A phase II study of hypofractionated proton therapy for prostate cancer

Figures & data

Table I. Five hypofractionated dose schedules.

					EQD2
	Daily dose (CGE)	Number of fractions	Tx day/week	Tx time (days)	Prostate cancer* (α/β = 1.5 Gy)	Acute effect^† (α/β = 10 Gy, Tp = 2.5, Tk = 7)	Late effect* (α/β = 3 Gy)
Reference dose in 2 Gy per fraction	2	36	Mon, Tue, Wed, Thu, Fri	49	72.0	72.0	72.0
Arm 1	3	20	Mon, Tue, Thu, Fri	32	77.1	69.6	72.0
Arm 2	3.6	15	Mon, Wed, Fri	32	78.7	63.8	71.3
Arm 3	4.7	10	Tue, Thu	30	83.3	58.2	72.4
Arm 4	7	5	Tue, Thu	14	85.0	55.5	70.0
Arm 5	7	5	Wed	28	85.0	46.3	70.0

CGE, cobalt gray equivalent = proton dose in Gy × 1.1; EQD2, equivalent dose in 2-Gy fractions; Tx, treatment.

*By Equation 1; ^†By Equation 2.

Figure 1. (A) A set of 3-mm-thick contrast computed tomography images was acquired for treatment planning. Three gold markers were inserted into the prostate. One of the three gold markers is not seen because it was inserted into a different axis. A balloon was inserted into the rectum and filled with 100 ml of saline. (B) Treatment planning was performed using bilateral beams with the Eclipse proton beam planning system (Ver. 8.1; Varian Medical System, Palo Alto, CA, USA). The planning goals included that at least 95% of the PTV received the prescribed dose, and that the volume receiving 50 Gy EQD2 should not exceed 30% for the rectum and bladder.

Table II. Patient characteristics.

	Arm 1 (n = 19)		Arm 2 (n = 16)		Arm 3 (n = 17)		Arm 4 (n = 18)		Arm 5 (n = 12)			Total (n = 82)
Characteristics	n	(%)	n	(%)	n	(%)	n	(%)	n	(%)	p-value*	n	(%)
Age median (range)	66 (44–72)		69 (57–82)		71 (61–85)		67 (46–74)		70 (53–80)			68 (44–85)
Gleason score											0.110
≤ 6	15	(79)	6	(38)	14	(82)	12	(67)	5	(42)		52	(63)
7	4	(21)	8	(50)	2	(12)	5	(28)	5	(42)		24	(29)
8–10	0	–	2	(13)	1	(9)	1	(6)	2	(17)		6	(7)
PSA peak (ng/ml)											0.476
< 10	12	(63)	11	(69)	13	(76)	13	(72)	6	(50)		55	(67)
10–20	6	(93)	3	(19)	3	(18)	5	(28)	6	(50)		23	(28)
> 20	1	(5)	2	(13)	1	(6)	0	–	0	–		4	(5)
T stage											0.252
T1	8	(42)	9	(56)	3	(18)	5	(28)	4	(33)		29	(35)
T2	10	(53)	4	(25)	11	(65)	12	(67)	7	(58)		44	(54)
T3	1	(5)	3	(19)	3	(18)	1	(6)	1	(8)		9	(11)
Risk group^†											0.276
low	10	(53)	5	(31)	6	(35)	5	(28)	2	(17)		28	(34)
intermediate	7	(37)	5	(31)	7	(41)	11	(61)	7	(58)		37	(45)
high	2	(11)	6	(38)	4	(24)	2	(11)	3	(25)		17	(21)

PSA, prostate-specific antigen.

*By χ²-analysis, ^†Risk group according to the National Comprehensive Cancer Network.

Table III. Maximum acute and late toxicity.

	Arm 1 (n = 19)		Arm 2 (n = 16)		Arm 3 (n = 17)		Arm 4 (n = 18)		Arm 5 (n = 12)			Total (n = 82)
Grade	n	(%)	n	(%)	n	(%)	n	(%)	n	(%)	p-value*	n	(%)
Acute toxicity
Skin											0.286
0	7	(37)	2	(13)	5	(29)	5	(28)	6	(50)		25	(30)
1	12	(63)	14	(88)	12	(71)	13	(72)	6	(50)		57	(70)
GI											0.583
0	18	(95)	13	(81)	15	(88)	15	(83)	9	(75)		70	(85)
1	1	(5)	3	(19)	2	(12)	3	(17)	3	(25)		12	(15)
GU												0.128
0	2	(11)	2	(13)	4	(24)	8	(44)	5	(42)		21	(26)
1	16	(84)	13	(81)	13	(76)	9	(50)	6	(50)		57	(70)
2	1	(5)	1	(6)	0	–	1	(6)	1	(8)		4	(5)
Late toxicity
Skin											0.950
0	10	(53)	9	(56)	8	(47)	11	(61)	7	(58)		45	(55)
1	9	(47)	7	(44)	9	(53)	7	(39)	5	(42)		37	(45)
GI											0.277
0	8	(42)	4	(25)	6	(35)	7	(39)	4	(33)		29	(35)
1	5	(26)	12	(75)	8	(47)	8	(44)	7	(58)		40	(49)
2	4	(21)	0	–	3	(18)	3	(17)	1	(8)		11	(13)
3	2	(11)	0	–	0	–	0	–	0	–		2	(2)
GU											0.122
0	16	(84)	11	(69)	7	(41)	11	(61)	9	(75)		54	(66)
1	3	(16)	5	(31)	6	(35)	5	(28)	3	(25)		22	(27)
2	0	–	0	–	4	(24)	2	(11)	0	–		6	(7)

GI, gastrointestinal; GU, genitourinary

*By two-tailed Fisher's exact test

Table IV. Patient-reported measures.

			Mean of within-patient change
	pre-RT (mean ± standard error) (n = 81)	half of SD of pre-RT	at the end of RT (n = 80)	7 mo (n = 81)	13 mo (n = 69)	25 mo (n = 51)	37 mo (n = 32)
AUA score (best 0 – worst 35)	10.7 ± 0.9	4.00	5.50*	−0.74	−0.90	0.00	−0.16
Urinary QoL score (best 1 – worst 7)	3.9 ± 0.1	0.66	0.47	−0.42	−0.32	−0.24	−0.55
Sexual function scale (best 0 – worst 100%)	37.6 ± 4.1	18.22	−0.42	1.35	12.89	9.00	14.40
Modified LENT-SOMA GU toxicity score (best 0 – worst 4)
Urinary frequency	2.7 ± 0.1	0.51	0.42	0.05	0.09	0.02	0.00
Nocturia	1.8 ± 0.1	0.45	0.42	0.16	0.22	0.14	0.00
Hematuria	1.0 ± 0.2	0.08	0.04	0.04	0.01	0.04	−0.03
Urgency of urination	2.1 ± 0.1	0.54	0.05	−0.15	−0.28	−0.24	−0.23
Dysuria	1.7 ± 0.1	0.43	0.54*	−0.21	−0.10	−0.02	−0.16
Modified LENT-SOMA GI toxicity score (best 0- worst 4)
Stool frequency	1.3 ± 0.1	0.24	0.22	0.08	0.04	0.06	0.00
Stool consistency	1.6 ± 0.1	0.25	0.09	0.15	0.07	0.00	0.00
Pain	1.1 ± 0.02	0.12	0.11	0.09	0.06	0.10	0.10
Mucosal discharge	1.1 ± 0.1	0.26	0.15	0.10	0.26	0.18	0.03
Urgency of defecation	1.6 ± 0.1	0.44	0.18	0.23	0.06	0.34	0.23
Rectal bleeding	1.0 ± 0.02	0.08	0.05	0.24*	0.66*	0.70*	0.52*

AUA, American Urological Association; QoL, quality of life; RT, radiation therapy; SD, standard deviation.

LENT-SOMA, Late Effects Normal Tissue Task Force-Subjective, Objective, Management

• Urinary QoL score: 1 (delighted); 2 (pleased); 3 (mostly satisfied); 4 (mixed); 5 (mostly dissatisfied); 6 (unhappy); 7 (terrible)

• Sexual function scale: 0–33% (no/slight dysfunction); 34–67% (moderate dysfunction); 68–100% (severe dysfunction)

• Asterisks (*) designate time points at which scores differed from those at pretreatment baseline by more than half a standard deviation and the comparison was significant (p < 0.01, by paired t-test).

Figure 2. Biochemical failure free survival (BCFFS) curves, according to the American Society for Therapeutic Radiology and Oncology (ASTRO) and Nadir + 2 ng/ml definitions, are presented. The four-year ASTRO and Nadir + 2 ng/ml BCFFS rates were 85% and 86%, respectively.

Table V. Previous studies.

								EQD2 (Gy)		EQD2 (Gy)		Overall		Intermediate-risk		≥ Grade 2 acute toxicity (%)		≥ Grade 2 late toxicity (%)
Reference	Inclusion criteria	No. of patients	Dose (Gy)/fraction	RT duration (weeks)	RT method	No. of neoadj-uvant. ADT	No. of Adjuvant ADT	Prostate cancer α/β = 1.5	Acute α/β = 10 Tp = 2.5 Tk = 7	Late α/β = 3	Median FU (mo) (range)	5 yr ASTRO BCFFS (%)	5 yr Nadir + 2 ng/mL BCFFS (%)	5 yr ASTRO BCFFS (%)	5 yr Nadir + 2 ng/mL BCFFS (%)	GU	GI	GU	GI
Arcangeli 2010 [14], 2011 [15]	localized, high-risk	85 83	80/40 62/20	8 5	3D-CRT	85 83	85 83	80.0 81.5	80.0 72.3	80.0 75.6	35 32	– –	high-risk 79 (3 yr) high-risk 87 (3 yr)	– –	– –	40 47	21 35	11 16	14 17
Kupelian 2007 [16]	localized	770	70/28	5.5	IMRT	459		80.0	78.9	77.0	45 (0–86)	82	83	85	83	19	9	7* (5 yr)	6* (5 yr)
Martin 2007 [17]	T1c–2, Nx, M0	92	60/20	4	IMRT & IGRT	3	5	77.1	74.2	72.0	38 (17–58)	76 (3 yr)	97 (14mo)	72 (3 yr)	85 (3 yr)	25	12	10*	6*
Madsen 2007 [18]	low-risk	40	33.5/5	1	Stereotactic	0	0	78.5	57.2	65.0	41 (12–60)	70 (4 yr)	90 (4 yr)	–	–	23	13	16* (4 yr)	9* (4 yr)
King 2009 [19]	low-risk	21	36.25/5	1	CyberKnife	0	0	90.6	62.7	74.3	33 (6–45)	–	–	–	–	–	–	29	15
		20	36.25/5	2				90.6	61.3	74.3
Pollack 2002 [20]	T1-T3,	150	70/35	7	3D-CRT	0	0	70.0	70.0	70.0	8.7 yr	64 (6 yr)	59 (8 yr)	–	76 (8 yr)	–	–	8 (10 yr)	13 (10 yr)
Kuban 2008 [21]	Nx, M0	151	78/39	8		0	0	78.0	78.0	78.0		70 (6 yr)	78 (8 yr)	–	86 (8 yr)	–	–	13 (10 yr)	26 (10 yr)
Current study	T1-T3, N0, M0	82	35/7–60/20	2.5–5	Proton	0	0	77.1–85.0	46.3–69.6	70.0–72.0	42 (11–52)	85 (4 yr)	86 (4 yr)	85 (4 yr)	90 (4 yr)	5	0	7	16

ADT, androgen–deprivation therapy; ASTRO, American Society for Therapeutic Radiology and Oncology; BCFFS, biochemical failure-free survival; EQD2, 2 Gy equivalent dose; FU, follow-up; GI, gastrointestinal; GU, genitourinary; IGRT, image-guided radiation therapy; IMRT, intensity-modulated radiation therapy; mo, month(s); RT, radiation therapy; 3D-CRT, three-dimensional conformal radiation therapy.

*Actuarial value

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