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Prostate Cancer: Radiation Therapy

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

External Beam Radiotherapy for Prostate Cancer

Indication:

Definitive external beam radiotherapy (EBRT) is a therapeutic option for all risk groups of organ-confined or locally advanced prostate cancer without distant metastases. Life expectancy should be at least 10 years. Marked obstructive lower urinary tract symptoms, high postvoid residual urine, or recurrent urinary retention argue against primary radiotherapy. In the ProtecT trial of low-risk prostate cancer, prostate cancer-specific mortality at 15 years was low and did not differ significantly among active monitoring, radical prostatectomy, and radiotherapy (Hamdy et al., 2023). Retrospective comparisons suggest oncologic advantages of radical prostatectomy in poorly differentiated tumors and in patients with high clinical risk (Boorjian et al., 2012; Chierigo et al., 2022). Radiotherapy is clearly superior to prostatectomy with regard to urinary incontinence.

Technique:

Radiation therapy has a dose-response relationship. Definitive EBRT is now delivered using image-guided and intensity-modulated techniques. With conventional fractionation, 76–80 Gy are typically delivered in single fractions of 1.8–2.0 Gy. Alternatively, moderate hypofractionation is established in suitable patients, e.g., 60 Gy in 20 fractions or 70 Gy in 28 fractions. The physical total dose cannot be compared directly between fractionation schedules. As the dose per fraction increases, the biologic effect per Gy increases; thus, a lower total dose with hypofractionation may correspond to a similar or higher biologically effective dose. Depending on the risk group, the target volume includes the prostate, parts of the seminal vesicles, and, if indicated, the pelvic lymphatic drainage pathways.

3D conformal radiotherapy:

Current standard technique of EBRT for prostate cancer. A planning CT is used to plan the target dose to the prostate virtually; the planning software also calculates the expected doses to sensitive adjacent structures. The prostate is irradiated from several directions (e.g., with four radiation fields), which should avoid traversing vital structures whenever possible. Individual apertures, so-called collimators, limit the radiation fields. In each field, the collimators irradiate the prostate while shielding vital structures. A full bladder should be maintained during prostate irradiation to reduce radiation exposure to the bladder. Radiation is delivered in fractions.

Image-guided radiotherapy (IGRT):

Precise patient positioning and exact repositioning before each fraction are prerequisites for successful radiotherapy. In IGRT, the position of the prostate is verified with image guidance before or during treatment, usually by cone-beam CT or radiographic verification of intraprostatic gold fiducial markers.

Intensity-modulated radiotherapy (IMRT):

In contrast to 3D conformal radiotherapy with homogeneous radiation fields, IMRT can modulate the intensity within each radiation field. This reduces the dose to organs at risk; IMRT is the preferred external-beam 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 parameters, such as rotation speed, aperture position, and dose rate, are continuously changed. The decisive advantage of VMAT is the marked reduction in treatment time per fraction.

Proton therapy:

Irradiation with charged particles offers advantages in dose delivery to the target tissue while sparing adjacent tissues. Since most energy is released at the end of the linear proton path (Bragg peak), the radiation effect lateral to and beyond the target is very low. However, a clinically relevant advantage over modern photon IMRT for localized prostate cancer has not been established.

Nerve-sparing radiotherapy:

Accurate treatment planning and radiation techniques can spare structures important for erection, such as the penile base and the apex of the seminal vesicles.

Irradiation of the pelvic lymphatic drainage pathways:

Pelvic nodal irradiation is generally not recommended for low- or intermediate-risk disease. It may be offered in high-risk disease; PSMA-positive pelvic lymph nodes on PSMA PET/CT should be specifically included in the target volume.

Adjuvant androgen deprivation therapy during and after EBRT:

The indication for androgen deprivation therapy (ADT) depends on the risk profile. Do not combine definitive radiotherapy with ADT in low-risk or favorable intermediate-risk disease. Combine EBRT with short-term ADT for 4–6 months in unfavorable intermediate-risk disease. In high-risk or locally advanced prostate cancer, combine EBRT with long-term ADT for 24–36 months; ADT may begin up to 6 months before radiotherapy.

Adverse Effects of Radiation Therapy

Adverse effects after radiotherapy are divided into acute adverse effects (within 90 days after treatment) and late adverse effects (more than 3 months after treatment); see the RTOG classification.

Urination:

Urgency symptoms, obstructive voiding symptoms up to urinary retention, gross hematuria, urethral stricture, and urinary incontinence may occur. The risk of relevant urogenital RTOG/EORTC toxicity ≥ grade 2 is approximately 30 %. Consider radical prostatectomy if marked obstructive voiding symptoms are present before EBRT. Severe adverse effects are rare and include vesical fistulae, severe hemorrhagic cystitis, and a contracted bladder with a capacity below 100 ml.

Defecation:

Fecal urgency, mucus discharge, and rectal bleeding may occur. The risk of relevant gastrointestinal RTOG/EORTC toxicity ≥ grade 2 is approximately 25 %. Severe adverse effects are rare and include rectal fistulae, intestinal stenosis, ileus, intestinal perforation, and life-threatening bleeding.

Erectile dysfunction:

Erectile dysfunction develops with a marked delay after radiotherapy and affects approximately 60 % of patients after 2 years (Stephenson et al., 2005).

Other adverse effects:

Radiation sickness and fatigue may develop immediately after irradiation. Beyond 10 years, the risk of secondary tumors induced by radiotherapy increases. After 5–8 years, the relative risk of bladder cancer increases by 50 % and that of rectal cancer by 70 %.

Biochemical Recurrence after EBRT

After curative radiotherapy, the PSA level declines slowly. The PSA nadir is often reached only after 18–36 months and is usually below 0.5–1.0 ng/ml; concomitant ADT can cause a temporarily much lower nadir. Biochemical recurrence is defined as a PSA increase of at least 2 ng/ml above the PSA nadir. Before local salvage therapy, confirm local recurrence by multiparametric MRI and prostate biopsy. Evaluate metastatic disease with PSMA PET/CT.

Salvage prostatectomy:

Small series have demonstrated the feasibility of radical prostatectomy for recurrence after EBRT. Urinary incontinence is substantially more frequent and more severe than after prostatectomy without previous irradiation. There is a relevant risk of adjacent-organ injury, particularly to the rectum or ureter. Patients with localized prostate cancer before EBRT and before salvage prostatectomy, a pre-prostatectomy PSA level < 10 ng/ml, and a life expectancy of more than 10 years are most likely to benefit from salvage prostatectomy.

Salvage radiotherapy:

Recent publications have challenged the earlier dogma that repeat radiotherapy after definitive radiotherapy is impossible. Salvage radiotherapy can be delivered with stereotactic irradiation or brachytherapy; adverse effects are lower than after salvage prostatectomy in selected series (Valle et al., 2021). Targeted radiotherapy of isolated lymph node or bone metastases is an experimental option to delay or avoid ADT (Farolfi et al., 2021).

Androgen deprivation therapy:

ADT is indicated for a PSA doubling time below 3–6 months, proven distant metastases, or symptomatic local progression. PSA doubling time is the key prognostic parameter; a doubling time below 3 months indicates a very unfavorable prognosis. The magnitude of the PSA decline after initiation of ADT also correlates with 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 medication, mucus discharge not requiring sanitary pads, pain requiring analgesics	Moderate urinary frequency (less than hourly), occasional hematuria, numerous telangiectasias
Grade 3	Diarrhea requiring parenteral support, severe mucus or blood discharge requiring sanitary pads, surgery for stenosis, bleeding requiring transfusion	Severe urinary frequency (<1/h), severe dysuria, frequent hematuria, bladder capacity below 150 ml
Grade 4	Perforations, fistulae, life-threatening hemorrhage, necrosis	Perforations, fistulae, severe hemorrhagic cystitis, bladder capacity below 100 ml
Grade 5	Any fatal complication	Any fatal complication

Prostate cancer: prostatectomy

Index

Prostate cancer: brachytherapy

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.
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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, https://www.leitlinienprogramm-onkologie.de/leitlinien/prostatakarzinom

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

Deutsche Version: Prostatakarzinom

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