrhagic cystitis and the development of a bladder capacity below 100 ml.

Defecation Symptoms:

Stool urge, mucus secretion or hematochezia in 33% of the patients after three years. The risk of RTOG/EORTC-relevant gastrointestinal toxicity ≥2 is approximately 25%. Severe side effects are rare and include fistulas, stenosis, intestinal perforation, and life-threatening bleeding.

Sexuality Symptoms:

Impotence develops with a time delay after radiotherapy and affects about 60% of the patients after two years (Stephenson u.a., 2005).

Other side effects:

Immediately after irradiation, soreness and fatique can develop. Symptoms can be mitigated by moderate aerobic training. Long-term side effects include the risk for secondary tumors. After 5–8 years, there is an increase of bladder carcinoma risk by 50%, and for a rectal carcinoma risk by 70%.

Biochemical Progress after Radiation Therapy

PSA progression after radiation therapy has different definitions:

If the patient wishes a local salvage therapy (=prostatectomy), a prostate biopsy should be indicated before further decisions. Furthermore, a PSMA-PET is a promising option for the exclusion of metastases.

Hormone Therapy for PSA Progression after Radiation Therapie

Standard therapy for PSA progression after EBRT is permanent hormone therapy, if PSA doubling time is below 3–6 months. PSA doubling time is the key prognosis parameter, a doubling time of less than 3 months indicates a very poor prognosis. PSA response after initiation of hormone therapy also correlates with the prognosis.

Salvage-Prostatectomy after Radiation Therapy

Smaller series with up to 80 patients were able to demonstrate the feasibility of radical prostatectomy after recurrence of EBRT. Urinary incontinence (major incontinence in up to 50%) is significantly higher than after Prostatectomy without previous irradiation. There is a relevant risk of neighboring organ injury (rectum or ureter). Profits from salvage prostatectomy can be expected with a localized prostate cancer before EBRT and before prostatectomy, with a PSA level before prostatectomy of less than 10 ng/ml and a life expectancy of more than 10 years.

 
RTOG Classification of long-term complications and toxicity after radiation therapy. RTOG=Radiation Therapy Oncology Group.
Gastrointestinal Urogenital
Grade 1 Increased frequency or change in quality of bowel habits not requiring medication Frequency, dysuria, urgency not requiring medication
Grade 2 Diarrhea requiring drugs, mucous discharge not necessitating sanitary pads, pain requiring analgesics Moderate urinary frequency (less than hourly), occasional hematuria, numerous telangiectasias
Grade 3 Diarrhea requiring parenteral support, severe mucous or blood discharge necessitating sanitary pads, requiring surgery for stenosis, bleeding requiring transfusion severe urinary frequency (<1/h), severe dysuria, frequent hematuria, bladder capacity below 150 ml
Grade 4 perforations, fistulas, life-threatening hemorrhage, necrosis perforations, fistulas, severe hemorrhagic cystitis, bladder capacity below 100 ml
Grade 5 any fatal complication any fatal complication







Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z





References

ASTRO 1997 ASTRO:
Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel.
In: Int J Radiat Oncol Biol Phys
37 (1997), Nr. 5, S. 1035–41

Coen, J. J. & Zietman, A. L.
Proton radiation for localized prostate cancer.
Nat Rev Urol, 2009, 6, 324-330.



Kattan u.a. 2003 KATTAN, M. W. ; ZELEFSKY, M. J. ; KUPELIAN, P. A. ; CHO, D. ; SCARDINO, P. T. ; FUKS, Z. ; LEIBEL, S. A.:
Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer.
In: J Clin Oncol
21 (2003), Nr. 24, S. 4568–71

Morris u.a. 2005 MORRIS, D. E. ; EMAMI, B. ; MAUCH, P. M. ; KONSKI, A. A. ; TAO, M. L. ; NG, A. K. ; KLEIN, E. A. ; MOHIDEEN, N. ; HURWITZ, M. D. ; FRAAS, B. A. ; ROACH, 3rd ; GORE, E. M. ; TEPPER, J. E.:
Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative.
In: Int J Radiat Oncol Biol Phys
62 (2005), Nr. 1, S. 3–19

Roach u.a. 2000 ROACH, M. ; LU, J. ; PILEPICH, M. V. ; ASBELL, S. O. ; MOHIUDDIN, M. ; TERRY, R. ; GRIGNON, D. ; MOHUIDDEN, M.:
Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials.
In: Int J Radiat Oncol Biol Phys
47 (2000), Nr. 3, S. 609–15

Roach, M.; Hanks, G.; Thames, H.; Schellhammer, P.; Shipley, W. U.; Sokol, G. H. & Sandler, H.
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference.
Int J Radiat Oncol Biol Phys 2006, 65, 965-974.
N. Mottet (Chair), J. Bellmunt, E. Briers (Patient Representative), R.C.N. van den Bergh (Guidelines Associate), M. Bolla, N.J. van Casteren (Guidelines Associate), P. Cornford, S. Culine, S. Joniau, T. Lam, M.D. Mason, V. Matveev, H. van der Poel, T.H. van der Kwast, O. Rouvière, T. Wiegel
Guidelines on Prostate Cancer of the European Association of Urology (EAU), https://uroweb.org/guideline/prostate-cancer/.


Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF):
Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, http://www.awmf.org/leitlinien/detail/ll/043-022OL.html (Zugriff am: 07.02.2016)


Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A.
Campbell-Walsh Urology
. Elsevier, 2015. ISBN 978-1455775675.


Stephenson, R. A.; Mori, M.; Hsieh, Y.; Beer, T. M.; Stanford, J. L.; Gilliland, F. D.; Hoffman, R. M. & Potosky, A. L.
Treatment of erectile dysfunction following therapy for clinically localized prostate cancer: patient reported use and outcomes from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study.
J Urol, 2005, 174, 646-50; discussion 650.


Viani, G. A.; Stefano, E. J. & Afonso, S. L.
Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials.
Int J Radiat Oncol Biol Phys, 2009, 74, 1405-1418


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