226 CHAPTER 6 Urological neoplasia
Management of localized prostate cancer: radical external beam radiotherapy (EBRT)
Advances in radiotherapy for localized prostate cancer have included the development of conformal and intensity-modulated techniques to minimize toxicity to the rectum and bladder. EBRT is administered with curative intent, often accompanied by neoadjuvant and adjuvant hormone therapy in high-risk disease.
In general, 2–3 years of hormonal therapy are given for high-risk disease, usually starting before the initiation of radiation therapy. While some data suggest that a shorter course of hormonal therapy (i.e., 6 months) may suffice for intermediate-stage disease, it is not considered standard. There is no role for adding hormonal therapy in low-risk disease.
Hypofractionation (delivery of a total dose of radiation but in a shorter time frame (i.e., 5 days) by use of various stereotactic body radiotherapy (SBRT) platforms has been promoted. Hypofractionation is currently not considered a standard treatment and is under study by groups such as the Radiation Therapy Oncology Group (RTOG).
Proton beam therapy (in contrast to photons used in standard radiation) is a very costly radiation technique that is gaining interest as more centers adopt this technology. The promise is that the side-effect profile may be improved using protons over standard radiation. The role of proton therapy remains to be determined.
Indications
These are clinically localized prostate cancer and life expectancy >5 years. Patients with Gleason score 2–4 disease appear to do as well with watchful waiting as with any other treatment, with 15-year follow-up.
Contraindications
•Severe lower urinary tract symptoms
•Inflammatory bowel disease
•Previous pelvic irradiation
Protocol
EBRT involves a 6- to 7-week course of daily treatments amounting to a dose of 60–72 Gy. Some centers use higher doses of radiation (up to 80 Gy) in an attempt to improve disease control.
Side effects
The use of contemporary radiation techniques that limit the exposure of normal tissues has greatly reduced the complication rates.
•Transient moderate/severe filling-type LUTS (common, rarely permanent)
•Hematuria, significant: 4%
•Moderate to severe gastrointestinal symptoms, bloody diarrhea, pain: 3–32% (common, rarely permanent)
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•Erectile dysfunction (ED) gradually develops in 30–50%.
•The risk of a second solid pelvic malignancy is estimated to be 1 in 300, falling to 1 in 70 long-term survivors.
Outcomes of EBRT
Definition of treatment failure
The traditional American Society of Therapeutic Radiation Oncologists (ASTRO) definition is 3 consecutive PSA increases measured 4 months apart for 2 years, thereafter every 6 months. Time to failure is midway through the 3 PSA measurements.
This has been recently updated to the so-called Phoenix definition PSA nadir + 2 ng/mL; the Phoenix definition is now preferred.1
Pretreatment prognostic factors
These include PSA, Gleason score, clinical stage, and percentage of positive biopsies.
5-year PSA failure-free survival
•85% for low risk (T1–2a or PSA <10 ng/mL or Gleason <7)
•50% for intermediate risk (T2b or PSA 10–20 or Gleason 7)
•33% for high risk without hormonal therapy (T2c or PSA >20 ng/mL or Gleason 8–10), improved with the use of neoadjuvant and adjuvant hormonal therapy
Treatment of PSA relapse post-EBRT
Hormone therapy, either as monotherapy or with antiandrogens, is currently the mainstay of treatment in this setting. However, local salvage treatment appears attractive, potentially offering another chance of cure if metastases cannot be demonstrated at repeat staging.
Salvage radical prostatectomy is technically demanding and can often be associated with poor outcomes; it appears best suited to younger patients in good health. Other local salvage treatments include cryotherapy and high-intensity focused ultrasound (HIFU), but outcomes data and access to these treatments are currently limited (see p. 230).
If salvage local treatment is being considered, repeat prostatic biopsies should be performed to demonstrate viable tumor cells. This should be at least 30 months post-EBRT, because fatally damaged cells may survive a few cell divisions. 1
1 Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, Sandler H (2006). 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 65(4):965–974.
228 CHAPTER 6 Urological neoplasia
Management of localized prostate cancer: brachytherapy (BT)
This is ultrasound-guided transperineal implantation of radioactive seeds, usually I125, less commonly Pd103, into the prostate. BT is minimally invasive, requires general anesthesia, and delivers up to 150 Gy. It is sometimes augmented by an EBRT boost.
Another approach is to use iridium192 wires, known as high-dose radiation (HDR), left for several hours in situ in a series of applications, either before or after EBRT. HDR is not widely available.
Indications for BT as monotherapy
BT is best for low-risk disease: localized T1–2a, Gleason <6, PSA <10 ng/ mL prostate cancer, with a life expectancy >5 years.
Indications for BT with EBRT
In the non-protocol setting, patients with intermediate-risk prostate cancer are sometimes treated in combination: T2b–T2c, Gleason 7, PSA 10–20 ng/mL.
Contraindications to BT
These include previous TURP (risk of incontinence); large-volume prostate (>60 mL), which causes difficulty with seed placement; and moderate to severe lower urinary tract symptoms (risk of retention).
High-risk prostate cancer does not do well with BT monotherapy and should not be performed.
Complications
•Perineal hematoma (occasional)
•Lower urinary tract symptoms (common), due to prostatic edema post-implant
•Urinary retention (5–20%)
•Incontinence (5%), if TURP is required to treat urinary retention
•ED affects up to 50% of patients; gradual onset
•Luteinizing hormone–releasing hormone (LHRH) analogue use to reduce prostatic volume prior to treatment is discouraged, as many men develop retention with this approach. A-Blockers are often used to treat LUTS.
Outcomes of BT
PSA rises in the first 3 months post-implant; it subsequently declines. As with EBRT, the ASTRO definition (see p. 227) has been used to define progression:
•5-year progression-free survival for T1 + 2a, Gleason d6, PSA <10 ng/ mL is 80–90%
•5-year progression-free survival for T2c, Gleason >6, PSA >10 ng/mL is 30–50%
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•8-year progression-free survival for T1 + 2a, Gleason <7, PSA <10 ng/mL is 79%
•12-year progression-free survival for T1 + 2a, Gleason <7, PSA <10 ng/mL is 66%
It is noteworthy that 50% of the patients in these published series had a normal PSA and Gleason score <5; these patients would have done well with watchful waiting. Patients with Gleason 8–10 do poorly after BT.
PSA progression continues steadily several years after treatment.
Outcomes of BT plus EBRT
Five-year progression-free survival is 75–95%.
Comparisons of BT or BT plus EBRT with RP and EBRT alone
•There are no randomized studies.
•In nonrandomized comparisons, an ageand tumor-matched radical prostatectomy series at 8 years yielded a progression-free survival of 98% (compared to 79% with BT).
•Outcome of BT appears inferior to that with EBRT and RP in men with
high-risk prostate cancer PSA >10–20 and Gleason score 7–10.
Rising PSA post-BT
Cryotherapy in an option if local recurrence is suspected; repeat staging and biopsy are indicated. Ultrasound images may be compromised in the setting of prior brachytherapy. Salvage prostatectomy can be considered in highly selected patients.
If metastatic disease is suspected or proven, hormone therapy is appropriate.