28 Prostate Jeff M. Michalski, Gregory S. Merrick,

28 Prostate

Jeff M. Michalski, Gregory S. Merrick, and Sten Nilsson

28.1 Anatomy

The prostate gland is a walnut-shaped solid organ that surrounds the male urethra between the base of the bladder and the urogenital diaphragm, and weighs about 20 g. The prostate is attached ante- riorly to the pubic symphysis by the puboprostatic ligament. It is separated from the rectum posteriorly by Denonvilliers’ fascia (retrovesical septum), which attaches above to the peritoneum and below to the urogenital diaphragm. The seminal vesicles and the vas deferens pierce the posterosuperior aspect of the gland and enter the urethra at the verumontanum (Fig. 28.1). The lateral margins of the prostate, usu-

J. M. Michalski, MD, MBA

Associate Professor in Radiation Oncology, Department of Radiation Oncology, Washington University School of Medi- cine, 4921 Parkview Place, St. Louis, MO 63110, USA G. S. Merrick, MD

Schiffl er Cancer Center and Wheeling Jesuit University, Wheeling, WV 26003, USA

S. Nilsson, MD, P hD

Profesor, Institution for Oncology Pathology, Karolinska Uni- versity Hospital, 17176 Stockholm, Sweden

CONTENTS

28.1 Anatomy 687 28.2 Natural History 688 28.2.1 Local Growth Patterns 688

28.2.2 Regional Lymph Node Involvement 690 28.2.3 Distant Metastases 694

28.3 Prognostic Factors 694

28.3.1 Tumor Stage, Pretreatment PSA, and Histological Features 694

28.3.2 Tumor Volume 695

28.4 Radiation Therapy Techniques 695 28.4.1 General Treatment Guidelines 695 28.4.2 External Irradiation 696

28.4.3 Conventional Radiation Therapy Techniques 696 28.4.3.1 Volume Treated 696

28.4.3.2 Beam Energy and Dose Distribution 698 28.4.3.3 Standard Tumor Doses

(Non-Conformal Treatment Planning) 699 28.4.4 Conformal Radiation Therapy Simulation and Treatment Planning 699

28.4.4.1 Patient Immobilization and Positioning 699 28.4.4.2 Clinical Target Volume Definition 700 28.4.4.3 Planning Target Volume Definition 702 28.4.4.4 Organs-at-Risk Definition 706 28.4.4.5 Beam Selection and Shaping 706

28.4.5 Intensity-Modulated Radiation Therapy 709 28.4.6 Dose Prescription for 3D CRT or IMRT 711 28.4.7 Considerations for Postoperative Irradiation 713 28.4.8 Postoperative Radiation Therapy Techniques 714 28.5 Prostate Brachytherapy 715

28.5.1 Introduction 715 28.5.1.1 Patient Selection 715 28.5.1.2 Prostate Size 715 28.5.1.3 Transition Zone 716

28.5.1.4 Median Lobe Hyperplasia 716

28.5.1.5 International Prostate Symptom Score 717 28.5.1.6 Prostatitis 717

28.5.1.7 Pubic Arch Interference 717

28.5.1.8 Transurethral Resection of the Prostate 717 28.5.1.9 Tobacco 718

28.5.1.10 Inflammatory Bowel Disease 718 28.5.1.11 Adverse Pathological Features 718 28.5.1.12 Prostatic Acid Phosphatase 718 28.5.2 Brachytherapy Planning 719 28.5.3 Post-Implant Evaluation 719 28.5.3.1 Isotope 720

28.5.4 Supplemental Therapies 721

28.5.4.1 External-Beam Radiation Therapy 721 28.5.4.2 Androgen Deprivation Therapy 721 28.5.5 PSA Spikes 721

28.5.6 Approaches to Minimize Morbidity 721 28.5.6.1 Urinary 721

28.5.5.2 Rectal Morbidity 722 28.5.5.3 Erectile Dysfunction 723

28.6 High-Dose-Rate Brachytherapy 724 28.6.1 Introduction 724

28.6.2 Technological Aspects 724

28.6.3 Radiobiological and Dose Fractionation Aspects 725 28.6.4 Clinical Outcome Data from HDR-BT Plus EBRT 725 28.6.5 Health-Related Quality-of-Life Data After

HDR-BT Plus EBRT 727

28.6.6 HDR-BT Monotherapy: Initial Experience 727 28.6.7 The Role of Neoadjuvant and Concomitant Endocrine Therapy 728

28.6.8 Discussion/Future Aspects 729

References 729

ally delineated against the levator ani muscles, form the lateral prostatic sulci.

In young men the prostate gland can be divided into four distinct zones (McLaughlin et al. 2005).

The central zone (CZ) surrounds the ejaculatory ducts. The anterior fibromuscular stroma (AFS) is an anterior band of fibromuscular tissue contigu- ous with the bladder muscle and external sphincter.

The transition zone (TZ) is the central component of the prostate that tends to hypertrophy with age. The hypertrophied TZ will compress the CZ and periure- thral glandular tissue, making it nearly impossible to identify these zones on ultrasound, CT, or MRI. The hypertrophied TZ is often called the central gland and is readily recognized on MRI (Villeirs et al.

2005). While in young men the peripheral zone (PZ) may make up 70% of the prostate tissue, it becomes condensed by an enlarged TZ in men with benign prostatic hypertrophy.

Myers et al. (1987), in a study of 64 gross pros- tatectomy specimens, noted variations in the shape and exact location of the prostatic apex and pointed out that the configuration of the external striated urethral sphincter was related to the shape of the prostatic apex. Two basic prostatic shapes were rec- ognized distinguished by the presence or absence of an anterior apical notch, depending on the degree of lateral lobe development and the position of its anterior commissure. Observations by these authors that the urethral sphincter is a striated muscle in contact with the urethra from the base of the bladder

to the perineal membrane corroborates the previous description by Oelrich (1980), who pointed out that there is no distinct superior fascia of the so-called urogenital diaphragm separating the sphincter muscle from the prostate. The anatomy of the male pelvis at right angles to the perineal membrane, through the membranous urethra, is illustrated in Fig. 28.2.

28.2

Natural History

28.2.1

Local Growth Patterns

Almost all clinically significant prostatic carcino- mas develop in the peripheral zone of the prostate, whereas benign prostatic hyperplasia arises pre- dominantly from the central (periurethral) portions (McNeal 1969). In recent years, more attention is being paid to tumor arising in the transitional zone. Transition zone cancers can grow relatively large before extending beyond the confines of the fibromuscular stroma. These tumors can produce substantial elevations of prostate-specific antigen (PSA). In a series of 148 cases of TZ prostate cancer, 70% were clinical stage T1c with a preoperative PSA of greater than 10 ng/ml in nearly two-thirds of the patients. On pathology review of the radical pros-

Fig. 28.1. a Sagittal diagram of pelvis illustrates anatomic relationships of the prostate. b Coronal MRI of prostate illustrates close relationship of prostate and bladder. (From Perez 1998)

a b

tatectomy specimens 80% of cancers originating in the TZ had organ-confined disease (Noguchi et al.

2000).

Breslow et al. (1977) found that 64% of 350 car- cinoma were present in a slice taken 5 mm from the distal end of the prostate; therefore, the urethra must be transected distal to the prostate to avoid leaving prostatic cancer behind (Blennerhassett and Vickery 1966; McNeal 1969). This is an important detail in the design of external irradiation portals or in brachytherapy of prostate cancer.

Jewett (1980) reported that multiple foci of tumor were found throughout the prostate in 77%

of prostatectomy specimens. Andriole et al. (1992) described bilateral lobe pathological involvement in 13 of 15 patients (87%) with clinical stage-A1 (T1a) cancer. In a series of 486 patients, Wise et al. (2002) reported that 83% of the cancers were multifocal;

therefore, the entire gland (with a margin) had to be treated.

As the tumor grows, it may extend into and through the capsule of the gland, invade seminal vesicles and periprostatic tissues, and later involve the bladder neck or the rectum. Tumor may invade the perineural spaces, the lymphatics, and the blood vessels producing lymphatic or distant metasta-

ses. The incidence of microscopic tumor extension beyond the capsule of the gland (at time of radical prostatectomy) in patients with clinical stages A2 or B ranges from 18 to 57% (Catalona and Smith 1994; Villers et al. 1991).

Oesterling et al. (1994), in an analysis of patients with stage-T1c disease treated with radical prosta- tectomy, noted that 53% had pathologically organ- confined tumors; 35% had extracapsular extension, and 9% had seminal vesicle invasion. In the latter group, 66% of patients had positive surgical mar- gins, an incidence comparable to that of clinical stage-T2 tumors. In a similar group of patients with stage-T1c tumors Epstein et al. (1994) found that 34% had established extracapsular extension, 6%

seminal vesicle invasion, and 17% positive surgical margins.

Stone et al. (1995) reported none of 13 patients with prostate-specific antigen (PSA) <4 ng/ml, 11 of 99 patients (11%) with PSA of 4.1–20 ng/ml, and 12 of 45 patients (27%) with PSA >20 ng/ml having positive seminal vesicle biopsy. None of the patients with stages T1a–T1c had positive seminal vesicle biopsies, compared with 2 of 33 (6%) with stage T2a, 14 of 80 (17.5%) with stage T2b, and 7 of 23 (30%) with stage T2c tumors. Seminal vesicle involvement

Fig. 28.2. Frontal section of male pelvis at right angles to the perineal membrane. (From Oelrich 1980) Ejaculatory duct

Prostate Endopelvic fascia

Ilium

Obtunator internus m.

Urethra Sphincter urethrae m.

Perineal memb.

Pudendal canal:

int. pudendal a.

int. pudendal v.

pudendal n.

Amp. ductus deferens Seminal vesicle

Puboprostatic lig.

Sheath of prostate

Pelvic diaphragm

Transversalis fascia Obturator memb.

Inf. pubic ramus (ischiopubic)

Deep fascia

Corpus covernosus penis Fascia lata

Bulbospongiosus m.

Corpus spongiosum penis Superfi cial perineal fascia Ischiocovernosus m.

Superfi cial perineal fascia

Corpus spongiosum penis

has been observed in 10% of patients with stage- A2 tumors to 30% of patients with stage-B2 lesions (Catalona and Bigg 1990).

Stock et al. (1995), in 120 patients with clinical stage-T1b to stage-T2c carcinoma of the prostate, in whom transrectal ultrasound-guided needle biop- sies of the seminal vesicles were performed, reported on 99 who also underwent laparoscopic lymph node dissection. The incidence of seminal vesicle involve- ment was correlated with PSA level, Gleason score, and clinical stage (Table 28.1). When PSA level and Gleason score were correlated, none of the patients with Gleason scores of 4 or lower showed seminal vesicle involvement, regardless of PSA level. Patients with Gleason scores of 5 and 6 and PSA of 4–20 ng/

ml had 10–11%, and those with PSA >20 ng/ml had 14% positive seminal vesicle biopsy. With Gleason scores of 7 or higher, 25% of patients with PSA of 4–20 ng/ml and 53% of those with PSA >20 ng/ml had seminal vesicle involvement.

D’Amico et al. (1995), in a pathological evalu- ation of 347 radical prostatectomy specimens, reported none of 38 patients with PSA <4 ng/ml or less having seminal vesicle involvement, in contrast to 6% of 144 patients with PSA of 4–10 ng/ml, 11%

of 101 with PSA of 10–20 ng/ ml, 36% of 45 with PSA of 20–40 ng/ml, and 42% of 19 with PSA >40 ng/ml.

The incidence of positive surgical margins was 11, 20, 33, 56, and 33%, respectively.

Roach (1993) proposed the following formula based on analysis of radical prostatectomy speci- mens to estimate the probability of seminal vesicle involvement:

SVI = PSA + (Gleason score minus 6) u 10

28.2.2

Regional Lymph Node Involvement

Tumor size and degree of differentiation affect the tendency of prostatic carcinoma to metastasize to regional lymphatics. The incidence of lymph node metastases was as high as 12–28% in clinical stage- T2 disease in the pre-PSA era (Middleton 1988).

Fowler and Whitmore (1981) reported that 40%

of 300 patients with apparently localized prostate cancer had pelvic lymph node metastases upon sur- gery. In the era of PSA screening, there has been a decrease in the incidence of pelvic lymph node metastases. Modern series report less than a 10%

incidence of lymph node involvement at radical prostatectomy (Danella et al. 1993).

Ohori et al. (1995), in 478 patients treated with radical prostatectomy, reported no pelvic lymph node metastases in 70 patients with stages T1a,b, 1 of 43 (2%) in patients with stage T1c, 5 of 96 (5%) with stage T2a, and 19 of 269 (7%) with stages T2b,c.

The incidence of seminal vesicle invasion was 6, 11, 5, and 17%, respectively.

In a review of 2439 patients treated with radical prostatectomy, Pisansky et al. (1996b) reported positive pelvic nodes in 12 of 457 (2.6%) with stag- es T1a–c, 15 of 456 (3.3%) with stage T2a, 130 of 1206 (10.8%) with stage T2b,c, and 81 of 320 (25%) with stage-T3 tumors.

Stock et al. (1995), in 99 patients who underwent laparoscopic lymph node dissection (Table 28.2),

Table 28.2. Correlation of PSA levels, Gleason score, clinical stage, and status of positive seminal vesicle biopsy specimen with incidence of positive pelvic lymph nodes. (From Stock et al. 1995)

Parameter No. of positive

seminal vesicle biopsy specimens

p value

PSA d10 2 (6)

PSA >10 7 (15) 0.3

PSA d20 2 (3)

PSA >20 7 (24) 0.003

Grade <7 1 (2)

Grade t7 8 (35) <0.0001

T1a–T2a 0 (0)

T2b–T2c 9 (18) 0.03

Positive seminal vesicle biopsy specimen

9 (50) Negative seminal vesicle

biopsy specimen

0 (0) <0.0001

Values in parentheses are percentages Table 28.1. Correlation of prostate-specifi c antigen (PSA) lev-

els, Gleason score, and clinical stage with positive seminal vesicle biopsy specimen. (From Stock et al. 1995)

Parameter No. of positive seminal vesicle biopsy specimens

p value

PSA d10 3 (6)

PSA >10 15 (21) 0.02

PSA d20 8 (9)

PSA >20 10 (37.5) 0.005

Grade <7 6 (7)

Grade t7 12 (37.5) <0.0001

T1a–T2a 2 (5)

T2b–T2c 16 (20) 0.03

Values in parentheses are percentages

correlated incidence of positive nodes with PSA, Gleason score, stage, and involvement of seminal vesicles. None of the patients with a Gleason score of 4 or lower, even with >20 ng/ml, had positive pelvic lymph nodes, and 8% in the group with Gleason scores of 5 or 6 had PSA levels of 4–10 ng/ml and had positive nodes; however, the incidence of posi- tive lymph nodes increased significantly (24%) in patients with PSA >20 ng/ml.

Bluestein et al. (1994), Narayan et al. (1994), Partin et al. (1993, 1997, 2001), and Spevack et al. (1996) have offered comparable models based on pathological data that may predict risk for lymph node metastases, to decide whether the patient should be subjected to a staging lymph- adenectomy (including laparoscopic technique) or considered for irradiation of the pelvic lymph nodes.

Stone et al. (1995) reported that none of 11 patients with PSA <4 ng/ml, 4 of 77 (9%) with PSA of 4–20 ng/ml, and 10 of 42 (24%) with PSA

>20 ng/ml had positive nodes. When correlated with clinical stage, none of the patients with stage T1b,c or stage T2a had positive nodes, com- pared with 10 of 69 (15%) with T2b and 4 of 17 (24%)

Table 28.3a. Clinical stage-T1c disease (nonpalpable, PSA elevated). (From Partin et al. 2001) PSA range

(ng/ml)

Pathological stage Gleason score

2–4 5–6 3+4 = 7 4+3 = 7 8–10

0–2.5 Organ confi ned 95 (89–99) 90 (88–93) 79 (74–85) 71 (62–79) 66 (54–76) Extraprostatic extension 5 (1–11) 9 (7–12) 17 (13–23) 25 (18–34) 28 (20–38)

Seminal vesicle (+) – 0 (0–1) 2 (1–5) 2 (1–5) 4 (1–10)

Lymph node (+) – – 1 (0–2) 1 (0–4) 1 (0–4)

2.6–4.0 Organ confi ned 92 (82–98) 84 (81–86) 68 (62–74) 58 (48–67) 52 (41–63) Extraprostatic extension 8 (2–18) 15 (13–18) 27 (22–33) 37 (29–46) 40 (31–50)

Seminal vesicle (+) – 1 (0–1) 4 (2–7) 4 (1–7) 6 (3–12)

Lymph node (+) – – 1 (0–2) 1 (0–3) 1 (0–4)

4.1–6.0 Organ confi ned 90 (78–98) 80 (78-83) 63 (58–68) 52 (43–60) 46 (36–56) Extraprostatic extension 10 (2–22) 19 (16–21) 32 (27–36) 42 (35–50) 45 (36–54)

Seminal vesicle (+) – 1 (0–1) 3 (2–5) 3 (1–6) 5 (3–9)

Lymph node (+) – 0 (0–1) 2 (1–3) 3 (1–5) 3 (1–6)

6.1–10.0 Organ confi ned 87 (73–97) 75 (72–77) 54 (49–59) 43 (35–51) 37 (28–46) Extraprostatic extension 13 (3–27) 23 (21–25) 36 (32–40) 47 (40–54) 48 (39–57) Seminal vesicle (+) – 2 (2–3) 8 (6–11) 8 (4–12) 13 (8–19)

Lymph node (+) – 0 (0–1) 2 (1–3) 2 (1–4) 3 (1–5)

>10.0 Organ confi ned 80 (61–95) 62 (58–64) 37 (32–42) 27 (21–34) 22 (16–30) Extraprostatic extension 20 (5–39) 33 (30–36) 43 (38–48) 51 (44–59) 50 (42–59) Seminal vesicle (+) – 4 (3–5) 12 (9–17) 11 (6–17) 17 (10–25)

Lymph node (+) – 2 (1–3) 8 (5–11) 10 (5–17) 11 (5–18)

with T2c tumors. Eleven of 23 patients (48%) with positive seminal vesicles also had positive nodes, compared with 3 of 107 (3%) with negative seminal vesicle biopsy.

Partin et al. (1997, 2001) analyzed surgical data from three academic institutions to develop vali- dated nomograms that predict lymph node involve- ment based on clinical stage, preoperative PSA and Gleason score. These nomograms are useful in pre- dicting the risk of lymph node involvement and aid in the decision to use elective pelvic lymph node radiation (Table 28.3).

Roach (1993) suggested a revised formula based on pathological findings in prostatectomy speci- mens incorporating clinical stage, to estimate the incidence of metastatic pelvic lymph nodes:

Risk of node positive =

2/3 PSA + [(GS-6) + TG-1.5] × 10,

where GS is Gleason score and TG is clinical tumor

group; TG is as follows: TG 1 (stages T1c and T2a)

is assigned a value of 1, TG 2 (T1b and T2b) is given

a value of 2, and TG 3 (T2c and T3) is assigned a

value of 3.

Table 28.3b. Clinical stage-T2a disease (palpable, <50% of one lobe). PSA prostate-specifi c antigen. (From Partin et al. 2001)

PSA range (ng/ml)

Pathological stage Gleason score

2–4 5–6 3+4 = 7 4+3 = 7 8–10

0–2.5 Organ confi ned 91 (79–98) 81 (77–85) 64 (56–71) 53 (43–63) 47 (35–59) Extraprostatic extension 9 (2–21) 17 (13–21) 29 (23–36) 40 (30–49) 42 (32–53)

Seminal vesicle (+) – 1 (0–2) 5 (1–9) 4 (1–9) 7 (2–16)

Lymph node (+) – 0 (0–1) 2 (0–5) 3 (0–8) 3 (0–9)

2.6–4.0 Organ confi ned 85 (69–96) 71 (66–75) 50 (43–57) 39 (30–48) 33 (24–44) Extraprostatic extension 15 (4–31) 27 (23–31) 41 (35–48) 52 (43–61) 53 (44–63) Seminal vesicle (+) – 2 (1–3) 7 (3–12) 6 (2–12) 10 (4–18)

Lymph node (+) – 0 (0–1) 2 (0–4) 2 (0–6) 3 (0–8)

4.1–6.0 Organ confi ned 81 (63–95) 66 (62–70) 44 (39–50) 33 (25–41) 28 (20–37) Extraprostatic extension 19 (5–37) 32 (28–36) 46 (40–52) 56 (48–64) 58 (49–66)

Seminal vesicle (+) – 1 (1–2) 5 (3–8) 5 (2–8) 8 (4–13)

Lymph node (+) – 1 (0–2) 4 (2–7) 6 (3–11) 6 (2–12)

6.1–10.0 Organ confi ned 76 (56–94) 58 (54–61) 35 (30–40) 25 (19–32) 21 (15–28) Extraprostatic extension 24 (6–44) 37 (34–41) 49 (43–54) 58 (51–66) 57 (48–65) Seminal vesicle (+) – 4 (3–5) 13 (9–18) 11 (6–17) 17 (11–26)

Lymph node (+) – 1 (0–2) 3 (2–6) 5 (2–8) 5 (2–10)

>10.0 Organ confi ned 65 (43–89) 42 (38–46) 20 (17–24) 14 (10–18) 11 (7–15) Extraprostatic extension 35 (11–57) 47 (43–52) 49 (43–55) 55 (46–64) 52 (41–62) Seminal vesicle (+) – 6 (4–8) 16 (11–22) 13 (7–20) 19 (12–29)

Lymph node (+) – 4 (3–7) 14 (9–21) 18 (10–27) 17 (9–29)

Table 28.3c. Clinical stage-T2b disease (palpable, >50 of one lobe, not on both lobes). (From Partin et al. 2001) PSA range

(ng/ml)

Pathological stage Gleason score

2–4 5–6 3+4 = 7 4+3 = 7 8–10

0–2.5 Organ confi ned 88 (73–97) 75 (69–81) 54 (46–63) 43 (33–54) 37 (26–49) Extraprostatic extension 12 (3–27) 22 (17–28) 35 (28–43) 45 (35–56) 46 (35–58) Seminal vesicle (+) – 2 (0–3) 6 (2–12) 5 (1–11) 9 (2–20)

Lymph node (+) – 1 (0–2) 4 (0–10) 6 (0–14) 6 (0–16)

2.6–4.0 Organ confi ned 80 (61–95) 63 (57–69) 41 (33–48) 30 (22–39) 25 (17–34) Extraprostatic extension 20 (5–39) 34 (28–40) 47 (40–55) 57 (47–67) 57 (46–68) Seminal vesicle (+) – 2 (1–4) 9 (4–15) 7 (3–14) 12 (5–22)

Lymph node (+) – 1 (0–2) 3 (0–8) 4 (0–12) 5 (0–14)

4.1–6.0 Organ confi ned 75 (55–93) 57 (52–63) 35 (29–40) 25 (18–32) 21 (14–29) Extraprostatic extension 25 (7–45) 39 (33–44) 51 (44–57) 60 (50–68) 59 (49–69)

Seminal vesicle (+) – 2 (1–3) 7 (4–11) 5 (3–9) 9 (4–16)

Lymph node (+) – 2 (1–3) 7 (4–13) 10 (5–18) 10 (4–20)

6.1–10.0 Organ confi ned 69 (47–91) 49 (43–54) 26 (22–31) 19 (14–25) 15 (10–21) Extraprostatic extension 31 (9–53) 44 (39–49) 52 (46–58) 60 (52–68) 57 (48–67) Seminal vesicle (+) – 5 (3–8) 16 (10–22) 13 (7–20) 19 (11–29)

Lymph node (+) – 2 (1–3) 6 (4–10) 8 (5–14) 8 (4–16)

>10.0 Organ confi ned 57 (35–86) 33 (28–38) 14 (11–17) 9 (6–13) 7 (4–10)

Extraprostatic extension 43 (14–65) 52 (46–56) 47 (40–53) 50 (40–60) 46 (36–59)

Seminal vesicle (+) – 8 (5–11) 17 (12–24) 13 (8–21) 19 (12–29)

Lymph node (+) – 8 (5–12) 22 (15–30) 27 (16–39) 27 (14–40)

At least two modern European series of extended lymph node dissection did discover a signifi- cantly increased number of men with lymph node metastases, compared with a similar group who had undergone standard lymph node dissection ( Heidenreich et al. 2002; Wawroschek et al.

2003). In both these series, PSA screening was not prevalent in the patient population. The incidence of lymph node metastases discovered by the extended pelvic lymph node dissection was 26.2–26.8%. This finding raises the question as to whether or not the incidence of lymph node metastases is underesti- mated in modern series.

Clark et al. (2003) performed a randomized trial of standard lymph node dissection vs an extended lymph node dissection in a series of 123 patients.

In that trial each patient served as his own control, with one side having a standard dissection and the other side an extended dissection. There was no difference in the rate of lymph node metasta- ses discovered with the extended dissection. The patient population was generally low risk with 72%

clinical stage T1c, 84.6% having a PSA of <10 ng/

ml and 67% with cancers of Gleason score 6 or less (Clark et al. 2003).

The pattern of lymph node metastases has been described by well-known series. Periprostatic and obturator nodes are involved first, followed by exter- nal iliac, hypogastric, common iliac, and periaortic nodes (Pistenma et al. 1979). While the incidence of metastases is less than in the past, the pattern of involvement is unchanged. Wawroschek reported a series of 194 patients who underwent an extended pelvic lymph node dissection. The overall rate of lymph node involvement was 26.8%. Table 28.4 demonstrates the number of node-positive patients who would have been detected, provided only that lymph nodes from different regions had been histo- logically investigated. These data suggest that 98%

of the involved lymph nodes would be covered by fields that encompassed the obturator, external, and internal iliac chains. Only 2% of lymph nodes would be missed if the presacral, pararectal, and paravesical nodes were omitted (Wawroschek et al. 2003).

Prognosis is closely related to the presence of regional lymph node metastases. Patients with positive pelvic lymph node metastasis have a sig- nificantly greater probability (>85% at 10 years) of developing distant metastasis than those with nega-

Table 28.3d. Clinical stage-T2c disease (palpable on both lobes). (From Partin et al. 2001) PSA range

(ng/ml)

Pathological stage Gleason score

2–4 5–6 3+4 = 7 4+3 = 7 8–10

0–2.5 Organ confi ned 86 (71–97) 73 (63–81) 51 (38–63) 39 (26–54) 34 (21–48) Extraprostatic extension 14 (3–29) 24 (17–33) 36 (26–48) 45 (32–59) 47 (33–61) Seminal vesicle (+) – 1 (0–4) 5 (1–13) 5 (1–12) 8 (2–19)

Lymph node (+) – 1 (0–4) 6 (0–18) 9 (0–26) 10 (0–27)

2.6–4.0 Organ confi ned 78 (58–94) 61 (50–70) 38 (27–50) 27 (18–40) 23 (14–34) Extraprostatic extension 22 (6–42) 36 (27–45) 48 (37–59) 57 (44–70) 57 (44–70) Seminal vesicle (+) – 2 (1–5) 8 (2–17) 6 (2–16) 10 (3–22)

Lymph node (+) – 1 (0–4) 5 (0–15) 7 (0–21) 8 (0–22)

4.1–6.0 Organ confi ned 73 (52–93) 55 (44–64) 31 (23–41) 21 (14–31) 18 (11–28) Extraprostatic extension 27 (7–48) 40 (32–50) 50 (40–60) 57 (43–68) 57 (43–70) Seminal vesicle (+) – 2 (1–4) 6 (2–11) 4 (1–10) 7 (2–15)

Lymph node (+) – 3 (1–7) 12 (5–23) 16 (6–32) 16 (6–33)

6.1–10.0 Organ confi ned 67 (45–91) 46 (36–56) 24 (17–32) 16 (10–24) 13 (8–20) Extraprostatic extension 33 (9–55) 46 (37–55) 52 (42–61) 58 (46–69) 56 (43–69) Seminal vesicle (+) – 5 (2–9) 13 (6–23) 11 (4–21) 16 (6–29)

Lymph node (+) – 3 (1–6) 10 (5–18) 13 (6–25) 13 (5–26)

>10.0 Organ confi ned 54 (32–85) 30 (21–38) 11 (7–17) 7 (4–12) 6 (3–10)

Extraprostatic extension 46 (15–68) 51 (42–60) 42 (30–55) 43 (29–59) 41 (27–57)

Seminal vesicle (+) – 6 (2–12) 13 (6–24) 10 (3–20) 15 (5–28)

Lymph node (+) – 13 (6–22) 33 (18–49) 38 (20–58) 38 (20–59)

tive nodes (<20%; Gervasi et al. 1989). Gervasi et al. (1989) reported that the risk of metastatic disease at 10 years was 31% for patients with negative lymph nodes compared with 83% for those with positive nodes. The risk of dying of prostate cancer was 17 and 57%, respectively.

Rukstalis et al. (1996) compiled data from the literature that documented the strong prog- nostic implications of the number of involved lymph nodes. In general, patients with a single metastatic lymph node have a 5-year survival rate ranging from 60 to 80%, whereas in those with more involved lymph nodes, the 5-year survival is 20–54%.

Metastases to the peri-aortic nodes are seen in 5–25% of patients, depending on tumor stage and histological differentiation (Pistenma et al. 1979).

They are associated with a higher incidence of dis- tant metastases and lower survival (Lawton et al.

1997).

28.2.3

Distant Metastases

Prostatic carcinoma metastasizes to the skeleton, liver, lungs, and occasionally to the brain or other sites, Perez et al. (1988) reported an overall inci- dence of distant metastases of 20% in stage B, 40%

in stage C, and 65% in stage D1.

28.3

Prognostic Factors

28.3.1

Tumor Stage, Pretreatment PSA, and Histological Features

The strongest prognostic indicators in carcinoma of the prostate are clinical stage, pretreatment PSA level, and pathological tumor differentiation (Perez 1998). This is a consequence of the more aggressive behavior and greater incidence of lymphatic and dis- tant metastases in the larger and less-differentiated tumors. Bastacky et al. (1993) noted that perineu- ral invasion on prostate biopsies is correlated with a higher probability of capsular penetration, and Bonin et al. (1997) reported a lower 5-year biochem- ical failure-free survival rate in the presence of peri- neural invasion (39 vs 65%; p = 0.0009) in patients with PSA <20 ng/ml treated with three-dimensional conformal radiation therapy (3D CRT).

D’Amico described a three-tiered prognostic risk-group categorization that utilizes pretreat- ment PSA, biopsy Gleason score, and clinical stage (D’Amico et al. 1998). Low-risk patients are those with a PSA d10 ng/ml and a Gleason Score of 2–6 and stages T1–T2c. Intermediate-risk patients have PSA of 10 ng/ml to d20 ng/ml and/or Gleason score 7, and no high-risk features. High-risk patients have PSA >20 ng/ml and/or Gleason score 8–10 and/or stage tT3. These risk categories were significantly associated with an increasing rate of biochemical failure using the ASTRO failure definition (1997).

In a pooled data set of 4839 patients, Kuban (2003) reported that pretreatment PSA, Gleason score, radiation dose, tumor stage, and year of treatment were all significant prognostic factors in a multi- variate analysis. The risk groups were defined as follows: low risk (group 1), stages T1b, T1c, or T2a, Gleason score d6, and PSA d10 ng/ml; intermediate risk (group 2), stage T1b, T1c, or T2a, Gleason score d7, and PSA >10 ng/ml but d20 ng/ml or stage T2b or T2c, Gleason score d7, and PSA d20 ng/ml; and high risk (group 3), Gleason score 8–10 or PSA >20 ng/ml.

The 5-year clinical DFS rate was 78, 66, and 49% for low-, intermediate-, and high-risk patients, respec- tively.

Kattan (2000) has developed a nomogram from patients treated at Memorial Sloan-Ketter- ing Cancer Center to predict outcome after 3D conformal radiation therapy that employs clinical parameters including stage, biopsy Gleason score, pretreatment PSA level, and whether neoadjuvant

Table 28.4. Percentage of node-positive patients who would have been detected if only lymph nodes from different regions had been histologically investigated (based on the results of sentinel lymphadenectomy in 194 patients with or without ad- ditional pelvic lymphadenectomy and with serial sections and immunohistochemistry of all sentinel lymph nodes.) (From Wawroschek et al. 2003)

Regions of lymphadenectomy Node-positive patients (%) Obturator fossa, external and internal

iliac region, presacral, pararectal, para- vesical

100 (93.2–100)

Obturator fossa, external and internal iliac region

98 (89.7–100)

Obturator fossa, internal iliac region 82.7 (69.7–91.8) Obturator fossa, external iliac region 65.4 (50.9–78)

Obturator fossa 44.2 (30.5–58.7)

hormone therapy was administered and the radia- tion dose administered. The nomogram has been validated using clinical data from the Cleveland Clinic.

28.3.2

Tumor Volume

Tumor volume is a powerful predictor for patient outcome. In a series of 151 patients undergoing radical prostatectomy, investigators found that the number positive biopsy sites, tumor bilaterally, and the percentage of biopsy sites positive for disease were all useful predictors of tumor volume in surgi- cal specimens (Poulos et al. 2004). Selek reported that the percentage positive prostate biopsy (PPPB) was a predictor of post-external beam radiotherapy PSA outcome in clinically localized prostate cancer.

The 5-year PSA failure-free survival rate was 79% vs 69% (p = 0.02) and the clinical disease-free survival

rate was 97% vs 86% (p = 0.0004) for patients with

<50% vs t50% PPPB (Selek et al. 2003).

28.4

Radiation Therapy Techniques

28.4.1

General Treatment Guidelines

The treatment volume guidelines used at Washing- ton University are outlined in Table 28.5. Patients are treated according to their risk category. Some patients may be a candidate for either external-beam radiation therapy or brachytherapy. Unless there are contraindications for one type of treatment, the choice of primary treatment modality often depends on patient choice. Elective pelvic lymph node irra- diation is used along with neoadjuvant hormone therapy when patients have a risk of lymph node

Table 28.5. Washington University 3D and IMRT Radiation Treatment Volume Guidelines. EBRT external-beam radiation ther- apy, HDR high dose rate, LN lymph node SV seminal vesicle, CTV clinical target volume, PTV planning target volume.

Risk group

Prognostic factors

Treatment T stage LN risk (%)

Pelvic node fi eld size (cm)

CTV boost PTV margin (mm)

Total PTV dose (EBRT; Gy) Low

risk

Stage T1b, T1c, or T2a, Gleason score d6, and PSA d10 ng/ml

EBRT to prostate or per- manent seed brachythera- py or HDR brachytherapy

T1–T2a – – Prostate 5–10 70.2–75.6

Inter- mediate risk

Stage T1b, T1c, or T2a, Gleason score d7 and PSA

>10–20 ng/ml; or stage T2b or T2c, Gleason score d7 and PSA d20 ng/ml

EBRT to prostate and seminal vesicles; external beam RT to prostate and seminal vesicles (45 Gy), and brachytherapy boost (permanent or HDR);

elective pelvic irradiation if LN risk >15% Neoadju- vant hormone therapy to be considered if LN risk

>15%

T1–T2a <15 – Prostate

and proxi- mal SV

5–10 70.2–75.6

T2b–c <15 – Prostate

and SV

5–10 73.8–75.6 T1–T2a t15 16.5u16.5 Prostate

and proxi- mal SV

5–10 70.2–75.6

T2b–c t15 16.5u16.5 Prostate and SV

5–10 73.8–75.6

High risk

Stage T3, Gleason score 8–10, PSA

>20 ng/ml

Neoadjuvant hormone therapy; adjuvant hormone therapy for Gleason score 8–10;

elective pelvic irradia- tion; prostate and seminal vesicle boost (EBRT or brachytherapy)

T1–T2a – 16.5u16.5 Prostate and proxi- mal SV

5–10 70.2–75.6

T2b–T3 – 16.5u20.0 Prostate and SV and EPE

5–10 73.8–75.6

a

From Kuban et al. 2003

b

LN risk = 2/3 PSA + [(GS-6) + TG-1.5] u 10

c

Pelvic fi elds receive 45 Gy/25fractions. All treatments are in 1.8 Gy per fraction

d

PTV margin varies by localization method and patient stability

metastases that exceeds 15% as determined by the Roach equation (Roach et al. 2003).

28.4.2

External Irradiation

With the advent of megavoltage equipment, an increase in the use of external irradiation rapidly emerged for the treatment of patients with car- cinoma of the prostate (del Regato et al. 1993).

Various techniques have been used, ranging from parallel anteroposterior (AP) portals with a perineal appositional field to lateral portals (box technique) or rotational fields to supplement the dose to the prostate (Bagshaw et al. 1988; del Regato et al.

1993; McGowan 1981), In recent years, 3D conformal and intensity-modulated radiation therapy (IMRT) techniques have been increasingly used (Hanks et al. 1996; Leibel et al. 1994; Perez 1998).

In patients in whom transurethral resection of prostate (TURP) has been carried out for relief of obstructive lower urinary tract symptoms, 4 weeks should elapse before radiation therapy begins in order to decrease sequelae (e.g., urinary inconti- nence, urethral strictures; Perez 1998).

28.4.3

Conventional Radiation Therapy Techniques

28.4.3.1 Volume Treated

When the pelvic lymph nodes are treated, the ante- rior and posterior field size is 16.5u16.5 cm at iso- center. Patients younger than 71 years of age with clinically localized disease and a risk of lymph node metastases that exceeds 15%, as well as all patients with stage-C (T3) lesions, are treated to the whole pelvis with four fields (45 Gy) and additional dose to complete 70 Gy or higher to the prostate, with a six- field 3D conformal or IMRT technique. For node- positive disease, the pelvic field size is increased to 16.5u20.5 cm at isocenter to cover the common iliac lymph nodes. The inferior margin of the field can be determined using an urethrogram with 25%

radiopaque iodinated contrast material. The inferior field edge usually is 1.5–2 cm distal to the junction of the prostatic and membranous urethra (usually at or caudal to the bottom of the ischial tuberosities).

The lateral margins should be about 1–2 cm from the lateral bony pelvis (Fig. 28.3a).

With lateral portals, which are used with the box technique (including the lymph nodes) or to irradi- ate the prostate with two-dimensional (2D) station- ary fields or rotational techniques, it is important to delineate anatomic structures of the pelvis and the location of the prostate in relation to the blad- der, rectum, and bony structures with computed tomography (CT) scan or magnetic resonance imag- ing (MRI).

The initial lateral fields encompass a volume similar to that treated with AP-posteroanterior (PA) portals. The anterior margins should be 1.5 cm posterior to the projection of the anterior cortex of the pubic symphysis (Fig. 28.3b). Some of the small bowel may be spared anteriorly, keeping in mind the anatomic location of the external iliac lymph nodes.

Posteriorly, the portals include the internal iliac nodes anterior to the S1–S2 interspace, which allows for some sparing of the posterior rectal wall distal to this level.

Figure 28.4 shows examples of digitally recon- structed radiograph (DRR) simulation films outlin- ing the AP and lateral portals used for the box tech- nique with coverage of the iliac nodes. For the boost with 2D treatment planning, the upper margin is 3–

5 cm above the pubic bone or acetabulum, depending on extent of disease and volume to be covered (i.e., prostate with or without seminal vesicles). The ante- rior margin is 1.5 cm posterior to the anterior cortex of the pubic bone. The inferior margin is 1.5 cm inferior to the genitourinary diaphragm as dem- onstrated by urethrogram. The posterior margin is 2 cm behind the marker rod in the rectum.

The reduced fields for treatment of the prostatic volume can be about 8u10 cm at isocenter for stages T1a–T2b to 10u12 or 12u14 cm for stages T2c–T3 or T4 (Fig. 28.3c) or ideally are anatomically shaped fields, using CT scans or MRI volume reconstruc- tions of the prostate and seminal vesicles. The semi- nal vesicles are located high in the pelvis and pos- terior to the bladder, which is particularly critical when reduced fields are designed in patients with clinical or surgical stage-T3b tumors. Perez et al.

(1993) demonstrated a correlation between size of the reduced portal and probability of pelvic tumor control.

The boost portal configuration and size should

be individually determined for each patient,

depending on clinical and radiographic assessment

of tumor extent. After the appropriate portals have

been determined, the central axis and some corners

of the reduced portals for both portals are tattooed

on the patient with India ink.

Fig. 28.3. a Diagrams of the pelvis show volumes used to con- ventionally irradiate the pelvic lymph nodes, when indicated, and the prostate. Lower margin is at or even 1 cm below ischial tuberosities. At Washington University, 15u15-cm portals at source-to-skin distance are used for selected stage-T1b, stage- T2, and all stage-T3 diseases, and for high-risk postoperative pa- tients, whereas for stage-N1 disease, 18u15-cm portals are used, when necessary, to cover all lymph nodes up to the bifurcation of the common iliac vessels. Sizes of reduced fi elds are larger (up to 12u14 cm) when the seminal vesicles and/or periprostatic tumor is irradiated compared with prostate boost only (up to 8u10 cm) or larger for patients with stage-T3 tumors. b Lateral portals used in conventional box technique to irradiate pelvic tissues and prostate. The anterior margin is 1 cm posterior to projected cortex of pubic symphysis. Presacral lymph nodes are included down to S2; inferiorly the posterior wall of rectum is spared. c Boost fi elds, lateral projection, are used to irradiate the prostate with conventional radiation therapy.

L5 S1 B

A

A B

C D

a

c

Fig. 28.4a,b. Anteroposterior (a) and lateral (b) virtual simulation digitally reconstructed radiographs (DRRs) for carcinoma of the prostate treating the pelvic lymph nodes. Note the relationship of the portals to the roof of the acetabulum, the pubic symphysis anteriorly, and the ischial tuberosities posteriorly.

a b

b

To simulate these portals with the patient in the supine position, a small plastic tube is inserted in the rectum to localize the anterior rectal wall. After thorough cleansing of the penis and surrounding areas with Betadine, using sterile technique, 28–40%

iodinated contrast material is injected in the urethra until the patient complains of mild discomfort, and AP and lateral radiographs are taken after the posi- tion of the small portals is determined under fluo- roscopic examination. For 3D CRT a topogram and a CT scan of the pelvis are performed. The urethro- gram documents the junction of the prostatic and bulbous urethra and accurately localizes (within 1 cm) the apex of the prostate, which may be diffi- cult to identify on CT scans without contrast. Care should be taken to avoid overdistension of the bul- bous urethra with contrast. Malone et al. (2000) reported that the prostate could be displaced an average of 6.1 mm due to the urethrogram. Others have described minimal movement due to the ure- throgram, suggesting that it may be related to tech- nique of urethrography and not to the contrast itself (Liu et al. 2004).

A great deal of controversy has developed in ref- erence to the most accurate anatomic location of the prostate apex. In a study of 115 patients, none of the urethrograms showed the urethral sphincter to be caudal to the ischial tuberosities; 10% were located

<1 cm cephalad to a line joining the ischial tuberosi- ties. If 2 cm or more are arbitrarily considered, 42.5%

of patients would have received unnecessary irradi- ation to small volumes of normal tissues (Sadeghi et al. 1996). Cox et al. (1994) evaluated urethrogram and CT scans of the pelvis for treatment planning in prostate cancer. Interobserver identification of the prostatic apex varied in 70% of cases. This vari- ability resulted in an inadequate margin (<1 cm) beneath the urogenital diaphragm in 5% of patients.

In contrast, placing the inferior border of the portal at the ischial tuberosities or the base of the penis, as seen on CT scans, ensured an adequate margin for all patients. They concluded that urethrography is more accurate than CT scanning in determining the inferior extent of the urogenital diaphragm.

Wilson et al. (1994) determined the anatomic location of the apex of the prostate in 153 patients undergoing 128-I implants by direct surgical expo- sure (133 patients) or transrectal ultrasound (TRUS;

20 patients). There was excellent agreement in the estimate of location of the prostatic apex between the two methods. It was located 1.5 cm or more above the ischial tuberosities in approximately 95%

of patients and within 1 cm in 98% (150 of 153).

Algan et al. (1995) reviewed the location of the prostatic apex in 17 patients in whom an MRI scan was obtained in addition to retrograde urethrogram and CT scan of pelvis for 3D treatment planning.

The location of the prostatic apex as determined by the urethrogram alone was, on average, 5.8 mm caudad to the location on the MRI, whereas the loca- tion of the prostatic apex as determined by CT/ure- throgram was 3.1 mm caudad to that on MRI. If the prostatic apex is defined as 12 mm instead of 10 mm above the urethrogram tip (junction of membra- nous and prostatic urethra), the difference between the urethrogram and MRI locations of the prostatic apex is no longer present.

Crook et al. (1995), in 55 patients with localized carcinoma of the prostate, placed one gold seed under TRUS at the base of the prostate near the seminal vesicles, at the posterior aspect, and the apex of the prostate. At the time of first simulation an urethrogram was performed, and the rectum was opacified with 10–15 cc of barium. The tip of the urethrogram cone varied in position from 0 to 2.8 cm above the most inferior aspect of the ischial tuberosities. At initial simulation the apex of the prostate was <2 cm above the ischial tuberosities in 42% of patients, <1.5 cm in 19%, and <1 cm in 8%

of patients. Because of variability in the thickness of the urogenital diaphragm, only 12 of 22 (55%) of these low-lying prostates would have been detected by urethrogram.

28.4.3.2

Beam Energy and Dose Distribution

Ideally, high-energy photon beams (>10 mV) should be used to treat these patients, which simplify tech- niques and decrease morbidity.

With photon-beam energies below 18 mV, lateral portals are always necessary to deliver part of the dose in addition to the AP–PA portals (box tech- nique). In our experience, an advantage of using the box technique is a decrease in erythema and skin desquamation in the intergluteal fold, which occurs more frequently with exclusively AP–PA portals.

The additional prostate dose is administered with anatomically shaped lateral and oblique or rota- tional portals.

For the reduced volume, a reasonable dose distri-

bution is obtained with bilateral 120q arc rotation,

skipping the midline anteriorly and posteriorly (60q

vectors). Figure 28.5 illustrates the dose distribution

for 8u10-cm bilateral 120q arcs using the 3D treat-

ment-planning software. It is readily apparent that this technique irradiates significantly more volume of bladder and rectum than 3D CRT.

28.4.3.3

Standard Tumor Doses (Non-Conformal Treatment Planning)

A frequently used minimum tumor dose to the pros- tate is 66–70 Gy for stage T1a when these patients are irradiated, 70–72 Gy for T1b, c-T2b tumors, and approximately 74 Gy for stage C. For stage T4 or node-positive lesions, treatment is usually pallia- tive, and the minimum tumor dose can be held at 60–65 Gy to decrease morbidity. Most institutions treat with daily fractions of 1.8–2 Gy, five fractions per week (Perez 1983; Taylor et al. 1979). Occa-

sionally, four weekly fractions of 2.25 Gy have been used (Bagshaw et al. 1985). At least two portals should be treated daily to improve tolerance to irra- diation.

Biggs and Russell (1988) described an average dose decrease of approximately 2% for patients with metallic hip prostheses who were treated with lat- eral portals, and an average increase of 2% for 10- mV X-rays and 5% for

Co.

The usual dose for the pelvic lymph nodes (when the latter are to be irradiated) is 45 Gy, with a boost (24–26 Gy) to the prostate or enlarged lymph nodes (5 Gy) through reduced fields (Perez 1998).

28.4.4

Conformal Radiation Therapy Simulation and Treatment Planning

The scientific basis and process of 3D CRT are described in Chapter 9. The process of 3D CRT plan- ning entails patient positioning and immobilization followed by acquisition of a treatment-planning CT data set. Defining target volumes and organs at risk is accomplished by contouring anatomy on a slice- by-slice basis. Radiation beams are created with vir- tual simulation software tools that are analogous to the operation of a conventional fluoroscopic iso- centric radiation therapy simulator. The radiation beams or apertures are shaped using a beam’s eye view (BEV) display and the contributing dose from each beam is entered into the treatment-planning software. Finally, the plan is reviewed using a vari- ety of dose display and analysis tools.

28.4.4.1

Patient Immobilization and Positioning

Patient immobilization devices are more frequently used in 3D CRT compared with traditional treat- ment planning. Some investigators have reported improved treatment setup accuracy with these devices, whereas others have reported no signifi- cant advantage with their use (Nutting et al. 2000;

Rosenthal et al. 1993). In a randomized study, Kneebone demonstrated that the average simula- tion-to-treatment deviation of the isocenter posi- tion was 8.5 mm in a control group and 6.2 mm in an immobilized group (p<0.001). The use of immobilization devices reduced isocenter devia- tions exceeding 10 mm from 30.9 to 10.6% in the immobilized arm (p<0.001). The average deviations

Fig. 28.5. a Isodose curves to deliver 68 Gy to the prostate with 18-mV photons, bilateral 120q arcs, and skipping 60q anterior and posterior vectors. b Isodose curves for irradiation of pel- vic lymph nodes and prostatic volume using anteroposterior/

posteroanterior and lateral fi elds to deliver 45 Gy to the pelvis and 26 Gy to prostate with reduced fi elds with bilateral 120q arcs. (From Perez 1998)

18 MV X-rays a

Prostate 16 MVX 120° Bilateral ARCS

b

Rectum 6500

3000

4200 5200 3140 6300

6200 Prostate Bladder trigome

PA

RT LT

120°

ARC

7100 7100

70006500 6000 5000 4000

3500

120°

ARC

in the anteroposterior, right–left, and superior–infe- rior directions were reduced to 2.9, 2.1, and 3.9 mm for the immobilized group, respectively (Kneebone et al. 2003). It is recommended that each radiation therapy center study and review the treatment setup variations with either method and choose the one that gives the best reproducibility.

There is significant debate regarding the appro- priate positioning for patients treated with localized carcinoma prostate. Some groups advocate a prone position which they claim minimizes prostate posi- tional uncertainty and decreases volume of rectum irradiated with conformal radiation therapy when the seminal vesicles are irradiated. Furthermore, in the prone position the seminal vesicles fall for- ward and increase the separation from the rectum (Zelefsky et al. 1997b). More recent data suggest that a prone position is associated with greater prostate motion accompanying normal ventilation.

The increased intra-abdominal pressure associ- ated with breathing in a prone position results in significant movement of the prostate and seminal vesicles. Dawson et al. (2000) evaluated the impact of breathing on the position of the prostate gland in four patients treated in four different positions in whom radiopaque markers were implanted in the periphery of the prostate using transrectal ultra- sound guidance. Fluoroscopy was performed in four different positions: prone in foam cast cradle; prone in thermoplastic mold; supine on a flat table; and supine with a false table under the buttocks. During normal breathing maximum movement of prostate markers seen in the prone position (cranial–caudal) ranged from 0.9 to 5.1 mm and anterior–posterior ranged up to 3.5 mm. In the supine position prostate movements during normal breathing was <1 mm in all directions; however, deep breathing resulted in movements of 3.8–10.5 mm in the cranial–caudal direction in the prone position (with and without thermoplastic mold). This range was reduced to 2.7 mm in the supine position and to 0.5–2.1 mm with the use of the false tabletop. Deep breathing resulted in anterior–posterior skeletal movements of 2.7–13.1 mm in the prone position, whereas in the supine position these variations were negligible.

Malone et al. (2000) also characterized inaccu- racies in prostatic gland location due to respiration observed fluoroscopically in 28 patients in whom three gold fiducial markers were implanted under ultrasound guidance at the apex, posterior wall, and base of prostate. Patients were immobilized on a cus- tomized thermoplastic shell placed on a rigid pelvic board. A second group of 20 patients were evaluated

both prone (with or without thermoplastic shell) and supine (without immobilization shell). When the patients were immobilized prone in the thermo- plastic shell, the prostate moved synchronously with respiration a mean distance of 3.3±1.8 mm (range 1–

10 mm). In 9 of 40 observations (23%) the displace- ments were 4 mm or greater. The respiratory-asso- ciated prostate movement decreased significantly when the thermoplastic shells were removed. Other investigators have confirmed this finding of pros- tate movement with respiration being significantly less in patients placed in a supine position (Dawson et al. 2000; Kitamura et al. 2002; Litzenberg et al. 2002; Malone et al. 2000; McLaughlin et al.

1999; Weber et al. 2000). Bayley (2004) conducted a randomized trial of the supine vs prone posi- tion in patients undergoing conformal radiation therapy. Twenty-eight patients were randomized to commence radiation therapy in the prone or supine position and then change to the alternate posi- tion midway through their treatment course. After placement of fiducial markers in the prostate for daily prostate localization, the patients underwent CT simulation and treatment planning in both posi- tions. Observed prostate motion was significantly less in the supine position than the prone position.

Pretreatment positioning corrections were required more often for patients in the prone position. A DVH (dose-volume histogram) analysis revealed more bladder wall, rectal wall, and small bowel in the high-dose volumes when patients were in the prone position than in the supine position. Finally, patients were more comfortable in the supine position than the prone position. Seven patients that started in the supine position refused to be treated in the prone position due to discomfort.

28.4.4.2

Clinical Target Volume Definition

Because prostate cancer is often found to be multifo- cal at the time of radical prostatectomy, the entire gland is commonly considered the gross tumor volume for radiation treatment-planning purposes.

The clinical target volume (CTV) may expand the gross tumor volume to account for direct extension or the CTV can be extended to encompass adjacent organs or regions of spread. In prostate cancer, the CTV may encompass the seminal vesicles and pos- sibly the regional pelvic lymph nodes.

Additional CTV margin for possible extraprostatic

extension (EPE) has been recommended by several

authors. In a study of radical prostatectomy specimens, Davis et al. (1999) demonstrated that EPE was present in 28% of 376 patients. The average radial EPE distance from the prostate capsule was 0.8 mm with a range of 0.04–4.4 mm. Sohayda and colleagues (2000) reported EPE in 35% of 265 cases. When EPE was present, it extended posterolateral in 53%, lateral in 24%, and posterior in 13%. The 90th percentile of EPE distance was 3.3 mm for patients with clinical T1–T2, pretreat- ment PSA of d10 ng/ml, and biopsy Gleason score of 6 or less. For patients with more unfavorable tumors, the 90th percentile of EPE extended to 3.9 mm. Both these series did not correct for possible specimen shrink- age related to formalin fixation. In another series of 712 prostatectomy specimens, Teh (2003) reported that the mean radial distance from the capsule was 2.93 mm (accounting for formalin fixation). The deci- sion to add additional CTV margin may be a function of both the total dose prescription and the degree of conformality expected to be achieved. With 3D CRT and escalated radiation doses, the tissues immediately adjacent to the prostate receive a dose of radiation that would be expected to control microscopic disease. On the other hand, with highly conformal radiation plans with IMRT or proton therapy, and small uncertainty margins for the PTV, marginal misses may be antici- pated unless an adequate CTV margin is added to account for microscopic EPE.

In selected patients it is necessary to outline the seminal vesicles, which in most patients are well demonstrated on the cross-section CT scans of the pelvis, superior, lateral, and posterior to the base of the prostate. The nomograms developed by Partin et al. (1993), Pisansky et al. (1996a) and Roach et al. (1997) may be used to determine the probability of seminal vesicle or pelvic lymph node involvement using clinical stage, pretreatment PSA, and Gleason score. Kestin et al. (2002) published an analysis of 344 radical prostatectomy specimens in which they measured the length of seminal vesicles, length of involvement by carcinoma, and percentage of semi- nal vesicle involved. They found an excellent correla- tion between the various prognostic parameters and the probability of seminal vesicle involvement. Also, in 81 patients with positive seminal vesicle involve- ment, the median length of tumor presence was 1 cm. In the entire population only 7% of patients had seminal vesicle involvement beyond 1 cm. They concluded that in selected patients seminal vesicles need to be treated and only 2.5 cm (approximately 60% of the seminal vesicle) should be included within the CTV, unless there is radiographic evi- dence of involvement.

When there is evidence of extraprostatic exten- sion on physical examination or imaging modalities, such as MRI (clinical stage T3), the seminal vesicles should be included for the total radiation dose pre- scription. In cases where the disease is confined to the gland (clinical stages T1–T2) and the risk of seminal vesicle invasion exceeds 15%, we define two clinical target volumes; the first encompasses the prostate and the seminal vesicles, and with the second, the boost target volume is the prostate alone. In these cases a radiation dose that controls subclinical dis- ease is prescribed to the first target volume and a higher dose is intended for the prostate itself.

As described in the section on conventional radi- ation therapy treatment planning, identification of the prostatic apex can be facilitated with a retro- grade urethrogram, which can be performed using 25% iodinated contrast material. The prostatic apex is 3–13 mm above the most proximal aspect of the urogenital diaphragm as defined by the urethro- gram (Rasch et al. 1999; Wilder et al. 1997). Care should be taken not to overinflate the urethra with iodinated contrast, as this may distend or move the prostate from its relaxed position.

Some authors feel that MRI may be more accu- rate in delineating the prostate and seminal vesicles ( Perrotti et al. 1996). Several publications have shown some discrepancy (0.5–1 cm) in defining the location of the apex of the prostate using CT scanning or MRI (Algan et al. 1995; Cox et al. 1994; Crook et al. 1995). Parker et al. (2003) studied co-registration of CT and MR images in the radiation treatment plan- ning of six patients with localized prostate cancer to assist with GTV delineation and identification of prostate position during radiation therapy. The over- all magnitude of contoured GTV was similar for MR and CT; however, there were spatial discrepancies in contouring between the two modalities. The greatest systematic discrepancy was at the posterior apical prostate border, which was 3.6 mm more posterior on MR- than CT-defined contouring.

At Washington University we treat the entire pros- tate as our CTV for patients with low-risk disease.

For patients with intermediate-risk disease we treat

the prostate and seminal vesicles to 55.8 Gy, followed

by a boost to the prostate alone (with appropriate

PTV margin, vide infra). When using IMRT we uti-

lize a single CTV for these patients to avoid the need

for two IMRT plans. In this case we treat the prostate

and the first 1–2 cm of seminal vesicle tissue in our

CTV (Fig. 28.6). For patients with stage-T3 disease,

we treat the prostate along with the seminal vesicles

to the total prescription dose.

28.4.4.3

Planning Target Volume Definition

The magnitude of the PTV margin is dependent upon several treatment-related factors. A technol- ogist’s inability to precisely reproduce a patient’s position on a daily basis is one contributing factor.

Some patients may move while on the treatment table because of fatigue or discomfort. Internal organs, including the prostate gland, can shift because of variable filling of the bladder and rectum. The shifts can be anisotropic with most movement occurring

in the anterior and posterior directions. Langen (2001) summarized institutional experiences study- ing setup errors and internal-organ motion. These studies investigated both internal organ motions and setup errors to determine an appropriate margin for the planning target volume. Increasing the size of the PTV margin increases the probability of encom- passing the CTV by the prescribed isodose from a complete course of radiation therapy. In order to assure that an adequate radiation dose is encom- passing all areas at risk of harboring disease, the radiation oncologist needs to include an appropriate

Fig. 28.6. Target volumes and organs at risk are defi ned on serial images of a treatment-planning CT scan. For illustration pur-

poses only every fourth CT image is displayed. The bladder (yellow) and rectum (orange) are contoured as solid organs. The

prostate (red) is contoured from its base superiorly to the apex at the genitourinary diaphragm. In this patient the fi rst 1 cm of

seminal vesicle tissue (violet) is included with the CTV and no attempt is made to treat them above this level. The PTV (cyan)

margin is 7 mm from the prostate border. In this example the fi ducial markers are seen inside the prostate gland

PTV margin. There is a trade-off between assuring nearly 100% coverage during each treatment and the volume of adjacent organs irradiated unneces- sarily.

Antolak et al. (1998), in a study of 17 patients with prostate cancer who underwent CT scanning for treatment planning and three subsequent CT scans obtained at approximately 2-week intervals during external-beam fractionated irradiation, observed CTV motion of 0.09 cm (left to right), 0.36 cm (cra- nial–caudal), and 0.41 cm (anterior–posterior) directions. Prostate mobility was not significantly correlated with bladder volume, but both prostate and seminal vesicle positions were significantly influenced by rectal volume. From this study, the authors concluded that margins between the CTV and PTV necessary to enclose 95% of the PTV were 7 mm in the lateral and cranial–caudal directions and 11 mm in the anterior–posterior direction.

In a study of 11 patients with repeated CT scans during a course of radiation therapy for prostate cancer, van Herk et al. (1995) showed that the larg- est deviation in prostate position was 2.7 mm in the anterior–posterior direction with a rotation about the left–right axis of 4q. They found that the apex of the prostate does not move, and the majority of any motion is rotation around the apex.

Zelefsky et al. (1999) evaluated prostate and seminal vesicle motion in 50 patients treated in the prone position using CT scans for initial treatment planning and three scans obtained throughout the course of radiation therapy. Before the initial CT scans, patients had an enema and were given 250 ml of bowel contrast by mouth. Patients had an empty bladder and 10 cc of air was inserted into the rectum via rectal catheter. Prior to all CT scans, patients voided, and no additional procedures were per- formed. Relative to the initial planning CT, mean displacements of the prostate were –1.2±2.9 mm in the AP, –0.5±3.3 mm in the superior/inferior, and – 0.6±0.8 mm in the lateral direction. The seminal ves- icle displacements were –1.4±4.9 mm, 1.3±5.5 mm, and –0.8±3.1 mm in the AP, superior–inferior (SI), and lateral directions, respectively. (Negative values indicated displacements to the posterior, inferior, and left directions.) A combination of rectal volume

>60 cc or a bladder volume >40 cc was found to be predictive for systematic deviations of the prostate and seminal vesicles of more than 3 mm. Based on the data and the prescription of irradiation dose to achieve at least 93% coverage of the CTV, Zelefsky et al. (1999) calculated the margins be added to the CTV for defining the PTV. Based on these reports,

it is apparent that beyond the CTV, additional mar- gins of 5–8 mm are necessary to provide adequate coverage of the prostate and 6–11 mm for adequate coverage of the seminal vesicles when there is no organ distension that would result in a systematic error.

Strategies to reduce the uncertainty in daily treatment delivery, and therefore to reduce the magnitude of the PTV margin, have been success- fully introduced. Each of these methods employs daily imaging of the prostate with the patient in the treatment position on the linear accelerator treatment table. Some institutions have employed radiopaque implanted fiducial markers that are subsequently imaged with electronic portal imag- ing devices. Crook et al. (1995) evaluated prostate motion in 55 patients in whom gold seeds were implanted at the base of the gland. Initial simula- tion was obtained in a supine position with a full bladder and was repeated after patients received 40 Gy. Prostate motion was observed in the pos- terior direction (5.6±4.1 mm) and in the inferior direction (5.9±4.5 mm). In 30% of patients the base of the prostate was displaced posteriorly and in 11%

in the inferior direction by >10 mm. Vigneault et al. (1997) investigated inter- and intrafraction daily motion of the prostatic apex relative to pelvic bony structures in 11 patients using radiopaque mark- ers implanted under ultrasound guidance near the prostatic apex. After the completion of treatment, a transrectal ultrasound performed in 8 of 11 patients verified that the position of the radiopaque markers had not shifted. Marker displacements up to 1.6 cm were measured between two consecutive days of treatment on portal images. The marker displace- ment relative to the center of the irradiation field was sensitive to both setup variations and internal prostate motion. The authors created treatment films (six consecutive electronic portal images during the same treatment fraction) and observed no visible intratreatment displacement of the mark- ers. The position of the fiducial markers visualized on daily port films or electronic portal images can be used to align isocenter on a daily basis to assure precise and accurate treatment of the PTV. Paired images need to be acquired in order to calculate the 3D position of the center of three fiducial markers.

We have begun to employ anterior oblique portal images for daily target localization because the density of the hips makes viewing the markers on lateral radiographs difficult (Fig. 28.7).

Transabdominal ultrasound has been used to

localize the prostate for treatment planning and

during daily radiation therapy delivery with an accuracy parallel to that of CT scanning of the pelvis (Fig. 28.8). Lattanzi et al. (1999, 2000) stud- ied 23 patients with CT simulations in whom pros- tate-only fields based on CT scans were created with no PTV margin. Ten of the patients also had prostate localization with a transabdominal ultra- sound system. The absolute magnitude difference in CT and ultrasound was small (AP mean 3±1.8 mm,

lateral mean 2.4±1.8 mm, superior/inferior mean 4.6±2.8 mm). The authors felt that transabdominal ultrasound was simple and expeditious, and they improved their ability to localize the position of the prostate with the patient at the treatment machine for daily irradiation.

Yan et al. (2000) have developed a strategy of adaptive radiation therapy. Patients undergo daily CT imaging during the first week of radiation ther-

Fig. 28.7a,b. A pair of a left and b right anterior oblique digitally reconstructed radiographs (DRR) with corresponding elec- tronic portal images demonstrating positions of intraprostatic fi ducial markers for daily setup localization. White arrows in- dicate the seed positions which have been previously defi ned on the treatment-planning CT, making their positions visible on the DRR. If necessary, offsets of the isocenter are calculated and the patient table position is shifted to bring the epicenter of the markers in alignment with the beam isocenter

a

b