Mixed-beam approach in locally advanced nasopharyngeal carcinoma: IMRT followed by proton therapy boost versus IMRT-only. Evaluation of toxicity and efficacy

Figures & data

Table 1. Patient, tumor and treatment characteristics.

Characteristics	Mixed beam	IMRT	p Value
	No. of patients (%)	No. of patients (%)
Total	27 (100)	17 (100)
Age (years): median (range)	49 (18–73)	54 (35–76)	.66
KPS			.43
100	20 (74)	14 (82.4)
90	6 (22.3)	3 (17.6)
80	1 (3.7)	0 (0)
Tumor histology			.91
WHO I	4 (14.8)	2 (11.8)
WHO II	19 (70.4)	13 (76.4)
WHO III	4 (14.8)	2 (11.8)
EBV status on biopsy specimen			.20
Positive	14 (51.9)	7 (41.1)
Negative	3 (11.1)	0 (0)
Not evaluated	10 (37)	10 (58.8)
Tumor stage (TNM 7th edition)			.35
T1	0 (0)	0 (0)
T2	0 (0)	0 (0)
T3	12 (44.4)	10 (58.8)
T4	15 (55.6)	7 (41.2)
Nodal stage (TNM 7th edition)			.49
N0	4 (14.8)	5 (29.4)
N1	8 (29.6)	3 (17.7)
N2	15 (55.6)	9 (52.9)
N3	0 (0)	0 (0)
Clinical stage (AJCC 7th edition)			.83
I–II	0 (0)	0 (0)
III	12 (44.4)	10 (58.8)
IVA	15 (55.6)	7 (41.1)
Induction chemotherapy			.04
Yes	16 (59.3)	15 (88.2)
TPF (taxol or taxotere – cisplatin – 5FU) for 3 cycles	14 (87.5)	9 (60)
	1 (6.25)	0 (0)
EC (epirubicin – cyclophosphamide) for 4 cycles	1 (6.25)	6 (40)
	11 (40.7)	2 (11.8)
PF (cisplatin-5FU) for 3 cycles
No	0 (0)	0 (0)
Concurrent chemoradiotherapy			.20
Yes	27 (100)	16 (94.1)
Weekly cisplatin	9 (33.3)	4 (25)
Cisplatin for 3 cycles	16 (59.3)	11 (68.7)
Weekly carboplatin	1 (3.7)	1 (6.3)
Weekly carboplatin and Taxol	1 (3.7)	0 (0)
No	0 (0)	1 (5.9)

IMRT: intensity modulated radiotherapy; KPS: Karnofsky Performance Status; WHO: World Health Organization; EBV: Epstein Barr virus; AJCC: American Joint Committee on Cancer; 5FU: 5-fluorouracil.

Table 2. Acute radiation-related toxicity of patients with nasopharyngeal tumor treated with a Mixed Beam approach or IMRT.

Toxicity according to CTCAE (V 4.03) scale	Mixed beam No. of patients = 27	IMRT No. of patients = 17	p Values
Skin
G0, n (%)	3 (11.1)	0 (0)	.66
G1, n (%)	9 (33.3)	8 (47.1)
G2, n (%)	15 (55.6)	9 (52.9)
G3, n (%)	0 (0)	0 (0)
Mucositis
G0, n (%)	0 (0)	0 (0)	.0002
G1, n (%)	11 (40.8)	2 (11.8)
G2, n (%)	13 (48.1)	2 (11.8)
G3, n (%)	3 (11.1)	13 (76.4)
Dysphagia
G0, n (%)	4 (14.8)	1 (5.9)	.36
G1, n (%)	11 (40.8)	7 (41.2)
G2, n (%)	8 (29.6)	5 (29.4)
G3, n (%)	4 (14.8)	4 (23.5)
Xerostomia
G0, n (%)	6 (22.2)	1 (5.9)	.02
G1, n (%)	19 (70.4)	10 (58.8)
G2, n (%)	2 (7.4)	6 (35.3)
G3, n (%)	0 (0)	0 (0)
Weight loss
G0, n (%)	8 (29.7)	2 (11.8)	.11
G1, n (%)	14 (51.8)	9 (52.9)
G2, n (%)	5 (18.5)	6 (35.3)
G3, n (%)	0 (0)	0 (0)
Enteral nutrition
Yes, n (%)	4 (14.8)	3 (17.7)	.81
No, n (%)	23 (85.2)	14 (82.3)
Dysphonia
G0, n (%)	19 (70.4)	16 (94.1)	.06
G1, n (%)	7 (25.9)	1 (5.9)
G2, n (%)	1 (3.7)	0 (0)
G3, n (%)	0 (0)	0 (0)
Hearing impairment
G0, n (%)	22 (81.5)	12 (70.6)	.64
G1, n (%)	5 (18.5)	5 (29.4)
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
Dysgeusia
G0, n (%)	15 (55.6)	11 (64.8)	.55
G1, n (%)	12 (44.4)	6 (35.2)
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
Pain (NRS scale) median	6	6	.34

pts: patients; CTCAE: Common Terminology Criteria Adverse Events; G: grade; NRS: numeric rating scale; NE: not evaluated.

p Value from Mantel–Haenszel Chi-squared test and Wilcoxon’s rank test for Pain scale.

Table 3. Late radiation-related toxicity of patients with nasopharyngeal tumor treated with a Mixed Beam approach or IMRT.

Toxicity according to CTCAE (V 4.03) scale	Mixed beam No. of patients = 26	IMRT No. of patients = 16	p Values
Skin
G0–1, n (%)	26 (100)	15 (93.75)	.55
G2, n (%)	0 (0)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Mucositis
G0–1, n (%)	26 (100)	15 (93.75)	.20
G2, n (%)	0 (0)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Dysphagia
G0–1, n (%)	26 (100)	16 (100)	1
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
Xerostomia
G0–1, n (%)	16 (61.54)	11 (68.75)	.15
G2, n (%)	10 (38.46)	5 (31.25)
G3, n (%)	0 (0)	0 (0)
Cranial nerve neuropathy
G0–1, n (%)	25 (96.16)	15 (93.75)	.12
G2, n (%)	1 (3.85)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Trismus
G0–1, n (%)	26 (100)	15 (93.75)	.51
G2, n (%)	0 (0)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Hearing impairment
G0–1, n (%)	25 (96.15)	15 (93.75)	.38
G2, n (%)	1 (3.85)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Dysgeusia
G0–1, n (%)	26 (100)	16 (100)	.71
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
CNS necrosis
G0–1, n (%)	26 (100)	16 (100)	1
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
Soft tissue necrosis
G0–1, n (%)	26 (100)	16 (100)	.38
G2, n (%)	0 (0)	0 (0)
G3, n (%)	0 (0)	0 (0)
Soft tissue fibrosis
G0–1, n (%)	26 (100)	15 (93.75)	.07
G2, n (%)	0 (0)	1 (6.25)
G3, n (%)	0 (0)	0 (0)
Optic nerve disorder
G0–1, n (%)	25 (96.15)	16 (100)	.77
G2, n (%)	1 (3.85)	0 (0)
G3, n (%)	0 (0)	0 (0)
Endocrine disorders
G0–1, n (%)	25 (96.15)	15 (93.75)	.61
G2, n (%)	1 (3.85)	1 (6.25)
G3, n (%)	0 (0)	0 (0)

pts: patients; CTCAE: Common Terminology Criteria Adverse Events; G: grade; CNS: central nervous system.

p Value from Mantel–Haenszel Chi-squared test.

Table 4. Absorbed doses for acute toxicity related-structures.

Organs at risk	IMRT-only				Mixed beam				p Value
	Median	Q1	Q3	(min, max)	Median	Q1	Q3	(min, max)
Pharyngeal axis (V66.5Gy)	11	7	17	(1, 69)	7	4	14	(0, 49)	.105
Cricopharyngeal inlet (D2%)	53.5	48.5	57.5	(10, 62)	48	45	51	(38, 65)	.02
Esophagus (max dose 0.03 cm^3)	55.5	38.5	57	(18, 75)	53	50	55	(24, 59)	.424
Esophagus (mean dose)	42	11.5	49	(5, 58)	41	35	46	(5, 49)	.96
Oral cavity (mean dose)	46	42	53	(40, 55)	42	40	43	(31, 60)	.015
Extended oral cavity (mean dose)	49	45	54	(43, 58)	47	45	49	(39, 65)	.089
Supraglottic larynx (Dmax 0.03 cm^3)	67	62	70	(59, 72)	60	57	64	(52, 73)	.008
Supraglottic larynx (mean dose)	44	42	52	(17, 60)	46	43	50	(34, 64)	.701
Parotid gland, ipsilateral (V30)	60	48	74	(35, 100)	95	62	100	(0, 100)	.03
Parotid gland, ipsilateral (mean dose)	39	37	46	(29, 55)	47	36	55	(0, 66)	.05
Parotid gland, contralateral (V30)	40	31	52	(5, 72)	65	52	94	(0, 100)	.007
Parotid gland, contralateral (mean dose)	32	26	38	(15, 50)	39	33	49	(0, 54)	.06

IMRT: intensity modulated radiotherapy; V66.5: volume (%) which received 66.5 Gy; D: dose; V30: volume (%) which received 30 Gy; ipsilateral parotid gland: the parotid gland that received the highest dose in terms of V30 and mean dose.

Comparison between patients treated with IMRT-only and mixed beam approach.

Table 5. Acute radiation-related toxicity profile: comparison between the cohort of patients treated with mixed beam and available literature data.

Toxicity according to CTCAE (V 4.03) scale	Mixed beam (current series) No. of patients 27	Chan et al. [15] No. of patients 23	Lewis et al. [25] No. of patients 9	Holliday et al. [26] No. of patients 10
Skin
G0, n (%)	3 (11.1)		0
G1, n (%)	9 (33.3)		0
G2, n (%)	15 (55.6)		5 (56)
G3, n (%)	0 (0)		4 (44)
Mucositis
G0, n (%)	0 (0)		0
G1, n (%)	11 (40.8)		0
G2, n (%)	13 (48.1)		8 (89)
G3, n (%)	3 (11.1)		1 (11)
Weight loss
G0, n (%)	8 (29.7)	Any grade	1 (11)
G1, n (%)	14 (51.8)	9 (38%)	5 (56)
G2, n (%)	5 (18.5)		3 (33)
G3, n (%)	0 (0)		0
Enteral nutrition
Yes, n (%)	4 (14.8)	11 (48)	2 (22)	2 (20)
No, n (%)	23 (85.2)	12 (52)	7 (78)	8 (80)

pts: patients; CTCAE: Common Terminology Criteria Adverse Events; G: grade.

Chan A, Adams J, Weyman E, et al. A phase II trial of proton radiation therapy with chemotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2012;84(3):S151–S152.

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Lewis GD, Holliday EB, Kocak-Uzel E, et al. Intensity-modulated proton therapy for nasopharyngeal carcinoma: decreased radiation dose to normal structures and encouraging clinical outcomes. Head Neck. 2016;38(Suppl. 1):E1886–E195.

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Holliday EB, Garden AS, Rosenthal DI, et al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: a case-match control study of intensity-modulated proton therapy and intensity-modulated photon therapy. Int J Part Ther. 2015;2(1):19–28.

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