Research Article

Research Article

Present status and advances in target delineation for intensity-modulated radiotherapy of nasopharyngeal carcinoma

Jin-Feng Rong and Jing-Bo Wu

Department of Oncology, First Affiliated Hospital of Sichuan Medical University, Luzhou, China

Corresponding author: Dr. Jing-Bo Wu, 25 TaiPing Rd., Luzhou 646000, China. Tel: (+86) 1398-0257136; E-mail: wjb6147@163.com


Citation: Rong JF, Wu JB. Present status and advances in target delineation for intensity-modulated radiotherapy of nasopharyngeal carcinoma. J Nasopharyng Carcinoma, 2016, 3(1): e29. doi:10.15383/jnpc.29.

Competing interests: The authors have declared that no competing interests exist.

Conflict of interest: None

Copyright: 2016 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


 

 

 

 



 

Abstract:

The treatment of nasopharyngeal carcinoma (NPC) has improved significantly owing to advances in radiation therapy, such as intensity-modulated radiotherapy (IMRT). However, the optimal delineation of the target area remains the subject of debate and continued study. Herein, we discuss the role of IMRT, and review recent studies demonstrating the benefits of decreasing clinical target volume according to the locoregional extension patterns of NPC as well as the benefits of target delineation on the basis of cervical fascia anatomy along with the benefits of replanning IMRT with neoadjuvant chemotherapy. Significant advances have been observed, and we anticipate further continued advances.

Keywords: nasopharyngeal carcinoma; intensity-modulated radiotherapy

 


Introduction

Nasopharyngeal carcinoma (NPC) is a common disease worldwide and radiotherapy is the mainstay of therapy for patients with this condition. Recent advances in the use of intensity-modulated radiotherapy (IMRT) have significantly improved the quality of life and prognosis of patients with nasopharyngeal carcinoma[1][2]. Phua Chee Ee et al.[3] have reported that IMRT possesses superiority in target coverage and normal tissue sparing when compared to two-dimensional radiotherapy and three-dimensional conformal radiotherapy. Rong et al.[4] and Wiezorek et al.[5] have reported that compared to traditional IMRT, helical tomotherapy, as an emerging technology of IMRT, achieved better target coverage with improved organ at risk sparing. However, several key issues in IMRT require further clarification, such as target delineation. Because of the unique anatomical position of the nasopharynx, with its many important surrounding structures, optimal target design to maximize the protection of normal tissues without compromising treatment results has become the subject of much recent research.

Target design

IMRT is a highly accurate technique of radiotherapy, delivered three-dimensionally in the precisely determined shape of the object to be irradiated. Therefore, accurate identification and sketching of the target object are important.

Gross tumor volume

Gross tumor volume (GTV) refers to the extent of tumor found in clinical and imaging examinations. GTV includes both the primary tumor and metastatic lymph nodes (LNs). The GTV in IMRT planning for NPC includes the primary tumor, retropharyngeal lymph nodes (RLNs), and all metastatic cervical LNs (CLNs). The diagnostic criteria for LN metastases[6] include a) any lateral RLN with a minimal axial diameter (MID) of ≥5 mm in the largest plane or any node in the median retropharyngeal group; b) a CLN in the jugulodigastric region with a MID ≥11 mm or any other CLN ≥10 mm; c) LNs of any size with central necrosis or a contrast-enhanced rim; d) nodal grouping, the presence of three or more aggregated LNs, each having an MID of 810 mm; and e) LNs of any size with extracapsular spread as characterized by irregular LN capsular enhancement, obliterated fat space between the node and adjacent tissues, and/or confluent LNs.

Clinical target volume

The clinical target volume (CTV) in IMRT planning for NPC includes CTV1 and CTV2. CTV1 is defined as high-risk regions including GTV (the primary tumor and RLN) with a 510-mm margin and the entire nasopharyngeal mucosa with a 5-mm submucosal volume.

CTV2 includes the low-risk areas of the nasopharynx and neck that require prophylactic irradiation; however, the optimal region to be irradiated remains controversial. At treatment centers in North America[7] and Singapore[8], CTV2 includes the entire nasopharynx, the posterior 1/4 to 1/3 of the nasal cavity, the maxillary sinuses, the parapharyngeal space, the pterygoid fossae, the anterior 1/2 to 2/3 of the clivus (the entire clivus, if involved), the skull base (foramen ovale on both sides), the inferior sphenoid sinus, the cavernous sinus, the retropharyngeal region (RP) on both sides, and levels II-V. The method of CTV2 delineation encompasses most anatomic sites surrounding the nasopharynx on both sides and does not differ according to the clinical stage. Thus, this method of delineation is suboptimal and lacks individualization.

The 2010 Chinese Consensus Guidelines for NPC IMRT planning[9] recommend that CTV2 should contain CTV1 as well as some high-risk structures based on the extend of tumor invasion, such as the posterior part of the nasal cavity and maxillary sinuses, the pterygopalatine fossa, the posterior part of the ethmoid sinus, the parapharyngeal space, the skull base (inferior sphenoid sinus, foramen lacerum, and foramen ovale), a part of the cervical vertebra, and the clivus. In the Consensus Guidelines, RLNs are separated from CLNs and it is proposed that the CTV2 of the RLN should refer to that of the primary tumor because of their close proximity. For patients with N0 disease, CTV2 should only include the RP on both sides and levels II, III, and Va. With unilateral LN involvement, CTV2 can include the entire ipsilateral neck and the contralateral RP and levels II, III, and Va; for LN involvement on both sides, the entire neck should be included.

Biological target volume

Biological target volume (BTV) refers to a target zone determined on the basis of a series of tumor biological factors influencing the radiation sensitivity of different areas of the tumor.In general, these factors include a lack of oxygen and blood supply; cellular proliferation, apoptosis and cell cycle regulation; oncogene and tumor suppressor gene mutations; tumor invasion; and the characteristics of tumor metastasis. Research in this field is very limited. Wen et al.[10] have proposed that the biological boosting target volume in patients with locally advanced NPC may include skull base dose-deficient, hypoxia, and tumor-burden volume.

Recent research on target reduction

Ng et al.[11] analyzed the patterns of locoregional failure after IMRT in 193 NPC patients and found that most locoregional failure occurred in field (within the 95% isodose lines), whereas marginal or outside field failure was uncommon. Orlandi et al.[12] reported similar results in 106 NPC patients who received IMRT. Therefore, the selective reduction of CTV2 volume to better protect normal tissues without affecting local tumor control has become a research focus in the field of IMRT planning for NPC.

Decreasing CTV according to the locoregional extension patterns of NPC

Ho et al.[13] studied the magnetic resonance (MR) images of 2920 NPC cases with a meta-analysis. They found that 85% of NPC cases presented with lymphadenopathy. The most commonly involved regions included the RLNs (69%) and level II LNs (70%). The overall probability of level III, IV, and V nodal involvement was 45%, 11%, and 27%, respectively. Levels IA/IB and VI nodal involvement rates were less than 3%. Nodal metastases followed an orderly pattern and the probability of skip metastasis between levels is 0.57.9%. According to these results, they hypothesized that limiting coverage to the RP and levels II, III, and Va nodes in patients with N0 disease or limiting coverage on the uninvolved neck in patients with N1 disease would not compromise regional control rates and disease-free survival, similar to the 2010 Chinese Consensus Guidelines. They also believed that the rarity of skip metastasis in NPC lymphatic drainage provides a basis to eliminate irradiation to the entire involved side of the neck, and requires only the irradiation of the area inferior to the involved level. Li et al.[14] analyzed 1920 NPC patients with positive LNs. The incidence rates of LN metastasis in the upper (RP and level II), middle (levels III and Va), and lower neck (levels IV, Vb, and supraclavicular fossa) were 99.6%, 30.2%, and 7.2%, respectively. Skip metastasis occurred in only 1.2% of patients. These findings are similar to those of Ho. They recommended a delineation of nodal CTV2 in accordance with the 2010 Chinese Consensus Guidelines. However, they proposed that the nodal CTV2 for patients with RLN metastasis should be the same as that for patients with level II involvement. Sun et al.[15] investigated 112 NPC patients who had a lateralized primary lesion. Of those, only 8% of patients had contralateral lymphadenopathy, and the most commonly involved regions were the retropharynx or level II. In patients with lateralized primary NPC, reduced cervical CTV coverage, including the contralateral level II, is feasible. This may help to better protect the cervical organs at risk, including the thyroid, larynx, and esophagus.

Target definition based on cervical fascia anatomy

According to the 2013 updated consensus guidelines[16], the boundary of the level II LNs is defined by the cranial-caudal edge of the C1 transverse process, the caudal-caudal edge of the hyoid bone, the lateral-deep surface of the sternocleidomastoid muscle, the medial-medial edge of the internal carotid artery/levator scapulae muscle, the anterior-posterior edge of the internal jugular vein, and the posterior-posterior edge of the sternocleidomastoid muscle. Wang et al.[17] retrospectively reviewed the MR images of 2679 NPC cases with LN involvement. Of the patients with level II disease, the upper border of metastatic nodes in 25.9% of cases was beyond the caudal edge of C1. Therefore, the suggested upper border of level II does not include all the involved level II nodes. Zhang et al.[18] collected the MR images of 100 serial cases of NPC with IIb positive LNs and analyzed the node distribution within level IIb and its adjacent area, along with the anatomy of the deep cervical fascia in the upper neck. On the basis of their studies, they proposed that the cranial-cranial edge of C1, the medial-lateral edge of the rectus capitis lateralis muscle, the obliquus capitis superior muscle, the obliquus capitis inferior muscle, the levator scapulae muscle, the posterior-at the C1 and C2 levels, and the gap between the sternocleidomastoid and splenius capitis muscle could be removed from CTV. They suggested that the impact on organs at risk could be minimized in a well-designed intensity-modified treatment plan based on cervical fascia anatomy. Kawashima et al.[19] reported that in 40 locally advanced NPC cases receiving IMRT, local control, locoregional control, and overall survival rates at 3 years were 91%, 89%, and 87%, respectively. Target definition along anatomically defined boundaries reduced the CTV without compromise of the therapeutic ratio.

Neoadjuvant chemotherapy and replanning intensity-modulated radiotherapy to reduce GTV

Niu et al.[20] retrospectively studied 32 patients with intracranial invasive NPC treated with TPF (75 mg/m2 docetaxel, 75 mg/m2 cisplatin, and 2500 mg/m2 5-FU every 3 weeks for 3 cycles) neoadjuvant chemotherapy and replanning IMRT with concurrent chemotherapy. When a safe margin between the target and the critical normal tissues existed, the outline of the GTV of the primary tumor (GTV-P) and the high-risk CTV (CTV-H) were mainly based on the enhanced MR images obtained before the neoadjuvant chemotherapy, and less frequently on the enhanced MR images obtained after neoadjuvant chemotherapy. Before the 23rd fraction of IMRT, a new nasopharyngeal enhanced MR study was acquired for all patients. The GTV-P and CTV-H were modified based on the tumor shrinkage shown on the new nasopharyngeal enhanced MR study and were reoutlined on the original computer tomography simulation scan. Objective responses were 93.7% (CR 15.6%) and 100% (CR 12%) for the primary tumor and CLNs, respectively, after neoadjuvant chemotherapy. The objective response rate was 100.0% for both the primary tumor and the CLNs 3 months after the completion of radiotherapy. Replanning IMRT reduced doses to the brain stem, optic nerve, optic chiasm, and temporal lobe. The 2-year local control rates and distant-metastasis free survival rates were 88.2% and 89.6%, respectively. Neoadjuvant chemotherapy and replanning IMRT according to tumor shrinkage during the treatment is essential to ensure reduced doses to normal tissues, and produces encouraging outcomes for NPC with intracranial invasion.

Problems and prospects

IMRT of NPC has undergone a rapid evolution, but some challenges remain, such as optimizing target delineation and determining the main causes of local failure. Recently, there have been various attempts to reduce target delineation, although the short-term effects have been encouraging, the follow-up time is only 23 years; further studies with longer follow-up are necessary. Furthermore, with ongoing advances in medicine and technology, more advanced radiotherapy techniques will emerge. One such technique, Volume-Modulated Arc Therapy, has achieved very high locoregional control with a favorable toxicity profile for patients with NPC[21]. We anticipate that the treatment of nasopharyngeal carcinoma will continue to improve.

Conflict of interest disclosures

The authors made no disclosures.

References

[1] Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, Sun Y, Lin AH, Liu MZ, Ma J.

How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2011;80:661-668.

[2] Peng G, Wang T, Yang KY, Zhang S, Zhang T, Li Q, Han J, Wu G. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol 2012;104:286-293.

[3] Phua Chee Ee V, Tan BS, Tan AL, Eng KY, Ng BS, Ung NM. Dose planning study of target volume coverage with intensity- modulated radiotherapy for nasopharyngeal carcinoma: Penang General Hospital experience. Asian Pac J Cancer Prev

2013;14:2243-2248.

[4] Rong Y, Tang G, Welsh JS, Mohiuddin MM, Paliwal B, Yu CX. Helical tomotherapy versus single-arc intensity-modulated arc therapy: a collaborative dosimetric comparison between two institutions. Int J Radiat Oncol Biol Phys 2011;81:284-296.

[5] Wiezorek T, Brachwitz T, Georg D, Blank E, Fotina I, Habl G, Kretschmer M, Lutters G, Salz H, Schubert K, Wagner D, Wendt TG. Rotational IMRT techniques compared to fixed gantry IMRT and tomotherapy: multi-institutional planning study for head-and-neck cases. Radiat Oncol 2011;6:20.

[6] Tang L, Li L, Mao Y, Liu L, Liang S, Chen Y, Sun Y, Liao X, Tian L, Lin A, Liu M, Ma J. Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma detected by magnetic resonance imaging: prognostic value and staging categories. Cancer 2008;113:347-354.

[7] Lee NY, Zhang Q, Pfister DG, Kim J, Garden AS, Mechalakos J, Hu K, Le QT, Colevas AD, Glisson BS, Chan AT, Ang KK. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol 2012;13:172-180.

[8] Tham IW, Hee SW, Yeo RM, Salleh PB, Lee J, Tan TW, Fong KW, Chua ET, Wee JT. Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the national cancer centre Singapore experience. Int J Radiat Oncol Biol Phys 2009;75:1481-1486.

[9] Committee of Chinese Clinical Staging of Nasopharyngeal Carcinoma. 2010 Consensus Guidelines for intensity-modulated radiotherapy target volume and dosimetric planning in nasopharyngeal carcinoma. Chin J Radiat Oncol 2011,20:267-269. [in Chinese]

[10] Wen G, Huang XB, Zhang WD, Lin XP, He ZC, Xia YF. [Primary exploration of individual biological boosting target volume for locally advanced nasopharyngeal carcinoma]. Zhonghua Yi Xue Za Zhi. 2012;92:3207-3210. Chinese.

[11] Ng WT, Lee MC, Hung WM, Choi CW, Lee KC, Chan OS, Lee AW. Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011;79:420-428.

[12] Orlandi E, Tomatis S, Potepan P, Bossi P, Mongioj V, Carrara M, Palazzi M, Franceschini M, Bergamini C, Locati L, Iannacone E, Guzzo M, Ibba T, Crippa F, Licitra L, Pignoli E, Fallai C. Critical analysis of locoregional failures following intensity-modulated radiotherapy for nasopharyngeal carcinoma. Future Oncol 2013;9:103-114.

[13] Ho FC, Tham IW, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence. BMC Cancer 2012;12:98. doi: 10.1186/1471-2407-12-98.

[14] Li WF, Sun Y, Chen M, Tang LL, Liu LZ, Mao YP, Chen L, Zhou GQ, Li L, Ma J. Locoregional extension patterns of nasopharyngeal carcinoma and suggestions for clinical target volume delineation. Chin J Cancer 2012;31:579-587.

[15] Sun Y, Yu XL, Zhang GS, Liu YM, Tao CJ, Guo R, Tang LL, Zhang R, Guo Y, Ma J. Reduction of clinical target volume in patients with lateralized cancer of the nasopharynx and without contralateral lymph node metastasis receiving intensity-modulated radiotherapy. Head Neck 2015 Feb 9. doi: 10.1002/hed.24020. 

[16] Grgoire V, Ang K, Budach W, Grau C, Hamoir M, Langendijk JA, Lee A, Le QT, Maingon P, Nutting C, O'Sullivan B, Porceddu SV, Lengele B. Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines. Radiother Oncol 2014;110:172-181.

[17] Wang X, Hu C, Ying H, He X, Zhu G, Kong L, Ding J. Patterns of lymph node metastasis from nasopharyngeal carcinoma based on the 2013 updated consensus guidelines for neck node levels. Radiother Oncol 2015;115:41-45.

[18] Zhang J, Pan L, Ren J, Lang J, Wen H, Wang J, Zhang S. Level IIb CTV delineation based on cervical fascia anatomy in nasopharyngeal cancer. Radiother Oncol 2015;115:46-49.

[19] Kawashima M, Ariji T, Kameoka S, Ueda T, Kohno R, Nishio T, Arahira S, Motegi A, Zenda S, Akimoto T, Tahara M, Hayashi R. Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition. Jpn J Clin Oncol 2013;43:1218-1225.

[20] Niu X, Chang X, Gao Y, Hu C, Kong L. Using neoadjuvant chemotherapy and replanning intensity-modulated radiotherapy for nasopharyngeal carcinoma with intracranial invasion to protect critical normal tissue. Radiat Oncol 2013;8:226.

[21] Guo R, Tang LL, Mao YP, Zhou GQ, Qi ZY, Liu LZ, Lin AH, Liu MZ, Ma J, Sun Y. Clinical outcomes of volume-modulated arc therapy in 205 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. PLoS One 2015;10:e0129679.


 

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

eISSN: 2312-0398

Asia Press is a professional Science, Technology and Medicine publisher, who owns rapid publication, Peer-Reviewed, Open Access Journals. Asia Press aims to promote “knowledge sharing”. As you know, the main barrier for free “knowledge sharing” is the cost of publishing and transfer. In order to encourage scholars and scientists to the max, and devote whole power to realize the aim of “knowledge sharing” and the benefit of “all” mankind, Asia Press performs a permanent policy of no charge for publication and access, and always open its door for authors worldwide.

© 2013-2017 by the Asia Press. All rights reserved.