Stereotactic Body Radiation Therapy for Prostate Cancer

Hiromichi Ishiyama; Bin S Teh; Simon S Lo; Thomas Mathews; Angel Blanco; Robert Amato; Rodney J Ellis; Nina A Mayr; Arnold C Paulino; Bo Xu; Brian E Butler

Disclosures

Future Oncol. 2011;7(9):1077-1086.

Clinical Data

Currently, there is no long-term level I evidence to establish that the SBRT regimens are superior to standard fractionation radiotherapy. However, several investigators have reported encouraging results of hypofractionated techniques for prostate cancer. More recently, some institutions have used SBRT as a boost after external beam radiation therapy (EBRT), and they also report encouraging results (Table 1).

Hypofractonation in the 2D Era

Lloyd-Davies et al. reported their 22 years experience between 1962 and 1984.^[6] They used 55 Gy in 12 fractions or 36 Gy in six fractions for prostate cancer treatment using three-field, four-field or double rotation technique. The authors reported no major early or late morbidity.

Hypofractionation With 3D Conformal Radiation Therapy

Lukka et al. reported a Phase III randomized trial in which conventional radiotherapy was used to compare 52.5 Gy in 20 fractions with 66 Gy in 33 fractions (non-inferiority investigation).^[7] A total of 470 patients received the standard fractionation and 466 patients received the abbreviated fractionation approaches. Biochemical or clinical failure in the standard fractionation and abbreviated arms were 52.95 and 59.95%, respectively. They could not exclude the possibility that the chosen hypofractionated regimen may be inferior to the standard regimen. Acute toxicity was found to be slightly higher in the abbreviated arm (11.4%) compared with the standard arm (7%); however, late toxicity was similarly low in both arms (3.2%). The other reports of hypofractionation with 3D-conformal radiation therapy^[8–12] are shown in Table 1.

Hypofractionation With Intensity-modulated Radiation Therapy

Pollack et al. compared 70.2 Gy in 26 fractions using intensity-modulated radiation therapy (IMRT) with 76 Gy in 38 fractions (randomized control trial).^[13,14] Up to 4 months of androgen deprivation was permitted, and long-term androgen deprivation was used for high-risk patients. With a median follow-up of 39 months, 5-year biochemical failure was 21% for the standard arm and 17% for the short arm. The 5-year grade 2 gastrointestinal (GI) toxicity or higher was 8 and 6%, and genitourinary (GU) toxicity was 17 and 25% for standard arm and hypofractionation arm, respectively. This study demonstrated that hypofractionation with IMRT is equivalent to standard fractionation. A relatively high GU toxicity rate was demonstrated, the reason for this is not clear from the abstract.^[14] The other reports^[15] are shown in Table 1.

Clinical Reports of SBRT

Among the clinical reports of SBRT, Freeman and King reported the longest follow-up result.^[16–19] A total of 41 low-risk patients received 36.25 Gy in five fractions. Patients were treated with implantable gold fiducials for daily localization, as well as intrafraction tracking performed every 30–90 s. With a median follow-up of 5 years, biochemically no evidence of disease (bNED) was 93%. There was no grade 3 late GI toxicity but only one grade 3 late GU toxicity.

Other SBRT studies also reported encouraging results, although their median follow-up does not reach 5 years.^[20–25]

A Phase I/II trial of SBRT using a linear accelerator and fiducial marker system was reported by Madsen et al..^[20] A total of 40 low-risk patients received 33.5 Gy in five fractions. With a median follow-up of 41 months, 4-year bNED was 90%. Acute grade 1 or 2 toxicities were 49% (GU) and 39% (GI). There was a single incident of grade 3 GU toxicity. Late grade 1 or 2 toxicities were 45% (GU) and 37% (GI).

Tang et al. reported the result of 30 patients, who received 35 Gy in five fractions, once a week over 29 days.^[21] At 6-months follow-up, there was no grade 3 toxicity in this report. They used this unique schedule for reducing acute toxicity without compromise of tumor control. They described that potentially slow doubling time of prostate cancer should not have any detrimental effect on tumor control in this weekly schedule over 29 days compared with a daily schedule over 5 days.^[21]

Friedland et al. reported on 112 patients with early-stage organ-confined prostate cancer treated with SBRT 35–36 Gy, administered in five consecutive fractions.^[22] A single case of grade 3 rectal toxicity was reported, although no other significant toxicity was seen.

Katz et al. reported the result of 304 patients treated either with 35 or 36.25 Gy in five fractions. Grade 2 or higher late GU toxicities were 2 and 6.3% for 35 and 36.25 Gy, respectively.^[23] Grade 2 or higher late GI toxicities were 0 and 2.9% for 35 and 36.25 Gy, respectively.

Bolzicco et al. reported the result of 45 low- and intermediate-risk prostate cancer patients treated with SBRT (35 Gy in five fractions).^[24] There was no acute toxicity greater than grade 2. Late toxicities consisted of one patient (2.2%) experiencing grade 2, one patient (2.2%) with grade 3 rectal and four patients (8.8%) with grade 1 urinary toxicity. No patient had biochemical failure at last follow-up.

Boike et al. reported the result of a Phase I dose–escalation study of SBRT. Three groups of 15 patients received 45, 47.5 and 50 Gy in five fractions.^[25] Patients were treated every other day to give time for tissue recovery. Their total dose and fraction size are the highest among the published reports (Table 1). For all patients, GI grade ≥2 and grade ≥3 toxicity occurred in 18 and 2%, respectively. GU grade ≥2 and grade ≥3 toxicity occurred in 31 and 4% of patients, respectively. They used a rectal balloon to displace the posterior rectal wall. Alpha-blocker (tamsulosin) was administrated for 6 weeks to reduce the risk of urinary complications. Dose escalation up to 50 Gy in five fractions did not demonstrate dose-limiting toxicity.

SBRT as a Boost of External Beam Radiation Therapy

Katz et al.^[26] reported preliminary results of a study of 73 patients treated with SBRT (18–21 Gy in three fractions) as a boost to EBRT (45 Gy). The median follow-up was 33 months. Less than 7% of patients experienced grade 2 toxicities and no higher grade acute toxicities occurred. There was one grade 4 and no grade 5 late toxicities. The 3-year bNED were 89.5 and 77.7% for intermediate- and high-risk patients, respectively.

Jabbari et al. reported the preliminary result of SBRT, not only as monotherapy (38 Gy in four fractions), but also as a post-whole-pelvis IMRT boost (19 Gy in two fractions and 45–50 Gy).^[27] With a median follow-up of 18.3 months, 42 and 11% of patients had grade 2 acute GU and GI toxicity, respectively, with no grade 3 or higher acute toxicity. Two patients experienced grade 3 late GU toxicity. All patients were without evidence of biochemical or clinical progression.

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Table 1. Reported hypofractionation schedules.
Study	n	Median follow-up (months)	Total dose (Gy)	Dose per fraction (Gy)	Free from PSA failure	Definition of failure	Late toxicity		Hormone (%)	Ref.
Study	n	Median follow-up (months)	Total dose (Gy)	Dose per fraction (Gy)	Free from PSA failure	Definition of failure	GU ≥2 (%)	GI ≥2 (%)	Hormone (%)	Ref.
Hypofractionation in 2D era
Lloyd-Davies	209	NA	55/36	4.6/6	NA	NA	NA	NA	NA	[6]
Hypofractionation with 3D-CRT
Lukka	466	68.4	52.5	2.625	Early stage, 40.05% (5 years)^†‡	Nadir+2	1.9^§	1.3^§	no	[7]
Soete^¶	36	2	56	3.5	NA	NA	NA	NA	NA	[8]
Yeoh	108	90	55	2.75	Early stage, 53% (7.5 years)^‡	Nadir+2/ASTRO^#	NA	NA	No	[9]
Lyvsey	705	48	50	3.125	Low, 82%; Int, 56%; High, 39% (5 years)	ASTRO	10^††	5^††	No	[10]
Akimoto	52	31	69	3	NA	NA	NA	25	All	[11]
Rene	129	51	66	3	Low and Int, 98% (5 years)	Nadir+2	32	25	NA	[12]
Hypofractionation with IMRT
Pollack	50	39	70.2	2.7	Int and High, 83% (5 years)	Nadir+2	25 (5years)	6 (5 years)	44	[13,14]
Kupelian	770	45	70	2.5	Low, 94; Int, 83%; High, 72% (5 years)	Nadir+2/ASTRO^#	7 (5 years)	6 (5 years)	60	[15]
SBRT
Madsen	40	41	33.5	6.7	Low, 90% (4 years)	Nadir+2/ASTRO^#	20	8	No	[20]
Freeman	41	60	36.25	7.25	Low, 92.7% (5 years)	Nadir+2	9.5	2.5	No	[19]
Tang	30	12	35^‡‡	7	NA	NA	13 at 6 months	13 at 6 months	3	[21]
Friedland	112	24	35–36	7–7.2	NA	NA	0	0.9	19	[22]
Katz	50, 254^§§	17, 30	35, 36.25	7, 7.25	Low, 99%, Int, 100%, High,83% (last follow-up)	Nadir+2	2, 6.3	0, 2.9	19	[23]
Bolzicco	45	20	35	7	Low and Int, 100%	NA	2.2	2.2	38	[24]
Jabbari	20	18.3	38	9.5	All risk groups, 100%	NA	13^¶¶	8^¶¶	47%	[27]
Boike	15, 15, 15^##	30, 18, 12	45, 47.5, 50	9, 9.5, 10	100%	Nadir+2	13, 20, 7	7, 7, 0	22	[25]
SBRT as a boost of EBRT
Katz	73	33	18–21 + EBRT 45	6–7	Int, 89.5%; high, 77.7% (3 years)	Nadir+2	5.5	8.2	50.6	[26]
Jabbari	18	18.3	19 + EBRT 45–50	9.5	All risk groups, 100%	NA	13^¶¶	8^¶¶	47	[27]

^†Including clinical failure.
^‡Risk criteria is not available.
^§Grade 3 or more. ^¶Including IMRT.
^#Result from nadir+2 is shown in this table.
^††n = 101 for toxicity assessment. ^‡‡Once a week over 29 days.
^§§Divided into two schedules.
^¶¶Including combination with EBRT. ^##Divided into three schedules.
CRT: Conformal radiation therapy; EBRT: External beam radiation therapy; GI: Gastrointestinal; GU: Genitourinary; High: High risk; IMRT: Intensity-modulated radiation therapy; Int: Intermediate risk; Low: Low risk; NA: Not applicable; PSA: Prostate-specific antigen; SBRT: Stereotactic body radiation therapy.

Table 2. Reported margin size, PTV constraints and type of machine.
Study	Institution	Machine	Margin size	PTV constraints	Ref.
Madsen	VMMC	Conventional linear accerelator	4–5 mm from prostate to block edge	100% to isocenter Prostate covered by 90% isodose line	[20]
Freeman	Stanford University and Naples RO	CyberKnife	GTV = prostate and proximal 1cm of seminal vesicle CTV = GTV + 3 mm anteriorly and laterally, 1 mm posteriorly PTV = CTV + 2 mm anteriorly, laterally and posteriorly	95% of PTV covered by prescription dose	[19]
Tang	University of Toronto	Conventional linear accerelator	CTV = prostate PTV = CTV + 4 mm	100% of CTV ≥35 Gy 99% of PTV ≥33.25 Gy Max≤105%	[21]
Friedland	Naples RO	CyberKnife	GTV = prostate and proximal 1 cm of seminal vesicle PTV = GTV + 3 mm posteriorly and 5 mm all other directions	95% of PTV covered by prescription dose	[22]
Katz	Winthrop University Hospital	CyberKnife	GTV for low risk = prostate GTV for intermediate, high risk = prostate + half of seminal vesicle PTV for low, intermediate risk = GTV + 3 mm posteriorly and 5mm all other directions PTV for high risk = GTV + 3 mm posteriorly, 8 mm involved side, 5 mm all other directions	96% of PTV covered by prescription dose	[23]
Bolzicco	San Bortolo Hospital	CyberKnife	GTV = prostate PTV = GTV + 3 mm posteriorly and 5 mm all other directions	95% of PTV covered by prescription dose	[24]
Jabbari	UCSF	CyberKnife	CTV = prostate ± seminal vesicle PTV = CTV + 2 mm (no overlap with rectum is allowed)	HDR-like plannning prescription isodose is in 60–80% range	[27]
Boike	University of Texas Southwestern	Tomotherapy or conventional linear accerelator	CTV = prostate PTV = GTV + 3 mm	95% of PTV covered by prescription dose	[25]

HDR: High-dose rate; Naples RO: Naples Radiation Oncology; PTV: Planning target volume; UCSF: University of California San Francisco; VMMV: Virginia Mason Medical Center.

Table 3. Isoeffective prescription for late complication at α:β = 3 Gy.
No. of fractions	Dose per fraction (Gy)	Total dose (Gy)	Normal tissue (α:β=3 Gy) normalized total dose (Gy)	Tumor (α:β=1.5 Gy) normalized total dose (Gy)
35	2.00	70.00	70.00	70.00
30	2.23	66.92	70.00	71.32
25	2.53	63.28	70.00	72.88
20	2.94	58.88	70.00	74.77
15	3.56	53.37	70.00	77.13
10	4.60	46.03	70.00	80.27
5	7.00	35.00	70.00	85.00

Table 4. Reported constraits in stereotactic body radiation therapy.
Study	Rectum	Bladder	Penile bulb	Urethra	Ref.
Madsen	NA				[20]
Freeman	V50% <50% V80% <20% V90% <10% V100% <5% V36 Gy <1 cm³	V37 Gy <10 cm³			[19]
Tang	V28 Gy ≤40% V32 Gy ≤33%	V32 Gy ≤40%	V20 Gy ≤ 90%		[21]
Friedland	V36 Gy <1 cm³	V37 Gy <10 cm³			[22]
Katz	NA				[23]
Bolzicco	D5% <38 Gy	D5% <40 Gy	D25% < 29 Gy	D5% <41 Gy	[24]
Jabbari	Max of wall <38 Gy Max of mucosa <28.5 Gy	Max <45.6 Gy		Max <45.6 Gy	[27]
Boike	Anterior wall <105% V90% of lateral wall <3 cm³ Posterior wall ≤45%	Max ≤105% V18.3 Gy <10 cm³		Max ≤105%	[25]

D: Dose; V: Volume.

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