Patient selection

Patients with disease localized to the prostate without evidence of lymph node or distant metastasis may be candidates for definitive EBRT. There are relatively few general contraindications to the use of radiation therapy for treatment of definitive disease. These include prior treatment with pelvic radiation therapy and presence of active autoimmune disease, particularly scleroderma and lupus. Inflammatory bowel disease may be considered a relative contraindication for patients undergoing pelvic node irradiation, since treatment may be poorly tolerated [6, 7], but may be safe for patients undergoing treatment to the prostate alone [8]. Patients with low‐ or very low‐risk group disease can be treated with either EBRT or brachytherapy. Patients with intermediate‐risk disease can be treated with EBRT ± androgen‐deprivation therapy (ADT) and ± brachytherapy or brachytherapy alone. Patients with high‐ and very high‐risk group disease are treated with EBRT ± ADT ± docetaxel chemotherapy and ± brachytherapy.

Combination external beam radiation therapy and brachytherapy

There are no high‐quality published data to support either using EBRT alone or combination EBRT and brachytherapy in the treatment of intermediate‐ to high‐risk prostate cancer. However, at the time of press, a large prospective, randomized Canadian trial, the ASCENDE‐RT trial, has reported in abstract form that combination therapy with EBRT and brachytherapy offers superior biochemical control when compared to EBRT alone in patients with intermediate‐ and high‐risk group prostate cancer when radiotherapy is given with androgen deprivation. In theory, the higher incidence of extracapsular extension and seminal vesicle invasion in intermediate‐ to high‐risk patients is more adequately covered by EBRT than brachytherapy, which is the rationale for avoiding brachytherapy alone in these patients. On the other hand, certain intermediate‐risk patients are likely to be candidates for brachytherapy alone. In a retrospective review of 668 brachytherapy patients, there was no statistically significant difference in the 8‐year actuarial biochemical relapse‐free survival (BRFS) between low‐ and intermediate‐risk patients, 98.4% and 98.2%, respectively [11]. These data suggest that most intermediate‐risk patients have a low risk of micrometastatic disease in the pelvis. Even though the risk of extracapsular disease is higher in these patients, these areas may be adequately covered by an implant, since most extracapsular disease is located within 5 mm of the prostate capsule [12]. In another series of combination therapy, where 63.4% of the intermediate‐risk patients had 50% or more positive biopsy needle cores, there was an 80% 15‐year BRFS [13]. These data suggest excellent long‐term control with the combined approach. However, despite high control rates, the additional use of EBRT may be detrimental in terms of higher rates of morbidity. Therefore, additional pathologic factors, such as number or percentage of positive cores, may be helpful to determine whether or not a combination treatment should be used.

Postprostatectomy external beam radiotherapy

Adjuvant or salvage EBRT is used in the postprostatectomy setting. Adjuvant radiation is given based on pathologic findings at surgery. In general, the indications for postprostatectomy adjuvant radiation therapy include: positive margins, seminal vesicle invasion, extracapsular extension, and detectable PSA. The European Association for Research and Treatment of Cancer (EORTC) 22911 prospective Phase III trial randomizing postprostatectomy patients with capsular penetration, positive margins, and/or seminal vesicle invasion to immediate radiation therapy of 60 Gy versus observation, showed an improvement in biochemical disease‐free survival (BDFS) and disease progression, but no overall survival advantage. The 5‐year progression‐free survival was 74% for patients undergoing radiation therapy versus 52% undergoing observation. The 5‐year rate of grade 3 urinary toxicity was 2.6% in the observation arm and 4.2% in the treatment arm (P = 0.0726). Similar findings were reported in a multi‐institutional randomized clinical trial comparing adjuvant radiation therapy of 60–64 Gy to observation with a median follow‐up of 10.5 years. The metastasis‐free survival was 64.5% in the treated group versus 56.9% in the observation group (P = 0.06) [14]. More provocatively, the SWOG 8794 trial, with similar design, has demonstrated improvements in biochemical control, local control, distant metastases‐free survival, and overall survival when immediate adjuvant radiotherapy is delivered for patients with pathologic T3 disease or positive margins [14].

Salvage radiation therapy is given when the patients experience a postsurgery biochemical recurrence. Salvage radiation has been shown to improve biochemical progression and early salvage radiation at low PSA levels is associated with improved BPFS and rates of distant metastases [15]. There are no trials comparing adjuvant and early salvage radiation therapy.

Definition of biochemical failure

Results are generally reported by risk group and using BRFS since significant overall survival data may require decades to obtain. The definition of biochemical failure was changed in 2006. The previous definition was the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure, which required three consecutive rises in PSA above the nadir. Because of problems including backdating and the phenomenon of a temporary benign PSA bounce [16], the Phoenix definition of PSA nadir plus 2 ng/ml has been adopted, which offers a better balance between sensitivity and sensitivity [17]. With either definition, the dependence of outcome on dose and risk group is clear.

Dose escalation

Numerous high‐quality prospective Phase III randomized trials demonstrate the importance of dose escalation in prostate cancer. These trials demonstrate that when radiation doses are increased from 64–70 Gy to 74–80 Gy, there is a 10–20% improvement in rates of biochemical control [18–22]. A meta‐analysis of randomized controlled trials suggested that high dose was beneficial for all risk groups compared to conventional dose treatments [23]. As these trials mature, more tangible clinical improvements are being noted in addition to biochemical control. The MD Anderson dose escalation trial has demonstrated with dose escalation improves rates of distant metastases and prostate cancer deaths in patients with high‐risk disease and PSA >10. These improvements in outcome were offset by an increase in the 10‐year incidence of Radiation Therapy Oncology Group (RTOG) grade 3 gastrointestinal toxicity was significantly higher with the 78 Gy dose (26% vs. 13%), partially attributed to outdated 3D planning techniques. Significantly higher grade 2 or greater gastrointestinal toxicity was also seen, but there was no significant difference in genitourinary toxicity [23]. Furthermore, a meta‐regression analysis predicted close to 100% biochemical control for doses around 90 Gy, especially for the low‐risk group.

Combination therapy

Randomized data demonstrating the benefit of combination therapy in patients with intermediate‐ and high‐risk disease is maturing and has been presented in abstract form (ASCENDE‐RT). Numerous retrospective studies also support combination therapy. Long‐term BRFS rates for 223 patients with clinical stage T1–T3 prostate cancer treated from 1987 to 1993 with ¹²⁵I or ¹⁰³Pd brachytherapy after 45 Gy neoadjuvant EBRT without ADT were reported using different risk models. The results for a subset of intermediate‐risk patients were described above. Overall, the 15‐year BRFS for the entire treatment group was 74%. By risk group, the 15‐year BRFSs were: low risk 85.8%, intermediate risk 80.3%, and high risk 67.8% (P = 0.002) [13]. Zelefsky et al. have reported that combination‐based treatment approaches improve PSA relapse survival as compared with contemporary dose‐escalated radiation alone [24].

Whole‐pelvis radiation therapy for high‐risk disease

Whole‐pelvis radiation therapy is used for high‐risk disease to treat microscopic involvement of the pelvic lymph nodes. The dose to the pelvis ranges from 4500 to 5040 cGy in standard fractionation. A higher dose to the prostate can be given as an external beam cone‐down or with brachytherapy. RTOG 94‐13 was a four‐arm study randomizing patients who are at greater than 15% risk of pelvic node metastasis to whole‐pelvis or prostate‐only radiation therapy and neoadjuvant or adjuvant ADT. At last analysis, it was not clear that there is an advantage to whole‐pelvis radiation over prostate‐only radiation [25]. Although a whole‐pelvic field has been standard for many trials treating high‐risk prostate cancer, two of which are described below, further research will be needed to answer the question definitively. Since treatment to the whole pelvis increases the morbidity of treatment, the answer is of the utmost importance.

Androgen deprivation for high‐risk disease

Neoadjuvant and concurrent ADT is generally recommended. RTOG 85‐31 demonstrated a significant improvement in disease progression and absolute survival at 10 years with the addition of ADT to standard EBRT whole‐pelvis plus cone‐down to total doses of between 65 and 70 Gy [26]. Between 1987 and 1992, 977 patients were randomized to goserelin with radiation therapy or at time of relapse. The 10‐year survival rate was 49% in the treatment arm versus 39% in the delayed arm (P = 0.002). The 10‐year local failure rate was 23% in the treatment arm versus 38% in the delayed arm (P < 0.0001). Similarly, a randomized Phase III trial of the EORTC showed a significant disease‐free survival (DFS) and overall survival in favor of hormone therapy. Between the years 1987 and 1995, 415 patients were randomized to whole‐pelvis radiation therapy of 50 Gy plus a 20 Gy prostate cone‐down with or without goserelin and cyproterone acetate. At median follow‐up of 65.7 months, there was a significantly improved 5‐year DFS of 74% versus 40% with the use of hormonal therapy (P = 0.0001).

The 5‐year overall survival was 78% in the hormone group versus 53% in the radiation therapy alone group (P = 0.0002) [27].

Anatomic considerations

By virtue of its anatomic location, anterior to the rectum and posteroinferior to the bladder, treatment to the prostate results in mainly acute urinary and rectal side‐effects. The urethra, running right through the gland, can hardly be avoided. Neurovascular bundles responsible for erectile function run alongside the right and left posterolateral apical aspects of the gland (Figure 134.1

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