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Chapter 38
Nasopharynx
Anne W. M. Lee
Carlos A. Perez
Stephen C. K. Law
Daniel T. T. Chua
Wei William I.
Vincent Chong
Anatomy
The nasopharynx is a cuboidal open chamber that begins at the posterior choana and slopes downward along the airway to the level of the free border of the uvula. Anteriorly it communicates with the nasal cavity via the choana, and inferiorly it continues into the oropharynx via the pharyngeal isthmus. The roof and the posterior wall are formed by the basisphenoid, the clivus, and the first cervical vertebra. The floor is the superior surface of the soft palate. The eustachian tube opens into the lateral wall of the nasopharynx. The posterior portion of the eustachian tube is cartilaginous and protrudes into the nasopharynx, making a ridge called the torus tubarius. Posterior to the torus is a recess called the fossa of Rosenmüller. The lateral and posterior walls of the nasopharynx are supported by the pharyngobasilar fascia, which is attached to the base of the skull (Fig. 38.1).
A number of foramina and fissures located in the base of the skull are important routes by which nasopharyngeal carcinoma (NPC) can extend intracranially and involve various cranial nerves (Fig. 38.2 and Table 38.1). The most important are the foramen lacerum and the foramen ovale, which are in close anatomic relationship with the cavernous sinus and hence cranial nerves III to VI (Fig. 38.3).
Histologically, the nasopharyngeal mucosa is covered by respiratory-type ciliated epithelium, but variable degrees of squamous metaplasia are common. The stroma is rich in lymphatic plexus and lymphoid tissue that often includes reactive lymphoid follicles; the epithelium is commonly infiltrated by many small lymphoid cells.
The lymphatics of the nasopharynx have three major pathways (63) (Fig. 38.4). One pathway drains into a small group of nodes that lies in the parapharyngeal space, in close proximity to cranial nerves IX to XII. The uppermost node is the retropharyngeal node called the node of Rouviere (Fig. 38.5). Another lymphatic pathway drains into the jugular chain to involve the jugulodigastric and deep jugular nodes. The third pathway drains into the spinal accessory chain; the uppermost node lies beneath the sternomastoid muscle at the tip of the mastoid process.
Epidemiology
NPC shows a distinct racial and geographical distribution. As reported by the International Agency for Research on Cancer (181), the annual incidence rate (per 100,000 per year) in 1988–1992 ranged from <1 among whites to >20 among Southern Chinese male populations. According to the Surveillance, Epidemiology, and End Results Cancer Statistics Review, the incidence rate of NPC in the United States during 1996–2000 was 1.1 for men and 0.4 for women.
In low-risk populations, a bimodal age distribution is observed. The first peak incidence occurs at 15 to 25 and the second peak at 50 to 59 years of age. In contrast, the incidence in high-risk populations rises after 30 years of age, peaks at 40 to 60 years, and declines thereafter (59). The age distribution is similar in both genders. The incidence rates in male populations are commonly two to threefold that of female populations.
Descendants from Chinese who have migrated to Western countries show progressively lower risk, but their incidence remains higher than the indigenous populations (8,93). The study by Dickson and Flores (55) reported that the incidence rate in Chinese who were born in the Orient was 20.5, compared with 1.3 for Chinese and 0.2 for white people born in Canada. Buell (8) reported that among Chinese in the United States, the American-born second generation had a lower risk than the Asian-born first generation, while California whites born in Southeast Asia had an increased risk compared with their American-born counterparts.
Furthermore, familial aggregation of NPC has been reported in diverse populations. In a study of Southern Chinese by Yu et al. (245), NPC was detected in 6% of first-degree relatives of NPC patients as compared with 1% of first-degree relatives of controls in the same neighborhood.
These epidemiologic observations suggest a multifactorial cause that includes both inherited genetic predisposition and environmental factors. The near constant association of Epstein-Barr virus (EBV) with nonkeratinizing NPC, irrespective of ethnic background, indicates a probable oncogenic role in the carcinogenesis (15). Supporting evidences include presence of EBV-DNA or RNA in nearly all tumor cells, its presence in a clonal episomal form indicating that the virus has entered the tumor cell before clonal expansion, and its presence in the precursor lesion of NPC, but not in normal nasopharyngeal epithelium (188). Exposure to carcinogens in traditional southern Chinese food (volatile nitrosamines in preserved salted fish, in particular) have been incriminated (75,184). Cigarette smoking, previous irradiation, occupational exposure to dust, smoke, and chemical fumes has also been implicated, but definitive conclusion is difficult.
Table 38.2 shows the changing epidemiology in different ethnic groups during different periods. The study by Lee et al. (120) of 21,768 new cases of NPC and 8664 related deaths registered in Hong Kong showed steady reduction in the age-standardized incidence rate (per 100,000 per year) from 28.5 in 1980–1984 to 20.2 in 1995–1999 for men, and from 11.2 to 7.8 for women. The total decrease thus amounted to 30% for both genders during this 20-year period (Fig. 38.6). Furthermore, the age-standardized mortality/incidence ratio decreased from 0.48 to 0.39 for men, and from 0.40 to 0.29 for women in the corresponding periods. As there was no substantial change in the proportion of Chinese in the community, the genetic background was relatively stable; the declining incidence was probably attributed to changing environmental risk factors as the lifestyle for most citizens changed progressively to a more Western style, particularly in terms of diets. Interestingly, review of the incidence in other representative communities during the same period shows that Hong Kong was thus far the only place where such encouraging reduction was achieved.
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Natural History
Local Extension
Carcinoma of the nasopharynx frequently arises from the lateral wall, with a predilection for the fossa of Rosenmüller (Fig. 38.1B). The tumor may obstruct the orifice of the eustachian tube or infiltrate the levator veli palatine muscle, leading to disequilibrium of air pressure in the middle ear and serous otitis media. The tumor may involve the mucosa or grow predominantly in the submucosa (197). Local infiltration is usually extensive; the frequency of involvement of various structures as shown by the magnetic resonance imaging (MRI) of 308 patients from Pamela Youde Nethersole Eastern Hospital (Hong Kong) (15) is summarized in Table 38.3.
Adjacent soft tissues are first infiltrated as tumors spread anteriorly into the nasal fossa, posterolaterally beyond the pharyngobasilar fascia to involve the parapharyngeal and the carotid spaces (Fig. 38.7), laterally to the pterygoid muscles, posteriorly to the prevertebral muscles, and inferiorly to the oropharynx. Beyond these structures, tumors further infiltrate anterolaterally to the pterygoid process, maxillary antrum, ethmoid sinus, the orbital apex (particularly through the inferior orbital fissure), and the infratemporal fossa; tumor may also spread further posteroinferiorly to involve the vertebral bodies and the hypopharynx.
Superiorly, tumors cause bony erosion of the skull base involving the floor of the sphenoid sinus, clivus, apex of petrous bone, and basal foramina. For a long time, NPC was believed to spread intracranially, mainly through the foramen lacerum (Fig. 38.8). The advent of MRI demonstrates unsuspected high frequency of perineural spread along the maxillary division (V2) and the mandibular division (V3) of the trigeminal nerve with subsequent intracranial extension through the foramen rotundum and foramen ovale (Fig. 38.9) (34,36,203).
Involvement of cranial nerves III to VI at the cavernous sinus occurs as tumors extend intracranially via the foramen lacerum and/or foramen ovale. As illustrated in Figure 38.3, the order of involvement is V and VI, followed by IV and III nerves. Sometimes the V3nerve is involved at the gasserian ganglion. In advanced cases, tumors involve the hypoglossal canal and jugular foramen. The IX to XII nerves are infiltrated at these regions or in the parapharyngeal space as they emerge from the base of the skull (33). Compression of the cervical sympathetic nerve may rarely occur.
Lymphatic Spread
As the nasopharynx has a rich submucosal lymphatic network, gross cervical lymphadenopathy is present in more than 70% of NPC patients at presentation (118). There is an orderly pattern of lymph node involvement from upper to lower neck (Fig. 38.10). King et al. (91) reported that the frequency of retropharyngeal nodes abnormality was as high as 94%, internal jugular nodes 72%, and spinal accessory nodes 57%, while submandibular (3%) and parotid (2%) involvements were rare. Other series showed that the jugulodigastric nodes are the most frequently involved (196).
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The study by Ng et al. (171) on the pattern of nodal involvement by radiologic levels based on MRI showed that the incidences in order of frequency were 94% at level II, 85% at level III, 80% retropharyngeal node, 46% VA, 19% IV, 17% VB, and 17% at level I (Fig. 38.11).
Hematogenous Dissemination
NPC is notorious for its predilection for hematogenous dissemination. Both the N-category and the T-category are the main risk-determining factors (112,117). Patients with lymphatic spread down to the supraclavicular fossa have an especially high risk of distant metastasis.
Gross evidence of distant metastases is uncommon at presentation (6%), but more than 30% of patients with advanced locoregional disease eventually died of distant failure (129). A study by Hui et al. (79) showed that the commonest metastatic site was bone, followed closely by liver and lung. Lung metastasis was associated with better prognosis than other sites; the median overall survival (OS) was 3.9 years. Brain and skin metastases are extremely rare (156,172).
Clinical Presentation
The frequency of different presenting symptoms and signs is summarized in Table 38.4. Both the studies by Chao and Perez (19) and Lee et al. (118) showed that painless enlargement of upper neck nodes was the most common presenting feature, followed by nasal symptoms and aural problems. About 20% of patients had signs of cranial nerve palsy at diagnosis. The V and VI nerves were the commonest involved, whereas I, VII, and VIII nerves were rarely affected (Table 38.5).
Lee et al. (122) further showed that there was significant association between the duration of symptoms before diagnosis and the presenting stage, which in turn affected survival. Increased awareness by both the public and the primary care doctors are necessary to minimize delay in diagnosis.
One special feature calling for increased awareness is that NPC is the commonest malignancy associated with dermatomyositis in endemic areas (137). Teo et al. (211) reported that 0.9% (10/1,154) NPC patients suffered from dermatomyositis.
Diagnostic and Staging Work-Up
Table 38.6 lists the diagnostic and staging procedures generally recommended for NPC. Detailed evaluation of locoregional
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extent should include endoscopic examination of the nasal cavities and whole pharynx, thorough testing of all cranial nerves, and assessment of neck node involvement. Cross-sectional imaging is mandatory to complete the staging process (70). MRI is the study of choice because of its superior sensitivity (36,169,173); computed tomography (CT) with axial and coronal cut with contrast is accepted as an alternative.
Ng et al. (169) compared the assessment by MRI versus CT: A significantly higher detection rate by MRI was observed for intracranial extension (57% vs. 36%), skull base involvement (60% vs. 40%), retropharyngeal node (58% vs. 21%), and prevertebral muscle infiltration (51% vs. 22%). Using MRI, the T-category was upstaged in 22% and down-staged in 4%; MRI missed none of the patients with bony erosion on CT. Another study by Nishioka et al. (173) similarly showed that MRI was superior in early detection of skull base involvement, resulting in 38% upstaged from T1-2 to T3-4.
The radiologic criteria advocated by Van den Brekel et al. (215) for defining a lymph node as metastatic are commonly recommended; these criteria include the presence of central necrosis, extracapsular spread, shortest axial diameter ≥10 mm (11 mm for jugulodigastric node and 5 mm for retropharyngeal node), or group of three of more lymph nodes that are borderline in size.
Detailed assessment of nodal enlargement by palpation and imaging should include the size and location of enlarged node, unilateral/bilateral involvement, and whether the lowest extent has reached the supraclavicular fossa (Fig. 38.11). A study by Lee et al. (121) of 5,020 patients showed that fixation (movable vs. fixed to skin and underlying structures) was also a strongly significant prognostic factor (p <.01). However, this is not included as an N-staging criterion because determination of fixation is subjective and varies with the examiner.
Comprehensive search for distant metastases is indicated for patients with advanced locoregional disease (particularly N3), and those with suspicious clinical or laboratory abnormalities. A comparative study by Chang et al. (16) showed that [18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET)
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was superior to conventional work-up (using chest radiograph, isotope bone scan, and abdominal ultrasonography) in detection of distant metastases: 12% of patients were upstaged to stage IVC by PET. N-category was the most significant factor for predicting distant metastases (p <.01); the incidence was as high as 56% (9/16) in patients with N3 disease. Hence, PET coupled with CT (Fig. 38.12) is the investigation of choice, if resource allows.
Staging System
An accurate staging system is crucial not only for predicting prognosis, but also for guiding treatment strategy for different risk groups, and facilitating exchange of experience between oncology centers. An international consensus was finally reached in 1997 that a customized system is required for NPC (61,200) because the natural behavior and therapeutic considerations are uniquely different from other head and neck cancers.
Table 38.7 shows the staging criteria and groupings of the current sixth edition of the staging system jointly used by the American Joint Committee on Cancer (70), and International Union Against Cancer (199) (AJCC/UICC). Figure 38.11 illustrates the anatomic boundaries used for defining the supraclavicular fossa.
The definition of masticator space (one of the staging criteria for T4) used in the staging handbook should be noted (70): “Extension of tumor beyond the anterior surface of the lateral pterygoid muscle, or lateral extension beyond the posterolateral wall of the maxillary antrum, and the pterygo-maxillary fissure,” is meant to be the same as that used for infratemporal fossa. Unfortunately, different definitions are used by radiologists (201), and this may lead to unnecessary con-fusion.
Although there is little controversy that the current AJCC/UICC system is superior to the past systems, assessment for continual suitability with changing investigation and treatment methods is needed. A recent study by the Hong Kong Nasopharyngeal Cancer Study Group (HKNPCSG) of 2,687 patients staged by CT and/or MRI during 1996–2000 (112) supports that the current system is overall a good system with fairly even distribution and accurate prognostication for all major end points. However, modifications by down-staging of T2a to T1, N3a to N2, and subgroup T2N0 to stage I, could result in more orderly increase in the hazard ratio (HR) of cancer-specific deaths (from 1 for stage I to 1.98 for II, 3.5 for III, 6.08 for IVA, and 8.62 for IVB), and better hazard consistency among subgroups of the same stage.
Retrospective application of these suggested criteria to 677 patients by Low et al. (153) from Singapore showed similar improvements. Further validation of this proposal with series
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staged by MRI and data from nonendemic countries are needed before universal recommendations can be made.
Pathologic Classification
Most malignant tumors arising in the nasopharynx are carcinoma, which is divided into three types (Fig. 38.13) according to the World Health Organization Classification, 2005 edition (15). Keratinizing squamous cell carcinoma (type 1) is characterized by the formation of keratin pearls or intracellular keratin.
Nonkeratinizing carcinoma (type 2), characterized by total absence of keratin formation, is further subdivided into differentiated (type 2.1) and undifferentiated subtypes (type 2.2). Although still widely quoted in the literature, the use of the numerical designation of types I, II, and III according to the original 1978 edition should be replaced by the current system. Lymphoepithelioma is considered as a morphologic variant of undifferentiated carcinoma. The third type of NPC is basaloid squamous cell carcinoma, which consists of closely packed small tumor cells forming a lobular and sometimes pallisading pattern, with focal squamous carcinoma components. This type is very rare; the frequency is less than 0.2% (15).
There are marked differences in histologic pattern among different ethnic groups (Table 38.8). The frequency of nonkeratinizing carcinoma ranged from 99% in Hong Kong to 75% in the United States (15). Pure nasopharyngeal carcinoma in situ is an extremely rare entity. Two of the three cases described by Pak et al. (179) transformed into invasive NPC in 40 to 48 months.
Other malignant tumors of the nasopharynx include nasopharyngeal papillary adenocarcinoma, plasmacytoma, minor salivary gland tumors, melanoma, rhabdomyosarcoma, and chordoma. The majority of lymphoma of the nasopharynx is non-Hodgkin's lymphoma, diffuse large B cell type.
Prognostic Factors
The extent of local infiltration and lymphatic extension, as reflected by the TNM staging, is the most important prognostic factor. In general, advanced T-category is associated with worse local control and survival; advanced N-category is associated with increased risk of distant failure and worse survival. The patterns of failure and survival rate for different stages are summarized in the section Results of Treatment.
The significance of parapharyngeal extension is controversial. The study by Chua et al. (45) showed that extension to the
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prestyloid space or the anterior portion of the masticator space was associated with lower 5-year local failure-free rate (L-FFR; 72% vs. 86%) and distant failure-free rate (D-FFR; 68% vs. 87%), when compared with those with no or minimal parapharyngeal involvement. Similar findings of significance were reported by other investigators (74,159,194).
However, Teo et al. (210), who first reported on possible significance of parapharyngeal extension, did not find any significant impact in a subséquent study of 903 patients (213). The study by Au et al. (4) of 1,294 patients, using the AJCC/UICC definition of extension beyond the pharyngobasilar fascia, also showed that parapharyngeal extension was not a significant factor on multivariate analysis. These differences might be related to the various definitions of parapharyngeal space used by different authors, suboptimal detection by CT, and mixing with retropharyngeal node metastases.
Although there is significant overall correlation between T-category and the gross volume of the primary tumor (GTV-P), there is considerable variability in tumor volume within the same stage (23,38,46,205) (Fig. 38.14). There is increasing evidence that tumor volume is an independent significant
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factor that can give better prediction of prognosis than T-category by the system of Ho (46) or AJCC/UICC fifth edition (23,205).
In 308 patients staged with MRI, Sze et al. (205) showed that patients with GTV-P <15 mL had significantly higher L-FFR than those ≥15 mL (97% vs. 82% at 3 years; p <.01). Multivariate analysis showed that GTV-P was a strongly significant factor independent of T-category by AJCC/UICC fifth edition; the risk of local failure increased by 1% for every 1 mL increase in volume. With increasing ease of calculation by computer software, further refinement of prognostication by incorporation of tumor volume as a staging criterion should be explored.
Although some series have not found age and gender to be of prognostic significance for NPC, most have reported significantly better prognosis for female and younger patients. Perez et al. (182) reported a 5-year survival rate of 45% in patients younger than 50 years of age in contrast with ≤27% in older patients. The study by Sham and Choy (193) also showed a higher 5-year survival rate in those younger than 40 years compared with older patients (50% vs. 40%), and female compared with male patients (45% vs. 28%). The study by Au et al. (4) similarly showed poorer survival in male patients (HR = 1.28) and patients older than 50 years (HR = 1.79).
Data on the prognostic significance of histologic types is difficult to interpret. Studies on Chinese patients showed no prognostic difference between the different histologic types (13), but histologies other than nonkeratinizing carcinoma were distinctly uncommon. Many studies from nonendemic regions showed that patients with keratinizing squamous cell carcinoma had a worse prognosis than those with nonkeratinizing carcinoma (66,88,163), but others did not find histology to be an independent prognostic factor (183). A study by Corry et al. (52)
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showed that within nonkeratinizing carcinoma, there is no prognostic difference between ethnic Asian and non-Asian patients.
Preliminary data suggest that circulating cell-free DNA of EBV is a useful prognostic marker. Studies by Lo et al. (152) and Lin et al. (148) showed that high pretreatment titers were associated with advanced stages and poor prognosis. A study focused on patients with stage I-II NPC by Leung et al. (138) showed that pretreatment plasma EBV-DNA concentration >4000 copies/mL was associated with a higher risk of distant failure. If confirmed, this will be useful for tailoring appropriate treatment for high-risk patients.
However, a report by Le et al. (110) showed no correlation between pretreatment EBV-DNA levels and survival, whereas the posttreatment titers were strongly significant predictor of outcome. The 2-year OS for patients with undetectable posttreatment EBV-DNA was significantly higher than for those having detectable titer: 94% versus 55% (p = .002).
The prognostic significance of posttreatment titers was also reported by Lo et al. (150) and Chan et al. (12). In a study of
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31 patients treated with induction chemotherapy followed by concurrent chemoradiotherapy, Chan et al. (12) showed that all patients who remained disease-free had plasma EBV-DNA ≤500 copies/mL, whereas 8 of 9 patients with treatment failure had titer increased to >500 copies/mL 2 to 16 months before clinical evidence of disease progression. More clinical data are awaited to determine the consistency and reliability of this test before recommendation for routine use.
Similar to other head and neck squamous cell carcinomas, epidermal growth factor receptor (EGFR) expression is common in NPC. Chua et al. (41) found expression of EGFR in 89% of NPC patients, and showed that overexpression was associated with a significantly poorer treatment outcome: The 5-year disease-specific survival for those with EGFR extent ≥25% was 48% compared to 86% for those with extent <25%. Ma et al. (158) studied several biomarkers (including p53, HER2, Ki67 antigen, microvessel density, and EGFR) in 78 patients, and showed that EGFR expression only was an independent prognostic factor.
The study by Hui et al. (78) showed that 58% of NPC patients had expression of hypoxia-inducible factor 1α and 57% had carbonic anhydrase IX; those with high expression of both markers had a worse progression-free survival.
Other biologic factors that might have prognostic significance include E-cadherin and β-catenin (248), tumor proliferative fractions or aneuploid status (242), c-erbB2 (191), p53 (164), nm23-HI (72), interleukin-10 (65), and vascular endothelial growth factor (187). However, clinical data are still scanty, and further validation is needed.
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Treatment Strategy
Because of the deep-seated location of the nasopharynx and the anatomic proximity to critical structures, radical surgical resection is very difficult. The role of surgery is limited to biopsy for histologic confirmation and salvage of persistent or recurrent disease.
Treatment strategy should be tailored to the specific pattern of failure for different risk groups. Historically, megavoltage radiation therapy (RT) has been the mainstay of treatment. Although excellent results have been achieved with early stages disease, the results are less satisfactory for advanced diseases. Numerous trials have studied the therapeutic gain by adding chemotherapy at different sequences. The current data essentially show that concurrent chemotherapy is the only sequence of combination with significant survival benefit.
Hence, the current recommendation is to treat patients with stage I-II disease with RT alone, and those with stage III-IVB (± bulky IIB) disease with concurrent chemoradiotherapy (CRT). Whether induction or adjuvant chemotherapy adds further benefit to concurrent CRT remains to be demonstrated.
Radiation Therapy
To achieve the best therapeutic ratio, every single step in the RT procedures (immobilization, localization of gross tumor and target volumes, optimization of dose fractionation, determination of treatment techniques, and precision in RT delivery) is important.
Treatment Preparation
All patients should have dental evaluation and dietitian consultation prior to commencement of RT. Patients should be advised to abstain from smoking and drinking alcohol. The patient is set up in a supine position with head extended. A customized thermoplastic mask covering the head to shoulder region is made to immobilize the patient (Fig. 38.15).
Computerized planning for intensity-modulated radiotherapy (IMRT) is recommended as far as resources allow. Planning CT covering from skull vertex to 2 cm below clavicles, with 3-mm slice thickness at gross tumor regions, is performed. Fusion of diagnostic MRI with planning CT is useful for more accurate delineation of tumor targets and critical structures (56) (Fig. 38.16).
For patients to be treated by conventional two-dimensional (2D) technique, mouth bite is useful to minimize the dose to the oral cavity and enlarged neck nodes are marked with wire before taking simulation films.
Dose, Time, and Fractionation
The majority of retrospective studies, based on patients irradiated with 2D techniques, have shown a significant dose-response. Both Marks et al. (162) and Vikram et al. (217) showed that local tumor control was significantly improved in patients who received >67 Gy to the tumor target. Perez et al. (183) reported that for patients with T1-2 tumors, the local tumor control rate was 100% for those given >70 Gy, compared with 80% for those given 66 to 70 Gy. However, local control for patients with T3-4 tumors did not rise above 55%, even with total dose >70 Gy. Similar findings were reported by Mesic et al. (165); better local control for T1-2 tumors was achieved with ≥70 Gy when compared with 60 Gy (94% vs. 76%), but no significant impact of higher doses or larger fields was noted in T3-4 tumors. These observations suggest that, in addition to consideration of prescribed dose, the problem of adequate coverage has to be overcome for advanced tumors.
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A study by Lee et al. (113) of 1,008 patients with T1 tumors irradiated by four different fractionation schedules showed that total dose was the most important radiation factor (p = .01). The hazard of local failure decreased by 8% per additional Gy. Fractional dose did not affect local control, but it was a significant risk factor for temporal lobe necrosis (115,123). Dose per fraction >2 Gy should be avoided (see section Sequelae of Treatment).
The impact of the time factor is more controversial. A randomized study by Marcial et al. (161) in which 62 patients were treated with split-course irradiation (30 Gy in 10 fractions in 2 weeks, a 3-week rest period, and then another 30 Gy in 10 fractions) and 59 patients with 66 Gy in 33 fractions in 6.5 to 7 weeks, showed no significant difference in 5-year local control (86% vs. 80%), nodal control (86% vs. 78%), or disease-free survival (40% vs. 30%).
However, Vikram et al. (217) observed that local tumor control in patients with interruption of RT for ≥21 days was significantly poorer than those without interruptions (34% vs. 67%). A study by Luo et al. (157) of 1,446 patients also showed similar findings for patients with advanced disease. Kwong et al. (99), in a study of 1,301 patients with T1-4 tumors, supported the significance of the time factor with the hazard of local failure increasing by 3% per additional day of prolongation. The general consensus is that prolongation is likely to be detrimental, even for nonkeratinizing NPC, but whether modest acceleration can achieve significant benefit has yet to be confirmed.
Hence, the prescription generally recommended for NPC is a total dose of about 70 Gy during 7 weeks to the gross tumor, and 50 to 60 Gy for elective treatment of potential risk sites.
Tumor Target Volumes
The GTV includes the primary nasopharyngeal tumor and involved lymph nodes as shown by clinical, endoscopic, and radiologic examinations. For patients given induction chemotherapy, it is recommended that the targets be based on the prechemotherapy extent.
Elective irradiation of bilateral cervical lymphatics is recommended in N0 patients. A study by Lee et al. (129) of patients with clinically negative findings in necks showed that patients with elective neck irradiation had significantly lower nodal relapse rate than those untreated (40% vs. 11%). Furthermore, despite successful salvage by subsequent treatment, patients with nodal relapse had a significantly higher incidence of distant metastases than those without relapse (21% vs. 6%).
The clinical target volume (CTV) covers the GTV, microscopic infiltration and anatomic structures at risk. Different centers may have different philosophies in defining the margins and dose level. For example, Table 38.9 shows the delineation criteria for different CTV currently used at Pamela Youde Nethersole Eastern Hospital. The CTV aimed at 70 Gy (CTV_70) includes the GTV with a 5 to 10 mm margin (if possible) and the whole nasopharynx. The CTV aimed at 60 Gy (CTV_60) covers high-risk local structures (including the parapharyngeal spaces, posterior third of nasal cavities and maxillary sinuses, pterygoid processes, base of skull, lower half of sphenoid sinus, anterior half of the clivus, and petrous tips), and lymphatic regions (including bilateral retropharyngeal nodes, levels II, III and VA). The CTV aimed at 50 Gy (CTV_50) covers the remaining levels IV to VB. The level I nodes can be spared for patients with N0 disease.
The planning target volume (PTV) covers the CTV and the margin needed for systemic and random setup variations. Different centers should gauge the range of variations in their actual practice for determining this margin. With proper immobilization and meticulous care in setup, an expansion margin of 2 mm was used at Pamela Youde Nethersole Eastern Hospital for delineating PTV.
Conventional 2D Treatment Techniques
The classic 2D technique used in Hong Kong is that of Ho (76), which composes two phases. Phase I consists of lateral-opposed facial-cervical fields for the primary tumor and enlarged neck nodes, together with a lower anterior cervical field for the lower cervical lymphatics. Phase II is used after 40 Gy to avoid the spinal cord. This consists of three fields (lateral-opposed plus anterior facial fields) for the nasopharyngeal region and an anterior cervical field for the whole neck. Typical radiologic landmarks and treatment portals are shown in Fig. 38.17. Shrinking field arrangement with cone-down after 50 to 60 Gy should be made whenever possible to maximize protection of critical structures.
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The advantage of the three-field technique in phase II is to minimize the dose to bilateral temporal lobes and temporomandibular joints. However, coverage may be inadequate for tumors with extensive posterolateral extension to the parapharyngeal spaces or caudal extension to oropharynx; supplementary dose via a posterolateral field with avoidance of neurologic structures is given to rectify this deficit (212).
Another 2D technique widely used in other centers is to use lateral-opposed portals throughout. The typical field arrangement used at Mallinckrodt Institute of Radiology (United States) is shown as an example (19) (Fig. 38.18A). Phase I consists of lateral-opposed fields that are angled posteriorly 5 degrees to ensure adequate coverage of the posterior wall of the nasopharynx, while reducing the dose to the contralateral lens and avoiding direct irradiation to the ipsilateral external and middle ear.
The posterior borders of the lateral fields are displaced anteriorly after about 43 Gy to shield the spinal cord. High-energy photons (18 MV) are used in phase II to deliver the last 20 to 25 Gy while diminishing the dose to the mandible and temporomandibular joints. With the shrinking field method, a boost of 5 to 10 Gy is delivered to the nasopharynx through reduced lateral portals for patients with T4 tumors.
The lower neck and supraclavicular fossa are treated with a single anterior field at 2-Gy daily fractions to 50 Gy given dose (Fig. 38.18B). Posterior neck nodes are given a supplementary dose of 5 to 15 Gy with 9-MeV electrons through small lateral fields.
Other options for phase II include arc rotation technique as designed by Wang (219) and the anterior infraorbital oblique fields technique of Fletcher (62).
Three-Dimensional (3D) Conformal Treatment Techniques
Development of computerized 3D treatment plans is an important technical advance for NPC with its typically concave tumor volumes. Several investigators have designed innovative multifield conformal plans; for example, the seven-field technique used at Memorial Sloan-Kettering Cancer Center (United States) (231) and the “Boomerang” technique (Fig. 38.19) used at Peter MacCallum Cancer Institute (Australia) (53). All of the evaluation studies showed better tumor dose coverage while reducing normal tissue dose in comparison with conventional 2D plans (20,95,218).
Leibel et al. (136) from Memorial Sloan-Kettering Cancer Center showed that the target volume underdosed at the 95% isodose level was reduced with 3D plans when compared with 2D plans (7% vs. 22%). With the mean tumor dose increased by an average of 13%, it was estimated that the probability of uncomplicated tumor control would increase by 15%.
However, subsequent analysis of 68 patients for whom this technique was used to deliver a boost of 20 to 26 Gy following phase I conventional 2D treatment for 50 Gy did not show significant improvement; the 5-year L-FFR was 77% and late toxicity grade ≥3 was 25% (231).
More encouraging results were achieved by Jen et al. (85), who retrospectively compared 72 patients treated with 3D conformal technique throughout with 108 patients treated with 2D technique. They reported significant improvement in 3-year L-FFR for T4 (86% vs. 47%), and event-free survival for both stage III (80% vs. 56%) and stage IV (82% vs. 33%). In addition, the
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incidence of xerostomia at 3 years was significantly reduced, although there were little differences for most other late toxicities.
IMRT Techniques
With the clear advantages of sculpting the high-dose volume with tight dose gradients around the targets, dosimetric studies from different centers all show that IMRT techniques can further improve the conformity of dose distribution for NPC (24,80,89,234). There is little controversy that this technique is advocated for treating NPC if resources permit. With the tight margin now employed, precision in target localization and RT delivery become even more important; all the precautions in treatment preparation and quality control must be strictly followed.
Another potential of interest is the possibility of biologic enhancement by simultaneous modulated accelerated-radiation therapy (SMART) as a new way of delivering accelerated fractionation (AF) schedule, a concept that was first reported by Butler et al. (9) for the treatment of other head and neck cancers with IMRT.
Various methods and dose fractionation schemes for IMRT are being explored by different investigators; Table 38.10 summarizes the key features and the results achieved. Most of the patients treated in these series also received additional
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chemotherapy and/or enhanced RT with boosts or AF. All reported most encouraging early results with local control in excess of 90% at 2 to 4 years.
At the University of California, San Francisco, conventional once-daily fraction was used for all patients. A total dose of 70 Gy at 2.12 Gy/fraction was given to the gross tumor, while the CTV (that included both potential microscopic infiltration and margin for setup error) received 60 Gy at 1.8 Gy/fraction, and the neck with clinically negative findings received 54 Gy at 1.65 Gy/fraction (7,135). Updated results of 118 patients by Bucci et al. (7) confirmed excellent locoregional control of 96%. However, distant failure was still high (28%) despite extensive use of concurrent-adjuvant CRT, the OS was 74% at 4 years. One patient died of torrential epistaxis without tumor recurrence was reported by Lee et al. (135).
At Memorial Sloan-Kettering Cancer Center, treatment was delivered with dynamic multileaf collimation, using seven coplanar 6-MV intensity-modulated fields, positioned every 30 degrees from the posterior and lateral directions. Wolden et al. (230) reported their experience on 74 patients: 59 were treated with AF using the concomitant boost method and 15 by the SMART method. For the latter group, a total dose of 70.2 Gy at 2.34 Gy/fraction was given to the gross tumor, and the “microscopic” PTV received 54 Gy at 1.8 Gy/fraction. The 3-year L-FFR was better than for patients treated by 3D conformal boost (91% vs. 79%), although the difference was not statistically significant.
Further dose escalation with SMART boost in 50 patients with T3 to 4 tumors was reported by Kwong et al. (100) from Queen Mary Hospital (Hong Kong). Their goal was to deliver a total dose of 76 Gy at 2.17 Gy/fraction to the gross tumor. Although the early result for locoregional control was excellent (96% at 2 years), there were serious concerns about late toxicities because 4% of patients had life-threatening bleeding from carotid artery pseudoaneurysm, and another 4% developed temporal lobe necrosis at a median follow-up of 2.1 years.
Kam et al. (90) from Prince of Wales Hospital (Hong Kong) prescribed a total dose of only 66 Gy at 2 Gy/fraction to the gross tumor, but supplemented this with an additional boost to 56% of patients. The 3-year L-FFR for their series of 63 patients was 92%; the incidence of xerostomia (grade 2) was only 23% and hearing loss (grade 3) was 13%. However, other serious late toxicities were substantial; 2% developed osteonecrosis of C1 and C2 vertebrae requiring surgical restoration, 3% developed temporal lobe necrosis, and 23% had endocrine dysfunction.
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Different centers have to work out what is their best affordable technique. Some centers only treat the primary tumor and upper neck with IMRT, while the lower neck is treated with a matching field. However, to avoid dose uncertainty at the match line due to the potential angles of IMRT beams, and to attain better control of dose to all normal tissues at the neck and lung apex, whole-volume IMRT technique is the preferred option.
Figure 38.20 shows the delineation of targets and the technique with nine coplanar beams (6-MV photon) covering the entire region that is currently used at Pamela Youde Nethersole Eastern Hospital. A total dose of 70 Gy at 2 Gy/fraction was given to the PTV for gross tumor, while the PTV for high-risk structures received 61.25 Gy at 1.75 Gy/fraction and the PTV for low-risk structures received 52.5 Gy also at 1.75 Gy/fraction by reducing the field size for the last five fractions. Instead of using SMART, patients with T3-4 tumors are treated with a moderate AF schedule of 2 Gy/fraction, six daily fractions per week (see section Dose Escalation and Altered Fractionation). Figures 38.21 and 38.22 illustrate the tumor targets and dose-distribution plan for patients with early and advanced disease, respectively.
Skillful specification of dose constraints is important for inverse planning. Different dose constraint templates have been designed (80,235). Overstringent control of normal tissue constraints might result in inadequate coverage of tumor targets; optimal balance is critical. An example of dose-constraint guidelines is provided in Table 38.11, which shows the guidelines currently used at Pamela Youde Nethersole Eastern Hospital. Top priority is given to critical neurologic structures, followed by tumor targets, organs with intermediate importance, and finally those with lesser importance. Doses to parotids and cochlea are reduced as much as possible, but without sacrificing coverage of tumor targets. Two sets of acceptance criteria are set, stringent ideals are attempted as far as possible, but safe compromise within tolerance will have to be considered for difficult cases.
Dose Escalation and Altered Fractionation
Excellent local tumor control has also been reported by giving additional boost to patients with early disease treated by conventional 2D technique. The most widely used method is brachytherapy. Different types of applicators have been designed for intracavitary brachytherapy and various isotopes have been used for interstitial treatment. Vikram (216) used permanent implantation with iodine-125. Wang (220) used low dose-rate brachytherapy with cesium sources, while most others used high dose-rate with the advent of after-loading equipment (Fig 38.23).
Table 38.12 summarizes reports on the use of brachytherapy as a boost for dose escalation. Most studies demonstrated that local control up to 90% to 95% could be achieved for T1-2 tumors without excessive late damages. The retrospective comparison by Wang (219) from Massachusetts General Hospital (United States) showed that patients given an
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additional 7 to 10 Gy boost by low dose-rate brachytherapy following 60 to 64 Gy by external beam radiation (EBRT) had significantly higher 5-year L-FFR than those treated by EBRT alone (91% vs. 60%; p <.01). A similar retrospective comparison by Teo et al. (209) showed excellent 5-year L-FFR of 95% in patients given an additional 18 to 24 Gy in three fractions by high dose-rate brachytherapy, but the gain over the group without boost was not statistically significant (95% vs. 90%; p = .17). In addition, the comparison by Ozyar et al. (177) of 106 patients with T1-4 tumors did not show any improvement (86% vs. 94%; p = .23). The exact benefit of dose escalation has yet to be addressed in prospective randomized studies.
One major limitation of brachytherapy is that the dose delivered is adequate only for superficial nonbulky tumors. Furthermore, optimal positioning of the applicators depends both on the individual clinician's skill and the patient's anatomic features. The advent of stereotactic radiosurgery or fractionated radiotherapy, enabling precise delivery of highly conformal RT with rapid dose falloff (Fig. 38.24), provides a valuable alternative for dose escalation. In the update from Stanford University Medical Center by Le et al. (111), excellent 3-year L-FFR of 100% was achieved in 45 patients with T1-4 tumors given a median SRT boost of 12 Gy following conventional RT to 66 Gy. However, despite the addition of CRT in 80% of the patients, the distant failure rate was 31% and OS was 75%. With a median follow-up of 31 months, 7% of patients developed asymptomatic temporal lobe necrosis, 2% developed retinopathy, and 9% developed cranial nerve paresis. The risk was especially high in patients with T4 tumors; late toxicity is a major concern.
Randomized trials on other head and neck cancers have confirmed that altered fractionation is an effective option for improving local control, but data that are specific for NPC are very scant. Separate evaluation is needed because acceleration may not be able to achieve similarly significant benefit for poorly
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differentiated carcinoma, and the risk of late toxicity may be more serious because of the proximity of neurologic structures. Extra caution is needed in designing fractionation schedules for NPC.
The use of AF for NPC was first reported by Wang (219). Using 1.6 Gy/fraction twice daily (BID), phase I with lateral-opposed fields was treated to 38.4 Gy, followed by 10 to 14 days rest, and then phase II with arc rotation for another 31.6 Gy with or without a brachytherapy boost of 7 Gy. Retrospective comparison showed that patients with T2-4 tumors treated by AF achieved significantly better 5-year results than those treated by conventional fractionation (CF), both in terms of L-FFR (65% vs. 47%) and disease-specific survival (DSS; 70% vs. 35%), but the benefits for T1 tumors were statistically insignificant. No excessive late damage was incurred.
However, using a similar schedule of 1.6 Gy/fraction BID (with a 4-hour interval) to 67 Gy, Leung et al. (139) observed that the incidence of temporal lobe necrosis was as high as 24% (4/17), compared to none (0/15) in patients treated with CF. In the study by Jen et al. (83) using conventional 2D technique and BID fractions with a 6-hour interval, 76 patients were given 1.2 Gy/fraction to a median dose of 80 Gy, and 12 patients were given AF at 1.6 Gy/fraction to a median dose of 70 Gy. When compared with 134 patients treated with conventional once-daily (QD) fractionation, there was no statistically significant difference in 5-year L-FFR (T1-3 tumors, 93% vs. 86%; T4 tumors, 44% vs. 37%). The results for T4 were especially disappointing. Although the 1.2 Gy/fraction schedule did not incur excessive toxicity, the incidence of symptomatic temporal lobe necrosis was as high as 27% in patients treated with the 1.6 Gy/fraction schedule (82). See section Sequelae of Treatment for further information on the influence of dose fractionation for brain necrosis.
The first randomized trial on AF for NPC by Teo et al. (208) used an uncommon schedule of 2.5 Gy/fraction QD for 8 fractions before randomization to an experimental arm using 1.6 Gy BID for another 32 fractions versus a control arm using 2.5 Gy QD for another 16 fractions. The trial was prematurely terminated because of excessive neurologic toxicities (49% vs. 23%). For this series of 159 patients (62% with T1-2 tumors), the AF arm did not achieve significant improvement in tumor control (5-year L-FFR, 89% vs. 85%).
To minimize the risk of late damage, the more moderate AF schedule of the Danish Head and Neck Cancer Study Group 6–7 Trials using 2 Gy/fraction, 6 fractions per week (175) was tested for NPC by Lee et al. (131). A retrospective comparison of patients irradiated to a total dose of 66 Gy with 2D technique showed that those treated with this AF schedule had significantly higher L-FFR than those treated with conventional five fractions per week. The benefit was significant particularly for T3-4 tumors (87% vs. 62%; p <.01). Furthermore, no significant increase in late toxicity was observed at 3 years (20% vs. 15%).
This schedule was hence used in the subsequent NPC-9902 Trial initiated by the HKNPCSG (132), which aimed to assess the therapeutic benefit by AF and/or concurrent-adjuvant CRT using the Intergroup-0099 regimen for patients with T3-4N0-1M0 nonkeratinizing carcinoma. The trial was stopped early because of slow accrual, but the 189 patients randomized were basically balanced in patient characteristics except for unfavorable gender distribution in the AF-alone arm (90% men). Preliminary results at 3 years showed that AF per se did not show significant improvement in event-free survival (EFS) when compared with CF alone (63% vs. 70%), but AF combined with CRT achieved strongly significant improvement (see section New Attempts with Concurrent Chemoradiotherapy).
Chemotherapy
Effective systemic therapy is needed for patients with advanced locoregional disease because of the notorious predilection for hematogenous dissemination and the need for further improvement of local control. Although NPC is well known for its
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chemoresponsiveness, review of the clinical trials on the value of chemotherapy shows contradictory results.
Up to the year 2004, there were 11 randomized trials comparing combined treatment versus RT alone published in the English literature. All except the one by Rossi et al. (190) used cisplatin-based regimens; the studied populations included patients with stages II-IVB by the current criteria of the AJCC/UICC Staging System (sixth edition); all patients were treated with conventional RT using 2D technique and CF.
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Of the five trials on induction chemotherapy (14,43,73,81,160), only the trial by the International Nasopharynx Cancer Study Group (81) using cisplatin, epirubicin, and bleomycin achieved significant improvement in EFS (58% vs. 35% at 3 years; p <.01). However, treatment mortality was substantially higher (8% vs. 1%), and no benefit in OS was shown even with longer follow-up (40% vs. 46% at 5 years) (71). The results of adjuvant chemotherapy have been even more disappointing; none of the three trials (32,98,190) achieved significant benefit in any end points.
The first trial that achieved significant survival benefit was the Intergroup-0099 Study (2), using cisplatin (100 mg/m2) on days 1, 22, and 43 in concurrence with RT (70 Gy in 35 fractions) followed by combination of cisplatin (80 mg/m2) and 5-fluorouracil (1 g/m2/day for 96 hours) on days 71, 99, and 127 during the post-RT phase. When compared with RT alone, significant benefit in both 3-year EFS (69% vs. 24%; p <.01) and OS (78% vs. 47%; p = .01) was first reported in 1996, and further confirmed with subsequent update (OS: 67% vs. 37% at 5 years; p <.01) (3). However, controversies remain, particularly regarding the actual magnitude of benefit, because the results of the RT-alone arm were grossly inferior to those achieved by most centers.
The trials on concurrent with or without adjuvant chemotherapy are summarized in Table 38.13. Among the subsequent trials, that by Lin et al. (146) using concurrent cisplatin and 5-fluorouracil, also achieved significant benefit in both EFS and OS, the gain in 5-year survival was 18% (OS: 72% vs. 54%; p = .002). However, in a subsequent reanalysis (147) with retrospective restaging of the accrued patients and more accurate segregation into different risk groups, the benefit was insignificant for the high-risk group.
Two other trials from Hong Kong, that by Chan et al. (11) using concurrent cisplatin and that by Kwong et al. (98) using concurrent uracil and tegafur with or without adjuvant cisplatin-combination, both showed borderline improvement in OS, with survival gain of around 10% (p ≥.06), but no corresponding improvement in EFS (p >.14).
A meta-analysis by Baujat et al. (5), based on updated patient data of 1,753 patients from eight accepted trials (2,11,14,32,43,73,81,98), showed a small but significant benefit by adding chemotherapy: The absolute gain for 5-year EFS was 10% (52% vs. 42%) and for OS it was 6% (62% vs. 56%). The reduction in the pooled HR of death was significant: 0.82, 95% confidence interval (CI): 0.71–0.94; p = .006 (Fig. 38.25). However, the treatment effect was heterogeneous because of significant interaction of timing (p = .03); the survival benefit was essentially confined to the concurrent subset.
More recent reports of confirmatory trials using the Intergroup regimen again showed varying conclusions (Fig. 38.26). The SQNP01 Trial by Wee et al. (222) of patients with stages III-IVB disease supported that the Intergroup regimen could achieve significant improvement in both EFS and OS for Asian patients; the 3-year survival gain was 15% (OS: 80% vs. 65%; p = .006). The preliminary results of the NPC-9901 Trial of patients with N2-3 diseases by the HKNPCSG (124) also showed
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significant improvement in 3-year EFS (72% vs. 62%; p = .027). However, with the favorable results by RT alone and aggressive salvage of treatment failures, no corresponding survival benefit was yet observed (78% vs. 78%), although the improvement in tumor control might translate into significant survival benefit with longer follow-up.
One serious concern about the Intergroup regimen is its efficacy for distant control. Preliminary results of the NPC-9901 Trial (124) showed that the improvement in D-FFR for patients with N2-3 disease was minimal (76% vs. 73%; p = .47). Furthermore, both the series treated by IMRT from University of California, San Francisco (7,135) and that by stereotactic boost from Stanford University Medical Center (111) showed disappointingly high incidence of distant failure (≥25%), despite achievement of excellent locoregional control (≥93%) and extensive use of the Intergroup regimen (≥75% of patients).
Another concern about CRT is tolerance and the risk of toxicities. No treatment-related mortality was observed in the Intergroup-0099 Trial, but both Asian confirmatory trials (124,222) reported 1% mortality by the same regimen. The
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NPC-9901 Trial (124) is the first trial that assesses the impact on late toxicity. Besides the expected increase in acute toxicities (84% vs. 53%; p <.01), the CRT arm also had significantly higher incidence of major late toxicities (28% vs. 13% at 3 years; p = .02) (Table 38.14). This was mostly due to increased otologic toxicities (14% vs. 8%), peripheral neuropathy (2% vs. 0%), and endocrine dysfunction (4% vs. 1%). The majority of toxicities were grade 3 in severity. Damages to neurologic structures were rare, but one patient (0.6%) in the CRT arm developed palsy of the last four cranial nerves and died of aspiration pneumonia. On the whole, the Intergroup regimen could be accepted as tolerable, but longer follow-up is needed for full assessment.
Even among American patients, the proportions who could complete the scheduled concurrent and adjuvant chemotherapy of the Intergroup regimen were only 63% and 55%, respectively (2). In addition to concern about the poor compliance and tolerance during the post-RT period, the contribution of the adjuvant component is also questionable, as none of the individual trials (32,98,190) or meta-analyses (5) showed any significant benefits.
However, since the currently available positive data are largely based on the Intergroup regimen, this remains the recommendation most commonly used; but patients should be duly informed that with improving RT technologies, the differential gain in survival might be smaller than initially thought, and there is increased risk of toxicities (both acute and late).
New Attempts with Concurrent Chemoradiotherapy
Building on the current achievement by concurrent CRT, different approaches for further improvement of treatment results have been explored (Table 38.15).
One strategy is to enhance the effectiveness of RT by changing the fractionation from CF to AF. Retrospective studies combining AF with concurrent-adjuvant CRT had shown reasonable tolerability and encouraging preliminary results (86,145,232). In a series of 50 patients (44% stage IVA-B) treated at Memorial Sloan-Kettering Cancer Center using the concomitant boost schedule to deliver 70 Gy in 6 weeks combined with the Intergroup regimen, Wolden et al. (232) showed that 3-year L-FFR of 89% and OS of 84% could be achieved. The study by Jian et al. (86) using a hyperfractionation schedule of 1.2 Gy BID to 74.4 Gy combined with CRT, achieved 3-year OS of 100% for T3 and 63% for T4.
The only randomized trial that attempted to study this combined strategy was the NPC-9902 Trial (132) of patients with T3-4N0-1M0 diseases. The fractionation schedule was 2 Gy per fraction, five fractions per week in CF arms and six fractions per week in AF arms. The preliminary results showed that CRT using the Intergroup regimen combined with AF achieved significantly better EFS than CF alone (94% vs. 70% at 3 years; p = .008) (Fig. 38.26). However, the sample size was small and follow-up was relatively short; the possibility of occult bias and chance effect could not be totally excluded. Hence, the findings could be taken only as hypothesis-generating, and further confirmation is needed.
Another strategy is to enhance the effectiveness of chemo-therapy by changing the timing from concurrent-adjuvant to an induction-concurrent sequence. Although induction chemotherapy per se did not achieve significant survival benefit, data from the meta-analyses by Baujat et al. (5) showed that this could significantly reduce the risk of locoregional failures by 24% and distant failures by 35% (Fig. 38.25). Another advantage is that patients' compliance and tolerance are substantially better during the induction phase than the adjuvant phase (133). This early use of potent combinations of cytotoxic drugs at full dose might be particularly advantageous for NPC with extensive locoregional infiltration, as this could shrink the primary tumor to give wider margin for irradiation (Fig. 38.27).
All five phase II studies using induction-concurrent CRT with CF reported encouraging preliminary results (1,12,87,174,189). Using a combination of cisplatin, 5-fluoruracil, and
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epirubicin as induction chemotherapy and cisplatin in concurrence with RT to 60 Gy, Rischin et al. (189) achieved excellent 4-year results in 35 patients (40% stage IV) with OS of 90%, distant control of 94%, and locoregional control of 97%.
For the most difficult stage IV patients with locoregional disease infiltrating or abutting neurologic structures, a more aggressive approach combining induction-concurrent CRT with AF has been explored at Pamela Youde Nethersole Eastern Hospital. Two different induction regimen have been tested:
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Cisplatin and 5-fluoruracil was used in the first pilot study by Lee et al. (133), and a newer combination of cisplatin and gemcitabine was used by Yau et al. (238). These were then followed by cisplatin in concurrence with RT to 70 Gy using the six fractions per week AF schedule. Given the grave prognosis of this notorious group in the past, 3-year OS of 71% (133) and 76% (238), respectively achieved in the two studies, were very encouraging. Further confirmation of efficacy is warranted.
Persistent/Recurrent NPC
Early Detection and Diagnosis
Despite improving control rate with primary treatment for NPC, local failure remains a problem for patients with advanced T-category. Distinction should be made between persistent disease (tumors that do not completely regress following primary treatment) and recurrent disease (tumors that re-emerge after initial complete regression) because the therapeutic considerations and prognosis are different.
As it takes time for tumors to regress following RT, one difficult decision is when to consider residual tumors as genuine persistence and proceed with salvage treatment. Kwong et al. (96) performed serial biopsies from the nasopharynx in 617 patients and showed that the percentage of positive biopsies dropped spontaneously from 29% in the first week after completion of RT to 12% by the ninth week and then rose again. The 5-year L-FFR was 82% for patients who achieved early histologic remission (<5 weeks), 77% for those with delayed remission (5 to <12 weeks), but only 54% for those with persistent tumors at 12 weeks, despite subsequent salvage treatment. The optimal time for intervention remains uncertain; avoidance of unnecessary overtreatment and excessive delay in treatment are both important, and an observation period of 8 weeks is a reasonable balance commonly used.
Early detection of locoregional failure is crucial for a better chance of salvage. However, both CT and MRI have relatively low sensitivity and specificity in detection of persistent/recurrent disease. Generally, MRI is superior to CT. Gong et al. (68) showed that recurrent tumor exhibited higher signal intensity on T1-weighted spin-echo images, whereas radiation fibrosis showed low or medium intensity in T1 and T2 images. The high-intensity feature, however, is not specific for tumor, and may be seen with radiation edema or infection. Technetium-99 m MIBI SPECT may be a useful tool. Kostakoglu et al. (94) showed that this was superior to MRI performed at 3 to 6 months post-RT in diagnosing complete response. The advent of FDG-PET is a valuable development. Yen et al. (241) compared FDG-PET and MRI in 67 NPC patients 4 to 70 months after completion of RT and showed that FDG-PET was superior to MRI in all aspects, including sensitivity (100% vs. 62%) and specificity (93% vs. 44%).
Preliminary data suggest that circulating cell-free DNA of EBV may be another useful tool for early detection of treatment failure. A longitudinal study by Lo et al. (151) showed that elevation of EBV-DNA titer was noted in patients with relapse up to 6 months before detectable clinical disease. However, this measurement is more sensitive for distant metastases than locoregional recurrence; up to one third of patients with locoregional recurrence did not show elevated EBV-DNA copies (229).
Additional Radiation for Persistent Disease
Brachytherapy has been widely used for locally persistent disease after a full course of EBRT (Table 38.16, part A). Excellent results with 5-year L-FFR in the range of 87% to 95% for patients with initial T1-2 a tumors have been reported (101,109,140,209,246). There is preliminary evidence suggesting that patients with initial T2b tumors could also be effectively treated by brachytherapy (143).
Stereotactic RT is a valuable advance for delivering additional EBRT. Yau et al. (239) studied 755 patients with T1-4 tumors and showed that 7% had positive biopsies 8 weeks after completion of primary RT. The 21 patients treated with fractionated stereotactic RT to a median dose of 15 Gy achieved a 3-year L-FFR of 82%, a result that was very close to corresponding L-FFR of 86% in the contemporary cohort with complete remission, and was substantially better than corresponding L-FFR of 71% in 24 patients treated with high dose-rate brachytherapy to a median dose of 20 Gy.
Reirradiation for Recurrent Disease
Aggressive salvage treatment should be attempted because long-term survival can be achieved for a substantial proportion of patients with early locoregional recurrence and useful palliation for those with extensive disease. However, there is a high risk of normal tissue damage. It is crucial to restrict the irradiation of normal tissue to a minimum.
The most important prognostic factor is the TNM stage of the tumor at the time of recurrence. Thorough restaging,
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including metastatic work-up, is needed. A study of 891 patients with local recurrence by Lee et al. (125) showed that 54% of patients also developed regional and/or distant failures. Another significant factor is reirradiation dose: Most series using EBRT with conventional 2D technique showed that doses ≥60 Gy were associated with better outcome (119,186,221).
A retrospective comparison by Lee et al. (116) of the symptomatic late toxicity rate in 487 patients with two courses of EBRT versus 3,635 patients with one course showed that the summated total biologic dose tolerated (BED-Σ) was higher than that expected with a single-course treatment (BED-1), suggesting partial recovery of normal tissues (particularly for patients with reirradiation after an interval >2 years). Assuming an α/β ratio of 3 Gy, the BED-Σ that incurred 20% toxicity at 5 years was 129% that of BED-1.
Brachytherapy has been widely used for treatment of recurrent NPC (Table 38.16, part B). Early-stage recurrent NPC could be effectively salvaged by brachytherapy alone (101,109). Kwong et al. (101), using interstitial implants with radioactive gold grains, reported a 5-year L-FFR of 63%; complications included headache (28%), palatal fistula (19%), and mucosal necrosis (16%). Law et al. (109), using iridium mold, achieved excellent local salvage up to 89%, but the complication rate was 53%.
The combination of brachytherapy and EBRT is useful, particularly when conventional 2D technique is used. Lee et al. (119) showed that patients reirradiated by combined modes had higher salvage rate than those by EBRT or brachytherapy alone: The 5-year L-FFR was 45%, 32%, and 29%, respectively. Similar pattern of superiority by combined method was reported by other investigators (64,141,186,219,221).
Stereotactic radiosurgery or fractionated stereotactic radiotherapy is another useful tool for retreatment of local recurrence. Control rates ranging from 53% to 86% have been reported (22,44,50,178). For advanced recurrence with extension beyond the nasopharynx, this method will give better dose coverage than brachytherapy. A higher salvage rate by adding stereotactic radiation (17,44,236) as a boost after EBRT has been reported. Although most series reported a low risk of complications, massive hemorrhage with potential fatal outcome has been described (44). To minimize this risk, radiosurgery should be avoided when there is direct tumor encasement of the carotid artery or when a high cumulative dose has already been delivered.
Table 38.17 summarizes the treatment outcome and severe late complications by external reirradiation. Past series using 2D technique achieved 5-year survival rates in the range of 21% to 41%, and the incidence of temporal lobe necrosis ranged from 2% to 27%. The use of 3D conformal radiotherapy showed improving results. Chang et al. (17) showed that none of the patients reirradiated by 3D technique developed temporal lobe necrosis compared with 14% in those reirradiated by 2D technique. Zheng et al. (247), reported a very encouraging 5-year local salvage rate of 71%, but the actuarial rate of late toxicities (grade 4) was still as high as 49%.
Preliminary reports using IMRT for reirradiation show encouraging short-term results. Using IMRT to deliver 68–70 Gy, Lu et al. (155) reported 100% salvage rate without any
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severe late complications in a series of 49 patients with a median follow-up of 9 months. Using IMRT to a median dose of 54 Gy in 31 patients (with or without induction chemotherapy and stereotactic boost), Chua et al. (48) reported a locoregional salvage rate of 56% and late complications (grade 3) of 25% at 1 year. Longer follow-up is clearly needed.
Chemoradiotherapy may also improve treatment outcome for recurrent NPC. Using gemcitabine and cisplatin as induction chemotherapy followed by reirradiation with IMRT in 20 patients (95% rT3-4), Chua et al. (42) reported a 1-year local salvage rate of 75%. In a study of 35 patients (66% rT3-4), Poon et al. (185) reported a 1-year EFS of 42% by concurrent cisplatin followed by adjuvant chemotherapy with cisplatin and 5-fluorouracil.
Surgical Treatment
For patients who develop local or nodal persistent/recurrent disease without distant metastasis, surgical salvage is an important option to consider. For patients with nodal failure following RT, lymph node involvement is often extensive, Radical neck dissection is the recommended salvage procedure (224). A study by Wei et al. (226) showed that salvage with radical neck dissection could achieve a 5-year nodal control rate of 66% and a disease-free survival of 37%. For those with tumor extending beyond the lymph node confines and involving nearby structures, addition of after-loading brachytherapy to the tumor bed following radical neck dissection might be useful (225).
For selected patients with persistent/recurrent disease localized in the nasopharynx, surgical salvage by nasopharyngectomy is an option. As the nasopharynx is located in the center of the head, adequate exposure for oncologic extirpation of the tumor is a great challenge. A number of approaches have been employed. These include an infratemporal approach from the lateral aspect (60), transpalatal, transmaxillary and transcervical approaches from the inferior aspect (58,166), and an anterolateral approach (227). As all the patients concerned have undergone prior radical RT, the associated morbidities of trismus and palatal fistula are common, but the mortalities associated with these surgical procedures have been low.
Recurrent NPC is frequently located in the pharyngeal recess on the lateral wall. Direct access to this region is essential for complete tumor extirpation. Wei and Sham (228) advocated the anterolateral approach or the maxillary swing approach for surgical salvage of localized failure in the nasopharynx. Following facial incisions and the appropriate osteotomies, the maxilla bone is swung laterally while attached to the anterior cheek flap as one osteocutaneous unit (Figs. 38.28 and 38.29). The nasopharynx with the persistent/recurrent tumor and its vicinity including the paranasopharyngeal region are then widely exposed for oncologic resection. At completion of nasopharyngectomy, the maxilla is returned and fixed to the rest of the facial skeleton with miniplates.
Wei et al. (228) studied 161 patients with salvage nasopharyngectomy using this approach performed at Queen Mary Hospital (Hong Kong) for recurrent NPC following primary treatment by radical RT. Twelve patients also had prior brachytherapy as a salvage procedure. Preoperative assessment showed the tumors of all patients were recurrent stage T1. Negative tumor resection margins, confirmed by frozen section, were achieved in 78% of patients, and the remaining patients had microscopic tumor at the internal carotid artery or the skull base detected during surgery, making further resection impossible. All patients recovered from this anterolateral approach nasopharyngectomy and were discharged. Associated morbidities included trismus of different degrees in 60% and palatal fistula in 25% of patients. Recent modification of the palatal incision has eliminated the problem of palatal fistula (168). In concurrence with other reports, satisfactory long-term results could be achieved for persistent/recurrent tumor that can be completely removed surgically. The 5-year local salvage rate was around 65% and disease-free survival was 54% (57,223).
Results of Treatment
The specific results of various new treatments have been summarized in the preceding respective sections. This section focuses on the overall results in major series of patients treated in the past two decades (Table 38.18).
Two of the representative series from the past, 5,037 patients treated at Queen Elizabeth Hospital (Hong Kong) during 1976–1985 (129) and 378 patients treated at M.D. Anderson Cancer Center (United States) during 1954–1992 (67,192), both reported very similar results with DSS of around 50% at 5 years
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and 45% at 10 years. The risk of delayed “relapse” is another feature of NPC that is distinct from other head and neck cancers; long-term follow-up is needed.
Almost all retrospective analyses have demonstrated steady improvement in treatment results when compared with historical data at the same institution. Taking the series that includes only patients treated from 1985 onward as contemporary series, the average 5-year survival now achieved is up to 70% (range in OS, 57% to 75%; DSS, 67% to 80%). Such encouraging results were reported not only from Asia (4,130,142), but also from Europe (180) and Australia (52).
Retrospective analyses by Su and Wang (202) of patients with NPC of different histologic types treated at Massachusetts General Hospital (United States) during 1979–1996 showed that Chinese race per se was not a significant prognostic factor. The 5-year OS for Chinese versus non-Chinese patients was 49% versus 56%. The study by Corry et al. (52) of patients with nonkeratinizing NPC treated at Peter MacCallum Cancer Institute (Australia) during 1985–1999 also showed that race had no significant impact. The 5-year OS for Asian versus non-Asian patients was 75% versus 63%.
A representative contemporary series reported by the HKNPCSG (130) of 2,687 patients treated in all public centers in Hong Kong during 1996–2000, with 53% of patients staged III-IVB by the current AJCC/UICC system, showed that a 5-year OS of 75% and DSS of 80% could now be achieved. Figure 38.30 shows the OS achieved for different stages during this era. Treatments during this period were not state of the art because of resource constraints; only 32% of the series were staged by MRI (the rest by CT), 90% were irradiated with conventional 2D technique to a median total dose of 66 Gy, and
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only 14% had additional treatment with concurrent chemotherapy and 9% sequential chemotherapy. Hence, similar, if not better, results should be achievable at least for nonkeratinizing NPC.
Review of contemporary series (Tables 38.18) shows that the average 5-year L-FFR was 80% (range, 74% to 85%), nodal-FFR was 90% (range, 80% to 94%), and D-FFR was 77% (range, 75% to 83%).
Excellent nodal control can usually be achieved. Based on the contemporary series with detailed results for different N-categories (130,142), the average 5-year nodal-FFR was 97% for N0, 95% for N1, 90% for N2, and 75% for N3. Routine surgery is not indicated; radical neck dissection should be reserved for those with nodal persistence or recurrence after RT.
T category is the most important prognostic factor for local control. Based on the contemporary series treated mostly by conventional 2D technique (4,130,142,158,159), the average 5-year L-FFR varied from 90% (range, 82% to 93%) for T1, 82% (range, 77% to 87%) for T2, 70% (range, 69% to 80%) for T3, to 68% (range, 58% to 77%) for T4 tumors. With all the technological development, dose escalation, and/or addition of concurrent chemotherapy, 3-year local control close to 100% has been reported (7,111,189).
Distant failure remains the most challenging problem. The risk correlates significantly with both T and N category, but N category is by far the most significant predicting factor. The study from the HKNPCSG (112) showed that the HR of distant failure in patients with N3b disease was as high as 6.26 (95% CI: 4.42 to 8.88) when compared with N0.
Based on the contemporary series with detailed results for different stages (49,130,142), the average 5-year D-FFR varied from 93% for stage I, 85% for stage II, 78% for stage III, to 60% for stage IVA-B. A study of 2,070 patients treated by RT alone in the HKNPCSG series (130) showed that both the presenting stage and achievement of locoregional control were significant predictors for distant failure. The 5-year D-FFR for stages I-IIB versus stages III-IVB were 90% versus 75% for patients who achieved locoregional control, but 81% versus 65% for those with locoregional failure (Fig. 38.31).
One difficulty in the interpretation of treatment results for different stages is that the phenomenon of stage migration inevitably occurs with changing investigation methods. Detailed analyses of the HKNPCSG series (130) showed that, together with simultaneous changes in treatment provisions, the MRI-staged patients achieved significantly better results for corresponding stages than those who were CT-staged. The treatment results of different stages in the two differently staged groups are shown in Table 38.19 as a reference for contemporary results.
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Sequelae of Treatment
Overall Incidence and Types
With the anatomic proximity to critical structures, the need for high radiation doses and adequate field coverage, the risks of radiation-induced toxicities are substantial. The diagnosis of irradiation injury can be difficult. A high degree of awareness is demanded and every effort must be made to exclude other possible causes (tumor recurrence in particular).
Table 38.20 lists the incidence of late toxicities following radical RT with conventional technique (without any concurrent chemotherapy) in five representative series with long-term follow-up. Both the studies on patients treated by RT alone at M.D. Anderson Cancer Center during 1954–1992 (192) and those treated at Mallinckrodt Institute of Radiology during 1956–1991 (19) showed an overall treatment mortality rate of 3%. Both showed encouraging reduction of severe toxicity in later years, even with the use of higher radiation doses. Sanguineti et al. (192) reported that the 10-year actuarial rate of severe toxicity (grade 4–5) decreased from 14% in 1954–1971 to 5% in 1983–1992. Chao and Perez (19) reported a similar reduction rate of toxicity (grade ≥3) from 17% in 1956–1965 to 4% in 1986–1991.
To minimize the risk of late damage, the importance of maximum conformity and precision in RT delivery cannot be overemphasized. The advent of IMRT enhances the feasibility of protecting normal tissues. All the studies using this technique have shown substantial sparing of parotid glands (90,97,135). However, it should be cautioned that attempts at dose escalation together with concurrent chemotherapy might lead to severe toxicities (100).
The extensive use of concurrent CRT increases the risk of toxicities. Preliminary data from NPC-9901 and NPC-9902 trials (124,132) showed significant increase in toxicities (grade ≥3) when patients treated with CRT using the Intergroup regimen were compared with those with RT alone (Table 38.14). Hearing loss is the most common problem with cisplatin-based regimens; RT technique with sparing of cochlea should be attempted as far as possible.
Temporal Lobe Necrosis
Temporal lobe necrosis (TLN) is the most worrisome complication; the study by Lee et al. (126) of 4,527 patients treated during 1976–1985 showed that this accounted for 65% (40/62) of all irradiation-induced deaths. In a study of 1,008 patients with T1 tumors, Lee et al. (115) showed that the 10-year actuarial incidence of TLN ranged from 4.6% to 18.6% for schedules
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with fraction sizes of 2.5 to 4.2 Gy. The fractional effect is the most significant risk factor.
In a subsequent study of 1,032 patients with T1-2 tumors treated with conventional 2D technique during 1990–1995, Lee et al. (123) showed that the incidence of symptomatic TLN ranged from 0% (with 2 Gy/fraction, five fractions/week, for 33 fractions) to 24% (3.5 Gy/fraction, three fractions/week, for 17 fractions), and 33% for an altered fractionation schedule (71.2 Gy in 5 weeks). Besides fractional effect, overall treatment time was also found to be a significant factor. Overacceleration and fractional dose >2 Gy should be avoided.
The presenting features in 102 patients with TLN were summarized by Lee et al. (127). Thirty-nine percent presented with vague symptoms (dizziness, poor memory, or behavioral changes); hence, diagnosis was often delayed. Only 31% had classic temporal lobe epilepsy with absence attacks, hallucinations, or déjà vu, and 14% had symptoms of headache, confusion, convulsion, or hemiparesis. Sixteen percent were asymptomatic.
The early classic radiologic feature is fingerlike white matter edema confined to the inferomedial part of the temporal lobes, followed by contrast-enhancing necrosis involving the grey matter (35) (Fig 38.32). Some lesions may resolve spontaneously; others remain stationary or progress to massive edema, cyst formation (Fig 38.33), acute hemorrhage (26), or develop brain abscess (27).
Control of temporal lobe epilepsy by anticonvulsants and close monitoring of symptoms or signs of increased intracranial pressure are the main treatments. Early promising results with high-dose steroids for more than 4 months were hampered with severe and sometimes fatal infection (127), and the apparent high remission rate shown on CT was not confirmed with MRI (114). Hence, intervention with steroids and/or surgery is usually reserved for markedly symptomatic patients.
The possible risk of Kluver-Bucy syndrome is a serious concern when considering bilateral temporal lobectomy (128). A study in Queen Elizabeth Hospital of 520 patients with TLN showed that 9% (49 patients) had temporal lobe surgery performed, and their postsurgery 5-year OS was 32%. Among the six patients who had bilateral lobectomy, none have had Kluver-Bucy syndrome thus far (S. C. K. Law, unpublished data, 2006).
The degree of cognitive dysfunction with TLN correlates with the volume and site of radionecrosis (31). Lesions predominantly in the right and the left side are associated with loss of visual and verbal memory, respectively. General intelligence is usually intact (30).
Brainstem Encephalopathy/Cervical Spinal Cord Myelopathy
In the past, this was a common neurologic sequelae leading to spastic paraparesis or quadriparesis. In the study by Lee et al. (126), 59% of the 44 affected patients progressed rapidly to a debilitated state and 34% died. There was no effective treatment to arrest this pathologic process. Fortunately, this sequela has become rare with improving RT technique and accuracy in delivery. Lee et al. (126) showed that all affected patients were treated before 1983.
Cranial Neuropathy
The last four cranial nerves, especially the twelfth, are the most frequently injured (126,142,149). This is related to marked fibrosis, particularly among patients with an additional boost
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dose to parapharyngeal space. Affected patients usually present with slurring of speech, twitching of neck muscles, and/or swallowing difficulties that can lead to fatal aspiration pneumonia. Wu et al. (233) studied 31 patients with post-RT dysphagia in NPC and found that 77% aspirated after the act of swallowing.
The sixth nerve is another commonly affected nerve, and is frequently associated with TLN (126). Isolated palsy of branches of the fifth nerve is less common, and optic neuropathy is rare with careful attention to the RT technique. Intracranial recurrence must be excluded before making a clinical diagnosis of radiation injury.
Endocrine Dysfunction
Amenorrhea and/or galactorrhea from hyperprolactinemia in female patients are the commonest presenting feature(s), followed by hypothyroidism and hypoadrenalism. Very few male patients complain of impotence or decreased libido.
Symptomatic hypothalamic-pituitary dysfunction was clinically observed in 5% of patients after a median latency of 5 years in the series reported by Lee et al. (126). However, detailed endocrine assessment and longitudinal study by Lam et al. (105) showed that biochemical dysfunction might be detected as early as 1 year after RT, and the 5-year incidence was up to 62% (104). The deficiency of releasing or inhibitory factors suggests that the main damage occurs at the hypothalamus (103,106). Deficiencies in growth hormone, gonadotropins, corticotrophin, and thyrotropin were found, in decreasing order of frequency.
Sham et al. (195), in a randomized trial of 152 patients treated with 2D technique using a hypofractionation schedule (3.5 Gy/fraction, three daily fractions/week, for 17 fractions), showed that additional shielding could significantly reduce the incidence of symptomatic endocrine dysfunction from 11% to 0%, and TLN from 21% to 0%. The importance of maximum conformity for protection of normal tissues cannot be overemphasized.
Aural Toxicity
Hearing loss is a common sequela, particularly for patients treated with concurrent CRT using cisplatin-based regimens. Kwong et al. (102) followed 132 NPC patients with serial audiograms for a median period of 30 months after RT, showed that 24% of patients developed sensorineural deafness (mainly affecting the high-frequency range). Grau et al. (69) further showed significant correlation between hearing loss and the cochlear dose. It should be noted that sudden deafness with late onset (more than 5 years) might result from vascular insufficiency and recover after treatment with a vascular expander like dextran 40 (243).
Another major mechanism of ear complications is dysfunction of eustachian tube (244), causing otitis media with effusion. Lau et al. (108) showed that tinnitus developed in 49% of patients, and persisted in 29% at 1 year. The benefit of prophylactic insertion of ventilation tubes is controversial. Chowdhury et al. (40) showed that patients with tubes inserted had less conductive hearing loss, tinnitus, and/or otitis. However, Skinner et al. (198) showed that this did not lead to long-term benefit for hearing. Chen et al. (21) showed that this might even worsen postirradiation otitis media, with increased risk of ascending infection from all adjacent irradiated areas.
Oral Complications
Xerostomia is almost universal with conventional RT using 2D technique. Jen et al. (84) showed that the salivary flow dropped by half after dose of 7.2 Gy, reached the nadir after 36 Gy, and then further dropped after completion of RT without recovery during the following 2 years. However, with parotid sparing by IMRT (mean parotid dose, 34 Gy), Lee et al. (135) from University of California, San Francisco, reported marked recovery, with grade 2 xerostomia decreasing from 64% at 3 months to 2.4% at 2 years.
Dental decay is commonly associated with xerostomia. Appropriate dental care with prophylactic fluoride treatment and extractions of decayed teeth prior to commencement of RT can help to reduce the risk of dental sequelae (6). Cheng et al. (28) showed that 2.7% of 1,758 patients developed osteoradionecrosis at the maxilla and 1.7% developed it at the mandible. They found no difference in the risk of oesteonecrosis between extractions performed before and after RT. Tong et al. (214) reported that the incidence of complications following post-RT extraction of posterior maxillary teeth could be as high as 29%, with 10.5% developing osteonecrosis.
Carotid Artery Injury/Epistaxis
Stenosis of the extracranial and pseudoaneurysm of the intracranial portion of carotid arteries are two potentially fatal complications. Cheng et al. (29) studied 96 patients with a mean follow-up of 6.7 years after RT for NPC and 96 healthy controls by color flow duplex ultrasonography. Severe stenosis with ≥70% occlusion at the internal or the common carotid artery was found in 16% of patients, but none among the controls. Ultrasound screening of carotids for high-risk patients (age more than 60 years, history of smoking, heart disease, cerebrovascular symptoms) was advocated.
Lam et al. (107) also detected carotid stenosis with ≥50% occlusion in 24 (30%) of 80 patients, 9 of whom had a history of stroke or transient ischemic attack. A high index of suspicion is required. Carotid endarterectomy or endoplasty may be needed for severe cases.
Ruptured pseudoaneurysm presents acutely with massive epistaxis/hemoptysis or severe otalgia, often with a catastrophic outcome (25). This has been reported following IMRT with dose escalation (100) and reirradiation for local recurrence (25). It usually affects the heavily irradiated petrous portion of the internal carotid artery. Urgent diagnosis with angiography and emergency intervention by endovascular occlusion or stenting could be life-saving.
Other causes of intractable epistaxis include severe telangiectasia and hypervascularization in the internal maxillary artery territory. Emergency embolization may also be considered.
Second Malignancies
Radiation-induced malignancy is a rare sequela. In one study, the incidence was 0.04% and the latency was more than 10 years (126). Maxillary osteosarcoma (54) and soft tissue sarcoma (92) are the usual histologic types. Surgery is the only chance of cure, but the prognosis is often poor. A second primary head and neck cancer is relatively uncommon for NPC patients, but Teo et al. (206) reported an excessive risk of tongue cancer at 0.13% per patient-year. The possibility of radiation carcinogenesis cannot be excluded.
Final Remarks
In summary, the current standard recommendation for NPC is RT alone for stages I-II, combined RT and concurrent chemotherapy for stages III-IVB (± bulky stage IIB). Intensity-modulated RT technique is preferred if resources allow. A total dose of about 70 Gy is generally recommended. The Intergroup-0099 regimen of cisplatin-based concurrent and adjuvant chemotherapy with RT at conventional fractionation remains the chemoradiotherapy regimen with the most
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supporting data. Further enhancement of efficacy by using accelerated fractionation for T3-4 tumors and/or changing the timing of chemotherapy to induction-concurrent sequence for stage IV is worth considering. Verification of these new strategies by randomized trials is awaited.
Patients should be duly informed that, with improving results achievable by modern RT techniques, the absolute magnitude of survival benefits by adding chemotherapy might not be large and that the new treatments do incur higher risk of toxicities. Yet the prognosis for patients with relapse is so gloomy that achieving radical eradication of the cancer by best-quality primary treatment is crucially important. Patients should be encouraged to consider the treatment option that could maximize the chance of tumor control. More accurate prognostication is needed for further refinement of treatment strategies tailored to individual risk patterns.
Medical progress in the battle against NPC is one of the most gratifying successes. This peculiar cancer was invariably lethal before the advent of megavoltage RT, and it was not until the mid-1960s that we saw the first reports showing 25% of patients alive at 5 years (167). Contemporary results show that 5-year overall survival 75% and above can be achieved. Furthermore, the age-standardized incidence rate (per 100,000 male populations) in Hong Kong (one of the most prevalent sites) has steadily decreased from the peak of 40 in 1978 to 16 in 2003. With concerted efforts by all, we are highly optimistic that even greater global success in reducing the health burden by this notorious cancer can be achieved in the near future.
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