Original Article
Combined Intensity-Modulated Radiotherapy Plus Raster-Scanned Carbon Ion Boost for Advanced Adenoid Cystic Carcinoma of the Head and Neck Results in Superior Locoregional Control and Overall Survival € ss, MSc2; Alexandra D. Jensen, MD, MSc1; Anna V. Nikoghosyan, MD1; Melanie Poulakis, DDS1; Angelika Ho 3 3 1 1 €kel, PhD ; Marc W. Mu €nter, MD ; Daniela Schulz-Ertner, MD ; Peter E. Huber, MD, PhD4; Thomas Haberer, PhD ; Oliver Ja € and Jurgen Debus, MD, PhD1
BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence C 2015 American Cancer Society. remains in field, and further C12 dose escalation should be evaluated. Cancer 2015;121:3001-9. V KEYWORDS: adenoid cystic carcinoma, carbon ions, carbon ion therapy, fractionated stereotactic radiotherapy, intensity-modulated radiotherapy, long-term results, malignant salivary gland tumors, raster scanning.
INTRODUCTION Adenoid cystic carcinomas (ACCs) are rare and comparatively radioresistant head and neck malignancies1-3 characterized by slow but aggressive growth patterns.4 Because of frequent perineural invasion, they often extend to the skull base and beyond. Radical surgery is rarely possible for patients with ACC, and radiotherapy (RT) doses 66 Gray (Gy) are needed to achieve long-term disease control.1,2 A Medical Research Council randomized trial investigated the use of neutron RT in the treatment of malignant salivary gland tumors (MSGTs), exploiting the higher relative biologic effectiveness of neutron RT in the late 1980s. That study demonstrated significantly improved local control rates in the neutron arm, albeit with significant late toxicity.5-7 The introduction of the raster-scanning technique for carbon ions (C12)8 offers the advantage of extremely sharp gradients and very precise dose delivery while avoiding high doses to adjacent critical structures and maintaining coverage of the target volume. Within the prospective pilot project, patients with ACC received a combined regimen of C12 and intensity-modulated RT (IMRT) in cooperation with the GSI Helmholtz Center for Corresponding author: Alexandra D. Jensen, MD, MSc, Department of Radiation Oncology, University of Heidelberg, INF 400, D-69120 Heidelberg, Germany; Fax: (011) 49-6221-56-5353; [email protected] 1 Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany; 2Medical Informatics and Regulatory Affairs, Heidelberg Ion Beam Therapy Center, Heidelberg, Germany; 3Heidelberg Ion Beam Therapy Center, Heidelberg, Germany; 4Molecular Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
Presented in part at the American Society of Clinical Oncology Annual Meeting; June 4-8, 2010; Chicago, Illinois, and at the International Federation of Head and Neck Oncologic Societies Fifth World Congress; July 26-30, 2014; New York, New York. We thank the referring centers for their trust and cooperation in the treatment and follow-up of these patients, without which this work would not have been possible. DOI: 10.1002/cncr.29443, Received: February 17, 2015; Revised: March 15, 2015; Accepted: March 31, 2015, Published online June 4, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
September 1, 2015
3001
Original Article
Heavy Ion Research (Darmstadt, Germany) whenever the beam was clinically available. Initial local control was promising and had moderate toxicity compared with high-precision photon techniques,9-11 which led to the establishment of this regimen as the treatment of choice in Germany. However, patient numbers were small in that study, and the follow-up was short. Here, we present results from all patients who received treatment for inoperable or subtotally resected ACCs within the pilot project from 1997 to 2008. We compared this cohort with patients who received treatment with modern photon RT at our institution throughout the same period. To our knowledge, this is the first report of long-term results of C12 therapy using the raster-scanning method for ACC. MATERIALS AND METHODS Selection of Treatment Technique
C12 therapy was available for medical purposes within 3 treatment periods per year from 1997 to 2008. At any other time, treatment consisted of high-precision photon techniques with either IMRT or fractionated stereotactic RT (FSRT). Immobilization, Target Volume Definition, and Treatment Planning
Immobilization with a custom-made Scotchcast mask (3M Deutschland GmbH, Neuss, Germany) as well as target delineation based on contrast-enhanced computed tomography scans (3-mm slice thickness) and magnetic resonance imaging scans for image correlation were the same in both groups. Two separate clinical target volumes (CTVs) were outlined: CTV1 included the macroscopic tumor and tumor bed, and CTV2 was the extended target volume and included CTV1 plus typical pathways of spread and ipsilateral lymph node levels (II and III). If the primary tumor was located at or crossed the midline, then bilateral lymph nodes were included. Planning target volumes (PTVs) were generated with a 3-mm margin around the CTVs. Note that the PTV margin was reduced at sites where it would extend into critical structures (ie, optic pathways), and no margin was added to organs at risk. Target volumes in both groups were drawn by a team of 3 specialists. C12 treatment plans were generated using the German Cancer Research Center (Heidelberg, Germany) inhouse system TRIP, incorporating biologic plan optimization according to the local effects model12 to account for increased biologic effectiveness and yielding photon Gray equivalents (GyE). Variations in biologic effective3002
ness caused by hypofractionation were not included in this model. Doses had to be converted according to the standard linear-quadratic model to yield the biologically effective dose (BED) in Gy. Photon treatment plans were created using the German Cancer Research Center in-house systems KonRad (optimization) and VIRTUOS (dose calculation, FSRT planning). FSRT was used until 1999, when IMRT became the standard technique for head and neck tumors at our institution. Target localization in all treatment techniques (C12, IMRT, and FSRT) was carried out using a frame-based, external stereotactic coordinate system. Dose Prescription and Organs at Risk
Both C12 doses and photon doses were normalized to the median PTV. Therefore, 50% of the PTV received 100% of the prescription isodose. In addition, it was required to cover the PTV (100%) with at least 90% of the prescription isodose. Normal tissue constraints were adhered to according to Emami et al.13 Doses were reduced beyond these values to as low as reasonably achievable without compromising PTV coverage. The mean dose to at least 1 parotid gland had to be 4 adverse events recorded in 57% of patients in the C12 group and only 27% of patients in the photon group. Most common late effects were hearing impairment (10%), loss of smelling sense (10%), and dysgeusia (12%) in the C12 group. Blood-brain barrier changes corresponding to grade 1 central nervous system (CNS) necrosis occurred in 2% of patients, 2 patients (3%) experienced visual impairment, and 1 patient with ACC of the lacrimal gland lost her vision due to retinal detachment (C12 group). The number of late events recorded was higher in the C12 group. In the photon group, loss of vision because of corneal ulceration (8%) was most frequently reported, and no cases of blood-brain barrier changes (CNS necrosis) were documented (Table 2). The median LC in the C12 group was 73.1 months (59.6% at 5 years) versus 37.6 months (39.9% at 5 years) in the photon group (P 5 .033) (Fig. 1); the median PFS was 59.1 months versus 32.0 months, respectively (P 5 .015) (Fig. 2); and the median OS was 102.1 months and 73.7 months, respectively (P 5 .015) (Fig. 3). Tentative estimates of 10-year LC, PFS, and OS were 42.2%, 27.4%, and 44.2%, respectively, in the C12 group versus 32%, 18%, and 19.6%, respectively, in the photon group. In the C12 group, LC (Fig. 4), PFS, and OS were independent of resection status (LC, P 5 .814; PFS, P 5 .914; OS, P 5 .929). In the photon-only group, LC and PFS were significantly worse for patients with inoperable tumors (LC, P 5 .008; PFS, P 5 .013; OS, 3003
Original Article TABLE 1. Patient Baseline Characteristics: Combined Carbon Ions Plus Intensity-Modulated Radiotherapy Versus Intensity-Modulated or Fractionated Stereotactic Radiotherapy Only No. of Patients (%) or Median [Range] Patient Characteristic Age at treatment, y Follow-up for all patients, mo Overall Still alive Site Base of skull/pterygoid bone Petrous bone/base of skull Paranasal sinus Parotid extending to base of skull Nasopharynx Maxilla Lacrimal gland Nasal cavity Mandible Trachea Base of tongue Tumor classification T2 T3 T4: T4a/T4b or subclassification unknown T4a T4b Lymph node classification: N1 Metastasis classification: M1 Surgery Subtotal resection Biopsy only Relapse strategy RT for relapse RT as part of primary treatment RT CTV1 boost Dose, mL Prescription, GyE BED, Gy
Carbon Ions 1 IMRT, n 5 58
IMRT/FSRT, n 5 37
53 [27-75]
56 [22-79]
74.2 [6.0-167.3] 82.7 [24.1-167.3]
62.9 [1.4-174.4] 66.3 [25.6-155.1]
7 (12)
5 (15) 2 (5) 11 (30) 5 (14) 3 (8) 6 (16) 3 (8)
23 (40) 13 (22) 8 (14) 3 (5) 2 (3) 1 (2) 1 (2)
P
.256
1 (3) 1 (3) 1 5 52 18 34 4 4
(2) (9) (90) (31) (58) (7) (7)
0 (0) 2 (5) 35 (94)
.181
>6 (>16) 4 (11) 3 (8)
40 (69) 18 (31)
19 (51) 18 (49)
.441
18 (31) 40 (69)
13 (35) 24 (65)
.483
170 [13-427] 72 [47.4-72.0] 76.5 [51.15-76.5]
180 [42.3-896] 66 [54.0-70.4] 66 [54.0-70.4]
Abbreviations: BED, biologically effective dose; CTV1, clinical target volume including the macroscopic tumor and tumor bed; FSRT, fractionated stereotactic radiotherapy; Gy, grays; GyE, gray equivalents; IMRT, intensity-modulated radiotherapy; N1, positive lymph node status; RT, radiotherapy.
P 5 .128). When only T4b tumors in the C12 group were analyzed, there was a trend toward improved LC (Fig. 5) and PFS in patients who underwent biopsy only compared with patients who underwent subtotal resection. Patients in the C12 group who were treated for locally recurrent ACC had significantly poorer LC compared with patients who received RT as part of their primary treatment (P 5 .019) (Fig. 6). However, this did not translate into a significant difference in PFS or OS. Locoregional relapse occurred in 29 patients in the C12 group and 23 patients in the photon group. The first site of relapse was within the high-dose area (PTV1; in-field) in 18 patients (62%), at the field edge (21%), out of field (1%), and unknown (4%). Imaging of the relapse site was available for 12 patients with recurrent disease in the photon group (52%); 11 of those patients relapsed in field (48%), and 1 patient 3004
relapsed in regional cervical lymph nodes (4%). For the remaining 11 patients, no imaging studies were available for comparison. Distant disease progression was observed in 22 patients in the C12 group and 16 patients in the photon group. The most common sites of distant metastases were pulmonary (C12 group, 64%; photon group, 44%), bone (C12 group, 27%; photon group, 31%), and brain (C12, 14%; photon group, 13%) metastases. DISCUSSION Given the complex anatomic situation in the head and neck as well as the necessary high doses for tumor control in MSGTs,1-3 achieving durable LC in patients with inoperable or gross residual disease is a challenge. The observed LC rate of almost 60% at 5 years in patients who received C12 treatment was significantly higher than that in the Cancer
September 1, 2015
Superior Overall Survival of C12 in ACC/Jensen et al
TABLE 2. Treatment-Related Toxicity at the Completion of Radiotherapy and Late Toxicity: Combined Carbon Ions Plus Intensity-Modulated Radiotherapy Versus Intensity-Modulated or Fractionated Stereotactic Radiotherapy Only No. of Patients (%) Toxicity
Carbon Ions 1 IMRT, n 5 58
Acute toxicity, CTC grade Mucositis 1 2 3 Unspecified Dysphagia, CTC grade 1 2 3 Unspecified Xerostomia, CTC grade 1 2 Unspecified Dermatitis, CTC grade 1 2 3 Middle ear effusion Tinnitus Otitis Mastoiditis Hearing impairment Epiphora Conjunctivitis Blepharitis Keratitis Visual impairment Double vision Rhinitis sicca Anosmia Lymphedema Trismus Dizziness Nausea Cephalgia Paraesthesia Documentation of acute adverse events 1 Event 2 Events 3 Events 4 Events Late toxicity Hearing impairment Middle ear effusion Epiphora Conjunctivitis sicca Corneal ulcer Xerophthalmia Sinusitis/rhinitis sicca Visual impairment Loss of vision Dysgeusia Anosmia Paraesthesia Cephalgia Blood-brain barrier changes/CNS necrosis I
14 (24) 26 (45) 4 (7)
IMRT/FSRT, n 5 37
3 11 11 3
(8) (30) (30) (8)
P
.423
13 (22) 5 (9) 1 (2) 1 (3) 13 (22) 12 (21) 16 (43) 28 (48) 14 (24) 2 (3) 9 (16) 2 (3) 4 (7) 1 (2) 9 (16) 2 (3) 19 (33)
21 (57) 9 (24) 1 (3) 5 (14)
.181
3 (8) 12 (32) 2 (5) 1 (3)
3 (5) 1 (3) 4 (7) 1 (2) 2 (3) 1 (2) 1 (2) 9 (16) 3 (5) 1 (2)
3 (8) 4 (11) 2 (5)
1 (2) 9 (16) 13 (22) 33 (57)
2 (5) 8 (22) 13 (35) 10 (27)
6 (10)
1 (3) 1 (3)
2 (3) 3 (5)
4 (7) 2 (3) 1 (2) 7 (12) 6 (10) 5 (9) 4 (6) 1 (2)
3 (8) 1 (3) 1 (3) 3 (8)
1 (3)
Abbreviations: CNS, central nervous system; CTC, Common Terminology Criteria for Adverse Events; FSRT, fractionated stereotactic radiotherapy; IMRT, intensity-modulated radiotherapy.
Cancer
September 1, 2015
3005
Original Article
Figure 1. Locoregional control is illustrated in patients with adenoid cystic carcinoma who received C121IMRT (the C12 group) versus those who received IMRT/FSRT only (the photon group). The locoregional control rate in the C12 group versus the photon group was 83.7% versus 55.6%, respectively, at 3 years; 59.6% versus 39.9%, respectively, at 5 years; and 42.2% versus 32%, respectively, at 10 years (P 5.033). The dashed lines correspond to the 95% confidence interval.
Figure 2. Progression-free survival is illustrated in patients with adenoid cystic carcinoma who received C121IMRT (the C12 group) versus those who received IMRT/FSRT only (the photon group). The progression-free survival rate in the C12 group versus the photon group was 73.9% versus 43.2%, respectively, at 3 years; 48.4% versus 27%, respectively, at 5 years; and 27.4% versus 18%, respectively, at 10 years (P 5.015). The dashed lines correspond to the 95%-confidence intervals.
photon group despite comparable baseline characteristics and stage distribution. Most patients had very advanced tumors, with >90% T4 tumors in both groups. All patients had visible residual disease; and 66% in the C12 group and 53% in the photon group were treated at very complex sites (paranasal sinuses, nasopharynx, base of skull), thus presenting 2 unfavorable prognostic criteria.4,14-16 Neutron RT has improved LC compared with photon RT.5,6 However, T4 tumor classification and resection status vary widely between series: almost all patients studied by Laramore et al and Douglas and colleagues had gross residual disease, resulting in an LC rate of 50% and 61%, respectively, at 5 years.6,7 In the series reported by Huber et al,
Combined Intensity-Modulated Radiotherapy Plus Raster-Scanned Carbon Ion Boost for Advanced Adenoid Cystic Carcinoma of the Head and Neck Results in Superior Locoregional Control and Overall Survival € ss, MSc2; Alexandra D. Jensen, MD, MSc1; Anna V. Nikoghosyan, MD1; Melanie Poulakis, DDS1; Angelika Ho 3 3 1 1 €kel, PhD ; Marc W. Mu €nter, MD ; Daniela Schulz-Ertner, MD ; Peter E. Huber, MD, PhD4; Thomas Haberer, PhD ; Oliver Ja € and Jurgen Debus, MD, PhD1
BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence C 2015 American Cancer Society. remains in field, and further C12 dose escalation should be evaluated. Cancer 2015;121:3001-9. V KEYWORDS: adenoid cystic carcinoma, carbon ions, carbon ion therapy, fractionated stereotactic radiotherapy, intensity-modulated radiotherapy, long-term results, malignant salivary gland tumors, raster scanning.
INTRODUCTION Adenoid cystic carcinomas (ACCs) are rare and comparatively radioresistant head and neck malignancies1-3 characterized by slow but aggressive growth patterns.4 Because of frequent perineural invasion, they often extend to the skull base and beyond. Radical surgery is rarely possible for patients with ACC, and radiotherapy (RT) doses 66 Gray (Gy) are needed to achieve long-term disease control.1,2 A Medical Research Council randomized trial investigated the use of neutron RT in the treatment of malignant salivary gland tumors (MSGTs), exploiting the higher relative biologic effectiveness of neutron RT in the late 1980s. That study demonstrated significantly improved local control rates in the neutron arm, albeit with significant late toxicity.5-7 The introduction of the raster-scanning technique for carbon ions (C12)8 offers the advantage of extremely sharp gradients and very precise dose delivery while avoiding high doses to adjacent critical structures and maintaining coverage of the target volume. Within the prospective pilot project, patients with ACC received a combined regimen of C12 and intensity-modulated RT (IMRT) in cooperation with the GSI Helmholtz Center for Corresponding author: Alexandra D. Jensen, MD, MSc, Department of Radiation Oncology, University of Heidelberg, INF 400, D-69120 Heidelberg, Germany; Fax: (011) 49-6221-56-5353; [email protected] 1 Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany; 2Medical Informatics and Regulatory Affairs, Heidelberg Ion Beam Therapy Center, Heidelberg, Germany; 3Heidelberg Ion Beam Therapy Center, Heidelberg, Germany; 4Molecular Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
Presented in part at the American Society of Clinical Oncology Annual Meeting; June 4-8, 2010; Chicago, Illinois, and at the International Federation of Head and Neck Oncologic Societies Fifth World Congress; July 26-30, 2014; New York, New York. We thank the referring centers for their trust and cooperation in the treatment and follow-up of these patients, without which this work would not have been possible. DOI: 10.1002/cncr.29443, Received: February 17, 2015; Revised: March 15, 2015; Accepted: March 31, 2015, Published online June 4, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
September 1, 2015
3001
Original Article
Heavy Ion Research (Darmstadt, Germany) whenever the beam was clinically available. Initial local control was promising and had moderate toxicity compared with high-precision photon techniques,9-11 which led to the establishment of this regimen as the treatment of choice in Germany. However, patient numbers were small in that study, and the follow-up was short. Here, we present results from all patients who received treatment for inoperable or subtotally resected ACCs within the pilot project from 1997 to 2008. We compared this cohort with patients who received treatment with modern photon RT at our institution throughout the same period. To our knowledge, this is the first report of long-term results of C12 therapy using the raster-scanning method for ACC. MATERIALS AND METHODS Selection of Treatment Technique
C12 therapy was available for medical purposes within 3 treatment periods per year from 1997 to 2008. At any other time, treatment consisted of high-precision photon techniques with either IMRT or fractionated stereotactic RT (FSRT). Immobilization, Target Volume Definition, and Treatment Planning
Immobilization with a custom-made Scotchcast mask (3M Deutschland GmbH, Neuss, Germany) as well as target delineation based on contrast-enhanced computed tomography scans (3-mm slice thickness) and magnetic resonance imaging scans for image correlation were the same in both groups. Two separate clinical target volumes (CTVs) were outlined: CTV1 included the macroscopic tumor and tumor bed, and CTV2 was the extended target volume and included CTV1 plus typical pathways of spread and ipsilateral lymph node levels (II and III). If the primary tumor was located at or crossed the midline, then bilateral lymph nodes were included. Planning target volumes (PTVs) were generated with a 3-mm margin around the CTVs. Note that the PTV margin was reduced at sites where it would extend into critical structures (ie, optic pathways), and no margin was added to organs at risk. Target volumes in both groups were drawn by a team of 3 specialists. C12 treatment plans were generated using the German Cancer Research Center (Heidelberg, Germany) inhouse system TRIP, incorporating biologic plan optimization according to the local effects model12 to account for increased biologic effectiveness and yielding photon Gray equivalents (GyE). Variations in biologic effective3002
ness caused by hypofractionation were not included in this model. Doses had to be converted according to the standard linear-quadratic model to yield the biologically effective dose (BED) in Gy. Photon treatment plans were created using the German Cancer Research Center in-house systems KonRad (optimization) and VIRTUOS (dose calculation, FSRT planning). FSRT was used until 1999, when IMRT became the standard technique for head and neck tumors at our institution. Target localization in all treatment techniques (C12, IMRT, and FSRT) was carried out using a frame-based, external stereotactic coordinate system. Dose Prescription and Organs at Risk
Both C12 doses and photon doses were normalized to the median PTV. Therefore, 50% of the PTV received 100% of the prescription isodose. In addition, it was required to cover the PTV (100%) with at least 90% of the prescription isodose. Normal tissue constraints were adhered to according to Emami et al.13 Doses were reduced beyond these values to as low as reasonably achievable without compromising PTV coverage. The mean dose to at least 1 parotid gland had to be 4 adverse events recorded in 57% of patients in the C12 group and only 27% of patients in the photon group. Most common late effects were hearing impairment (10%), loss of smelling sense (10%), and dysgeusia (12%) in the C12 group. Blood-brain barrier changes corresponding to grade 1 central nervous system (CNS) necrosis occurred in 2% of patients, 2 patients (3%) experienced visual impairment, and 1 patient with ACC of the lacrimal gland lost her vision due to retinal detachment (C12 group). The number of late events recorded was higher in the C12 group. In the photon group, loss of vision because of corneal ulceration (8%) was most frequently reported, and no cases of blood-brain barrier changes (CNS necrosis) were documented (Table 2). The median LC in the C12 group was 73.1 months (59.6% at 5 years) versus 37.6 months (39.9% at 5 years) in the photon group (P 5 .033) (Fig. 1); the median PFS was 59.1 months versus 32.0 months, respectively (P 5 .015) (Fig. 2); and the median OS was 102.1 months and 73.7 months, respectively (P 5 .015) (Fig. 3). Tentative estimates of 10-year LC, PFS, and OS were 42.2%, 27.4%, and 44.2%, respectively, in the C12 group versus 32%, 18%, and 19.6%, respectively, in the photon group. In the C12 group, LC (Fig. 4), PFS, and OS were independent of resection status (LC, P 5 .814; PFS, P 5 .914; OS, P 5 .929). In the photon-only group, LC and PFS were significantly worse for patients with inoperable tumors (LC, P 5 .008; PFS, P 5 .013; OS, 3003
Original Article TABLE 1. Patient Baseline Characteristics: Combined Carbon Ions Plus Intensity-Modulated Radiotherapy Versus Intensity-Modulated or Fractionated Stereotactic Radiotherapy Only No. of Patients (%) or Median [Range] Patient Characteristic Age at treatment, y Follow-up for all patients, mo Overall Still alive Site Base of skull/pterygoid bone Petrous bone/base of skull Paranasal sinus Parotid extending to base of skull Nasopharynx Maxilla Lacrimal gland Nasal cavity Mandible Trachea Base of tongue Tumor classification T2 T3 T4: T4a/T4b or subclassification unknown T4a T4b Lymph node classification: N1 Metastasis classification: M1 Surgery Subtotal resection Biopsy only Relapse strategy RT for relapse RT as part of primary treatment RT CTV1 boost Dose, mL Prescription, GyE BED, Gy
Carbon Ions 1 IMRT, n 5 58
IMRT/FSRT, n 5 37
53 [27-75]
56 [22-79]
74.2 [6.0-167.3] 82.7 [24.1-167.3]
62.9 [1.4-174.4] 66.3 [25.6-155.1]
7 (12)
5 (15) 2 (5) 11 (30) 5 (14) 3 (8) 6 (16) 3 (8)
23 (40) 13 (22) 8 (14) 3 (5) 2 (3) 1 (2) 1 (2)
P
.256
1 (3) 1 (3) 1 5 52 18 34 4 4
(2) (9) (90) (31) (58) (7) (7)
0 (0) 2 (5) 35 (94)
.181
>6 (>16) 4 (11) 3 (8)
40 (69) 18 (31)
19 (51) 18 (49)
.441
18 (31) 40 (69)
13 (35) 24 (65)
.483
170 [13-427] 72 [47.4-72.0] 76.5 [51.15-76.5]
180 [42.3-896] 66 [54.0-70.4] 66 [54.0-70.4]
Abbreviations: BED, biologically effective dose; CTV1, clinical target volume including the macroscopic tumor and tumor bed; FSRT, fractionated stereotactic radiotherapy; Gy, grays; GyE, gray equivalents; IMRT, intensity-modulated radiotherapy; N1, positive lymph node status; RT, radiotherapy.
P 5 .128). When only T4b tumors in the C12 group were analyzed, there was a trend toward improved LC (Fig. 5) and PFS in patients who underwent biopsy only compared with patients who underwent subtotal resection. Patients in the C12 group who were treated for locally recurrent ACC had significantly poorer LC compared with patients who received RT as part of their primary treatment (P 5 .019) (Fig. 6). However, this did not translate into a significant difference in PFS or OS. Locoregional relapse occurred in 29 patients in the C12 group and 23 patients in the photon group. The first site of relapse was within the high-dose area (PTV1; in-field) in 18 patients (62%), at the field edge (21%), out of field (1%), and unknown (4%). Imaging of the relapse site was available for 12 patients with recurrent disease in the photon group (52%); 11 of those patients relapsed in field (48%), and 1 patient 3004
relapsed in regional cervical lymph nodes (4%). For the remaining 11 patients, no imaging studies were available for comparison. Distant disease progression was observed in 22 patients in the C12 group and 16 patients in the photon group. The most common sites of distant metastases were pulmonary (C12 group, 64%; photon group, 44%), bone (C12 group, 27%; photon group, 31%), and brain (C12, 14%; photon group, 13%) metastases. DISCUSSION Given the complex anatomic situation in the head and neck as well as the necessary high doses for tumor control in MSGTs,1-3 achieving durable LC in patients with inoperable or gross residual disease is a challenge. The observed LC rate of almost 60% at 5 years in patients who received C12 treatment was significantly higher than that in the Cancer
September 1, 2015
Superior Overall Survival of C12 in ACC/Jensen et al
TABLE 2. Treatment-Related Toxicity at the Completion of Radiotherapy and Late Toxicity: Combined Carbon Ions Plus Intensity-Modulated Radiotherapy Versus Intensity-Modulated or Fractionated Stereotactic Radiotherapy Only No. of Patients (%) Toxicity
Carbon Ions 1 IMRT, n 5 58
Acute toxicity, CTC grade Mucositis 1 2 3 Unspecified Dysphagia, CTC grade 1 2 3 Unspecified Xerostomia, CTC grade 1 2 Unspecified Dermatitis, CTC grade 1 2 3 Middle ear effusion Tinnitus Otitis Mastoiditis Hearing impairment Epiphora Conjunctivitis Blepharitis Keratitis Visual impairment Double vision Rhinitis sicca Anosmia Lymphedema Trismus Dizziness Nausea Cephalgia Paraesthesia Documentation of acute adverse events 1 Event 2 Events 3 Events 4 Events Late toxicity Hearing impairment Middle ear effusion Epiphora Conjunctivitis sicca Corneal ulcer Xerophthalmia Sinusitis/rhinitis sicca Visual impairment Loss of vision Dysgeusia Anosmia Paraesthesia Cephalgia Blood-brain barrier changes/CNS necrosis I
14 (24) 26 (45) 4 (7)
IMRT/FSRT, n 5 37
3 11 11 3
(8) (30) (30) (8)
P
.423
13 (22) 5 (9) 1 (2) 1 (3) 13 (22) 12 (21) 16 (43) 28 (48) 14 (24) 2 (3) 9 (16) 2 (3) 4 (7) 1 (2) 9 (16) 2 (3) 19 (33)
21 (57) 9 (24) 1 (3) 5 (14)
.181
3 (8) 12 (32) 2 (5) 1 (3)
3 (5) 1 (3) 4 (7) 1 (2) 2 (3) 1 (2) 1 (2) 9 (16) 3 (5) 1 (2)
3 (8) 4 (11) 2 (5)
1 (2) 9 (16) 13 (22) 33 (57)
2 (5) 8 (22) 13 (35) 10 (27)
6 (10)
1 (3) 1 (3)
2 (3) 3 (5)
4 (7) 2 (3) 1 (2) 7 (12) 6 (10) 5 (9) 4 (6) 1 (2)
3 (8) 1 (3) 1 (3) 3 (8)
1 (3)
Abbreviations: CNS, central nervous system; CTC, Common Terminology Criteria for Adverse Events; FSRT, fractionated stereotactic radiotherapy; IMRT, intensity-modulated radiotherapy.
Cancer
September 1, 2015
3005
Original Article
Figure 1. Locoregional control is illustrated in patients with adenoid cystic carcinoma who received C121IMRT (the C12 group) versus those who received IMRT/FSRT only (the photon group). The locoregional control rate in the C12 group versus the photon group was 83.7% versus 55.6%, respectively, at 3 years; 59.6% versus 39.9%, respectively, at 5 years; and 42.2% versus 32%, respectively, at 10 years (P 5.033). The dashed lines correspond to the 95% confidence interval.
Figure 2. Progression-free survival is illustrated in patients with adenoid cystic carcinoma who received C121IMRT (the C12 group) versus those who received IMRT/FSRT only (the photon group). The progression-free survival rate in the C12 group versus the photon group was 73.9% versus 43.2%, respectively, at 3 years; 48.4% versus 27%, respectively, at 5 years; and 27.4% versus 18%, respectively, at 10 years (P 5.015). The dashed lines correspond to the 95%-confidence intervals.
photon group despite comparable baseline characteristics and stage distribution. Most patients had very advanced tumors, with >90% T4 tumors in both groups. All patients had visible residual disease; and 66% in the C12 group and 53% in the photon group were treated at very complex sites (paranasal sinuses, nasopharynx, base of skull), thus presenting 2 unfavorable prognostic criteria.4,14-16 Neutron RT has improved LC compared with photon RT.5,6 However, T4 tumor classification and resection status vary widely between series: almost all patients studied by Laramore et al and Douglas and colleagues had gross residual disease, resulting in an LC rate of 50% and 61%, respectively, at 5 years.6,7 In the series reported by Huber et al,
