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

Abstract

Objective: To compare radiation-induced toxicity and dosimetry parameters in patients with locally advanced nasopharyngeal cancer (LANPC) treated with a mixed-beam (MB) approach (IMRT followed by proton therapy boost) with an historic cohort of patients treated with a full course of IMRT-only.

Material and methods: Twenty-seven patients with LANPC treated with the MB approach were compared to a similar cohort of 17 patients treated with IMRT-only. The MB approach consisted in a first phase of IMRT up to 54–60 Gy followed by a second phase delivered with a proton therapy boost up to 70–74 Gy (RBE). The total dose for patients treated with IMRT-only was 69.96 Gy. Induction chemotherapy was administrated to 59 and 88% and concurrent chemoradiotherapy to 88 and 100% of the MB and IMRT-only patients, respectively. The worst toxicity occurring during the entire course of treatment (acute toxicity) and early-late toxicity were registered according to the Common Terminology Criteria Adverse Events V4.03.

Results: The two cohorts were comparable. Patients treated with MB received a significantly higher median total dose to target volumes (p = .02). Acute grade 3 mucositis was found in 11 and 76% (p = .0002) of patients treated with MB and IMRT-only approach, respectively, while grade 2 xerostomia was found in 7 and 35% (p = .02) of patients treated with MB and IMRT-only, respectively. There was no statistical difference in late toxicity. Local progression-free survival (PFS) and progression-free survival curves were similar between the two cohorts of patients (p = .17 and p = .40, respectively). Local control rate was 96% and 81% for patients treated with MB approach and IMRT-only, respectively.

Conclusions: Sequential MB approach for LANPC patients provides a significantly lower acute toxicity profile compared to full course of IMRT. There were no differences in early-late morbidities and disease-related outcomes (censored at two-years) but a longer follow-up is required to achieve conclusive results.

Introduction

Radiotherapy (RT) represents the cornerstone of treatment for nasopharyngeal cancers (NPCs). Over recent decades, the photon-based radiation technique has improved significantly and the association with concurrent platinum-based chemotherapy was established as the standard of care [1–3]. These advances have led to improved tumor control and overall survival in patients with NPC [1–4]. Nevertheless, local control (LC) for tumors extending through the base of the skull (cT3-T4) remains a challenge due to the proximity of nervous tissues (spinal cord, brainstem, optic pathway and brain) that often hinders adequate dose coverage of target volumes, even using IMRT [5,6].

Recently, proton therapy has been advocated as the newest irradiation technique that could potentially reduce toxicity and/or improve clinical outcomes for tumors located near critical structures [7]. Compared to IMRT, proton therapy achieved significantly better local tumor control in patients with paranasal and sinonasal cancers [7–14]. Preliminary data have also been published for locally advanced NPC (LANPC) patients, and the toxicity profile seems to be lower than that of patients treated with IMRT [15,16].

Proton therapy can be delivered either as an exclusive treatment or associated with external beam photon therapy in accordance with the so-called ‘mixed-beam’ (MB) techniques, which reserve protons only for the boost phase. Different studies are currently ongoing (NCT00592501, NCT00797290, NCT03183271) investigating the MB approach in head and neck tumors but conclusive results are not yet available [17–19].

We aimed to evaluate the acute toxicity profile of patients with LANPC treated with a sequential MB approach at different Italian centers in collaboration with the Italian National Centre for Oncological Hadrontherapy (CNAO), Italy, where a proton beam is available for patient treatment [20]. Moreover, preliminary results on early-late toxicity and disease-related outcomes were also presented. Results were compared to those observed in an historic cohort of patients with similar tumor characteristics treated with IMRT-only.

Material and methods

From June 2012 to November 2017, 27 consecutive patients diagnosed with LANPC were treated with a photon-proton MB approach. Photon treatments (IMPRT-phase) were delivered in different Italian centers while the proton therapy was delivered at the CNAO, in accordance with the phase-II clinical trial for proton boost treatment of locally advanced head and neck tumors approved by the CNAO Ethical Review Board (trial no.: CNAO 06/2011, version: 1.0; 31.08.2011, ClinicalTrials.gov ID: NCT03183271) [19]. All enrolled patients gave their written informed consent for both the IMRT and proton boost treatment and the use of their anonymized data for research purposes.

For the present study, we compared patients treated with the MB approach to an historic cohort of patients, with LANPC treated with IMRT-only at European Institute of Oncology IRCCS (IEO) between November 2006 and February 2015. The retrospective analysis of IMRT-only approach was part of a research focused on image-guided RT (IGRT) for head and neck cancer notified to the Ethical Committee at the IEO (notification no. 94/11). All the patients included in the control group gave their consent for use of their anonymized data for research and educational purposes.

Inclusion criteria for both cohorts were: histological diagnosis of keratinizing/non-keratinizing/basaloid-squamous-cell primary NPC, stage cT3–T4 (cN0–N3, cM0), availability of clinical data during treatment and follow-up including acute toxicity, availability of dosimetric data. Histologic characteristics were defined according to the WHO classification. No patients had undergone surgery before their radiation treatment. Clinical tumor staging was defined according to the TNM staging classification (7th edition) and clinical staging following the American Joint Committee of Cancer and International Union Against Cancer (AJCC/UICC, 7th ed.) guidelines.

Contouring guidelines and dose constraints

For all patients, a simulation computed tomography (CT) with contrast medium injection was performed. Head and shoulder thermoplastic masks were used for patient immobilization. For patients treated with MB, an additional simulation CT and MR were performed at the CNAO about one week before the beginning of proton-boost phase. Contouring of tumor volumes and organs at risk followed available guidelines for head and neck tumors [21,22]. For patients treated within the MB protocol, target volume contours, prescription doses, and constraint doses for organs at risk were discussed between the CNAO and the patient’s reference center and defined at the beginning of the course of treatment. Dose constraints applied to normal tissues followed international recommendation and guidelines [22] (dose constraints used at the CNAO and literature references are reported in Supplementary materials S1).

Dose prescriptions

Dose prescriptions for all dose levels were similar between the two groups (MB and IMRT-only). For patients treated with an MB approach, the first IMRT-phase was administered up to 54 Gy (2 Gy/fraction) encompassing both elective lymph nodes and gross tumor volume (low-risk volume CTV1). The final phase (up to 70–74 Gy considering proton RBE of 1.1) has been always administered by proton therapy with pencil-beam active scanning (high-dose volume CTV3). This volume encompassed the macroscopic disease (both primary tumor and lymph nodes) assessed at diagnosis. The choice to perform the boost up to 70 or 74 Gy depended on the possibility to irradiate the target volume without exceed constraints of the surrounding healthy tissues. An intermediate-high-risk volume (encompassing the tumor route of spread and high-risk lymph nodes – CTV2) was administered by photons (using a simultaneous integrated boost) or with protons (using a sequential proton therapy boost) according to whether the tumor was not or was located near to nervous structures, respectively.

The target coverage was included in the optimization problems by means of near-minimum dose objectives (D98%), while hotspot was avoided through near-maximum dose constraints (D2%). Moreover, before the beginning of the RT course, the photon plan of the reference center was sent to the CNAO for final approval.

For the historical cohort of patients treated with the IMRT-only approach, three dose levels, were prescribed: CTV3 received 69.96–70 Gy (2.12–2 Gy/fraction), CTV2 received 59.4 Gy (1.8 Gy/fraction) and CTV1 received 56.1 Gy (1.7 Gy/fraction). Criteria to define the extension of different CTVs were similar to those applied for patients treated with an MB approach.

Follow-up evaluation

Follow-up was performed every 3 months for the first 3 years, every 4–6 months for the subsequent 3 years and once a year after 5 years from the end of treatment for both patients treated with an MB approach and those treated with IMRT-only. Response to treatment was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. LC was defined as the achievement of clinical and radiological complete response to treatment without locoregional recurrences at any time of the follow-up. Progression-free survival (PFS) and local progression-free survival (LPFS) were also assessed.

Toxicity data

Acute toxicity was considered as the worst grade of radiation-related side effects according to Common Terminology Criteria Adverse Events (CTCAE V 4.03) occurred during the RT course. Due to the shorter follow-up of patients treated with an MB approach, late toxicity was censored at two-year follow-up. Data on the toxicity profile were prospectively collected for patients treated with the MB approach. For the historical cohort of patients treated with the IMRT-only approach, a retrospective data collection was performed.

Different OARs were contoured (according to Brouwer et al. [21]) to quantify dosimetric differences between the two cohorts of patients.

Statistical methods

Patient and tumor characteristics are presented with absolute frequencies and percentages when classified as categorical variables and with median values and interquartile range for continuous variables. Differences in frequencies of acute and late toxicities between the two cohorts of patients were evaluated by the Chi-squared test, the Fisher exact test when data was sparse, or the Mantel–Haenszel test to investigate a trend. Differences in continuous variables, such as doses, between the two cohorts were assessed through Wilcoxon’s rank tests.

PFS and LPFS curves were estimated by the Kaplan–Meier method, and differences between the two cohorts were assessed by the log-rank test. All statistical tests were two-sided, and results with p<.05 were considered statistically significant. Statistical analyses were performed using the SAS statistical software (Cary, NC, USA, version 9.02 for Windows).

Results

Patients and treatment

For the MB group, 27 patients were analyzed. For the IMRT phase, 20 patients were treated at the IEO while seven patients were treated at different Italian cancer centers (University of Turin, University of Eastern Piedmont Orientale, ICS Maugeri Clinical Scientific Institute). The proton boost phase was performed at the CNAO for all patients. The MB cohort was compared with an historical group of 17 consecutive patients treated with IMRT-only at the IEO. Patient, tumor and treatment characteristics are summarized in Table 1.

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.

The median total dose was 70 Gy (range 64–74 Gy) for the MB group and 70 Gy (range 68–70 Gy) for IMRT-only group, respectively. For the MB group, the median duration of IMRT and proton therapy courses was 42 days (mean 43 days, range 36–58 days) and nine days (mean 10 days, range 4–17 days), respectively. The median interval between the end of IMRT and the beginning of proton therapy (weekend excluded) was two days (mean two days, range 0–13 days). Six patients had an interval IMRT-proton boost >5 days: one patient (13 days) due to toxicity occurring during the IMRT phase (weight loss >10%), five patients due to logistic reasons or patients’ personal issues. The median total treatment time (IMRT and proton therapy) was 58 days (mean 50 days, range 50–75 days). For the IMRT-only group, median treatment time was 50 days (mean 51 days, range 46–61 days) (dose prescriptions of patients treated with an MB approach are reported in Supplementary materials S2).

For the historical cohort of patients treated with IMRT-only, three dose levels were prescribed. All patients but one (who received a sequential boost) were treated with a simultaneous integrated boost technique.

Toxicity data

Acute toxicity is summarized in Table 2. For the MB group, no patient developed grade 3 skin toxicity while 11% of patients developed grade 3 acute mucositis. Four patients (15%) suffered from grade 3 dysphagia requiring enteral nutrition. Most patients (81.5%) had a weight loss <10% compared to their baseline value. In the IMRT-only group, most patients (76%) suffered from grade 3 mucositis. Four patients developed grade 3 dysphagia, and three of them required enteral nutrition (18%).

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.

Late toxicity profile (censored at two-years) was available for 26 and 16 patients treated with MB and IMRT-only, respectively (Table 3). No patients experienced severe (grades 3 and 4) toxicity.

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.

Clinical outcome

In the MB group, one patient died 5 months after the end of treatment from non-tumor related causes without a clinical and/or radiologic evaluation of the tumor response. Therefore, 26 patients were available for clinical outcome analysis after a median follow-up of 25 months (range 7–69 months). At the last follow-up, 22 patients were alive and disease-free. All patients but one achieved a complete tumor response and no patient developed local and/or regional recurrences. Two-year PFS and LPFS were 76 and 94%, respectively.

In the IMRT-only group, one patient died one week after the end of IMRT as a result of treatment-related toxicity. Therefore, clinical outcome was assessed in 16 patients. After a median follow-up of 51 months (range 6–122 months), LC was obtained in 13 (81.5%) patients. One patient did not achieve a complete response to treatment on the primary NPC. Complete response of neck lymph node was achieved by all but one patient who was treated with surgical lymph node dissection. Three patients experienced tumor local progression after 19, 51 and 82 months, respectively. At the time of last follow-up, 15 (88%) patients were alive: 11 patients without disease and 4 patients with distant metastasis. Two-year PFS and LPFS were 69 and 89%, respectively.

Comparison between MB approach versus IMRT-only

The two cohorts of patients were comparable (Table 1). Patients treated with MB received a significantly higher median total dose to target volume compared with patients treated with IMRT-only (Wilcoxon’s rank test p = .02).

Comparison of acute toxicities between the two groups of patients is reported in Table 2. Absorbed dose to acute toxicity-related structures are summarized in Table 4. The cricopharyngeal inlet, oral cavity and supraglottic larynx absorbed a significant lower dose (D2%, mean dose, maximum dose, respectively) in patients treated with a MB approach compared to those treated with IMRT-only. The clinical impact was a trend toward a lower toxicity profile in terms of grade 0 weight loss (29 vs. 11% in MB and IMRT-only, respectively), although the requirement of enteral nutrition was found to be quite similar (15 vs. 18% in MB and IMRT-only, respectively) between the two analyzed groups.

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.

No statistically significant differences were found between the two groups for late toxicity (Table 3).

Results showed non-statistically significant differences of LPFS and PFS curves between the two cohorts of patients (log-rank p = .17 and p = .40, respectively). LC rate was 96 and 81% for patients treated with MB approach and IMRT-only, respectively.

Discussion

Acute radiation-related toxicity in patients with NPC treated with IMRT-only has been extensively described in the literature. Grade 3 mucositis was registered in 26 and 27% of patients in large series of NPC patients [23,24]. Dosimetric property of proton therapy translates into a more favorable toxicity profile. McDonald et al., in a retrospective analysis comparing 14 patients with NPC treated with full protons and 26 with IMRT (comprehensively or matched to protons), found that both the oral cavity and the esophagus absorbed a lower dose in patients treated with protons, leading to a lower G-tube dependency and morphine requirements [16]. In a report by Chan et al. on a series of 23 patients with T4-NPC treated with full proton therapy [15], feeding tube positioning was required in 48% of patients. Lewis et al. reported data of nine patients (33% T3–T4 NPC) treated with intensity-modulated proton therapy: one patient had a grade 3 mucositis, and no patients had clinically evident inflammation of the anterior oral cavity [25]. Subsequently, the same institution compared 10 patients treated with intensity-modulated proton therapy with 20 patients treated with IMRT-only [26]. In agreement with their previous dosimetric analysis, the authors found that patients treated with IMRT received a higher dose to the oral cavity with a higher need for feeding tube insertion as compared to patients treated with protons. Therefore, the toxicity profile of the present cohort is in line with the previous reports of patients treated only with protons (Table 5). Moreover, the incidence of acute mucositis was found to be significantly lower as compared to an historic cohort of patients treated with IMRT-only. The corresponding dosimetric analysis showed a lower absorbed dose to the oral cavity mucosa in patients treated with an MB approach compared to those treated with a full course of IMRT. Despite this, the difference of oral cavity absorbed dose between the two groups analyzed in the present series was too small to justify a relevant clinical impact (median dose 46 vs. 49 Gy for MB and IMRT-only patients, respectively). The better acute toxicity profile of the present cohort could, therefore, be justified by two factors: (1) we evaluated the dosimetric profile of the whole oral cavity (termed the extended oral cavity) and protons have been demonstrated to reduce the absorbed dose mainly at the anterior part of oral cavity [25] and (2) the favorable dosimetric profile on the oral cavity when the proton beam was administered as a boost probably permitted the patient to avoid the highest grade of mucositis which generally arises just during the last two weeks of IMRT-only treatments. We found significantly lower doses received both by the cricopharyngeal inlet (which was demonstrated to be associated with acute dysphagia [27]) and supraglottic larynx. The clinical impact was a trend toward a lower toxicity profile in terms of grade 0 weight loss, although the requirement of enteral nutrition was found to be quite similar between the two analyzed groups. Results of our dosimetric analysis showed that the volume of parotid glands receiving 30 Gy (V30) was higher for patients treated with MB compared to those treated with IMRT-only. This finding might be justified by two main factors: (1) the higher doses prescribed to the target volume in patients treated with MB and (2) the fact that proton therapy treatment plans were not optimized to spare parotid glands. Nevertheless, despite the higher absorbed dose, the two-year xerostomia rate resulted to be not statistically different between the two groups. Moreover, the absolute rate of severe xerostomia remained very low since no patients treated with an MB approach experienced a grade 3 xerostomia at 2-year follow up. Lewis et al. described similar results in a cohort of patients treated with a full course of proton therapy for NPC [25]. No severe chronic xerostomia were also observed for patients treated with IMRT-only, in line with literature data [24]. Moreover, results of the present analysis also showed a slight significant difference in acute xerostomia with patients treated with IMRT-only experiencing a worse toxicity. The clinical impact of this finding needs further investigation.

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.

Results of early-late toxicity profile (censored at two-years) showed no statistically significant differences between the two groups, although soft tissue fibrosis resulted to be slightly lower in patients treated with an MB approach. These preliminary data need to be confirmed with longer ongoing patient follow up.

Different studies demonstrated that treatment outcome was significantly affected by the volume of under-dosed areas [5,6,28]. Thanks to its physical properties, proton therapy can optimize the dose coverage of LANPC [29,30]. The Massachusetts General Hospital obtained a 100% LC rate after a 28-month follow-up with a two-year disease-free survival of 90% [15]. Nevertheless, final results on clinical outcome of two ongoing studies are still pending [17,18]. Preliminary oncologic results of the present cohort are also very promising since all but one patient treated with an MB approach obtained a complete tumor response. The retrospective dosimetric analysis of the one patient who did not achieve a tumor response revealed that the dose to the 95% of tumor volume (D₉₅) was only 63 Gy (RBE) corresponding to the 85% of prescribed total dose (74 Gy RBE). Finally, the LC rate was, therefore, higher for patients treated with MB approach compared to IMRT-only (96 and 81%, respectively). Although not statistically significant, a trend in favor of MB approach versus IMRT-only was also observed for the two-year LPFS (94 vs. 89%) and PFS (76 vs. 69%). Longer follow-up on a larger cohort of patients is needed to confirm these preliminary findings.

Proton therapy can be delivered as exclusive or with a mixed beam approach as described in the present cohort. On a technical point of view, a relevant advantage of the MB approach compared to a full course of proton therapy is that limiting the proton phase to the treatment of macroscopic disease (boost phase), the treated volume is reduced to the upper part of the neck region, consequently minimizing uncertainties related to the shoulder and neck position and also to tissue inhomogeneity due to the tumor shrinkage which occurs during the course of radiation treatment. Indeed, from a technical perspective, the finite range of protons, besides increasing conformity and the capability to spare unnecessary dose to healthy tissues, the risk arises of undesired plan degradation even for minimal setup errors. This potential lack of robustness makes some delivery angles rather challenging with respect to ballistic precision. In clinical practice, large nodal volumes are difficult to treat with protons because of possible variation in both shoulder position and neck angle. Proton therapy can be safely delivered either with an accurate IGRT and extra attention in the use of immobilization devices or, more practically, with posterior angled beams passing through the treatment couch modeled in the planning system [31]. However, despite immobilization, some residual setup uncertainty still remains and great care should be taken when delivering the beam through regions of tissue heterogeneity [32]. Of note, the use of a rotating gantry could overcome some of this technical issues. The MB approach could allow the impact of cost and logistic issues to be lessened by shortening the course of proton therapy to the last part of the treatment (10–14 Gy (RBE) boost). The present study shows that the MB approach is feasible and fosters the collaboration with different RT centers with particle therapy facilities.

We are aware of certain limitations of the present analysis, mainly related to the low number of patients, and the retrospective nature of data related to patients treated with IMRT-only. In particular, the retrospective collection of toxicity data for the historical cohort of patients treated with IMRT could underestimate the acute and late effects of the radiation treatment. Moreover, the variation in doses (54 or 60 Gy) to the elective volumes leads to variation in both acute and late side effects limiting the conclusion of the study.

Nevertheless, to our knowledge, this is the first study providing a comprehensive report on feasibility and radiation-acute toxicity profile of patients treated with the MB approach. We believe that this analysis provides useful information for the current ongoing and future trials on proton therapy in head and neck tumors. Preliminary results on long-term toxicity and clinical outcome are encouraging, and results of the still ongoing data collection will be presented in future publications.

Acknowledgments

The authors sincerely thank Pierre Blanchard, Head and Neck and Genitourinary Oncology Department of Radiation Oncology, Gustave Roussy, Villejuif, France, for his comments and suggestions.

Disclosure statement

No potential conflict of interest was reported by the author(s).