Posted at the Institutional Resources for Unique Collection and Academic Archives at Tokyo Dental College,
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Title
Prognostic factors of adenoid cystic carcinoma of
the head and neck in carbon-ion radiotherapy: The
impact of histological subtypes.
Author(s)
Alternative
Ikawa, H; Koto, M; Takagi, R; Ebner, DK; Hasegawa,
A; Naganawa, K; Takenouchi, T; Nagao, T; Nomura, T;
Shibahara, T; Tsuji, H; Kamada, T
Journal
Radiotherapy and oncology, 123(3): 387-393
URL
http://hdl.handle.net/10130/4982
Right
This is an open access article distributed under
the terms of the Creative Commons CC BY license,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
work is properly cited.
Carbon ion therapy
Prognostic factors of adenoid cystic carcinoma of the head and neck in
carbon-ion radiotherapy: The impact of histological subtypes
Hiroaki Ikawa
a,b,⇑, Masashi Koto
a, Ryo Takagi
a, Daniel K. Ebner
a,c, Azusa Hasegawa
a,
Kensuke Naganawa
a, Toshinao Takenouchi
a, Toshitaka Nagao
d, Takeshi Nomura
b, Takahiko Shibahara
e,
Hiroshi Tsuji
a, Tadashi Kamada
aaHospital of the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Sciences and Technology, Chiba;bDepartment of Oral Medicine, Oral and
Maxillofacial Surgery, Tokyo Dental College, Japan;c
Brown University Alpert Medical School, Providence, USA;d
Department of Anatomic Pathology, Tokyo Medical University; and
e
Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Japan
a r t i c l e i n f o
Article history: Received 2 March 2017
Received in revised form 20 April 2017 Accepted 25 April 2017
Available online 18 May 2017 Keywords:
Carbon-ion radiotherapy Adenoid cystic carcinoma Head and neck cancer Histological subtypes Solid pattern
a b s t r a c t
Purpose: The aim of this study was to evaluate the effect of histological subtypes of head and neck ade-noid cystic carcinoma (ACC) on the results of carbon-ion radiotherapy (CIRT).
Material and methods: Of the 113 patients with ACC who were treated with CIRT between December 2006 and July 2013, 100 patients with identified histological subtypes were enrolled in this study. CIRT at a total dose of 57.6 or 64.0 Gy (RBE) was administered in 16 fractions. Histological grading was defined as the presence or absence of a solid growth pattern.
Results: Median follow-up was 60 months. 5-Year local control (LC), overall survival (OS) and distant metastasis free survival (DMFS) of all patients were 68.6%, 74.8% and 65.7%, respectively. On multivariate analysis, the prescribed dose (p = 0.001) and gross tumor volume (p = 0.002) were significant indepen-dent risk factors for LC. No significant difference for local control of solid/non-solid growth patterns was found (p = 0.093). Solid growth pattern was an independent risk factor for both OS (p = 0.033) and DMFS (p = 0.024).
Conclusions: CIRT appears able to locally control solid growth pattern ACC in the head and neck. Improved intervention is needed to extend DMFS and OS.
Ó 2017 The Authors. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 123 (2017) 387–393 This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/). Adenoid cystic carcinoma (ACC) of the head and neck (HNACC)
is one of the most prevalent salivary gland malignancies[1]. Histo-logically, ACC can be categorized into three growth patterns: crib-riform, tubular and solid. Tumors composed of solid patterns show a more aggressive behavior than cribriform and tubular patterns, and are the strongest risk factor for loco-regional recurrence and distant metastasis after surgery, the current standard treatment
[2–10].
Photon therapy is indicated in cases of inoperable ACC, but local control (LC) remains insufficient, with rates reported between 26.5 and 56%[11,12]. Fast neutron therapy, perhaps owing to a higher liner energy transfer (LET), improved local control of ACC com-pared with photon radiotherapy [13]. Douglas and colleagues reported a series of 151 patients with HNACC treated with fast neutron therapy, finding 5-year locoregional control and overall
survival (OS) of 57% and 72%, respectively. However, fast neutrons have an inferior dose distribution when compared with particle irradiation, potentially leading to over irradiation of healthy tissue or insufficient dose delivered. Carbon-ions have a similar LET to fast neutrons, resulting in a larger relative biological effectiveness (RBE) compared to photons or protons[14]. Moreover, the physical characteristics of carbon ions, owing to the ability to generate a spread-out Bragg peak (SOBP), allow for an improved dose distri-bution compared to fast neutron. As such, carbon-ion radiotherapy (CIRT) may be capable of definitive treatment for locally advanced HNACC. Jensen et al.[15]reported a series of 309 HNACC patients treated with intensity modulated radiotherapy and CIRT-boost, yielding a 5-year LC and OS of 58.5% and 74.6%, respectively. Mizoe and colleagues[16]reported on 69 patients with locally advanced HNACC treated with CIRT alone. In their study, 5-year LC and OS were 73% and 68%, respectively.
However, the impact of the histological subtype of ACC in definitive radiotherapy, including CIRT, is unclear. The aim of this
http://dx.doi.org/10.1016/j.radonc.2017.04.026
0167-8140/Ó 2017 The Authors. Published by Elsevier Ireland Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⇑ Corresponding author at: Hospital of the National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Sciences and Technol-ogy, 4-9-1 Anagawa, Inage-ku, Chiba-shi 263-8555, Japan.
E-mail address:[email protected](H. Ikawa).
Contents lists available atScienceDirect
Radiotherapy and Oncology
study is to evaluate the effect of histological subtypes, specifically solid vs non-solid growth pattern, on CIRT for HNACC.
Materials and methods Patient and tumor characteristics
Eligibility criteria of patients receiving definitive CIRT for head and neck cancer have been described previously [16]. From December 2006 to July 2013, 113 patients with HNACC received CIRT in our institute. Of these, 100 patients with identified histo-logical subtypes according to the World Health Organization clas-sification were enrolled in this study. The characteristics of the patients and tumors are summarized inTable 1.
This study was approved by the local Institutional Review Board (15-001) and was carried out in accordance with the Declaration of Helsinki. This trial is registered with UMIN-CTR (http://www.umin. ac.jp/ctr/index-j.htm), identification number 000024598.
Histological subtypes
Tumor histology was separated into solid and non-solid histo-logical subtypes [10]. In this study, 17 patients were diagnosed with solid histology, and 83 patients without.
Carbon-ion radiotherapy
Patients were positioned in customized cradles and immobi-lized with a low-temperature thermoplastic shell. A set of 2.5-mm-thick computed tomography (CT) images was taken for treat-ment planning. Magnetic resonance imaging (MRI) was routinely performed for the identification of the tumor, after planning CT
image fusion. Determination of the gross tumor volume (GTV) was based on contrast-enhanced MRI. The clinical target volume (CTV) had minimum margins of 5.0 mm added around the GTV. CTV included neural tracts to the skull base and peripheral site so as to account for potential perineural spread. A margin of 2– 3 mm was added around the CTV to create the planning target vol-ume (PTV). The CTV margins of areas proximal to critical organs (e.g. eye wall, optic nerve, optic chiasm and brain stem) were reduced as necessary. Three-dimensional treatment planning was performed using HIPLAN software (National Institute of Radiologi-cal Sciences, Chiba, Japan)[17].
CIRT dose was expressed in photon-equivalent doses, defined as the physical dose multiplied by the RBE of the carbon ions. The bio-logical flatness of the SOBP was normalized by the survival fraction of the human salivary gland tumor cells at the distal region of the SOBP, where the RBE of carbon ions is estimated to be 3.0[14].
CIRT was administered on a fractionated schedule comprising 57.6 or 64.0 Gy (RBE) in 16 fractions in 4 weeks. In this study, 33 patients were treated with 57.6 Gy (RBE) and 67 with 64.0 Gy (RBE).
Evaluation
Followup consisted of CT or MRI every 3 months for the first 2 years post-treatment years, and thereafter every 3–6 months depending on patient condition. Local control was defined as no evidence of tumor regrowth in the PTV.
Acute reactions in normal tissues were classified according to the Radiation Therapy and Oncology Group (RTOG) scoring system. Late reactions were classified according to the National Cancer Institute Common Terminology of Criteria for Adverse Effect (CTCAE) version 4.0.
Statistical analyses
The cumulative incidences of LC, OS and distant metastasis free survival (DMFS) were evaluated using the Kaplan–Meier method. Age, gender, surgical history, prescribed dose, T classification, N classification, histological subtypes, tumor site, and GTV were eval-uated as potential risk factors for LC, OS, and DMFS. Subgroups were compared using the univariate log-rank test. All statistically-significant (p < 0.05) factors on univariate analysis were included in a multivariate analysis using the Cox proportional hazards model. P-values less than 0.05 were considered statisti-cally significant, and all statistical tests were 2-sided. These statis-tical tests were performed with the assistance of SPSS ver. 19 (IBM SPSS, IBM Corporation, Somers, NY).
Results
Median follow-up was 60 months (range, 6–116 months). No patient was lost to follow-up. Of the 32 patients with local recur-rence, 29 developed recurrence within the PTV and 3 on the margin of the PTV. One patient developed cervical lymph node metastasis. Of the 33 patients with loco-regional recurrence, 20 patients received salvage treatments: 10 received surgery, 6 repeat CIRT, 3 Cyber Knife, and 1 boron neutron capture therapy. 30 patients developed distant metastasis. The most common site for distant metastasis was lung (70%), followed by bone (17%), and liver (6%). 20 patients died of their disease, and 9 of unrelated causes. The cumulative 5-year LC, OS, and DMFS of all patients were 68.6% (95% confidence intervals [CI], 71.6–90.1), 74.8% (95% CI, 82.4–97.8) and 65.7% (95% CI, 70.3–91.3), respectively (Fig. 1).
Table 1
Patients and tumor characteristics. Age (y) Median 57 (Range) (19–79) Gender Male 35 Female 65 History of operation Yes 15 No 85 T classification T1-3 27 T4 61 No specific T classification 12 N classification N0 94 N1 5 N2 1 N3 0 M classification M0 100 M1 0
Solid components in ACC
Presence 17
Absence 83
Tumor site
Nasal cavity and paranasal sinus 50
Oral cavity, pharynx and salivary grand 42
Others 8
GTV, (ml)
Median (Range) 38.6
(0.6–235.3) Abbreviations: ACC, Adenoid cystic carcinoma; GTV, Gross tumor volume.
Risk factors for local recurrence
On univariate analysis, a prescribed dose of 57.6 Gy (RBE), GTV (>38 ml) and solid growth pattern were found to be risk factors for LC. The 5-year LC of patients treated with a total dose of 57.6 Gy (RBE) (33 patients) or 64.0 Gy (RBE) (67 patients) were 40.5% and 82.9%, respectively. The 5-year LC of patients with non-solid (83 patients) and solid histologies (17 patients) were 74.1% and 35.0%, respectively. For patients receiving 57.6 Gy (RBE), the 5-year LC of non-solid (26 patients) and solid histologies (7 patients) were 53.4% and 0% (p = 0.001), respectively (Fig. 2). For patients receiving 64 Gy (RBE), 5-year LC of non-solid (57 patients) and solid histologies (10 patients) were 83.0% and 83.3% (p = 0.210), respectively (Fig. 3). On multivariate analysis, the prescribed dose of 57.6 Gy (RBE) (hazard ratio [HR] = 3.771, 95% CI = 1.716–8.289, p = 0.001) and GTV (HR = 3.363, 95%CI = 1.568–7.214, p = 0.002) were demonstrated to be significant independent risk factors for
LC (Table 2). Solid growth pattern histology (HR = 2.085, 95%
CI = 0.884–4.918, p = 0.093) did not demonstrate a significant dif-ference on multivariate analysis.
Risk factors for overall survival and distant metastasis free survival Regarding OS, T-classification (p = 0.039), histological subtype (p = 0.00007) and GTV (p = 0.0002) were risk factors in univariate analysis. The 5-year OS of the patient with non-solid and solid his-tologies were 84.9% and 41.2%, respectively. Multivariate analysis showed that solid growth pattern (HR = 2.426, 95% CI = 1.075– 5.472, p = 0.033) and GTV (HR = 3.629, 95% CI = 1.374–9.579,
p = 0.009) were demonstrated to be significant independent risk factors for OS (Table 2).
Regarding DMFS, N classification (p = 0.038), histological sub-type (p = 0.001) and GTV (p = 0.002) were found to be risk factors in univariate analysis. The 5-year DMFS of patients with non-solid and non-solid histologies were 72.8% and 29.7%, respectively. On multivariate analysis, N classification greater than N0 (HR = 2.994, 95% CI = 1.004–8.931, p = 0.049), solid growth pattern (HR = 2.708, 95% CI = 1.139–6.441, p = 0.024) and GTV (HR = 2.370, 95% CI = 1.011–5.557, p = 0.047) were demonstrated as significant independent risk factors for DMFS (Table 2).
Reactions of normal tissues
Regarding acute reactions, grade 3 mucosal reactions were observed in 37 patients, and grade 3 skin reaction in 1 patient. No grade 4+ mucosal or skin reactions were observed. Regarding late reactions, grade 3 was observed in 27 patients. These included grade 3 cataract in 10 patients, grade 3 osteoradionecrosis in 7 patients, grade 3 central nervous system necrosis in 2 patients, grade 3 mucosal reactions in 2 patients, grade 3 glaucoma in 2 patients, and grade 3 optic nerve disorder in 2 patients. Three patients were diagnosed with grade 4 radiation-induced brain injury (RIBI) after CIRT. These patients developed localized brain necrosis with severe clinical symptoms and received surgical treat-ment. Their symptoms resolved following surgery, and they are alive today without clinical symptoms related to the brain injury. Grade 4 vision loss occurred in 5 patients, due to tumor proximity to their optic nerve.
Discussion
The literature strongly suggests that ACC with a solid histolog-ical pattern is a risk factor for LC following surgery[6,7]. However, there remains little literature describing the influence of solid his-tology on RT, including with CIRT. In this study, a comparatively large series of ACC with identified histological subtypes treated with CIRT was retrospectively evaluated for prognostic factors. On multivariate analysis, the solid pattern was found to not be a risk factor for local failure, with control dependent largely on dose and size of tumor treated. As such, CIRT appears capable of treating operable and inoperable locally advanced ACC without regard to the underlying histology, achieving comparatively good local control.
This advancement is beneficial not only in terms of reducing potential post-surgical morbidity, but also because the exact clas-sification of ACC histology remains under discussion. ACC often shows a mixed pattern of each component and is usually classified according to the predominant pattern[3]. Two different histologi-cal grading systems are used, allowing discrimination of poor prog-nosis patients depending upon the amount of solid component present in the tumor. In the Perzin/Szanto system[2,3], ACC is con-sidered high grade if more than 30% of the tumor consists of a solid component. In the alternative Spiro system[1], more than 50% of solid parts are considered high grade. The debate on the role and actual importance of histological grading of ACC has continued for decades. Some authors advocate that ACC should be predomi-nantly solid to influence treatment decisions, whereas others stip-ulate that the presence of a solid pattern, regardless of amount
delineates a high-grade tumor [18–21]. As such, van Weert S et al.[10]suggested to delineate based solely on whether a solid component is present, and thus report tumor histology as solid-positive or -negative. Because the inter-observer variability of solid tumor component presence is very low, its reproducibility is high and its predictive value is comparable to the traditional grading systems. In our study, the amount of specimen obtained by biopsy was insufficient to use the traditional grading systems, and so con-sequently the Solid ± system was applied. One limitation of the current study owes to this biopsy-dependent method of histologi-cal diagnosis: as biopsy samples reveal a limited portion of tumor, the presence of solid pattern may be underestimated.
Although some reports have examined the importance of histo-logical subtype as a prognostic factor for HNACC after definitive RT
[12,22–24], the ultimate prognostic significance of the histological subtype of HNACC remains undecided.
Iseli et al.[12]reported 159 patients with HNACC who were treated with surgery alone (54 patients), surgery + RT (95 patients), or RT alone (10 patients). 124 patients had tubular, cribriform or mixed pattern, and 35 solid. They found that solid pattern did not have a significantly different LC in surgical cases, and that superior local control was offered by combination radiation + sur-gery versus sursur-gery or radiation alone. However, no analysis was made with regard to histological subtype in the RT-only group. Takagi et al’s[22]report on the outcomes of 80 cases of ACC trea-ted with either proton radiotherapy or CIRT mirrors this, in that pathological subtypes are not shown to be significantly associated with OS and LC, but analysis was made with regard to neither his-tological subtype nor specific radiation type used.
Fig. 2. Local control rate of patients treated with a total dose of 57.6 Gy (RBE) according to the histological subtype. The patients with tumors composed of a solid pattern (solid +) showed a significant higher recurrence rate than those without tumors composed of a solid pattern (solid ) (p = 0.001).
Histological subtypes have been analyzed in fast neutron RT (FNRT). Pötter R and colleagues [23] evaluated a series of 72 patients treated with FNRT for HNACC. 66 of these patients had identified histological subtypes, with cribriform pattern in 25 patients, tubular in 24, and solid in 17 patients. On multivariate analysis, histological subtype (solid pattern) was a significantly adverse predictive factor of recurrence-free survival and OS, respectively. Brackrock and colleagues [24] identified a similar result, with histological subtype linked to overall survival, but hav-ing no significant role in local control.
Our study demonstrated significantly worse LC for solid-subtype on univariate analysis; however, this effect disappeared on multivariate analysis, where prescribed dose differences and size of GTV were found to be significant. In this trial, the use of two doses were the result of the phase I/II trial in which these patients took part, conducted between 1994 and 1997[25], which recommended a dose of 57.6 Gy (RBE) when a wide range of skin or mucosa was present in the target volume. Since that initial trial, advancements in treatment techniques and clinical experience have improved technical sparing of skin and mucosa, and therefore a dose of 64.0 Gy (RBE) is now more commonly employed[26]. As such, the low-dose cohort included here may belay the actual potential of CIRT in treating this disease. Of note, solid-type dis-played a significantly higher recurrence rate than non-solid-type (p < 0.05) in patients treated with a total dose of 57.6 Gy (RBE); no such difference was seen at 64 Gy (RBE). As such, subtype-independent LC enhancement appears viable with increased CIRT dose.
Overall, there is a relative dearth of literature focusing on speci-fic solid vs non-solid histologies for HNACC, with radiotherapy-only patients generally comprising nonsurgical, advanced-disease
patients. The most comprehensive series have been those using FNRT, finding advantage in utilization of high LET in local control of solid-subtype ACC. On CIRT treatment evaluation, this LET-based treatment efficacy enhancement appears present: on multivariate analysis, no difference was found between solid and non-solid histology HNACC treated with CIRT, with poor solid-subtype outcomes seen only in the low-dose cohort. Dose escala-tion to 64.0 Gy (RBE) eliminated this subtype-dependent distinc-tion; technological advancements in scanning-beam and gantry-based treatment delivery may afford even better local control without severe side effect.
With regard to the relationship between clinicopathologic parameters and survival, previous reports have showed that the positive surgical margin and local recurrence after definitive treat-ment are negative prognostic factors for patient survival[6,7]. van Weert S et al.[6]reported that close and positive microscopic mar-gins are strong predictors for poor survival in a series of 105 cases of ACC. Zhang et al.[7]reported on 200 patients treated with sur-gery and/or postoperative RT for head and neck ACC, finding that local recurrence was a significant risk factor for disease-specific survival. These findings suggested that local control after definitive treatment is important for OS. In locally advanced cases, surgical resection may be limited by critical adjacent structures. Therefore, ACC arising from sites close to the skull base have a significantly higher risk of local recurrence. Here, though, T classification appeared to have no impact on LC. As such, the apparent histology-independent treatment afforded by CIRT, and subse-quent local control achieved, may improve OS. Unfortunately, sur-vival differences between subtypes remain, owing to distant failure; enhanced systemic intervention is needed.
Fig. 3. Local control rate of patients treated with a total dose of 64 Gy (RBE) according to the histological subtype. There was no significant difference between patients with tumors with (solid +) and without (solid ) a solid pattern (p = 0.210).
It is well known that distant metastasis is a key adverse prog-nostic factor for OS[9]. In our study, long-term survival of patients with ACC was likely related to the development of distant metas-tasis. Prospective trials of chemotherapy in metastatic ACC are lim-ited, and the optimum regimen is unclear; CIRT combination with adjuvant immuno/chemotherapy may be necessary.
Conclusion
In this study of 100 patients with ACC, CIRT appears a promising treatment option for ACC of the head and neck. Solid type histology has no impact on local control at sufficiently high doses, with lar-ger differences in local control potentially seen if inadequate dose is provided. On the other hand, solid growth pattern remains a sig-nificant factor for development of distant metastasis, and thereby weighs on patient overall survival and progression-free survival. Dose escalation may prove valuable in improving the efficacy of the CIRT beam, while improved methods of diminishing or elimi-nated distant metastasis are needed.
Funding support
No specific funding was disclosed.
Conflict of interest disclosures The authors made no disclosures.
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Factors n Local recurrence Overall survival Distant metastasis
Univariate analysis
Multivariate analysis Univariate analysis
Multivariate analysis Univariate analysis
Multivariate analysis p value HR 95% CI p value p value HR 95% CI p value p value HR 95% CI p value Age 57 54 0.263 0.561 0.784 <57 46 Gender Male 35 0.184 0.102 0.307 Female 65 History of operation Yes 17 0.599 0.381 0.375 No 83 Prescribed dose 57.6 Gy (RBE) 33 0.00017 3.771 1.716–8.289 0.001 0.096 1.475 0.690–3.152 0.316 0.842 64.0 Gy (RBE) 67 T classification T1-3 27 0.105 0.039 1.289 0.530–3.135 0.575 0.279 T4 61 No specific T classification 12 N classification N0 94 0.129 0.266 0.038 2.994 1.004–8.931 0.049 N1-3 6
Solid components in ACC
Presence 17 0.001 2.085 0.884–4.918 0.093 0.00007 2.426 1.075–5.472 0.033 0.001 2.708 1.139–6.441 0.024
Absence 83
Tumor site Nasal cavity and
paranasal sinus
50 0.190 0.974 0.245
Oral cavity, pharynx and salivary grand
42
Others 8
GTV
38 ml 50 0.0005 3.363 1.568–7.214 0.002 0.0002 3.629 1.374–9.579 0.009 0.002 2.370 1.011–5.557 0.047
<38 ml 50
Abbreviations: HR, hazard ratio; CI, confidence interval; ACC, Adenoid cystic carcinoma; GTV, Gross tumor volume.
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