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Intensity modulated radiation therapy in nasopharyngeal carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases 132 (2015) 147–151
Available online at
ScienceDirect www.sciencedirect.com
Review
Intensity modulated radiation therapy in nasopharyngeal carcinoma S. Haberer-Guillerm ∗ , E. Touboul , F. Huguet Département d’oncologie radiothérapie, hôpital Tenon, AP–HP, groupe hospitalier des hôpitaux universitaires de l’Est Parisien (HUEP), faculté de médecine Pierre et Marie Curie, université Paris 6, 4, rue de la Chine, 75020 Paris, France
a r t i c l e
i n f o
Keywords: Nasopharyngeal carcinoma Conformal intensity-modulated radiation therapy Target volumes Late effects Xerostomia
a b s t r a c t Radiation therapy (with associated chemotherapy) is the standard treatment for nasopharyngeal carcinoma. Conformal intensity-modulated radiation therapy is a new and particularly interesting technique for these tumors, due to their complex volumes close to many critical organs. Better dosimetric results and improved protection of adjacent healthy tissue have been shown compared with conventional 2D or 3D radiation therapy, with significantly reduced side-effects, notably xerostomia. Excellent local control rates have been reported. © 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction Nasopharyngeal carcinoma, especially when of the undifferentiated type, differs from other head and neck cancers geographically and ethnically and by its association with Epstein-Barr virus and specific treatment requirements. Treatment is hindered by the anatomic proximity of numerous critical organs, restricting indications for surgery to biopsy for initial histologic diagnosis and to cases of relapse. Radiation therapy (RT) is the keystone of local treatment [1]. In locally advanced cancer, the overall survival benefit of associating radiation therapy and chemotherapy was demonstrated in Baujat et al.’s meta-analysis, especially when the association was concomitant [2]. The efficacy of adjuvant chemotherapy is under assessment, certain retrospective reports suggesting an impact on tumor control [3]. Progress in imaging (magnetic resonance imaging (MRI) and positron emission tomography coupled to computed tomography (PET-CT)) has improved initial extension assessment in nasopharyngeal carcinoma [4], enhancing the precision of RT planning. More recently, conformal intensity-modulated radiation therapy (IMRT) has become standard clinical practice. IMRT uses multiple small radiation beams of varying intensities and shapes thanks to a multileaf collimator. This optimizes tumor area coverage while protecting healthy neighboring organs.
∗ Corresponding author. E-mail address: [email protected] (S. Haberer-Guillerm). http://dx.doi.org/10.1016/j.anorl.2014.02.008 1879-7296/© 2014 Elsevier Masson SAS. All rights reserved.
The present study successively examines the various radiation target volumes and healthy organs to be spared (organs at-risk: OARs) and the fractionation and dose options. We shall also review the data demonstrating the specific benefit of IMRT over 2D and 3D strategies. Finally, we shall report results for local control, and look at foreseeable future developments.
2. Definition of target volumes RT planning requires target volumes to be defined on a CT-scan for dosimetry. This is performed in dorsal decubitus, with a 5-point thermoformed contention mask (immobilization of head, neck and shoulders), without and, if possible, with intravenous iodized contrast injection, and thin (3 mm) slice acquisition from vertex to superior mediastinum. The target volumes to be defined are as follows [5].
2.1. GTV Gross tumor volume (GTV) is the tumor mass visible on clinical examination, endoscopy and imaging. It includes the nasopharyngeal tumor (tumoral GTV) and involved lymph nodes (nodal GTV). GTV after neoadjuvant chemotherapy includes not only the residual volume but the whole initial tumor and involved lymph nodes. Delineation is improved by fusion of the planning CT scan and the initial MRI. However attractive the option may seem, fusion with PET-CT is not recommended in routine practice, for lack of validation in the literature.
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Nasopharyngeal carcinoma being highly lymphophilic, nodal CTV systematically includes bilateral levels II to V (Robbins classification) and the bilateral retropharyngeal lymph-node areas [10,11]. 2.3. PTV Planning target volume (PTV) is delineated geometrically by drawing a 3–5 mm margin around the tumoral or lymph-node CTV, to allow for uncertainty related to patient positioning and systematic or variable internal movement. 2.4. Organs at risk (OARs) Healthy organs are also delineated, to ensure protection: brainstem, brain (temporal lobe and posterior fossa), spinal cord, optic chiasm, cochlea, optic nerves, lens, parotid glands, submandibular glands, mandible, temporomandibular joints, pharyngeal constrictor muscles, larynx, esophagus, and thyroid and pituitary glands. 3. IMRT dose prescription
Fig. 1. Example of CTV definition including nasopharynx, posterior third of nasal cavities and maxillary sinuses (anteriorly), parapharyngeal space (laterally) and clivus and retropharyngeal space (posteriorly).
2.2. CTV Clinical target volume (CTV) includes GTV plus any immediately neighboring microscopic tumor or lymph-node extensions, taking account of the natural extension pathways of nasopharyngeal carcinoma. CTV thus includes: • above: the inferior part of the sphenoid sinus, and the middle cranial fossa, including foramina (ovale and lacerum); • below, the oropharyngeal mucosa; • laterally, the parapharyngeal spaces; • anteriorly, the posterior part of the nasal cavities and the pterygomaxillary fossa; • posteriorly, the retropharyngeal space and clivus [1,6,7] (Figs. 1 and 2).
Some authors also include the cavernous sinus (superiorly), pterygoid muscles and carotid space (laterally) and the posterior third of the maxillary sinuses (anteriorly) in the CTV [7–9].
IMRT uses 5 to 7 radiation beams, with fluence adjusted from fraction to fraction. Planning is inverse: i.e., dose ranges to be delivered to the PTV and OARs are determined initially by the physician, and dosimetry seeks to remain within these predefined limits. IMRT enables a tailored dose to be delivered within the volume to be treated, several CTVs and thus several distinct PTVs being defined. Dose per PTV is determined according to risk of invasion (Fig. 3) [12]. There are a number of IMRT techniques: SIB (Simultaneous Integrated Boost), SMART (Simultaneous Modulated Accelerated Radiation Therapy), or sequential (partially conformal 3D RT and partially IMRT). In SIB the highest dose per fraction is delivered to the highest-risk PTV, which usually includes the GTV, with lower doses to medium or low-risk PTVs. High-risk PTV dose per fraction is around 2 Gy/day. SMART combines integrated boost and accelerated radiation with a smaller number of fractions; high-risk PTV dose per fraction is thus greater than 2.2 Gy/day, and often around 2.3 Gy/fraction [12]. Table 1 shows examples of dose levels and fractionation in nasopharyngeal carcinoma IMRT [13–16]. 4. Dose escalation Retrospective studies of nasopharyngeal carcinoma indicate a tumoricidal dose of ≥ 70 Gy. Dose escalation has been described in nasopharyngeal carcinoma, by brachytherapy or conformal or stereotaxic radiation, but with increased late toxicity [17,18].
Fig. 2. Example of delineation with tumoral GTV (red) and tumoral CTV (pink).
S. Haberer-Guillerm et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 132 (2015) 147–151
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Fig. 3. Example of dosimetry of a nasopharyngeal carcinoma (axial, sagittal and coronal slices). Red: high-risk PTV; dark blue: medium-risk PTV; turquoise: low-risk PTV. Table 1 Examples of fractionation in IMRT.
Technique High-risk PTV Medium-risk PTV Low-risk PTV
Hong Kong [13,15]
RTOG 0225 [14]
MSKCC [16]
SIB 70 Gy in 35 fractions of 2 Gy 63 Gy in 35 fractions of 1.8 Gy 56 Gy in 35 fractions of 1.6 Gy
SIB 70 Gy in 33 fractions of 2.12 Gy 60 Gy in 33 fractions of 1.82 Gy 54 Gy in 33 fractions of 1.64 Gy
SIB/2 plans 70 Gy in 33 fractions of 2.12 Gy 59.4 Gy in 33 fractions of 1.8 Gy 50.4 Gy (3D)
SMART 70.2 Gy in 30 fractions of 2.34 Gy 54 Gy in 30 fractions of 1.8 Gy
SIB: simultaneous integrated boost; SMART: simultaneous modulated accelerated radiation therapy; 3D: 3D conformal radiation therapy.
IMRT appears to be a promising means of increasing PTV doses while sparing OARs. Kwong et al., however, in a series of 50 patients with T3-T4 nasopharyngeal lesions treated by concomitant chemotherapy and RT with IMRT up to 76 Gy by 2.17 Gy fractions, reported 96% locoregional control at 25 months’ follow-up but increased late toxicity, with 4% of patients showing temporal necrosis and 4% severe epistaxis [19]. Late toxicities are mainly due to the increased dose per fraction. Special attention should therefore be paid to the risk of late OAR toxicities in case of dose per fraction exceeding 2 Gy. Thanks to the cellular hypoxia marker 18F-fluoromisonidazole, PET-CT may in future improve the targeting of dose escalation. This marker could indicate hypoxic and radioresistant tumor areas, defining an HTV (hypoxic tumor volume). A dosimetric study in 8 patients by Choi et al. reported a dose escalation in the HTV up to 78 Gy (by 2.6 Gy fractions) to be feasible in 75% of cases [20]. The clinical benefit of this attitude remains to be proven. 5. Benefit of IMRT 5.1. Local control Dosimetric studies demonstrated benefit for IMRT over conformal RT in nasopharyngeal carcinoma, with improved dose homogeneity and PTV coverage [21,22]. Peng et al. [23], in a prospective study, recently reported that IMRT provided significantly better 5-year locoregional control than
2D RT (90% vs 85%, P = 0.04). However, no phase-III randomized trials have as yet compared IMRT versus 3D conformal RT. Several teams have published results, but retrospectively; the RTOG 0225 study is a non-randomized phase-II trial [13,14,16,24–31] (cf. Table 2). Even so, all series showed excellent control, exceeding 90%.
5.2. Protection of healthy organs In nasopharyngeal carcinoma, radiation therapy may induce late complications due to partial irradiation of neighboring healthy organs, also increased which concomitant chemotherapy: xerostomia, dysphagia, dental problems, neurologic disorders (temporal lobe necrosis, cranial nerve damage, impaired cognitive function, hearing loss), cervical fibrosis, carotid stenosis, or endocrine disorders due to involvement of the thyroid gland or hypothalamicpituitary axis. Tuan et al. [32], in a large cohort of 796 patients treated by exclusive 2D RT at 66–70 Gy, recently reported high rates of late toxicities, with 73% of patients showing at least one complication and, especially, a 46% rate of xerostomia (grade not specified). Kam et al. [22] reported that IMRT significantly reduced mean and maximum OAR doses compared to 2D or 3D RT. Clinical benefit of such reduced OAR irradiation was reported by Peng et al., with significantly fewer long-term side-effects (neurologic, salivary, muscular and cutaneous toxicity) (P < 0.05), while Ma et al.
Table 2 Publications on IMRT in nasopharyngeal carcinoma. Author
Date
Type of study
Number of patients
Stage
Median FU (months)
Locoregional progression free survival
Metastatic progression free survival
Lee [13] Kwong [24] Kam [25] Wolden [16] Lin [26] Tham [27] Lee [14] Ng [28] Lai [29] Su [30] Wang [31]
2002 2004 2004 2006 2009 2009 2009 (RTOG) 2011 2011 2012 2013
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective non-randomized Retrospective Retrospective Retrospective Prospective non-randomized
67 33 63 74 323 195 68 193 512 198 300
T1-4N0-3 T1N0-1 T1-4N0-3 T1-4N0-3 T2-4N0-3 T1-4N0-3 T1-4N0-3 T1-4N0-3 T1-4N0-3 T1-2N0-1 T1-4N0-3
31 24 29 35 30 36 30 30 NR 50 47
4 years: 98% 3 years: 92% 3 years: 98% 3 years: 93% 3 years: 98% 3 years: 89% 2 years: 91% 2 years: 96% 5 years: 97% 5 years: 98% 4 years: 94%
4 years: 66% 3 years: 100% 3 years: 79% 3 years: 78% 3 years: 90% 3 years: 89% 2 years: 85% 2 years: 90% 5 years: 84% 5 years: 98% 4 years: 85%
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Table 3 Studies comparing late toxicity in nasopharyngeal cancer between IMRT and 3D or 2D RT. Author (year)
Study
Number of patients
TNM
Salivary flow (mL/min)
EORCT QLQ H&N35
Xerostomia ≥ grade 2
Pow (2006) [34]
IMRT versus 2D
51
T2N0-1
12 months (P < 0.001)
NR
Kam (2007) [35]
IMRT versus 2D
60
T1-2N0-1
NR
Fang (2008) [36] Pow (2011) [37]
IMRT versus 3D IMRT
203 57
T1-4 N0-3 T1-2N0-1
1 year 39 vs 82% (P < 0.001) NR NR
Peng (2012) [23]
IMRT versus 2D
616
T1-4 N0-3
12 months 0.27 vs 0.05 (P < 0.001) 12 months 0.41 vs 0.20 (P < 0.001) NR 24 months 0.36 NR
12 months (P < 0.001) 24 months (P < 0.001) NR
> 6 months 30 vs 69% (P < 0.001)
NR: not reported; EORTC QOL H&N 35: EORTC Quality of Life Scale.
reported improved quality of life at more than 2 years’ follow-up [23,33]. Three randomized studies compared IMRT versus 2D RT [23,34,35] and one prospective non-randomized study compared IMRT versus 3D RT [36]. On varying criteria (common toxicity criteria, salivary flow, quality of life), all four found significantly lower rates of xerostomia with IMRT (Table 3) [37]. In the future, OAR sparing may be further enhanced by dynamic arc therapy, enabling circular irradiation with continuous adaptation of multileaf collimator positioning according to target and OAR volumes. Initial dosimetric studies reported excellent conformation to target volumes, with improvement over conventional IMRT and reduced radiation time [38]. 6. Adaptive radiation therapy In nasopharyngeal carcinoma, IMRT uses steep dose gradients in dosimetric planning, especially for OARs such as the spinal cord and brainstem. This requires strict quality control before and during therapy, notably including daily control of patient positioning. Over 6–7 weeks’ treatment, anatomic changes may nevertheless appear, due to weight-loss, tumor response or salivary gland hypotrophy, modifying the initially planned dosimetry with a risk of increased OAR irradiation and poorer tumor volume cover. Several authors have recommended a systematic second planning CT scan performed halfway through treatment, around the 25th fraction [39]. The clinical benefit of this attitude remains to be proven, and it cannot yet be recommended in routine practice [40]. 7. Conclusion In recent years, IMRT has become the standard attitude in nasopharyngeal carcinoma. It optimizes target volume cover and allows significantly less irradiation of healthy organs than conventional 2D or 3D RT. This leads to a lower rate of late toxicities, notably xerostomia. Benefit with respect to 3D RT in terms of locoregional control and survival, however, has yet to be demonstrated in randomized trials, although all data published to date reported excellent rates of local control: > 90% at 3 years. Improved locoregional control and survival in nasopharyngeal carcinoma may be achieved by dose escalation targeted by metabolic imaging (18-fluoromisonidazole (F-MISO) PET), or associated targeted therapies (bevacizumab, cetuximab) to avoid metastatic failure. Late toxicity may be also reduced by arc therapy, enhancing OAR sparing. Disclosure of interest F. Huguet: Merck, Roche.
S. Haberer-Guillerm and E. Touboul declare that they have no conflicts of interest concerning this article.
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S. Haberer-Guillerm et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 132 (2015) 147–151 [19] Kwong DL, Sham JS, Leung LH, et al. Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;64(2):374–81. [20] Choi W, Lee SW, Park SH, et al. Planning study for available dose of hypoxic tumor volume using fluorine-18-labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer. Radiother Oncol 2010;97(2):176–82. [21] Xia P, Fu KK, Wong GW, et al. Comparison of treatment plans involving intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2000;48(2):329–37. [22] Kam MK, Chau RM, Suen J, et al. Intensity-modulated radiotherapy in nasopharyngeal carcinoma: dosimetric advantage over conventional plans and feasibility of dose escalation. Int J Radiat Oncol Biol Phys 2003;56(1):145–57. [23] Peng G, Wang T, Yang KY, et al. 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(3):286–93. [24] Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for earlystage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function. Cancer 2004;101(7):1584–93. [25] Kam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys 2004;60(5):1440–50. [26] Lin S, Pan J, Han L, et al. Nasopharyngeal carcinoma treated with reducedvolume intensity-modulated radiation therapy: report on the 3-year outcome of a prospective series. Int J Radiat Oncol Biol Phys 2009;75(4):1071–8. [27] Tham IW, Hee SW, Yeo RM, et al. Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the national cancer centre singapore experience. Int J Radiat Oncol Biol Phys 2009;75(5):1481–6. [28] Ng WT, Lee MC, Hung WM, et al. Clinical outcomes and patterns of failure after intensity-modulated radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011;79(2):420–8. [29] Lai SZ, Li WF, Chen L, et al. 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(3):661–8.
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[30] Su SF, Han F, Zhao C, et al. Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone. Int J Radiat Oncol Biol Phys 2012;82(1):327–33. [31] Wang R, Wu F, Lu H, et al. Definitive intensity-modulated radiation therapy for nasopharyngeal carcinoma: long-term outcome of a multicenter prospective study. J Cancer Res Clin Oncol 2013;139(1):139–45. [32] Tuan JK, Ha TC, Ong WS, et al. Late toxicities after conventional radiation therapy alone for nasopharyngeal carcinoma. Radiother Oncol 2012;104(3):305–11. [33] Ma L, Guo Q, Zhang Y, et al. The effect of intensity-modulated radiotherapy versus conventional radiotherapy on quality of life in patients with nasopharyngeal cancer: a cross-sectional study. Head Neck Oncol 2013;5(1):8. [34] Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for earlystage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66(4):981–91. [35] Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25(31):4873–9. [36] Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving three-dimensional conformal radiotherapy vs. intensity-modulated radiotherapy-a longitudinal study. Int J Radiat Oncol Biol Phys 2008;72(2):356–64. [37] Pow EH, Kwong DL, Sham JS, et al. Can intensity-modulated radiotherapy preserve oral health-related quality of life of nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys 2012;83(2):e213–21. [38] White P, Chan KC, Cheng KW, et al. Volumetric intensity-modulated arc therapy vs conventional intensity-modulated radiation therapy in nasopharyngeal carcinoma: a dosimetric study. J Radiat Res 2013. [39] Wang W, Yang H, Hu W, et al. Clinical study of the necessity of replanning before the 25th fraction during the course of intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2010;77(2):617–21. [40] Gregoire V, Jeraj R, Lee JA, et al. Radiotherapy for head and neck tumours in 2012 and beyond: conformal, tailored, and adaptive? Lancet Oncol 2012;13(7):e292–300.
Available online at
ScienceDirect www.sciencedirect.com
Review
Intensity modulated radiation therapy in nasopharyngeal carcinoma S. Haberer-Guillerm ∗ , E. Touboul , F. Huguet Département d’oncologie radiothérapie, hôpital Tenon, AP–HP, groupe hospitalier des hôpitaux universitaires de l’Est Parisien (HUEP), faculté de médecine Pierre et Marie Curie, université Paris 6, 4, rue de la Chine, 75020 Paris, France
a r t i c l e
i n f o
Keywords: Nasopharyngeal carcinoma Conformal intensity-modulated radiation therapy Target volumes Late effects Xerostomia
a b s t r a c t Radiation therapy (with associated chemotherapy) is the standard treatment for nasopharyngeal carcinoma. Conformal intensity-modulated radiation therapy is a new and particularly interesting technique for these tumors, due to their complex volumes close to many critical organs. Better dosimetric results and improved protection of adjacent healthy tissue have been shown compared with conventional 2D or 3D radiation therapy, with significantly reduced side-effects, notably xerostomia. Excellent local control rates have been reported. © 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction Nasopharyngeal carcinoma, especially when of the undifferentiated type, differs from other head and neck cancers geographically and ethnically and by its association with Epstein-Barr virus and specific treatment requirements. Treatment is hindered by the anatomic proximity of numerous critical organs, restricting indications for surgery to biopsy for initial histologic diagnosis and to cases of relapse. Radiation therapy (RT) is the keystone of local treatment [1]. In locally advanced cancer, the overall survival benefit of associating radiation therapy and chemotherapy was demonstrated in Baujat et al.’s meta-analysis, especially when the association was concomitant [2]. The efficacy of adjuvant chemotherapy is under assessment, certain retrospective reports suggesting an impact on tumor control [3]. Progress in imaging (magnetic resonance imaging (MRI) and positron emission tomography coupled to computed tomography (PET-CT)) has improved initial extension assessment in nasopharyngeal carcinoma [4], enhancing the precision of RT planning. More recently, conformal intensity-modulated radiation therapy (IMRT) has become standard clinical practice. IMRT uses multiple small radiation beams of varying intensities and shapes thanks to a multileaf collimator. This optimizes tumor area coverage while protecting healthy neighboring organs.
∗ Corresponding author. E-mail address: [email protected] (S. Haberer-Guillerm). http://dx.doi.org/10.1016/j.anorl.2014.02.008 1879-7296/© 2014 Elsevier Masson SAS. All rights reserved.
The present study successively examines the various radiation target volumes and healthy organs to be spared (organs at-risk: OARs) and the fractionation and dose options. We shall also review the data demonstrating the specific benefit of IMRT over 2D and 3D strategies. Finally, we shall report results for local control, and look at foreseeable future developments.
2. Definition of target volumes RT planning requires target volumes to be defined on a CT-scan for dosimetry. This is performed in dorsal decubitus, with a 5-point thermoformed contention mask (immobilization of head, neck and shoulders), without and, if possible, with intravenous iodized contrast injection, and thin (3 mm) slice acquisition from vertex to superior mediastinum. The target volumes to be defined are as follows [5].
2.1. GTV Gross tumor volume (GTV) is the tumor mass visible on clinical examination, endoscopy and imaging. It includes the nasopharyngeal tumor (tumoral GTV) and involved lymph nodes (nodal GTV). GTV after neoadjuvant chemotherapy includes not only the residual volume but the whole initial tumor and involved lymph nodes. Delineation is improved by fusion of the planning CT scan and the initial MRI. However attractive the option may seem, fusion with PET-CT is not recommended in routine practice, for lack of validation in the literature.
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Nasopharyngeal carcinoma being highly lymphophilic, nodal CTV systematically includes bilateral levels II to V (Robbins classification) and the bilateral retropharyngeal lymph-node areas [10,11]. 2.3. PTV Planning target volume (PTV) is delineated geometrically by drawing a 3–5 mm margin around the tumoral or lymph-node CTV, to allow for uncertainty related to patient positioning and systematic or variable internal movement. 2.4. Organs at risk (OARs) Healthy organs are also delineated, to ensure protection: brainstem, brain (temporal lobe and posterior fossa), spinal cord, optic chiasm, cochlea, optic nerves, lens, parotid glands, submandibular glands, mandible, temporomandibular joints, pharyngeal constrictor muscles, larynx, esophagus, and thyroid and pituitary glands. 3. IMRT dose prescription
Fig. 1. Example of CTV definition including nasopharynx, posterior third of nasal cavities and maxillary sinuses (anteriorly), parapharyngeal space (laterally) and clivus and retropharyngeal space (posteriorly).
2.2. CTV Clinical target volume (CTV) includes GTV plus any immediately neighboring microscopic tumor or lymph-node extensions, taking account of the natural extension pathways of nasopharyngeal carcinoma. CTV thus includes: • above: the inferior part of the sphenoid sinus, and the middle cranial fossa, including foramina (ovale and lacerum); • below, the oropharyngeal mucosa; • laterally, the parapharyngeal spaces; • anteriorly, the posterior part of the nasal cavities and the pterygomaxillary fossa; • posteriorly, the retropharyngeal space and clivus [1,6,7] (Figs. 1 and 2).
Some authors also include the cavernous sinus (superiorly), pterygoid muscles and carotid space (laterally) and the posterior third of the maxillary sinuses (anteriorly) in the CTV [7–9].
IMRT uses 5 to 7 radiation beams, with fluence adjusted from fraction to fraction. Planning is inverse: i.e., dose ranges to be delivered to the PTV and OARs are determined initially by the physician, and dosimetry seeks to remain within these predefined limits. IMRT enables a tailored dose to be delivered within the volume to be treated, several CTVs and thus several distinct PTVs being defined. Dose per PTV is determined according to risk of invasion (Fig. 3) [12]. There are a number of IMRT techniques: SIB (Simultaneous Integrated Boost), SMART (Simultaneous Modulated Accelerated Radiation Therapy), or sequential (partially conformal 3D RT and partially IMRT). In SIB the highest dose per fraction is delivered to the highest-risk PTV, which usually includes the GTV, with lower doses to medium or low-risk PTVs. High-risk PTV dose per fraction is around 2 Gy/day. SMART combines integrated boost and accelerated radiation with a smaller number of fractions; high-risk PTV dose per fraction is thus greater than 2.2 Gy/day, and often around 2.3 Gy/fraction [12]. Table 1 shows examples of dose levels and fractionation in nasopharyngeal carcinoma IMRT [13–16]. 4. Dose escalation Retrospective studies of nasopharyngeal carcinoma indicate a tumoricidal dose of ≥ 70 Gy. Dose escalation has been described in nasopharyngeal carcinoma, by brachytherapy or conformal or stereotaxic radiation, but with increased late toxicity [17,18].
Fig. 2. Example of delineation with tumoral GTV (red) and tumoral CTV (pink).
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Fig. 3. Example of dosimetry of a nasopharyngeal carcinoma (axial, sagittal and coronal slices). Red: high-risk PTV; dark blue: medium-risk PTV; turquoise: low-risk PTV. Table 1 Examples of fractionation in IMRT.
Technique High-risk PTV Medium-risk PTV Low-risk PTV
Hong Kong [13,15]
RTOG 0225 [14]
MSKCC [16]
SIB 70 Gy in 35 fractions of 2 Gy 63 Gy in 35 fractions of 1.8 Gy 56 Gy in 35 fractions of 1.6 Gy
SIB 70 Gy in 33 fractions of 2.12 Gy 60 Gy in 33 fractions of 1.82 Gy 54 Gy in 33 fractions of 1.64 Gy
SIB/2 plans 70 Gy in 33 fractions of 2.12 Gy 59.4 Gy in 33 fractions of 1.8 Gy 50.4 Gy (3D)
SMART 70.2 Gy in 30 fractions of 2.34 Gy 54 Gy in 30 fractions of 1.8 Gy
SIB: simultaneous integrated boost; SMART: simultaneous modulated accelerated radiation therapy; 3D: 3D conformal radiation therapy.
IMRT appears to be a promising means of increasing PTV doses while sparing OARs. Kwong et al., however, in a series of 50 patients with T3-T4 nasopharyngeal lesions treated by concomitant chemotherapy and RT with IMRT up to 76 Gy by 2.17 Gy fractions, reported 96% locoregional control at 25 months’ follow-up but increased late toxicity, with 4% of patients showing temporal necrosis and 4% severe epistaxis [19]. Late toxicities are mainly due to the increased dose per fraction. Special attention should therefore be paid to the risk of late OAR toxicities in case of dose per fraction exceeding 2 Gy. Thanks to the cellular hypoxia marker 18F-fluoromisonidazole, PET-CT may in future improve the targeting of dose escalation. This marker could indicate hypoxic and radioresistant tumor areas, defining an HTV (hypoxic tumor volume). A dosimetric study in 8 patients by Choi et al. reported a dose escalation in the HTV up to 78 Gy (by 2.6 Gy fractions) to be feasible in 75% of cases [20]. The clinical benefit of this attitude remains to be proven. 5. Benefit of IMRT 5.1. Local control Dosimetric studies demonstrated benefit for IMRT over conformal RT in nasopharyngeal carcinoma, with improved dose homogeneity and PTV coverage [21,22]. Peng et al. [23], in a prospective study, recently reported that IMRT provided significantly better 5-year locoregional control than
2D RT (90% vs 85%, P = 0.04). However, no phase-III randomized trials have as yet compared IMRT versus 3D conformal RT. Several teams have published results, but retrospectively; the RTOG 0225 study is a non-randomized phase-II trial [13,14,16,24–31] (cf. Table 2). Even so, all series showed excellent control, exceeding 90%.
5.2. Protection of healthy organs In nasopharyngeal carcinoma, radiation therapy may induce late complications due to partial irradiation of neighboring healthy organs, also increased which concomitant chemotherapy: xerostomia, dysphagia, dental problems, neurologic disorders (temporal lobe necrosis, cranial nerve damage, impaired cognitive function, hearing loss), cervical fibrosis, carotid stenosis, or endocrine disorders due to involvement of the thyroid gland or hypothalamicpituitary axis. Tuan et al. [32], in a large cohort of 796 patients treated by exclusive 2D RT at 66–70 Gy, recently reported high rates of late toxicities, with 73% of patients showing at least one complication and, especially, a 46% rate of xerostomia (grade not specified). Kam et al. [22] reported that IMRT significantly reduced mean and maximum OAR doses compared to 2D or 3D RT. Clinical benefit of such reduced OAR irradiation was reported by Peng et al., with significantly fewer long-term side-effects (neurologic, salivary, muscular and cutaneous toxicity) (P < 0.05), while Ma et al.
Table 2 Publications on IMRT in nasopharyngeal carcinoma. Author
Date
Type of study
Number of patients
Stage
Median FU (months)
Locoregional progression free survival
Metastatic progression free survival
Lee [13] Kwong [24] Kam [25] Wolden [16] Lin [26] Tham [27] Lee [14] Ng [28] Lai [29] Su [30] Wang [31]
2002 2004 2004 2006 2009 2009 2009 (RTOG) 2011 2011 2012 2013
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective non-randomized Retrospective Retrospective Retrospective Prospective non-randomized
67 33 63 74 323 195 68 193 512 198 300
T1-4N0-3 T1N0-1 T1-4N0-3 T1-4N0-3 T2-4N0-3 T1-4N0-3 T1-4N0-3 T1-4N0-3 T1-4N0-3 T1-2N0-1 T1-4N0-3
31 24 29 35 30 36 30 30 NR 50 47
4 years: 98% 3 years: 92% 3 years: 98% 3 years: 93% 3 years: 98% 3 years: 89% 2 years: 91% 2 years: 96% 5 years: 97% 5 years: 98% 4 years: 94%
4 years: 66% 3 years: 100% 3 years: 79% 3 years: 78% 3 years: 90% 3 years: 89% 2 years: 85% 2 years: 90% 5 years: 84% 5 years: 98% 4 years: 85%
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Table 3 Studies comparing late toxicity in nasopharyngeal cancer between IMRT and 3D or 2D RT. Author (year)
Study
Number of patients
TNM
Salivary flow (mL/min)
EORCT QLQ H&N35
Xerostomia ≥ grade 2
Pow (2006) [34]
IMRT versus 2D
51
T2N0-1
12 months (P < 0.001)
NR
Kam (2007) [35]
IMRT versus 2D
60
T1-2N0-1
NR
Fang (2008) [36] Pow (2011) [37]
IMRT versus 3D IMRT
203 57
T1-4 N0-3 T1-2N0-1
1 year 39 vs 82% (P < 0.001) NR NR
Peng (2012) [23]
IMRT versus 2D
616
T1-4 N0-3
12 months 0.27 vs 0.05 (P < 0.001) 12 months 0.41 vs 0.20 (P < 0.001) NR 24 months 0.36 NR
12 months (P < 0.001) 24 months (P < 0.001) NR
> 6 months 30 vs 69% (P < 0.001)
NR: not reported; EORTC QOL H&N 35: EORTC Quality of Life Scale.
reported improved quality of life at more than 2 years’ follow-up [23,33]. Three randomized studies compared IMRT versus 2D RT [23,34,35] and one prospective non-randomized study compared IMRT versus 3D RT [36]. On varying criteria (common toxicity criteria, salivary flow, quality of life), all four found significantly lower rates of xerostomia with IMRT (Table 3) [37]. In the future, OAR sparing may be further enhanced by dynamic arc therapy, enabling circular irradiation with continuous adaptation of multileaf collimator positioning according to target and OAR volumes. Initial dosimetric studies reported excellent conformation to target volumes, with improvement over conventional IMRT and reduced radiation time [38]. 6. Adaptive radiation therapy In nasopharyngeal carcinoma, IMRT uses steep dose gradients in dosimetric planning, especially for OARs such as the spinal cord and brainstem. This requires strict quality control before and during therapy, notably including daily control of patient positioning. Over 6–7 weeks’ treatment, anatomic changes may nevertheless appear, due to weight-loss, tumor response or salivary gland hypotrophy, modifying the initially planned dosimetry with a risk of increased OAR irradiation and poorer tumor volume cover. Several authors have recommended a systematic second planning CT scan performed halfway through treatment, around the 25th fraction [39]. The clinical benefit of this attitude remains to be proven, and it cannot yet be recommended in routine practice [40]. 7. Conclusion In recent years, IMRT has become the standard attitude in nasopharyngeal carcinoma. It optimizes target volume cover and allows significantly less irradiation of healthy organs than conventional 2D or 3D RT. This leads to a lower rate of late toxicities, notably xerostomia. Benefit with respect to 3D RT in terms of locoregional control and survival, however, has yet to be demonstrated in randomized trials, although all data published to date reported excellent rates of local control: > 90% at 3 years. Improved locoregional control and survival in nasopharyngeal carcinoma may be achieved by dose escalation targeted by metabolic imaging (18-fluoromisonidazole (F-MISO) PET), or associated targeted therapies (bevacizumab, cetuximab) to avoid metastatic failure. Late toxicity may be also reduced by arc therapy, enhancing OAR sparing. Disclosure of interest F. Huguet: Merck, Roche.
S. Haberer-Guillerm and E. Touboul declare that they have no conflicts of interest concerning this article.
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