ORIGINAL ARTICLE
Carbon ion radiotherapy for locally advanced squamous cell carcinoma of the external auditory canal and middle ear Masashi Koto, MD, PhD,1* Azusa Hasegawa, DDS, PhD,1 Ryo Takagi, DDS, PhD,1 Go Sasahara, MD, PhD,1 Hiroaki Ikawa, DDS, PhD,1 Jun-etsu Mizoe, MD, PhD,2 Keiichi Jingu, MD, PhD,3 Hirohiko Tsujii, MD, PhD,1 Tadashi Kamada, MD, PhD,1 Yoshitaka Okamoto, MD, PhD,4 Organizing Committee for the Working Group for Head and Neck Cancer 1
Research Center for Charged Particle Therapy Hospital, National Institute of Radiological Sciences, Chiba, Japan, 2Nagoya Proton Therapy Center, Nagoya, Japan, 3Department of Radiation Oncology, Tohoku University School of Medicine, Sendai, Japan, 4Department of Otolaryngology, Chiba University School of Medicine, Chiba, Japan.
Accepted 24 October 2014 Published online 26 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23905
ABSTRACT: Background. The prognosis of advanced squamous cell carcinoma (SCC) of the external auditory canal and middle ear remains poor. Carbon ion radiotherapy (C-ion RT) has shown promise for locally advanced head and neck cancer. Therefore, we evaluated the safety and efficacy of C-ion RT for locally advanced SCC of the external auditory canal and middle ear. Methods. The cases of 13 patients with advanced (T3 and T4) SCC of the external auditory canal and middle ear who received C-ion RT as the primary treatment were reviewed.
INTRODUCTION Carcinomas of the external auditory canal and middle ear are rare. The incidence is estimated to be 1 to 6 patients per million populations per year.1–3 Squamous cell carcinoma (SCC) is the most common histological subtype. There is no universal consensus on the optimal treatment for SCC of the external auditory canal and middle ear because of its scarcity. However, in general, the following standard treatments are used for SCC of the external auditory canal and middle ear classified according to the Pittsburgh staging system4: surgery or radiotherapy for T classification T1 tumors and surgery with or without radiotherapy for T2, T3, and T4 tumors. Although excellent clinical results for patients with early stage SCC of the external auditory canal and middle ear have been reported,5–8 the prognosis of patients with advanced-stage disease, particularly T4, remains poor. Xie et al8 found that, in a series of 39 patients with temporal bone SCC treated with surgery with radiotherapy, the 2year overall survival (OS) rate was 22.3% for patients with T4 tumors or positive lymph nodes. Moreover, in a multi-
*Corresponding author: M. Koto, Research Center for Charged Particle Therapy Hospital, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku 263-8555 Chiba, Japan. E-mail: [email protected] Contract grant sponsor: This study was supported by the The Research Project with Heavy Ions at the National Institute of Radiological Sciences (NIRS)–Heavy Ion Medical Accelerator in Chiba (HIMAC).
512
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
Results. The median follow-up for all patients and the 7 surviving patients was 12 and 32 months, respectively. The 1-year and 3-year local control and overall survival (OS) rates were 72% and 54% and 70% and 40%, respectively. Severe temporal bone necrosis was observed in 2 patients. Conclusion. C-ion RT is effective and generally safe for locally advanced C 2015 Wiley PeriodiSCC of the external auditory canal and middle ear. V cals, Inc. Head Neck 38: 512–516, 2016
KEY WORDS: carbon ion radiotherapy, squamous cell carcinoma, external auditory canal, middle ear, temporal bone
institutional retrospective review, Ogawa et al9 reported a 1-year disease-free survival (DFS) rate of 0% in 16 patients with T3 or T4 SCC of the external auditory canal and middle ear treated with radiotherapy alone. Carbon ion radiotherapy (C-ion RT) was initiated at the National Institute of Radiological Sciences (NIRS) in 1994. C-ions exhibit high linear energy transfer and display good dose-localizing properties compared with other ion species and photons.10,11 Therefore, C-ion RT is expected to be effective for radioresistant tumors. For cancers in the head and neck region, C-ion RT is mainly performed for non-SCCs, such as salivary gland carcinoma and mucosal malignant melanoma. C-ion RT has shown promising results for locally advanced head and neck cancer in a phase II clinical trial.12,13 SCC of the head and neck region is generally radiosensitive; however, radiotherapy is often unable to control locally advanced SCC of the external auditory canal and middle ear. Therefore, C-ion RT may be a viable treatment option for locally advanced SCC of the external auditory canal and middle ear. Accordingly, the purpose of this study was to evaluate the effectiveness and safety of C-ion RT for patients with locally advanced SCC of the external auditory canal and middle ear.
MATERIALS AND METHODS The treatment protocol for head and neck cancer was reviewed and approved by the NIRS Ethical Committee
CARBON
TABLE 1. Patient and treatment characteristics. Characteristics
Sex Male/female Age, y Median/range Primary site External auditory canal Middle ear Tumor grade Well-differentiated Moderately differentiated Poorly differentiated Unknown T classification T3/T4 N classification N0/N1/N2b Facial nerve palsy Yes/no Dural involvement Yes/no Parotid invasion Yes/no TMJ involvement Yes/no Treatment characteristics GTV, mL Median/range PTV, mL Median/range Prescribed dose 57.6 GyE/16 fractions 64.0 GyE/16 fractions
No. of patients
2/11 53/45–71 11 2 9 2 1 1 4/9 10/2/1 5/8 8/5 8/5 6/7 41/6–84 159/70–310 8 5
Abbreviations: TMJ, temporomandibular joint; GTV, gross tumor volume; PTV, planning target volume; GyE, Gray equivalent.
on Human Clinical Research, and all patients provided written informed consent. A retrospective case review was undertaken of all patients with SCC of the external auditory canal and middle ear who were treated with C-ion RT at the NIRS between June 1997 and May 2013. A total of 13 patients were enrolled in the study. All patients received C-ion RT as a primary treatment. Patient and treatment characteristics are summarized in Table 1. All primary tumors were classified according to the Pittsburgh Staging System. Before treatment, 3 patients had T3 disease, and 10 patients had T4 disease. Patients with metastatic lymph nodes that were localized around the primary tumor were included. Lymph node status and distant metastasis were classified using the TNM staging system for cancers of the head and neck region. Two patients were classified as N1 and 1 patient as N2b. All patients were classified as M0.
ION RADIOTHERAPY FOR
SCC
OF THE EAR
at the distal region of the spread-out Bragg peak, where the RBE of carbon ions was assumed to be 3.0. C-ion RT was administered on a fractionation schedule comprised of 64.0 GyE/16 fractions for 4 weeks. When a wide range of skin or mucosa was included in the target volume, a dose of 57.6 GyE/16 fractions for 4 weeks was used. The patients were positioned in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized using a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan). A set of CT images of 2.5-mm thickness was obtained for treatment planning with the immobilization devices. MRI, after fusing with the planning CT image, was routinely used for identification of the tumor. Determination of the gross tumor volume (GTV) was based on contrast-enhanced MRI. The clinical target volume (CTV) had a minimum margin of 5 mm added around the GTV. In cases with possible tumor invasion into adjacent sites, CTV1 included whole anatomic sites, and CTV2 was limited to the GTV. The planning target volume (PTV)1 and PTV2 had margins of 3 to 5 mm added around the CTV1 and CTV2, respectively. The PTV1 was irradiated initially with 36 GyE/9 or 10 fractions and, thereafter, PTV2 was irradiated to a total dose of 64.0 or 57.6 GyE/16 fractions. The target reference point dose was defined as the isocenter, and the PTV was encompassed by the minimum 90% dose line of the reference point dose. The CTV and PTV margins of areas close to the brain and skin were reduced as necessary. Multiportal irradiation was planned fundamentally to avoid severe normal tissue reactions. Three-dimensional treatment planning was performed using original HIPLAN software (NIRS, Chiba, Japan). During C-ion RT, patients received no concomitant therapy, and, after completion, patients received no adjuvant therapy, such as surgery or chemotherapy. No patients received prophylactic neck irradiation. Treatment methods for local recurrence and distant metastasis had no limitations.
Evaluation and follow-up examinations All patients underwent a CT and MRI examination before treatment to determine clinical stage. Acute reactions in normal tissues were classified according to the Radiation Therapy and Oncology Group scoring system. Late reactions were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Effect version 4.0. Local control was defined as no evidence of tumor regrowth in the PTV1. Regional control was defined as no evidence of recurrence in both the temporal bone outside of the PTV1 and regional lymph nodes. Oncologic status was followed using CT or MRI every 2 to 3 months for the first 2 years after C-ion RT and every 3 to 6 months thereafter.
Statistical analyses Carbon ion radiotherapy Doses of carbon ions were expressed in photonequivalent doses (Gray equivalent [GyE]), defined as the physical doses multiplied by the relative biological effectiveness (RBE) of the carbon ions.10 The biological flatness of the spread-out Bragg peak was normalized by the survival fraction of the human salivary gland tumor cells
Local control, OS, and DFS rates were determined using the Kaplan–Meier method and compared among the different subgroups using the log-rank test. All analyses were calculated from the first day of C-ion RT. A p value below .05 was considered significant. Statistical analyses were performed using SPSS software version 11 (SPSS, Chicago, IL). HEAD & NECK—DOI 10.1002/HED
APRIL 2016
513
KOTO ET AL.
FIGURE 1. Local control rate in the patient cohort (n 5 13).
FIGURE 3. Overall survival and disease-free survival rates in the patient cohort (n 5 13).
Univariate analysis of risk factors for local control and survival
RESULTS Local control and survival The median observation period was 12 months (range 5 2–80 months) for all patients and 32 months (range 5 2–80 months) for the 7 surviving patients. No patients were lost to follow-up. The 1-year and 3-year local control rates were 75.2% (95% confidence interval [CI] 5 50.6% to 99.8%) and 56.4% (95% CI 5 19.5% to 93.3%), respectively (see Figure 1). Four patients developed local recurrence. Of the 3 patients who developed regional recurrence, 2 patients had local recurrence. Of the 2 patients who developed distant metastasis, 1 patient had local recurrence. A representative case is shown in Figure 2. The 1-year and 3-year OS rates were 72.7% (95% CI 5 46.4% to 99.1%) and 41.6% (95% CI 5 10.9% to 72.2%), respectively. The 1-year and 3-year DFS rates were 49.9% (95% CI 5 20.9% to 78.9%) and 37.4% (95% CI 5 7.0% to 67.7%), respectively (see Figure 3). Of the 6 patients who died, 5 patients died of their original disease, and 1 patient died of intercurrent disease without recurrence.
Table 2 shows the results of the univariate analysis of risk factors for local control and OS. Young age was a significant risk factor for local control. Male sex and young age were risk factors for OS. Tumor and treatment characteristics were not significant risk factors for local control or OS.
Toxicity Acute skin reactions to C-ion RT occurred. Grade 1, grade 2, and grade 3 skin reactions were observed in 5 patients, 6 patients, and 2 patients, respectively. Severe vertigo and tinnitus did not occur during C-ion RT. Regarding late reactions, 2 patients, who were treated with a total dose of 57.6 GyE, developed grade 3 temporal bone necrosis with skin ulcers. Of these 2 patients, 1 died from distant metastases without local recurrence, and the other died from intercurrent cause. Four patients were judged to have maximum grade 2 brain injuries. These patients developed localized brain necrosis. However, mild headache was the only clinical symptom, which eventually disappeared. All patients had tumor-induced
FIGURE 2. A 71-year-old woman presented with squamous cell carcinoma of the right external auditory canal. (A) MRI revealed a tumor with intracranial invasion and clivus involvement (T4N0M0). (B) Dose distribution of carbon ion radiotherapy (C-ion RT). C-ion RT was administered at 57.6 Gray equivalent (GyE)/16 fractions. Isodose lines correspond to 96%, 90%, 60%, 50%, 30%, and 10% dose areas. The planning target volume 2 is demarcated by yellow lines. (C) MRI 6 years after C-ion RT. The tumor was controlled. The patient developed localized brain necrosis with mild headache as the only clinical symptom. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
514
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
CARBON
TABLE 2. Univariate analysis for the local control and overall survival rates. Clinical factors
Age, y 53
Carbon ion radiotherapy for locally advanced squamous cell carcinoma of the external auditory canal and middle ear Masashi Koto, MD, PhD,1* Azusa Hasegawa, DDS, PhD,1 Ryo Takagi, DDS, PhD,1 Go Sasahara, MD, PhD,1 Hiroaki Ikawa, DDS, PhD,1 Jun-etsu Mizoe, MD, PhD,2 Keiichi Jingu, MD, PhD,3 Hirohiko Tsujii, MD, PhD,1 Tadashi Kamada, MD, PhD,1 Yoshitaka Okamoto, MD, PhD,4 Organizing Committee for the Working Group for Head and Neck Cancer 1
Research Center for Charged Particle Therapy Hospital, National Institute of Radiological Sciences, Chiba, Japan, 2Nagoya Proton Therapy Center, Nagoya, Japan, 3Department of Radiation Oncology, Tohoku University School of Medicine, Sendai, Japan, 4Department of Otolaryngology, Chiba University School of Medicine, Chiba, Japan.
Accepted 24 October 2014 Published online 26 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23905
ABSTRACT: Background. The prognosis of advanced squamous cell carcinoma (SCC) of the external auditory canal and middle ear remains poor. Carbon ion radiotherapy (C-ion RT) has shown promise for locally advanced head and neck cancer. Therefore, we evaluated the safety and efficacy of C-ion RT for locally advanced SCC of the external auditory canal and middle ear. Methods. The cases of 13 patients with advanced (T3 and T4) SCC of the external auditory canal and middle ear who received C-ion RT as the primary treatment were reviewed.
INTRODUCTION Carcinomas of the external auditory canal and middle ear are rare. The incidence is estimated to be 1 to 6 patients per million populations per year.1–3 Squamous cell carcinoma (SCC) is the most common histological subtype. There is no universal consensus on the optimal treatment for SCC of the external auditory canal and middle ear because of its scarcity. However, in general, the following standard treatments are used for SCC of the external auditory canal and middle ear classified according to the Pittsburgh staging system4: surgery or radiotherapy for T classification T1 tumors and surgery with or without radiotherapy for T2, T3, and T4 tumors. Although excellent clinical results for patients with early stage SCC of the external auditory canal and middle ear have been reported,5–8 the prognosis of patients with advanced-stage disease, particularly T4, remains poor. Xie et al8 found that, in a series of 39 patients with temporal bone SCC treated with surgery with radiotherapy, the 2year overall survival (OS) rate was 22.3% for patients with T4 tumors or positive lymph nodes. Moreover, in a multi-
*Corresponding author: M. Koto, Research Center for Charged Particle Therapy Hospital, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku 263-8555 Chiba, Japan. E-mail: [email protected] Contract grant sponsor: This study was supported by the The Research Project with Heavy Ions at the National Institute of Radiological Sciences (NIRS)–Heavy Ion Medical Accelerator in Chiba (HIMAC).
512
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
Results. The median follow-up for all patients and the 7 surviving patients was 12 and 32 months, respectively. The 1-year and 3-year local control and overall survival (OS) rates were 72% and 54% and 70% and 40%, respectively. Severe temporal bone necrosis was observed in 2 patients. Conclusion. C-ion RT is effective and generally safe for locally advanced C 2015 Wiley PeriodiSCC of the external auditory canal and middle ear. V cals, Inc. Head Neck 38: 512–516, 2016
KEY WORDS: carbon ion radiotherapy, squamous cell carcinoma, external auditory canal, middle ear, temporal bone
institutional retrospective review, Ogawa et al9 reported a 1-year disease-free survival (DFS) rate of 0% in 16 patients with T3 or T4 SCC of the external auditory canal and middle ear treated with radiotherapy alone. Carbon ion radiotherapy (C-ion RT) was initiated at the National Institute of Radiological Sciences (NIRS) in 1994. C-ions exhibit high linear energy transfer and display good dose-localizing properties compared with other ion species and photons.10,11 Therefore, C-ion RT is expected to be effective for radioresistant tumors. For cancers in the head and neck region, C-ion RT is mainly performed for non-SCCs, such as salivary gland carcinoma and mucosal malignant melanoma. C-ion RT has shown promising results for locally advanced head and neck cancer in a phase II clinical trial.12,13 SCC of the head and neck region is generally radiosensitive; however, radiotherapy is often unable to control locally advanced SCC of the external auditory canal and middle ear. Therefore, C-ion RT may be a viable treatment option for locally advanced SCC of the external auditory canal and middle ear. Accordingly, the purpose of this study was to evaluate the effectiveness and safety of C-ion RT for patients with locally advanced SCC of the external auditory canal and middle ear.
MATERIALS AND METHODS The treatment protocol for head and neck cancer was reviewed and approved by the NIRS Ethical Committee
CARBON
TABLE 1. Patient and treatment characteristics. Characteristics
Sex Male/female Age, y Median/range Primary site External auditory canal Middle ear Tumor grade Well-differentiated Moderately differentiated Poorly differentiated Unknown T classification T3/T4 N classification N0/N1/N2b Facial nerve palsy Yes/no Dural involvement Yes/no Parotid invasion Yes/no TMJ involvement Yes/no Treatment characteristics GTV, mL Median/range PTV, mL Median/range Prescribed dose 57.6 GyE/16 fractions 64.0 GyE/16 fractions
No. of patients
2/11 53/45–71 11 2 9 2 1 1 4/9 10/2/1 5/8 8/5 8/5 6/7 41/6–84 159/70–310 8 5
Abbreviations: TMJ, temporomandibular joint; GTV, gross tumor volume; PTV, planning target volume; GyE, Gray equivalent.
on Human Clinical Research, and all patients provided written informed consent. A retrospective case review was undertaken of all patients with SCC of the external auditory canal and middle ear who were treated with C-ion RT at the NIRS between June 1997 and May 2013. A total of 13 patients were enrolled in the study. All patients received C-ion RT as a primary treatment. Patient and treatment characteristics are summarized in Table 1. All primary tumors were classified according to the Pittsburgh Staging System. Before treatment, 3 patients had T3 disease, and 10 patients had T4 disease. Patients with metastatic lymph nodes that were localized around the primary tumor were included. Lymph node status and distant metastasis were classified using the TNM staging system for cancers of the head and neck region. Two patients were classified as N1 and 1 patient as N2b. All patients were classified as M0.
ION RADIOTHERAPY FOR
SCC
OF THE EAR
at the distal region of the spread-out Bragg peak, where the RBE of carbon ions was assumed to be 3.0. C-ion RT was administered on a fractionation schedule comprised of 64.0 GyE/16 fractions for 4 weeks. When a wide range of skin or mucosa was included in the target volume, a dose of 57.6 GyE/16 fractions for 4 weeks was used. The patients were positioned in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized using a low-temperature thermoplastic shell (Shellfitter; Kuraray, Osaka, Japan). A set of CT images of 2.5-mm thickness was obtained for treatment planning with the immobilization devices. MRI, after fusing with the planning CT image, was routinely used for identification of the tumor. Determination of the gross tumor volume (GTV) was based on contrast-enhanced MRI. The clinical target volume (CTV) had a minimum margin of 5 mm added around the GTV. In cases with possible tumor invasion into adjacent sites, CTV1 included whole anatomic sites, and CTV2 was limited to the GTV. The planning target volume (PTV)1 and PTV2 had margins of 3 to 5 mm added around the CTV1 and CTV2, respectively. The PTV1 was irradiated initially with 36 GyE/9 or 10 fractions and, thereafter, PTV2 was irradiated to a total dose of 64.0 or 57.6 GyE/16 fractions. The target reference point dose was defined as the isocenter, and the PTV was encompassed by the minimum 90% dose line of the reference point dose. The CTV and PTV margins of areas close to the brain and skin were reduced as necessary. Multiportal irradiation was planned fundamentally to avoid severe normal tissue reactions. Three-dimensional treatment planning was performed using original HIPLAN software (NIRS, Chiba, Japan). During C-ion RT, patients received no concomitant therapy, and, after completion, patients received no adjuvant therapy, such as surgery or chemotherapy. No patients received prophylactic neck irradiation. Treatment methods for local recurrence and distant metastasis had no limitations.
Evaluation and follow-up examinations All patients underwent a CT and MRI examination before treatment to determine clinical stage. Acute reactions in normal tissues were classified according to the Radiation Therapy and Oncology Group scoring system. Late reactions were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Effect version 4.0. Local control was defined as no evidence of tumor regrowth in the PTV1. Regional control was defined as no evidence of recurrence in both the temporal bone outside of the PTV1 and regional lymph nodes. Oncologic status was followed using CT or MRI every 2 to 3 months for the first 2 years after C-ion RT and every 3 to 6 months thereafter.
Statistical analyses Carbon ion radiotherapy Doses of carbon ions were expressed in photonequivalent doses (Gray equivalent [GyE]), defined as the physical doses multiplied by the relative biological effectiveness (RBE) of the carbon ions.10 The biological flatness of the spread-out Bragg peak was normalized by the survival fraction of the human salivary gland tumor cells
Local control, OS, and DFS rates were determined using the Kaplan–Meier method and compared among the different subgroups using the log-rank test. All analyses were calculated from the first day of C-ion RT. A p value below .05 was considered significant. Statistical analyses were performed using SPSS software version 11 (SPSS, Chicago, IL). HEAD & NECK—DOI 10.1002/HED
APRIL 2016
513
KOTO ET AL.
FIGURE 1. Local control rate in the patient cohort (n 5 13).
FIGURE 3. Overall survival and disease-free survival rates in the patient cohort (n 5 13).
Univariate analysis of risk factors for local control and survival
RESULTS Local control and survival The median observation period was 12 months (range 5 2–80 months) for all patients and 32 months (range 5 2–80 months) for the 7 surviving patients. No patients were lost to follow-up. The 1-year and 3-year local control rates were 75.2% (95% confidence interval [CI] 5 50.6% to 99.8%) and 56.4% (95% CI 5 19.5% to 93.3%), respectively (see Figure 1). Four patients developed local recurrence. Of the 3 patients who developed regional recurrence, 2 patients had local recurrence. Of the 2 patients who developed distant metastasis, 1 patient had local recurrence. A representative case is shown in Figure 2. The 1-year and 3-year OS rates were 72.7% (95% CI 5 46.4% to 99.1%) and 41.6% (95% CI 5 10.9% to 72.2%), respectively. The 1-year and 3-year DFS rates were 49.9% (95% CI 5 20.9% to 78.9%) and 37.4% (95% CI 5 7.0% to 67.7%), respectively (see Figure 3). Of the 6 patients who died, 5 patients died of their original disease, and 1 patient died of intercurrent disease without recurrence.
Table 2 shows the results of the univariate analysis of risk factors for local control and OS. Young age was a significant risk factor for local control. Male sex and young age were risk factors for OS. Tumor and treatment characteristics were not significant risk factors for local control or OS.
Toxicity Acute skin reactions to C-ion RT occurred. Grade 1, grade 2, and grade 3 skin reactions were observed in 5 patients, 6 patients, and 2 patients, respectively. Severe vertigo and tinnitus did not occur during C-ion RT. Regarding late reactions, 2 patients, who were treated with a total dose of 57.6 GyE, developed grade 3 temporal bone necrosis with skin ulcers. Of these 2 patients, 1 died from distant metastases without local recurrence, and the other died from intercurrent cause. Four patients were judged to have maximum grade 2 brain injuries. These patients developed localized brain necrosis. However, mild headache was the only clinical symptom, which eventually disappeared. All patients had tumor-induced
FIGURE 2. A 71-year-old woman presented with squamous cell carcinoma of the right external auditory canal. (A) MRI revealed a tumor with intracranial invasion and clivus involvement (T4N0M0). (B) Dose distribution of carbon ion radiotherapy (C-ion RT). C-ion RT was administered at 57.6 Gray equivalent (GyE)/16 fractions. Isodose lines correspond to 96%, 90%, 60%, 50%, 30%, and 10% dose areas. The planning target volume 2 is demarcated by yellow lines. (C) MRI 6 years after C-ion RT. The tumor was controlled. The patient developed localized brain necrosis with mild headache as the only clinical symptom. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
514
HEAD & NECK—DOI 10.1002/HED
APRIL 2016
CARBON
TABLE 2. Univariate analysis for the local control and overall survival rates. Clinical factors
Age, y 53
