Oral Oncology 50 (2014) 228–233
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Prognostic value of prepontine cistern invasion in nasopharyngeal carcinoma treated by intensity-modulated radiotherapy Tsung-Min Hung a, Chien-Cheng Chen b, Chien-Yu Lin a, Shu-Hang Ng b, Chung-Jan Kang c, Shiang-Fu Huang c, Chun-Ta Liao c, Kang-Hsing Fan a, Hung-Ming Wang d,⇑, Joseph Tung-Chieh Chang a,⇑ a
Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan d Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 27 August 2013 Received in revised form 3 December 2013 Accepted 6 December 2013 Available online 6 January 2014 Keywords: Nasopharyngeal carcinoma Intensity-modulated radiotherapy Prognosis Prepontine cistern invasion Distant metastasis Intracranial extension Head and neck cancer
s u m m a r y Objectives: To investigate the prognostic value of prepontine cistern invasion (PPCI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Materials and methods: Five hundred and four non-disseminated NPC patients who underwent magnetic resonance imaging examination before radical IMRT between November 2000 and December 2008 were retrospectively reviewed. The diagnostic criteria for PPCI were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern. Results: The median follow-up of the patients in this study was 63.5 months. PPCI was found in 44 patients (25% of T4 patients). The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) of all patients, with and without PPCI, were 44.3% and 70.5% (p < 0.001), 84.4% and 89.1% (p = 0.376), 66.6% and 87.3% (p < 0.001), and 59.6% and 80.2% (p < 0.001), respectively. In T4 patients with PPCI and without PPCI, the 5-year PFS, LC, DMFS, and OS were 44.3% and 62.5% (p = 0.023), 84.4% and 84.9% (p = 0.946), 66.6% and 83.1% (p = 0.022), and 59.6% and 71.0% (p = 0.045), respectively. Using multivariate analysis, PPCI was found to be an independent poor prognostic factor for PFS (HR = 1.816; p = 0.007), DMFS (HR = 1.928; p = 0.045), and OS (HR = 1.798; p = 0.016). Conclusion: Prepontine cistern invasion was an independent prognostic factor for poor DMFS and OS but not LC in NPC patients treated with IMRT, even within T4 patients. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Nasopharyngeal carcinoma (NPC) is radiosensitive and is mainly treated by radiotherapy (RT). Recently, a new RT technique, intensity-modulated radiotherapy (IMRT), has been shown to achieve very good local tumor control [1–6]. No prominent differences were observed between the local control provided by IMRT for various primary tumor (T) categories; one study showed that, following IMRT, only T4 NPC had poor local control [4], whereas two other studies found no significant differences in local control between the various T categories of NPC [5,6]. These results indicate that IMRT can achieve better target coverage than 2D RT techniques. However, suboptimal target coverage
may occur with IMRT if the target is near a critical organ to prevent serious complications. The brainstem is an important critical organ in the treatment of NPC. Tumors with prepontine cistern invasion may have inadequate RT dose coverage in the region near the brainstem owing to the target being very close to the critical organ. This study was undertaken to evaluate the prognostic value of prepontine cistern invasion (PPCI) in NPC patients treated with IMRT, as well as to determine whether patients with or without PPCI have different treatment outcomes and disease failure patterns. Materials and methods Patients
⇑ Corresponding authors. Address: Department of Radiation Oncology, Division of Medical Oncology, Department of Internal Medicine, Taipei Chang Gung Head and Neck Oncology Group, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan, Taiwan. Tel.: +886 3 3281200x2613; fax: +886 3 3280797. E-mail addresses: [email protected], [email protected] (J.T-C. Chang). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.12.005
This study was approved by the Institutional Review Board of our hospital. Five hundred and four NPC patients with biopsy-proven, non-disseminated, newly diagnosed NPC who underwent magnetic resonance imaging examination before radical IMRT between
T.-M. Hung et al. / Oral Oncology 50 (2014) 228–233
November 2000 and December 2008 were retrospectively reviewed. The characteristics of all patients were summarized in Table 1, and T4 patients with and without PPCI were in Table 2. The pretreatment evaluation included head and neck magnetic resonance imaging (MRI), nasopharyngeal fiberoscopy, a bone scan, a chest X-ray (CXR), and abdominal sonography. The bone scan was optional when [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was performed. A total of 437 (86.7%) patients underwent a PET study before treatment. All patients were restaged according to the seventh edition of the American Joint Committee on Cancer (7th AJCC) staging system. Primary treatment consisted of RT alone or cisplatin-based chemoradiotherapy (CCRT), according to the tumor stage. The reasons for patients with advanced disease did not receive CCRT were medical comorbidities or patient refusal. Thirty-one stage IVA–B patients, who were participating in a randomized trial, received epirubicin-based induction chemotherapy before cisplatin-based CCRT. The median radiation dose was 72 Gy (range, 70–76 Gy), and IMRT was used in all patients. Ideally, the maximum dose to the brainstem was below 54 Gy; however, exposure of 61% of the brainstem volume to 60 Gy was acceptable if the target was very close to the brainstem. All patients were followed-up in the outpatient clinic every 1–3 months in the first and second year, every 4–6 months during the third to fifth years, and then every 6–12 months thereafter. Flexible nasopharyngeal fiberoscopy was performed during each visit. Head-and-neck MRI, a CXR, and a bone scan were performed 3 months after the treatment was completed. Any suspected residual or recurrent lesions were biopsied to confirm the disease; however, if the biopsy was not feasible or yielded a negative result, a follow-up MRI study was performed after approximately 3 months. Computed tomography that included the head, neck, lung, and liver was performed annually or when clinically indicated during
Table 1 Patient characteristics in all patients (n = 504). Characteristic Age (years) Median Range Gender Male Female Pathology classification Keratinizing Non-keratinizing T category T1 T2 T3 T4 N category N0 N1 N2 N3 Clinical stage I II III IVA–B Treatment modality RT alone CCRT Chemo + CCRT Prepontine cistern invasion Yes No
No. (%) 48.6 15–84 355 (70.4) 149 (29.6) 45 (8.9) 459 (91.1) 218 (43.3) 41 (8.1) 69 (13.7) 176 (34.9) 46 (9.1) 209 (41.5) 156 (31.0) 93 (18.5) 17 (3.4) 124 (24.6) 155 (30.8) 208 (41.3) 56 (11.1) 417 (82.7) 31 (6.2) 44 (8.7) 460 (91.3)
Abbreviations: RT, radiotherapy; CCRT, concurrent chemoradiation; Chemo + CCRT, induction chemotherapy and concurrent chemoradiation.
229
the follow-up period. The disease recurrence was confirmed by image-guided biopsy if possible and close clinical or image follow-up was pursued if a biopsy was not feasible or yielded a negative result. A PET study, for disease re-staging, was suggested for patients with disease relapse. Patients who developed distant metastases were still observed for local or regional disease relapse. For patients with relapse, salvage treatment (RT, surgery, or chemotherapy) was provided for those individuals with a good performance status, and the decision about treatment type was based on the patient preference.
Magnetic resonance imaging MRI was performed with two 1.5-Tesla units (Vision, Siemens Medical Solutions, Erlangen, Germany; Intera, Phillips Medical Systems, Best, The Netherlands) and one 3.0-Tesla unit (Tim Trio, Siemens Medical Solutions, Erlangen, Germany) using the spin-echo (SE) technique. All patients underwent MRI before and after gadolinium–diethylenetriamine pentaacetic acid (Gd–DTPA) injection. The scanning field of view ranged from the superior margin of the temporal lobe to the level of the supraclavicular fossa with a head and neck coil. Pre-contrast SE T1-weighted images in the axial and sagittal sections and T2-weighted fat-suppressed fast SE images in the axial and coronal planes were obtained. All of the image planes were scanned using 4-mm-thick slices with a 1-mm intersection gap. After intravenous Gd-DTPA injection at a dose of 0.1 mmol per kg of body weight, T1-weighted fat-suppressed axial, sagittal, and coronal sequences were performed using 4-mm thick slices with a 1-mm intersection gap.
Image assessment and criteria for prepontine cistern invasion The MRI results were independently evaluated by two experienced radiologists and one head and neck cancer specialist. Any disagreement was resolved by consensus. The diagnostic criteria for prepontine cistern invasion were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern with a convex configuration rather than the original concave border of the posterior clival wall (Fig. 1).
Statistical analysis The following endpoints were evaluated: progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS). The failure of PFS was local, regional, or distant progression or death as a result of any cause. Survival was defined as the time between the date of RT initiation and the date of failure or last follow-up. The survival function was estimated using the Kaplan–Meier method. Univariate analysis was performed using the log-rank test. The chi-square test was used to compare the clinical features between the T4 patients with and without PPCI. Multivariate analysis using the Cox proportional hazard model was used to calculate the hazard ratio (HR) with a 95% confidence interval (95% CI) and to test independent significance by backward elimination of insignificant explanatory variables. In the multivariate analysis, the following parameters were included in the model as the covariates for each analysis: age (
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Prognostic value of prepontine cistern invasion in nasopharyngeal carcinoma treated by intensity-modulated radiotherapy Tsung-Min Hung a, Chien-Cheng Chen b, Chien-Yu Lin a, Shu-Hang Ng b, Chung-Jan Kang c, Shiang-Fu Huang c, Chun-Ta Liao c, Kang-Hsing Fan a, Hung-Ming Wang d,⇑, Joseph Tung-Chieh Chang a,⇑ a
Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan d Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan b c
a r t i c l e
i n f o
Article history: Received 27 August 2013 Received in revised form 3 December 2013 Accepted 6 December 2013 Available online 6 January 2014 Keywords: Nasopharyngeal carcinoma Intensity-modulated radiotherapy Prognosis Prepontine cistern invasion Distant metastasis Intracranial extension Head and neck cancer
s u m m a r y Objectives: To investigate the prognostic value of prepontine cistern invasion (PPCI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Materials and methods: Five hundred and four non-disseminated NPC patients who underwent magnetic resonance imaging examination before radical IMRT between November 2000 and December 2008 were retrospectively reviewed. The diagnostic criteria for PPCI were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern. Results: The median follow-up of the patients in this study was 63.5 months. PPCI was found in 44 patients (25% of T4 patients). The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) of all patients, with and without PPCI, were 44.3% and 70.5% (p < 0.001), 84.4% and 89.1% (p = 0.376), 66.6% and 87.3% (p < 0.001), and 59.6% and 80.2% (p < 0.001), respectively. In T4 patients with PPCI and without PPCI, the 5-year PFS, LC, DMFS, and OS were 44.3% and 62.5% (p = 0.023), 84.4% and 84.9% (p = 0.946), 66.6% and 83.1% (p = 0.022), and 59.6% and 71.0% (p = 0.045), respectively. Using multivariate analysis, PPCI was found to be an independent poor prognostic factor for PFS (HR = 1.816; p = 0.007), DMFS (HR = 1.928; p = 0.045), and OS (HR = 1.798; p = 0.016). Conclusion: Prepontine cistern invasion was an independent prognostic factor for poor DMFS and OS but not LC in NPC patients treated with IMRT, even within T4 patients. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Nasopharyngeal carcinoma (NPC) is radiosensitive and is mainly treated by radiotherapy (RT). Recently, a new RT technique, intensity-modulated radiotherapy (IMRT), has been shown to achieve very good local tumor control [1–6]. No prominent differences were observed between the local control provided by IMRT for various primary tumor (T) categories; one study showed that, following IMRT, only T4 NPC had poor local control [4], whereas two other studies found no significant differences in local control between the various T categories of NPC [5,6]. These results indicate that IMRT can achieve better target coverage than 2D RT techniques. However, suboptimal target coverage
may occur with IMRT if the target is near a critical organ to prevent serious complications. The brainstem is an important critical organ in the treatment of NPC. Tumors with prepontine cistern invasion may have inadequate RT dose coverage in the region near the brainstem owing to the target being very close to the critical organ. This study was undertaken to evaluate the prognostic value of prepontine cistern invasion (PPCI) in NPC patients treated with IMRT, as well as to determine whether patients with or without PPCI have different treatment outcomes and disease failure patterns. Materials and methods Patients
⇑ Corresponding authors. Address: Department of Radiation Oncology, Division of Medical Oncology, Department of Internal Medicine, Taipei Chang Gung Head and Neck Oncology Group, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan, Taiwan. Tel.: +886 3 3281200x2613; fax: +886 3 3280797. E-mail addresses: [email protected], [email protected] (J.T-C. Chang). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.12.005
This study was approved by the Institutional Review Board of our hospital. Five hundred and four NPC patients with biopsy-proven, non-disseminated, newly diagnosed NPC who underwent magnetic resonance imaging examination before radical IMRT between
T.-M. Hung et al. / Oral Oncology 50 (2014) 228–233
November 2000 and December 2008 were retrospectively reviewed. The characteristics of all patients were summarized in Table 1, and T4 patients with and without PPCI were in Table 2. The pretreatment evaluation included head and neck magnetic resonance imaging (MRI), nasopharyngeal fiberoscopy, a bone scan, a chest X-ray (CXR), and abdominal sonography. The bone scan was optional when [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was performed. A total of 437 (86.7%) patients underwent a PET study before treatment. All patients were restaged according to the seventh edition of the American Joint Committee on Cancer (7th AJCC) staging system. Primary treatment consisted of RT alone or cisplatin-based chemoradiotherapy (CCRT), according to the tumor stage. The reasons for patients with advanced disease did not receive CCRT were medical comorbidities or patient refusal. Thirty-one stage IVA–B patients, who were participating in a randomized trial, received epirubicin-based induction chemotherapy before cisplatin-based CCRT. The median radiation dose was 72 Gy (range, 70–76 Gy), and IMRT was used in all patients. Ideally, the maximum dose to the brainstem was below 54 Gy; however, exposure of 61% of the brainstem volume to 60 Gy was acceptable if the target was very close to the brainstem. All patients were followed-up in the outpatient clinic every 1–3 months in the first and second year, every 4–6 months during the third to fifth years, and then every 6–12 months thereafter. Flexible nasopharyngeal fiberoscopy was performed during each visit. Head-and-neck MRI, a CXR, and a bone scan were performed 3 months after the treatment was completed. Any suspected residual or recurrent lesions were biopsied to confirm the disease; however, if the biopsy was not feasible or yielded a negative result, a follow-up MRI study was performed after approximately 3 months. Computed tomography that included the head, neck, lung, and liver was performed annually or when clinically indicated during
Table 1 Patient characteristics in all patients (n = 504). Characteristic Age (years) Median Range Gender Male Female Pathology classification Keratinizing Non-keratinizing T category T1 T2 T3 T4 N category N0 N1 N2 N3 Clinical stage I II III IVA–B Treatment modality RT alone CCRT Chemo + CCRT Prepontine cistern invasion Yes No
No. (%) 48.6 15–84 355 (70.4) 149 (29.6) 45 (8.9) 459 (91.1) 218 (43.3) 41 (8.1) 69 (13.7) 176 (34.9) 46 (9.1) 209 (41.5) 156 (31.0) 93 (18.5) 17 (3.4) 124 (24.6) 155 (30.8) 208 (41.3) 56 (11.1) 417 (82.7) 31 (6.2) 44 (8.7) 460 (91.3)
Abbreviations: RT, radiotherapy; CCRT, concurrent chemoradiation; Chemo + CCRT, induction chemotherapy and concurrent chemoradiation.
229
the follow-up period. The disease recurrence was confirmed by image-guided biopsy if possible and close clinical or image follow-up was pursued if a biopsy was not feasible or yielded a negative result. A PET study, for disease re-staging, was suggested for patients with disease relapse. Patients who developed distant metastases were still observed for local or regional disease relapse. For patients with relapse, salvage treatment (RT, surgery, or chemotherapy) was provided for those individuals with a good performance status, and the decision about treatment type was based on the patient preference.
Magnetic resonance imaging MRI was performed with two 1.5-Tesla units (Vision, Siemens Medical Solutions, Erlangen, Germany; Intera, Phillips Medical Systems, Best, The Netherlands) and one 3.0-Tesla unit (Tim Trio, Siemens Medical Solutions, Erlangen, Germany) using the spin-echo (SE) technique. All patients underwent MRI before and after gadolinium–diethylenetriamine pentaacetic acid (Gd–DTPA) injection. The scanning field of view ranged from the superior margin of the temporal lobe to the level of the supraclavicular fossa with a head and neck coil. Pre-contrast SE T1-weighted images in the axial and sagittal sections and T2-weighted fat-suppressed fast SE images in the axial and coronal planes were obtained. All of the image planes were scanned using 4-mm-thick slices with a 1-mm intersection gap. After intravenous Gd-DTPA injection at a dose of 0.1 mmol per kg of body weight, T1-weighted fat-suppressed axial, sagittal, and coronal sequences were performed using 4-mm thick slices with a 1-mm intersection gap.
Image assessment and criteria for prepontine cistern invasion The MRI results were independently evaluated by two experienced radiologists and one head and neck cancer specialist. Any disagreement was resolved by consensus. The diagnostic criteria for prepontine cistern invasion were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern with a convex configuration rather than the original concave border of the posterior clival wall (Fig. 1).
Statistical analysis The following endpoints were evaluated: progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS). The failure of PFS was local, regional, or distant progression or death as a result of any cause. Survival was defined as the time between the date of RT initiation and the date of failure or last follow-up. The survival function was estimated using the Kaplan–Meier method. Univariate analysis was performed using the log-rank test. The chi-square test was used to compare the clinical features between the T4 patients with and without PPCI. Multivariate analysis using the Cox proportional hazard model was used to calculate the hazard ratio (HR) with a 95% confidence interval (95% CI) and to test independent significance by backward elimination of insignificant explanatory variables. In the multivariate analysis, the following parameters were included in the model as the covariates for each analysis: age (
