Nasopharyngeal Cancer

Fig. 8.1

Dosimetric comparison of treatment plans for intensity-modulated radiation therapy (IMRT) vs. 3D-conformal RT vs. traditional RT. Axial dose distributions through the center of the nasopharynx and neck for IMRT (left), 3D-conformal RT (middle), and traditional treatment plans (right). Note the relatively poor coverage of the skull base and medial nodal regions in the traditional plan and the improved dose conformality of the IMRT plan (From: Hunt et al. [4], with permission from Elsevier)

8.2.2 Salivary Function and Treatment Compliance

The most common complication of RT for NPC is a decline in salivary function, known as xerostomia, due to a damage of nearby salivary structures. The symptoms of xerostomia can significantly affect a patient’s quality of life [6]. The severity of xerostomia depends mostly on the dose and volume of salivary gland within the radiation field. Dosimetric comparisons have revealed that a mean dose of 26 Gy or less to the parotid glands is necessary to preserve salivary function [7, 8].

The main benefit of IMRT over conventional RT for NPC is the ability to spare the parotid glands. Two phase III randomized controlled trials assigned patients to receive either 2D RT or IMRT with parotid-sparing techniques and evaluated outcomes at 1 year after treatment. The first trial found that IMRT was associated with superior quality of life outcomes [9]. The second study also found benefits in observer-rated xerostomia outcomes and preservation of parotid function (measured by parotid flow rate) with the use of IMRT [10], as well as a trend towards improvement in patient-reported xerostomia outcomes. The same study revealed the somewhat surprising finding that xerostomia quality of life scores only correlated weakly with both salivary flow rates and observer-rated xerostomia outcomes. Therefore, evaluation of both patient-reported and physician-reported outcomes remains important. Regardless, both phase III studies showed improved xerostomia outcomes with the use of IMRT compared with conventional 2D RT.

The lesser toxicity associated with IMRT may also improve treatment compliance or the ability of patients to tolerate the prescribed therapy. A multi-institutional trial of IMRT by the Radiation Therapy Oncology Group, RTOG 0225, showed that 90 % of patients were able to receive the full 70-Gy prescribed dose and that 88 % of the patients with T2b or higher or N+ disease were able to receive the full three cycles of concurrent cisplatin [11]. These findings compare favorably to previous studies that used conventional RT techniques, for example, chemotherapy compliance rates were 63 % in the Intergroup 0099 trial, 71 % in a Singapore randomized trial, and 52 % in the Hong Kong NPC-9901 trial [3, 12, 13].

8.2.3 Disease Control

In addition to improving toxicity outcomes, excellent disease control outcomes have been reported by several institutions. Lee et al. reported findings from an initial series of patients with NPC treated with IMRT, with an incredible 4-year local control rate of 97 %, despite 70 % of patients in that study having locally advanced disease [14]. Kwong et al. reported the first prospective series, with 3-year outcomes of 100 % local control (LC), 92.3 % regional control, and 100 % overall survival (OS) rates [15]. These excellent outcomes are supported by additional published series from many individual institutions, comprehensively reviewed by Wong et al. (Table 8.1) [16]. The RTOG 0225 trial further demonstrated the feasibility of implementing IMRT techniques across the multiple US institutions [11]. That phase II study reported excellent 2-year outcomes of 93 % LC, 89 % local-regional control (LRC), and 80 % OS rates (Table 8.1).

Table 8.1

Published studies of IMRT for nasopharyngeal cancer

Reference	Stage	No. of patients	Median follow-up time, mo	Time point, y	Local control rate, %	Regional control rate, %	Freedom from DM rate, %	Overall survival rate, %
Lee et al. (2002) (UCSF) [14]	All	67	31	4	97	98	66	88
Kwong et al. (2004) (Hong Kong) [15]	T1 N0–1	33	24	3	100	92	100	100
Kam et al. (2004) (Hong Kong) [22]	All	63	29	3	92	98	79	90
Wolden et al. (2006) (MSKCC) [24]	All	74	35	3	91	93	78	83
Kwong et al. (2006) (Hong Kong) [23]	III–IVB	50	25	2	96	NA	94	92
Lee et al. (2009) (RTOG 0225) [11]	All	68	31	2	93	91	85	80
Lin et al. (2010) (China) [25]	IIB–IVB	370	31	3	95	97	86	89
Lee et al. (2012) (RTOG 0615) [19]	IIB–IVB	42	30	2	NA	NA	91	91

Abbreviations: DM distant metastasis, UCSF University of California, San Francisco, RTOG Radiation Therapy Oncology Group

Notably, other factors may contribute to improvements in LRC associated with IMRT, including the use of chemotherapy, better supportive care, and technologic advances in imaging that provide better tumor delineation. Other limitations associated with historical comparisons include changes in the criteria for disease staging over time as well as improved staging with the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) [17]. For example, because MRI is more sensitive than computed tomography (CT) for detecting minimal skull base involvement or intracranial extension, the T category tends to be upstaged when MRI is used rather than CT.

8.3 Techniques

8.3.1 Diagnostic Work-Up for Target Volume Delineation

Disease staging should include both CT and MRI of the head and neck. CT is important for assessing cortical bone involvement; MRI provides superior visualization of skull base involvement and tumor invasion into soft tissue structures compared with CT [18]. Infiltration of disease into the bone marrow is best seen as hypodense regions relative to normal marrow on T1-weighted non-contrast MRI scans. Fusion of the skull base portion of the CT scan with the MRI scan should aid in delineating the gross tumor volume (GTV). MRI also allows retropharyngeal lymph nodes to be distinguished from primary tumor, whereas CT may not.

Enlarged retropharyngeal lymph nodes should be considered a gross disease. Involvement of other lymph node regions is suggested by the presence of central necrosis, extracapsular spread, or nodal diameters of 1 cm or more. PET/CT may help to clarify involvement of borderline lymph nodes. Generally, because NPC has a high likelihood of nodal spread, any nodes suspected of harboring disease should be considered a gross disease.

8.3.2 Simulation and Daily Localization

The patient should be set up for treatment simulation supine, with the neck extended. The immobilization device to be used should include at least the head and neck; if possible, shoulders should also be immobilized to ensure the reproducibility of patient setup from day to day, especially when an extended-field IMRT plan is to be used. A bite block can be placed during treatment simulation and throughout treatment to move the tongue away from the high-dose regions in the nasopharynx.

CT-based treatment simulation should involve 3-mm-thick scan slices with intravenous contrast to help delineate the GTV, particularly the lymph nodes. The isocenter is typically placed immediately above the arytenoids. Image registration and fusion applications with MRI and PET should be used to help delineate target volumes, especially regions of interest that encompass the GTV, skull base, brainstem, and optic chiasm.

8.3.3 Target Volume Delineation and Treatment Planning

Several IMRT dose-fractionation regimens have been used for NPC (Table 8.2). Excellent LRC rates in excess of 90 % have been reported with the use of these regimens.

Table 8.2

IMRT dose and fractionation schemes

Dose and fractionation	Study institution and reference
	RTOG [19]	Fujan [20]	SKL [43]	PWH [22]
Gross disease, Gy	69.96	66.0–69.75	68	6,674
Gross disease, Gy/fraction	2.12	2.2–2.25	2.27	2
High-risk region, Gy	59.4	60–60.45	60	60
High-risk region, Gy/fraction	1.8	1.95–2.0	2	1.82
Low-risk region, Gy	50–54.12	54–55.8	50–54	54–60
Low-risk region, Gy/fraction	1.64–2.0	1.8	1.8–2.0	2
Margin around GTV, mm^a	10	8–13	NA	13

Abbreviations: RTOG Radiation Therapy Oncology Group, SKL State Key Laboratory of Oncology in Southern China (Guangzhou), PWH Prince of Wales Hospital, Hong Kong, GTV gross tumor volume, CTV clinical target volume, PTV planning target volume

^aMargin is for primary tumor (GTV70), which includes CTV expansion of GTV and PTV expansion

Several acceptable definitions of target volumes, including the GTV, the clinical target volume (CTV), and planning target volume (PTV), have been used at different institutions, as reviewed by Wong et al. [16]. The RTOG established a guideline for target volume delineation with RTOG 0225, which was successfully implemented in that multi-institutional study [11]. Suggested target volumes for the GTV and high-risk CTV are described in the following sections (Tables 8.3 and 8.4 and Figs. 8.2, 8.3, and 8.4). In a recent RTOG 0615 trial, the lower-than-expected 2-year LRC rate of 84 % was attributed to an increased incidence of major deviations in target volume [19]. Thus, attention must be paid to accurate target delineation to avoid marginal misses when using IMRT.

Table 8.3

Definitions of target volumes for gross disease

Target volumes	Definition and description
GTV_70* (The subscript 70 denotes the radiation dose delivered)	Primary: All gross diseases on physical examination and imaging (see above regarding the importance of MRI)
	Neck nodes: All nodes ≥1 cm or those with necrotic center
CTV_70*	GTV₇₀ + ≥5 mm margin; around critical structures like the brainstem, 1 mm margin is acceptable
PTV_70*	CTV₇₀ + 3–5 mm, depending on comfort level of daily patient positioning. Around critical structures like the brainstem, 1 mm margin is acceptable

Table 1.1 from: Lee NY, Le QT, O’Sullivan B, Lu JJ (2003) Chapter 1. Nasopharyngeal carcinoma. Target Volume Delineation and Field Setup: A Practical Guide for Conformal and Intensity-Modulated Radiation Therapy, with kind permission from Springer Science + Business Media

*PTV₇₀ receives 2.12 Gy/fraction to 70 Gy over 33 fractions. For treatment of nodes that are small (i.e., ~1 cm), the lower dose of 63 Gy (PTV₆₃) can be considered at the discretion of the treating physician

Table 8.4

Definition of target volumes for high-risk subclinical region

Target volumes	Definition and description
CTV_59.4*	CTV_59.4 should encompass CTV₇₀ with a 5-mm margin and regions at risk for microscopic disease which include
	Entire nasopharynx
	Anterior 1/2 or 2/3 of the clivus (entire clivus, if involved)
	Skull base (ensuring coverage of foramen ovale where V3 resides)
	Pterygoid fossa
	Parapharyngeal space
	Inferior sphenoid sinus (entire sphenoid sinus in T3-T4 disease)
	Posterior 1/3 of the nasal cavity/maxillary sinuses (ensuring coverage of pterygopalatine fossae where V2 resides)
	Inferior soft palate
	Retropharyngeal lymph nodes
	Retrostyloid space
	Bilateral nodal levels IB through V**
	Include cavernous sinus for advanced T3-T4 lesions
	Importance of reviewing bone window while contouring on CT scan to ensure coverage of skull base foramina
PTV_59.4*	CTV_59.4 + 3–5 mm, depending on the comfort of physician, but around critical structures like the brainstem, 1-mm margin is acceptable

Table 1.2 from: Lee NY, Le QT, O’Sullivan B, Lu JJ (2003) Chapter 1 Nasopharyngeal Carcinoma. Target Volume Delineation and Field Setup: A Practical Guide for Conformal and Intensity-Modulated Radiation Therapy. Reproduced with kind permission from Springer Science + Business Media

*High-risk subclinical dose (PTV_59.4): 1.8 Gy/fraction to 59.4 Gy, for lower-risk subclinical regions excluding the nasopharynx/skull base regions where they are always considered high risk, can consider 1.64 Gy/fraction to 54 Gy (PTV₅₄), i.e., N0 neck or low neck (levels IV and VB) at the discretion of the treating physician

**Level IB can be omitted in node-negative disease. At discretion of physician, level 1B may also be spared in low-risk node positive patients (e.g., isolated retropharyngeal nodes or isolated level IV nodes are considered low risk for level 1B involvement). At the same time, treatment of level 1B should be considered in node-negative patients with certain features (e.g., involvement of hard palate or nasal cavity)

Fig. 8.2

Delineation of target volumes in a case of T1N1 nasopharyngeal carcinoma (NPC). GTV70 (inner contour, red) and CTV59.4 (green) contours in a patient with T1N1 NPC with coverage of the retropharyngeal and level II nodes (Figure 1.2 from: Lee NY, Le QT, O’Sullivan B, Lu JJ (2003) Chapter 1 Nasopharyngeal Carcinoma. Target Volume Delineation and Field Setup: A Practical Guide for Conformal and Intensity-Modulated Radiation Therapy, with kind permission from Springer Science + Business Media)

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