Won Kyung Cho and Dongryul Oh contributed equally to this work.
This study aimed to report the clinical outcomes following selective neck irradiation (SNI) with lower elective radiation therapy (RT) dose in treating nasopharyngeal cancer (NPC) patients.
A total of 347 NPC patients received definitive RT according to our SNI policy and were retrospectively analyzed. The clinical target volumes (CTVs) were subdivided into CTV at high risk (CTV-HR) and CTV at low risk (CTV-LR). The typical doses to gross tumor volume (GTV), CTV-HR, and CTV-LR were 68.4-70.0 Gy, 54.0-60.0 Gy, and 36.0 Gy.
With the median follow-up of 68.1 months (range, 2.3 to 197.1 months), the 5-year rates of loco-regional control and progression-free survival in all the patients were 85.0% and 70.8%, respectively. Thirty patients developed regional failure and the regional control rates at 3 and 5 years were 92.6% and 91.4%, respectively. The sites of regional failure in relation to the target volume were exclusively inside GTV/CTV-HR in 20, inside and outside GTV/CTVHR in three, and exclusively outside GTV/CTV-HR in seven, which were 5.7%, 0.9%, and 2.0% of total patients, respectively.
The clinical outcomes by the current SNI policy were feasible and comparable to those following classic elective nodal irradiation policy.
Radiation therapy (RT) has long been the mainstay treatment for the patients with non-metastatic nasopharynx cancer (NPC), which can lead to 62%-80% of 5-year overall survival (OS) rate [
NPC is associated with lymph node (LN) metastasis frequently (60%-90%) at time of diagnosis [
Our institution has employed the SNI policy with lower radiation dose in treating the NPC patients for longer than two decades, and the current study is to report our experiences of the clinical outcomes and toxicities.
After approval by the institutional review board, 347 patients who received definitive RT for newly diagnosed non-metastatic NPC from January 2001 to December 2015 were retrospectively reviewed. All patients underwent thorough physical examination, histopathologic confirmation, and computed tomography (CT) scan of the head and neck region. Magnetic resonance imaging was done in 108 patients (31.1%), in whom the skull base and/or intracranial invasion was suspected. Systemic staging work-up’s during the early study period included whole body bone scintigraphy and abdominal ultrasonography in 54 patients (15.6%), which were later replaced by whole-body 5-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET-CT) in 293 (84.4%). Clinical T-stage (cT) and clinical N-stage (cN) categories were allocated according to the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual [
All the patients underwent CT simulation. The delineation of the gross tumor volume (GTV) of the primary tumor and LN was done with reference to all the clinically available information including physical examination and imaging studies. The diagnosis of metastatic LNs was based either on cyto-histologic confirmation or on more than one of the following radiologic criteria: short axis ≥ 1 cm (cervical LN) or ≥ 6 mm (retropharyngeal LN); findings of contrast enhancement, round shape, central nodal necrosis, and/or irregular margin with infiltration to the surrounding structure; and evident FDG uptake regardless of the LN size [
The majority of patients (n=289, 83.3%) were treated by RT combined with chemotherapy, while RT alone was delivered to 58 patients (16.7%), who either had cT1-2N0 disease or medical comorbidities contraindicating chemotherapy (
During the early part of the current study, 3DCRT was the main technique applied to 152 patients (43.8%). By serial shrinking and adaptive re-plans, twice during the course, the typical doses delivered to GTV, CTV-HR, and CTV-LR were 70.0 Gy, 54.0 Gy, and 36.0 Gy over 7 weeks by daily 1.8 Gy or 2.0 Gy per fraction, respectively. During the later part, when the Korean Health Insurance Policy began to cover the IMRT cost, IMRT by helical tomotherapy was mainly used to treat 195 patients (56.2%). The simultaneous integrated boost and adaptive re-plan were employed when using IMRT, and the typical doses to GTV, CTV-HR, and CTV-LR were 68.4 Gy, 60.0 Gy, and 36.0 Gy over 6 weeks, respectively. The typical fractional dose to GTV and CTV were 2.2 Gy and 2.0 Gy during the first 18 fractions and 2.4 Gy and 2.0 Gy during the remaining 12 fractions.
The first clinical evaluation was done with CT scan taken in 1 month of RT completion, and the second evaluation was done with PET-CT in 3 months of the first evaluation. The subsequent follow-up evaluations were scheduled at every 3-4 months’ interval during the first 2 years, at every 6 months’ interval during the third year, and then annually thereafter. Loco-regional failure was defined as the reappearance or new lesion development at the primary site and/or regional lymphatics. The durations of loco-regional control (LRC), progression-free survival (PFS), and OS were calculated from the date of RT start till the date of the event or the last follow-up. The rates of LRC, PFS, and OS were calculated using the Kaplan-Meier methods. All the analyses were conducted using the SPSS Statistics ver. 20 (IBM Corp., Armonk, NY).
The study was approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2011-11-105-002) and performed in accordance with the principles of the Declaration of Helsinki. The informed consent was waived.
The patients’ characteristics are summarized in
The median follow-up duration was 68.1 months (range, 2.3 to 197.1 months), during which 100 patients (28.8%) developed disease progression and 83 (23.9%) died, respectively. The 5-year rates of LRC, PFS, and OS were 85.0%, 70.8%, and 81.1%, respectively. Distant metastasis was the most common component observed in 59 patients (17.1%), followed by components of regional and local failures in 30 (8.7%) and 28 (8.1%), respectively (
The sites of regional failure in 30 patients were classified in relation to the target volumes: failure exclusively within CTV-HR in 20 (5.7%); failure synchronously inside and outside CTV-HR in three (0.9%); and failure exclusively outside CTV-HR in seven (2.0%), respectively (
Most previous clinical trials regarding NPC treatment advocated the routine bilateral entire neck irradiation from the retropharyngeal LNs to the level IV/V [
The current guidelines regarding the ENI volume delineation are based on the anatomic landmarks which include the hyoid bone, cricoid cartilage, posterior margin of the sternocleidomastoid muscle, and the line between shoulder and neck junction to medial clavicle end [
The ENI dose of 44-64 Gy to the clinically uninvolved lymphatics has usually been recommended in most head and neck cancer types [
In addition, there were several clinical studies that addressed the feasibility of lower ENI dose in treating head and neck cancer [
One may raise an argument in that one should not take the risk of recurrence by reducing ENI volume and dose, as the RT toxicities may not be severe if IMRT is used. However, a recent study regarding the oral health quality of the head and neck cancer patients following IMRT reported that the salivary flow was recovered only by 40% and suggested that further reduced dose to the salivary glands is warranted [
Despite the retrospective nature, the current study is the first one reporting the clinical outcomes following reduced ENI volume and lower ENI dose of 36 Gy in treating the NPC patients. The clinical outcomes of the current study could support the feasibility of authors’ policy of SNI with lower elective dose in treating nasopharyngeal cancer. Thorough image evaluation and meticulous peer review in target delineation process are deemed integral points for the successful execution of the SNI policy. Larger prospective clinical trials, however, might be warranted to endorse our conclusions.
Conflict of interest relevant to this article was not reported.
The policy of selective neck irradiation with differential radiation dose plan employed in the current study is illustrated: (A) 66-72 Gy to gross tumor volume (GTV) of primary tumor and metastatic lymph nodes; (B) 54-60 Gy to clinical target volume at high risk (CTV-HR) that included 1.0-1.5 cm margin to nodal GTV; and (C) 36 Gy to clinical target volume at low risk (CTV-LR) that included 2-2.5 cm distal margin from CTV-HR.
Patterns of failure in 100 patients.
The sites of regional failures in relation to target volume and detail of seven patients who developed regional failure in or outside clinical target volume at low risk (CTV-LR). GTV, gross tumor volume; CTV-HR, clinical target volume at high risk. RT, radiotherapy; NED, no evidence of disease; DOD, dead of disease; M, male.
Patients’ characteristics
Characteristic | No. (%) (n=347) |
---|---|
51 (16-86) | |
Male | 267 (76.9) |
Female | 80 (23.1) |
ECOG 0-1 | 336 (96.8) |
ECOG 2 | 11 (3.2) |
Keratinizing squamous cell carcinoma | 56 (17.0) |
Non-keratinizing carcinoma, differentiated type | 67 (20.4) |
Undifferentiated carcinoma | 197 (59.9) |
Unclassified | 9 (2.7) |
CT | 3 (0.9) |
CT, MRI | 51 (14.7) |
CT, FDG-PET | 236 (68.0) |
CT, MRI, FDG-PET | 57 (16.4) |
cT1 | 157 (45.2) |
cT2 | 45 (13.0) |
cT3 | 80 (23.1) |
cT4 | 65 (18.7) |
cN0 | 50 (14.4) |
cN1 | 97 (28.0) |
cN2 | 148 (42.7) |
cN3 | 52 (15.0) |
RT alone | 58 (16.7) |
NAC+RT | 1 (0.3) |
CCRT alone | 188 (54.2) |
NAC+CCRT | 10 (2.9) |
CCRT+AC | 89 (25.6) |
NAC+CCRT+AC | 1 (0.3) |
3D-CRT | 152 (43.8) |
IMRT | 195 (56.2) |
ECOG, Eastern Cooperative Oncology Group; CT, computed tomography; MRI, magnetic resonance imaging; FDG, 5-fluorodeoxyglucose; PET, positron emission tomography; RT, radiation therapy; NAC, neoadjuvant chemotherapy; CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; 3D-CRT, 3 dimensional conformal RT; IMRT, intensity-modulated RT.
Comparison of regional control rates and survival between the current study and other studies employing entire neck irradiation
Study | No. of patients | Median FU (mo) | Regional control rate | Survival outcomes (%) |
---|---|---|---|---|
Wolden et al. (2006) [ |
74 | 35 | 93% at 3 yr | OS 83 at 3 yr |
DFS 67 at 3 yr | ||||
Wong et al. (2010) [ |
175 | 34 | 93.3% at 3 yr | OS 87.2 at 3 yr |
DMFS 86.6 at 3 yr | ||||
Wang et al. (2013) [ |
300 | 80.2 | 95.1% at 4 yr | OS 96.1 at 4 yr |
DMFS 87.4 at 4 yr | ||||
Au et al. (2018) [ |
3,328 | 80.2 | 91.5% at 8 yr | OS 68.5 at 8 yr |
DFS 62.6 at 8 yr | ||||
Current study | 347 | 68.1 | 92.6% at 3 yr | OS 87.1 at 3 yr |
DFS 74.7 at 3 yr |
FU, follow-up; OS, overall survival; DFS, disease-free survival; DMFS, distant metastasis-free survival.