Dr. med. Dirk Manski

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Prostate Cancer: Results and Side Effects of Radiation Therapy


Guidelines and review literature: (EAU Guidelines Prostate Cancer) (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 ten 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 (Morris et al., 2005).

Technique of External Beam Radiation Therapy:

There exists a clear dose-response relationship for the outcome of radiation therapy. The standard radiation dose in older studies was 64–72 Gy. Technical modifications made dose escalation in the prostate safe and helped to avoid damage to vital structures such as the urethra, rectum, and bladder. Using modern radiotherapy (see below), a radiation dose of 76–78 Gy is recommended; this is associated with improved oncological outcomes, while late urogenital toxicities are not significantly increased (Gauter u.a., 2017).

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 scan, 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 fundamental prerequisite for a successful radiation therapy is the exact positioning of the patient for each irradiation. For the irradiation of the prostate, a full bladder is essential. 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 of 76–78 Gy is reached.

Image-guided radiotherapy (IGRT):

The fundamental prerequisite for successful radiotherapy is the precise positioning of the patient for each irradiation. In IGRT, the position of the prostate is checked before each irradiation using various imaging techniques (CT, US).

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 and modulated in intensity. Thus, the radiation may be modified not only by multileaf collimators but also by the change in intensity in the radiation beam. IMRT helps to spare surrounding structures and lowers the rate of side effects; it is the currently recommended radiation modality (Yu et al., 2016).

Volumetric modulated arc therapy (VMAT)

VMAT is a further development of IMRT. The linear accelerator rotates around the patient while several control variables, such as the rotation speed, the apertures, and the dose rate, are continuously changed. The decisive advantage of VMAT is the significant reduction in treatment time per fraction.

Hypofractionated radiotherapy:

Hypofractionated radiotherapy with a higher single dose and lower total dose results in a significantly shorter treatment duration. Hypofractionation (e.g., 20 × 3.0 Gy in four weeks) shows slightly increased gastrointestinal and urogenital side effects with comparable oncologic efficacy (Dearnaley et al., 2016).

Proton Therapy for Prostate Cancer:

The irradiation with charged particles offers advantages concerning 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. Initial 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 the base of the penis and the apex of the seminal vesicles, are spared.

Irradiation of the pelvic lymph nodes:

Irradiation of the pelvic lymph nodesis not recommended for low-risk prostate cancer. New randomized trials have been started (Dirixet al., 2014a); the German guideline mentions irradiation of the pelvic lymph nodes as an option in intermediate and high-risk prostate cancer.

Results of External Beam Radiation Therapy for Prostate Cancer

Randomized trials prove a 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 EAU guideline recommends the duration of adjuvant hormone therapy to be six months for intermediate risk and 24–36 months for high risk, with hormone therapy starting two months prior to radiation therapy.

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 three 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 relevant urogenital toxicity (grade 2–5 RTOG/EORTC) is approximately 30%. If pronounced obstructive voiding symptoms exist 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 relevant gastrointestinal toxicity (grade 2–5 RTOG/EORTC) is approximately 25%. Severe side effects are rare and include fistulas, stenosis, intestinal perforation, and life-threatening bleeding.

Erectile dysfunction:

Erectile dysfunction 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 fatigue can develop. Symptoms can be mitigated by moderate aerobic training. Long-term side effects include the risk of secondary tumors. After 5–8 years, the relative risk of bladder carcinoma increases by 50%, and for rectal carcinoma by 70%.

Biochemical Progress after Radiation Therapy

A PSA rise above 2 ng/ml over PSA nadir after radiation therapy is regarded as a biochemical recurrence after radiotherapy (Roach et al., 2006). If the patient wishes a local salvage therapy, a prostate biopsy and PSMA-PET needed before further decisions.

Salvage-Prostatectomy after Radiation Therapy

Smaller series with up to 80 patients were able to demonstrate the feasibility of radical prostatectomy for recurrence after 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). Patients with localized prostate carcinoma before EBRT and before prostatectomy, a pre-prostatectomy PSA level of less than 10 ng/ml, and a life expectancy of more than ten years are the most likely to benefit from salvage prostatectomy.

Salvage radiotherapy:

The longstanding dogma that salvage radiotherapy is not possible after definitive radiotherapy is challenged by recent publications. Salvage radiotherapy is possible with the help of stereotactic irradiation or brachytherapy, and the side effects are less than after salvage prostatectomy (Valle et al., 2021).

Hormone Therapy for PSA Progression after Radiation Therapy

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


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. EAU-Guidelines Guidelines on Prostate Cancer of the European Association of Urology (EAU), https://uroweb.org/guidelines/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, https://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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