The Current Status of the Delineation and Determination of the Targets and the Radiation Protocols for Nasopharyngeal Cancer with Intensity-Modulated Radiotherapy

The impact of the imaging modalities on delineation of the primary NPC lesion

In considering the display of the spread of primary NPC lesions, with the exception of judgment and visualization of cranial base erosion, magnetic resonance imaging (MRI) is superior to computed tomography (CT) in providing better details of the tumor extension in the parapharyngeal and retropharyngeal spaces, as well as the spread through the foramen to the sphenoid, ethmoid, and cavernous sinuses and the brain. But, because of its sensitivity to artifacts, long examination time, inferior spatial accuracy, difficulty in set-up, and lack of electron density data necessary for heterogeneity corrections, MRI alone is not useful as the imaging vector in IMRT treatment planning.

The dual use of CT and MRI scans, for the time being, may be the ideal imaging modality, because the complementary information contained in the two modalities can provide more accurate tumor definition, which permits narrowing of the differences among physicians in delineating the targets. Emami et al.^[7] studied the influence of MRI on target volume delineation in NPC patients, and found that MRI-based target volumes were on average 74% larger than CT volumes, and either MRI or CT alone-based target volumes partially underestimated the true extent of the tumor. Hence the authors suggested that it may be prudent to perform CT/MRI fusion and use the composite CT+MRI target volume in treatment planning. Nishioka et al.^[8] reported that the incidence of skull-base abnormalities in NPC patients found by MRI were notably higher than that found by CT. Among those who did not show bone erosion on CT nor cranial nerve symptoms on clinical examination, the incidence of skull-base invasion found by MRI was as high as 38%, emphasizing the importance to combine MRI with CT to evaluate the skull-base abnormalities and to properly stage the NPC cases. Up to now, the earliest and the best results reported in the literature in treatment of NPC with IMRT, used both CT and MRI. In most cases the CT/MRI fusion was performed to contour the gross tumor volume (GTV)^[5]. Accurate target delineation was a prerequisite to guarantee better results.

The integration of positron emission tomography (PET) into radiotherapy treatment planning has provided more valuable biological information to define the target, and has definitely changed the conventional way of defining the target based on anatomic morphological imaging. Since the clinical implementation of integrated PET/CT which spared the inconvenience of multi-scans and reduced the match-up error of image recording, target contouring has become more efficient and accurate through a direct display of a fused image of the functional with anatomic structures. Nishioka et al.^[9] studied the impact of PET on the radiotherapy treatment planning for NPC, and showed that 90% of the CT and MRI target volume coincided with the PET volume. The irradiation fields needed to be modified in only 2 out of 19 cases, but they observed that PET added more valuable biological information concerning the spatial extension of the tumor. Chao et al.^[10] showed Cu-ATSM PET hypoxic imaging could guide a high dose to the hypoxic region, and thereby improve the outcome for the head and neck cancers treated with IMRT. However PET/CT is still in its initial phase of study for radiotherapy planning. Its high cost and lack of medical reimbursement currently prevent its wide-spread clinical use.

Retropharyngeal nodes usually are merged with the primary NPC lesion, and are hard to identify separately from CT images. The retropharyngeal space on CT scans is butterfly-shaped, and is defined as follows: cranial, base of skull; caudal, cranial edge of the body of the hyoid bone; anterior, fascia under the pharyngeal mucosa; posterior, prevertebral muscles; lateral, sternocleidomastoid muscle and medial edge of the internal carotid artery; medial, midline^[11]. Neither the AJCC6th nor the 1992 Fuzhou staging system clearly stated whether retropharyngeal nodes should be classified into N or T categories. Tang et al.^[12] reported that the incidence of retropharyngeal node metastasis was 51.5% (386/749). They suggested it should be classified into T categories and be staged as T2 based on its prognosis after radiotherapy. From the point of view of radiotherapy for NPC primary lesions, it is reasonable to include the retropharyngeal nodes in the primary nasopharyngeal gross tumor volume, because they are close to the nasopharyngeal cavity and require irradiation at the same dose level as the primary lesion, even though they are part of the lymph system.

CT-based delineation of lymph node levels

Whether or not there is metastatic lymphatic drainage in the neck, the neck node levels Ib, II, III, IV and V need to be irradiated for NPC cases. The authentic neck node classification is the Robbins classification recommended by the Committee for Head and Neck Surgery and Oncology of the American Academy for Otolaryngology-Head and Neck Surgery. In this system the neck nodes are systematically classified into 6 levels including 8 node groups, the boundaries of each being defined by surgically visible bones, muscles, blood vessels or nerves^[13]. Because regular neck node dissection can not reach to the retropharyngeal node area, it is not included in this classification system.

The problem of how to translate the anatomic boundaries of those node levels visible in the surgical procedure into the describable landmarks seen on CT scans, is the key question challenging radiation oncologists in reaching consensus guidelines when contouring the node regions. In the wake of this point, several groups have tried to translate the anatomic boundaries of the various neck node levels on CT-or MRI-scans. Among them, two proposals, the so-called Rotterdam guidelines from Nowak et al.^[14,15], and the so-called Brussels guidelines from Gregoire et al.^[16], appear to the most widely used in clinical practice. Due to the wide discrepancies existing between the two proposals, Vincent Gregoire from the St-Luc University Hospital led a discussion panel with representatives from major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, endorsed the final consensus guidelines in 2003 (Table 1)^[11]. These consensus guidelines narrowed the differences among the radiation oncologists when delineating the neck node levels on CT scans, and is currently widely used and recommended in clinical practice. However, the justification of neck node delineation based on these consensus guidelines is still waiting to be verified by long-term results of node regional control, and the pattern analysis of neck node recurrence.

The differences of the definitions of the targets, dose prescribed, and fractionation in IMRT planning protocols for NPC from the main cancer centers across the world

Table 2 summarizes the most representative IMRT planning protocols from the main cancer centers across the world. These include the definition of the targets, the prescribed dose, and fractionation for NPC. The definition of the GTV was clear, and a consensus was reached among those centers. It was defined as the primary nasopharyngeal lesion plus the metastatic enlarged lymph nodes. The criteria for metastatic lymph nodes in CT scans are as follows: ① the diameter of the short axis is ≥1 cm, or ②<1 cm, but with signs of central necrosis or ring enhancement, or ③3 or more cluster lymph nodes with the least diameter larger than 8 mm, or ④with the signs of extra capsular extension (including the peripheral irregular enhancement, partial or entire disappearance of the neighboring fat space and fusion of the nodes). The actual nominal prescribed dose to the GTV is more than 70 Gy, with larger than conventional fractionation, the biological effective dose is close to or even more than 80 Gy.

The ICRU Report 50 clearly defined the clinical target volume (CTV). It surrounds the primary tumor and consists of tissue perceived to potentially harbor microscopic sub-clinical cancerous extensions. It can not be indicated by the radiological scans, and usually a definite margin is added to the GTV based on the tumor site and its biological characteristics. With the exception of the protocols of the UCSF^[18,19] and Cancer Center of the Sun Yat-Sen University^[6], others have clearly stated that the CTV should include the immediate high-risk structures as the entire nasopharyngeal cavity, retropharyngeal space, clivus, base of the skull, pterygoid plates and muscles, parapharyngeal space, partial sphenoid and ethmoid sinus and posterior third of the nasal cavity and maxillary sinus. The dose prescribed for the CTV is 60~70 Gy. The CTV1 defined by the planning protocol of the Cancer Center of the Sun Yat-Sen University is not large enough to cover those primary high risk structures, however its CTV2 is large enough to cover those structures, but the prescribed dose is as low as 54 Gy/30fx. Therefore, there are some lower dose regions which exist between CTV2 and CTV1 compared with those of other centers.

The primary high risk structures are only partially included in the PTVm defined by the MSKCC protocol, and their dose prescribed is as low as 54 Gy/30fx, with a further shrunken area covered with a lower dose level. Even with this therapy, the results reported by the MSKCC were as follows: 3-year local control, 91%; regional control, 93% and survival, 83% for the 74 NPC cases treated with IMRT. However, 69 out of the 74 cases (92%) were treated concurrently with chemotherapy, so it is possible that the chemotherapy was a contributing factor for the high locoregional control.

Results from the Cancer Center of Sun Yat-Sen University were similar to those reported by the MSKCC (3-year locoreginal control was 93.2% and the survival was 85.1% for 122 NPC cases treated with IMRT alone). Results from the UCSF were a 4-year locoreginal control of 98% and a total survival of 88% for 67 NPC cases. Among them75% were Stage III+IV, and only 1 primary and 1 regional recurrences were found with a median follow-up of 31 months. From the analysis of those results, combined with their respective definition of the primary CTV and dose prescribed, there is strong reason to believe that the primary CTV should include the immediate high-risk structures as the entire nasopharyngeal cavity, retropharyngeal space, clivus, base of the skull, pterygoid plates and muscles, parapharyngeal space, partial sphenoid and ethmoid sinus, and the posterior third of the nasal cavity and maxillary sinus. The dose prescribed should be at least 60 Gy for those structures.

There were also differences related to the dose prescribed to the upper and middle neck node regions in the protocols of those cancer centers. The protocol from the Queen Marry Hospital of Hong Kong prescribed 70 Gy/35fx to the bilateral neck node level Ib, II, III and VA^[21]. The prescribed dose to those regions in the protocols of the Prince of Wales Hospital of Hong Kong^[20] and the Cancer Hospital of Chinese Academy of Medical Sciences^[22] was 60~66 Gy/33fx. However the protocols of the UCSF, RTOG0225^[17], MSKCC and Cancer Center of Sun Yat-Sen University prescribed 50.4~54 Gy/30~33 fx to those regions.

The upper cervical region is the most common site for NPC lymph node metastasis, with about 80% of the patients having node metastasis in this region. Even with negative findings by radiological examinations, many researchers still rank the bilateral upper neck as a high-risk region and differentially prescribe a higher than preventive irradiation dose^[23,24]. However, level Ib and II nodes are anatomically close neighbors of the sub-mandibular glands, deep lobes of the parotids and mucosa of the oral cavity. A higher dose prescribed to the upper neck in the IMRT plan will jeopardize sparring those structures from a high radiation dose, and thereby prevent the realization of the main goals of IMRT which are to preserve their normal functions.

The Queen Marry Hospital reported complications as high as 78% of level 3 mucositis and 46% level 3 epidermitis in its NPC study with IMRT. It was reasoned that the high rate of complications was related to its protocol plan with a larger radiation dosage to the cervical area. The study of Eisbruch et al.^[25] revealed that there was a relationship between the preservation of parotid function and the threshold dose of irradiation, i.e. when the mean dose of irradiation to the parotids was less than 26 Gy, most functions of the parotids would be saved.

A series of studies on head and neck cancer management with IMRT showed that it could be balanced between good regional control and parotid function preservation when 60 Gy was prescribed to the upper cervical high-risk regions^[5,26]. Furthermore, a higher dose delivered to a larger cervical area will result in an increase in long-term complications such as hypotrophy of the cervical muscles and fibrosis. There is still a need for longer follow-up studies with a larger number of cases. Therefore, a well-balanced dose level of 60 Gy to the upper cervical regions could be recommended at this time.