Nasopharyngeal Cancer

Editors: Bailey, Byron J.; Johnson, Jonas T.; Newlands, Shawn D.
Title: Head & Neck Surgery - Otolaryngology, 4th Edition

Copyright 2006 Lippincott Wi lliams & Wilkins
> Tabl e of Contents > Vol ume Two > VIII - Head and Neck Surgery > 117 -
Nasopharyngeal Cancer
117
Nasopharyngeal Cancer
William I. Wei
Anatomical ly, the nasopharynx is conti nuous wi th the nasal cavi ties and serves
as a passage for air duri ng breathing. Because of its bony framework, it remains
patent under normal circumstances. Nasopharyngeal carcinoma (NPC) i s a
squamous cell carcinoma (SCC) arising from the epitheli al lining of the
nasopharynx. This neoplasm coul d arise from any site in the nasopharynx and is
more frequentl y seen at the fossa of Rosenmll er, the recess located medial to
the medi al crura of the eustachian tube.
A group of 14 patients with this mal ignancy was first reported i n the English
li terature in 1901 (1). The first comprehensive seri es reporting clinicopathologic
features of 114 patients with NPC i n Hong Kong was publi shed i n 1941 (2).
Nasopharyngeal carcinoma is a relatively uncommon malignant disease in most
countries wi th its age-adjusted incidence less than 1 per 100,000 (3). It occurs
more frequentl y, however, i n the Inuits of Alaska (4) and ethni c Chinese in the
southern part of China, especial ly from the province of Guangdong. The recent
reported inci dence of NPC among men and women in Hong Kong in the southern
part of the Guangdong province was 20 to 30 per 100,000 and 15 to 20 per
100,000, respecti vely (3). The i ncidence of NPC remains high among those
Chinese who have immigrated to Southeast Asi a countries or North America, but
is low among those Chi nese born in North Ameri ca (5,6). Thi s suggests that
geneti c, ethnic, and environmental factors may pl ay a role i n the etiology of the
disease.
The consumption of salted fi sh is one of the causative factors of NPC frequently
mentioned This may be related to the carci nogenic compound, nitrosamine,
detected on the sal ted fish (7). A subsequent case-control study, however,
showed that only frequent consumption of salted fi sh before 10 years of age is
associated with increased ri sk of developi ng NPC (8).The Epstein-Barr virus
(EBV) has also been considered to play an oncogeni c role i n thi s tumor, because
the EBV genome i s frequently detected in the biopsy specimens of NPC (9). In
view of the ubiquitous presence of this virus in the human popul ation, it is
unlikel y that EBV is the only causative agent of NPC. In the first-degree relatives
of patients wi th NPC, thei r i ncidence of developi ng this mali gnancy i s six times
higher than controls (10). This suggests that genetic factor might have an
important role i n the etiol ogy of NPC. Comparative genomic hybridi zati on studies
have demonstrated alterations in mul tiple chromosomes such as the deleti on of
regions at 14q, 16p, 1p, and amplification of 12q and 4q (11,12). Tumor
suppressi ve genes also have been recentl y l ocated in chromosome 14q (13).
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Histopathology
The mali gnant epi thelial cells of NPC are large pol ygonal cells with a syncytial
character. Their nuclei are round or oval with scanty chromatin and distinct
nucl eoli. The cel ls are frequentl y intermingled with l ymphoi d cel ls in the
nasopharynx, gi vi ng ri se to the term l ymphoepitheli oma (14). Electron
microscopy studies have confirmed the squamous origi n of these cells, including
those undi fferentiated carcinomas that are a form of epidermoid SCC with
mini mal di fferentiati on (15).
The hi stol ogic classifi cation of NPC proposed by the World Health Organization
(WHO) (16) in 1978 categorized tumors into three groups:
T Type I: those typical kerati ni zing SCC with intercel lular bridges, simil ar to
those found in the rest of the upper aerodigestive tract (Fig. 117.1).
T Type II: nonkeratinizing epidermoid carci nomas. They show evidence of
maturation but without defi nite squamous differentiation (Fig. 117.2).
T Type III: undifferentiated or poorl y differentiated carcinomas. These cells
have indistinct cel l margi ns with hyperchromatic nuclei. (Fig. 117.3).
In North Ameri ca, approximately 25% of patients with tumor have type I
histology, 12% type II, and 63% type III. The corresponding histologi c
distribution i n southern Chinese pati ents i s 3%, 2%, and 95%, respectivel y (17).
An alternati ve cl assifi cation divi ded tumors into two histologic types, namely
squamous cell carcinomas and undi fferenti ated carcinomas of the
nasopharyngeal type (UCNT) (18). This second classifi cation took into
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Figure 117.1 Squamous cell carci noma of the nasopharynx. The tumor cel ls
are l arge wi th eosi nophi lic cytopl asm and show features of keratinization
(hematoxylin and eosi n - 400). (See also Col or Plate 51.)
consideration its correl ati on with EBV serology. Patients with SCC have a lower
EBV ti ter, whereas those with UCNT have el evated titers.
Figure 117.2 Nonkeratinizi ng differentiated carcinoma of the nasopharynx.
The tumor cell s have a papi llary configuration and appear more
hyperchromatic than the undi fferenti ated carcinoma. The nuclei at the
periphery show pali sading (hematoxyli n and eosi n - 400). (See also Col or
Plate 52.)
Figure 117.3 Undifferentiated carcinoma of the nasopharynx. Tumor cells
are typi cally composed of nests or islands of pl eomorphic polygonal cells
with large vesicular nucl ei and prominentnucleoli . The tumor nests are often
surrounded by a lymphoid stroma, which i s part of the nasopharyngeal
stroma (hematoxylin and eosin - 400). (See also Color Pl ate 53.)
On clinical grounds, biopsies obtai ned from patients with NPC sometimes show a
mixed hi stologic pattern. The recent WHO cl assi fication has taken i nto account
this mixed pattern and also the associ ati on of the EBV wi th type II and III
tumors. The hi stol ogic types of NPC are now cl assifi ed into two groups: either as
SCC or nonkerati ni zing carcinomas, with the second group subdivided i nto
differentiated and undifferentiated carcinomas (19). This new classificati on has
al so been shown to have a prognosti c beari ng, the undifferentiated carcinomas
have a higher l ocal tumor control rate with radi otherapy, and a hi gher i ncidence
of distant metastasis (20,21).
Clinical Presentations
Pati ents with NPC present with one or more of the four groups of symptoms.
These groups of symptoms are rel ated to the location of the primary tumor, their
infil tration of structures in the vicinity of the nasopharynx, or metastasis to the
cervical lymph nodes.
A tumor mass in the nasopharynx can l ead to the symptoms of nasal obstruction
and discharge. Wi th a small tumor, the obstruction i s unilateral and with tumor
growth the symptoms can become bi lateral. When the tumor ulcerates, the
patient may present wi th epistaxi s. The amount of bleeding is usually trivial and
the frequent presentation is the presence of al tered blood in the postnasal dri p,
especi all y in the morni ng.
Tumor bulk in the nasopharynx, wi th or without posterol ateral extensi on i nto the
paranasopharyngeal space, is
frequently associated with dysfunction of the eustachian tube. This can lead to
fluid coll ecti on in the middl e ear and the pati ents may experi ence unilateral
conductive deafness and other otologi c symptoms (e.g., otalgia and ti nni tus).
Serous otitis medi a was noted in 41% of 237 patients newl y di agnosed with NPC
and, thus, when a Chinese adult patient presents with this symptom, the
otolaryngologi st should consider the possi bili ty of NPC (22).
When the primary tumor grows superiorl y to infiltrate the skull base, the patient
will experi ence headache. When the upward extension of tumor affects the
cavernous si nus and i ts l ateral wall, the thi rd, fourth, and sixth cranial nerves
can be affected and the patient will present with di plopia. When the tumor
extends to involve the foramen ovale, the fifth crani al nerve can be affected and
facial pain and numbness experienced. Crani al nerve involvement i n patients
with NPC is approximately 13% (23) to 30% (24), dependi ng on disease stage.
In view of the high propensi ty of NPC to metastasize to cervi cal lymph nodes,
the most frequent presenting symptom is a painless neck mass, frequently
appearing in the upper neck. As the nasopharynx is a mi dline structure, it is not
uncommon to see patients presenting with bi lateral cervical lymph nodes.
Pati ents presenting with symptoms related to distant metastasis are relati vely
uncommon in NPC. Skeletal metastasi s to the vertebra, li ver, and lung are the
sites where distant metastases are encountered.
Because of the nonspeci fic nature of the nasal and aural symptoms and the
inconspicuous nature of the painless cervical l ymph node, however, most
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patients wi th NPC have NPC di agnosed only when thei r tumor has reached
advanced stages. A retrospective analysi s of 4,768 patients showed that the
symptoms at presentation were neck mass i n 76%, nasal symptoms in 73%,
aural symptoms in 62%, and cranial nerve palsy i n 20% of patients (25). In
most reports, the mal e-to-female ratio was 3:1 and the median age was 50
years. The presenti ng symptoms in young pati ents were si milar to those of
adul ts (26).
Diagnosis
When patients present with symptoms of NPC, they should be evaluated clinical ly
for physical signs of NPC (e.g., the presence l ymph nodes in the neck, fl uid in
the middle ear, and cranial nerve invol vement). Indi rect examinati on of the
postnasal space shoul d be carried out wi th a mirror, al though the anatomic
variation of the nasopharynx in some patients precludes an adequate evaluation
of the region. Other investigations toward the di agnosis of NPC are the
estimation of anti body levels against EBV, imaging studies, and endoscopic
exami nation of the nasopharynx and biopsy.
Serology
Epstein-Barr virus affects human in various forms. It can cause i nfecti ous
mononucleosis and has also been found to be associated wi th Burkitt l ymphoma
and NPC. EBV belongs to the herpes virus fami ly and the EBV-specific antigens
can be grouped into earl y repli cative antigens, l atent phase antigens, and l ate
anti gens. In patients with NPC, their antibody, i mmunogl obulin A (IgA), response
to the earl y antigen (EA) of the first group, and the vi ral capsid antigen (VCA) of
the third group has been shown to be of diagnosti c val ue (27).
The IgA anti-VCA is more sensi tive but less specifi c than the IgA anti-EA. In
population screening studies thousands of apparently heal thy i ndividuals, those
with elevated titers of these antibodi es had an incidence of harbori ng subclini cal
NPC ranging from 3% (28) to 5% (29) and their annual detecti on rate of NPC
was 30 times higher than for the population as a whole (28). The findings were
confi rmed by a recent report from Tai wan in whi ch 9,699 men were studi ed, who
had a one-off bl ood sample for their EBV serol ogy, which subsequently correlated
with the cancer registry and death registry over a 15-year period. Those with
elevated anti-EBV titers have a 30 ti mes greater chance of developi ng NPC (30).
When a spectrum of antibodi es agai nst one of the latent phase antigens of the
EBV-associated nucl ear antigen (EBNA) was eval uated, both the specificity and
sensiti vity of the test exceeded 92% (31).
The IgA anti-VCA level has also been shown to be related to the stage of the
disease, and the level may decrease foll owi ng therapy (32); i ts value as a tumor
marker in evaluating tumor eradicati on and detection of recurrence has not been
establ ished (33). In recent years, cel l-free DNA of the EBV has been detected in
patients wi th NPC and it has been evaluated as a tumor marker (34). It,
however, has a moderate sensiti vi ty, especially when the pri mary tumor is small
and when radiotherapy has been gi ven (35).
Imaging Studies
Clinical exami nation, together with endoscopic exami nation, can provi de val uable
informati on on tumor extensi on on the mucosal surface, but cannot determi ne i ts
deep extension, including skull base erosion, and intracranial spread. This
informati on i s provided by cross-secti onal i magi ng studies. These i nvestigations
are essenti al today to document the extent of the disease in the nasopharynx
and i n the planni ng delivery of radiation (36).
Computed tomography (CT) can demonstrate the soft ti ssue extensi on i n the
nasopharynx and laterally into the paranasopharyngeal space (37) (Fig. 117.4).
It i s sensi tive in detecting bone erosion, especially that of the skull base. Tumor
extension intracrani all y through the foramen oval e wi th peri neural spread can
al so be detected, whi ch provi des evi dence of cavernous sinus i nvolvement
without skull base erosion (38). CT can show bone regeneration after therapy,
whi ch indi cates compl ete eradication of tumor (39).
Magnetic resonance imaging (MRI) provides multi planar i magi ng abil iti es and is
better than CT in differentiating tumor from inflammation of soft tissues. MRI is
al so more sensiti ve at evaluati ng retropharyngeal and deep cervical nodal
metastases (40). MRI can detect bone marrow
infil tration by tumors, whereas CT cannot detect this ki nd of infiltration unless
associated bony erosion exists. It is important to detect this marrow infiltration
because it is associated with an i ncreased risk of di stant metastases (41). MRI,
however, cannot evaluate details of bone erosion, and CT should be performed
when the status of the skull base needs to be evaluated.
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Figure 117.4 Computed tomography (axial vi ew) showing tumor in the
nasopharynx (T).
Another contribution of cross-sectional imaging studies i n NPC i s toward the
therapeuti c aspects. Because CT or MRI determines the primary tumor extent
with unprecedented precision, it enables radiotherapy treatment to be designed
and admini stered more accuratel y and effectively, resul ting in an i mproved
outcome (42). Thi s is parti cularl y appli cable recently wi th the intensity
modulated radi otherapy (IMRT),
whi ch makes use of composite CTC"MRI targets (43), and this enabl es
radiotherapy to be targeted even more accurately onto tumor while sparing
adjacent normal ti ssues.
Both CT and MRI, however, have rel ati vel y low sensi tivity i n detection of tumor
recurrence (44) because recurrent NPC after radi otherapy can exhi bit a range of
signal intensi ties and contours, and these can be diffi cult to interpret (45).
Positron emission tomography (PET) is reported to be more sensitive than cross-
secti onal imaging studies in detecti ng persistent and recurrent NPC (46), both at
the primary site and in the neck (Fi g. 117.5) The preci se detecti on of distant
metastases at diagnosis is difficult. Studies have concluded that bone scans,
li ver scinti graphy (47), and marrow biopsy (48) are of li ttle val ue. They shoul d
only be used for those patients with hi gh ri sk of distant spread (e.g., those with
N3 disease) (49).
Endoscopic Examination
A confirmed di agnosi s of NPC requires a posi tive biopsy taken from the tumor i n
the nasopharynx. The nasopharynx can be adequately examined under topi cal
anesthesia with endoscopes. The ri gid Hopkin telescopes, both 0 and 30,
give an excell ent view of the nasopharynx on the insertion side (Figs. 117.6 and
117.7). In cases of a devi ated septum, a 70 endoscope inserted through the
opposite nasal cavity can al so provi de adequate visual izati on of the tumor. This
Figure 117.5 A: Axial vi ew of positron emissi on tomography superimposed
with computed tomography image, showing increased activity at the primary
site in the nasopharynx si gnifying presence of tumor (DUURZ). B: Sagittal
view of the same patient. (See also Col or Plate 54.)
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70 endoscope inserted behind the soft palate all ows visualization of the roof of
nasopharynx and both eustachi an tube openings (Fig. 117.8). These rigi d
endoscopes do not have a suction or bi opsy channel. Blood and mucus coveri ng
the tumor should be removed by a separate sucti on devi ce for a clear view of the
pathol ogy. Bi opsy forceps should also be inserted al ong side the endoscope to
take a biopsy of the tumor under direct visi on.
Figure 117.6 Rigid endoscope (0) i nserted through the l eft nasal cavi ty
and tumor in the nasopharynx is identifi ed (7XPRU).
The flexible endoscope al lows thorough examination of the entire nasopharynx,
even when i t is inserted through one nasal cavity. Its ti p can be maneuvered
behind the nasal septum to the opposite side. It has a suction channel and a
biopsy forceps can be inserted through it to take a bi opsy of the tumor under
direct visi on. Despi te al l these advantages, the visual image gathered with the
flexible endoscope i s inferior to that of the rigid endoscope and the si ze of the
biopsy
forceps is also small ; thus onl y subopti mal tissue may be obtained. Someti mes,
a l arger biopsy forceps can be i nserted by the side of the fl exi ble endoscope to
obtain more substantial amount of tissue for hi stol ogic examination.
Staging
The different cl inical staging systems for NPC each have thei r merits. The
Ameri can Joint Committee on Cancer/Union Internationale Contre l e Cancer
(AJCC/UICC) system, preferred in America and Europe, fol lows the usual patterns
Figure 117.7 Rigid endoscope (30) i nserted through the left nasal cavity
of the same patient and tumor i n the nasopharynx identified (7XPRU). The
posteri or edge of the septum is vi sible (6).
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Figure 117.8 Rigid endoscope (70) i nserted through the oral cavity,
inspecting the nasopharynx from below. Posterior edge of the nasal septum
(6) ri ght eustachi an tube orifice (DUURZ) and nasopharyngeal tumor can be
seen extending from the ri ght lateral wall onto the roof of the nasopharynx
(7XPRU).
of staging for head and neck malignanci es (Table 117.1), whereas Ho' s system
(50), which i s frequently used in Asia, has its nodal classification, refl ecti ng
better prognosti c signifi cance (Table 117.2).
Incorporati ng experi ences gai ned from various centers around the world and
taki ng into account a number of prognostic factors, incl uding skull base erosion,
involvement of cranial nerves, tumor extension to paranasopharyngeal space,
and the location and size of the cervi cal nodes, a revi sed AJCC/UICC staging
system was publi shed in 1997. Stage T1 tumor i n the new stagi ng system
includes both T1 and T2 classifi ed under the ol d system. The new stage T2
tumors cover those that had extended to the nasal fossa, oropharynx, or
paranasopharyngeal space. The new stage T3 tumor incl udes those that had
extended to the skull base or other paranasal si nuses. The new stage T4 tumors
cover those that had extended into the i nfratemporal fossa, orbi t, hypopharynx,
and cranium, or to the cranial nerves. For cervi cal lymph node, stage N1 under
the new system refers to unilateral nodal involvement; stage N2 bilateral nodal
disease that had not reached N3 designation, irrespective of the size, number,
and anatomi c location of the nodes. N3 refers to lymph nodes l arger than 6 cm
(N3a) or nodes that had extended to the supraclavi cular fossa (N3b) (51). This
new staging system has enabled di sease to be staged more preci sely accordi ng
to the extensiveness of NPC and has been shown to predict survival (52,53).
Treatment
Radiotherapy
In view of the nasopharynx location, lying in close proximi ty to important
structures, and the i nfiltrati ve nature of NPC, surgi cal resection of the primary
tumor is chal lenging. NPC, however, is radiosensitive and, thus, radiotherapy has
been the primary treatment modal ity for decades. Radi otherapy, although
effective, can al so produce undesirabl e compl ications because NPC at the base of
skul l is surrounded by the brai n stem, spinal cord, pi tuitary-hypothalami c axi s,
temporal lobes, eyes, middle and inner ears, and parotid glands. All these organs
li mit the amount of radiation that can be delivered to the tumor. Because NPC
tends to infil trate and spread toward these dose-l imiti ng organs, it is difficult to
shi eld these structures without compromising the dose deli vered to the pri mary
tumor. Because of the high incidence of occult neck node invol vement, the neck
is usually included i n the radiation field electively (54). Good locoregional
control can be achi eved and once locoregional relapse occurs, an increased risk
exists of devel oping di stant metastases (55).
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TABLE 117.1 AMERICAN JOINT COMMITTEE ON
CANCER STAGING FOR NASOPHARYNGEAL CANCER
Tumor in nasopharynx (T)
T1 Tumor confined to the nasopharynx
T2 Tumor extends to soft tissues of oro-pharynx and/or nasal fossa
T2 a wi thout parapharyngeal extensi on
T2 b with parapharyngeal extension
T3 Tumor i nvades bony structures and/or paranasal sinuses
T4 Tumor with i ntracranial extension and/or i nvol vement of cranial
nerves, infratemporal fossa, hypopharynx, or orbit
Regional Lymph Nodes (N)
The distri bution and the prognostic impact of regional lymph node
spread from nasopharynx cancer, particularl y of the undi fferenti ated
type, is different than that of other head and neck mucosal cancers and
justifi es use of a di fferent N cl assi fication scheme.
NX Regional lymph nodes cannot be assessed
N0 No regi onal l ymph node metastasis
N1 Uni lateral metastasi s i n l ymph node(s), 6 cm or l ess in greatest
di mensi on, above the supraclavi cul ar fossa
N2 Bil ateral metastasis in lymph node(s), 6 cm or l ess in greatest
di mensi on, above the supraclavi cul ar fossa
N3 Metastasis in a lymph node(s)
N3a greater than 6 cm i n dimensi on
N3b extensi on to the supraclavi cular fossa
Distant Metastasi s (M)
MX Di stant metastasi s cannot be assessed
M0 No distant metastasis
M1 Di stant metastasi s
Stage grouping
Stage 0 T1s N0 M0
Stage I T1 N0 M0
Stage IIA T2a N0 M0
Stage IIB T1 N1 M0
T2 N1 M0
T2a N1 M0
T2b N0 M0
T2b N1 M0
Stage III T1 N2 M0
T2a N2 M0
T2b N2 M0
T3 N0 M0
T3 N1 M0
T3 N2 M0
Stage IVA T4 N0 M0
T4 N1 M0
T4 N2 M0
Stage IVB Any T N3 M0
Stage IVC Any T Any N M1
From Fleming ID, Cooper JS, Henson DE, et al., eds. AJCC cancer
staging manual, 5th ed. Phil adel phia: Lippincott-Raven,
1997:33C"35, with permi ssion.
TABLE 117.2 HO STAGING FOR NASOPHARYNGEAL
CANCER
T: Primary tumor
T1: Tumor confined to nasopharynx (space behind choanal ori fices
and nasal septum and above posterior margin of soft palate in
resting position)
T2: Tumor extended to nasal fossa, oropharynx, or adjacent
muscles or nerves bel ow base of skul l
T3: Tumor extended beyond T2 limits and subclassfied as foll ows:
T3a: Bone involvement below base of skull (floor of sphenoi d si nus is
i ncl uded in this category)
T3b: Invol vement of base of skull
T3c: Invol vement of cranial nerve(s)
T3d: Invol vement of orbits, laryngopharynx (hypopharynx), or
i nfratemporal fossa
N: Regional lymph nodes
N0: No node pal pabl e or nodes thought to be beni gn
N1: Node(s) whol ly in upper cervical l evel, bounded below by
the skin crease extending laterally and backward from or just
Radiotherapy for NPC usual ly starts with large lateral opposing faciocervi cal
fiel ds that cover the primary tumor and the upper neck lymphatics i n one
volume, with matching l ower anterior cervical fi eld for lower neck lymphati cs.
When the spinal cord dose reaches 40 to 45 Gy, two opti ons exist for the second
phase of treatment. The del ivery of radi ation can ei ther be changed from the
original fiel ds to l ateral opposi ng facial fields with another anterior facial fiel d
for the pri mary tumor, with matching anteri or cervi cal fiel d for the neck
lymphatics (50). Alternatively, radiation treatment can be continued using the
lateral opposingfaci ocervical fields, but these fi elds are reduced i n size to avoid
the spinal cord, whi le the superi or-posterior lymphatic are treated with el ectron
fiel ds (56,57).
below thyroid notch (l aryngeal emi nence)
N2: Node(s) pal pabl e between crease and supraclavi cular fossa, the
upper l imit being a l ine joi ni ng the upper margin of the sternal
end of the clavicle and the angle formed by the l ateral surface
of the neck and the superior margin of the trapezius
N3: Node(s) pal pabl e in the supraclavicul ar fossa and/or ski n
i nvol vement in the form of carcinoma en cuirasse or satell ite
nodul es above the cl avicles
M: Metastases
M0: No hematogenous metastases
M1: Hematogenous metastases present, and/or l ymph nodal
metastases below the cl avicle
Stage grouping
I T1, N0
II T2 and/or N1
III T3 and/or N2
IV N3 (any T)
V M1
From Ho JH. Stage classificati on of nasopharyngeal carcinoma: a review.
Internati onal Agency for Research on Cancer, Publi cation No. 20,
1978;99C"113, wi th permi ssion.
In general , the radiation dose given to the pri mary tumor i s in the range of 65 to
75 Gy and that to the invol ved neck nodes is 65 to 70 Gy. For el ecti ve radiation
of node-negati ve neck, the dose given is 50 to 60 Gy. This treatment has
successfully controll ed T1 and T2 tumors in 75% to 90% of cases, and T3 and T4
tumors in 50% to 75% of cases (58,59). Nodal control is achieved i n 90% of
patients wi th N0 and N1 diseases, but the regional control rate drops to 70% for
N2 and N3 cases (58).
For T1 and T2 tumors, empl oyi ng a booster dose usi ng intracavitary
brachytherapy has i mproved tumor control by 16% (60). Although stereotactic
radiosurgery has al so been used to del iver the booster dose (61), the
hypofracti onated treatment is associated with undesi rable side effects and is
probabl y better reserved for the treatment of persistent and recurrent disease
(62).
The major li mitations of two-dimensional planning for NPC can now be el iminated
with three-di mensi onal conformal radiotherapy and IMRT (63,64). When the
tumor extension i s close to the dose-li miting organs, IMRT is distinctl y useful
because it further i mproves the dose differential between the tumor and the
dose-l imiti ng organs (65,66). IMRT also eliminates the dose uncertainty problem
at the junction between the pri mary tumor and neck lymphatic target volumes,
because it enables the pri mary tumor and the upper neck nodes to be treated i n
one volume.
Excel lent locregional control has been achieved with IMRT in the management of
NPC (67). Fol lowing IMRT, prospective study has confirmed the recovery of
sali vary functions withi n 2 years (68). Sati sfactory results were also achi eved
with IMRT for recurrent NPC, and the degree of short-term control was
encouragi ng (69). The limi tati on of IMRT remai ns its preci sion i n determining the
junction of tumor and the adjacent normal structures. Unti l the opti mal safety
margin that needs to be covered between gross tumor and adjacent ti ssues is
establ ished, the planning of cli ni cal target vol ume for IMRT should be performed
cautiously.
Other attempts to enhance the results of radiotherapy include accelerated
fractionati on (70), accel erated hyperfracti onation (71), and a combination of one
or other of these treatments with chemotherapy (72,73).
Chemotherapy
For the management of NPC cases, especial ly those with advanced locoregi onal
disease, chemotherapy has been appl ied i n combination with radiotherapy.
Chemotherapy, consisting of ci spl ati n, can be given before, during, or after
radiation; thus there were studies that reported resul ts on neoadjuvant,
concurrent, and adjuvant chemotherapy with radiotherapy, respectively.
The Intergroup 1997 study first showed that using chemotherapy with
radiotherapy i mproved overal l survival when compared with usi ng radiotherapy
al one (74). Thi s study incl uded many patients wi th wel l-differentiated carcinoma
and i nitially doubts were rai sed whether it was appl icable to NPC i n the endemic
areas. A subsequent study from Taiwan confirmed the benefit of this approach
(75).
Two neoadjuvant studies (76,77) reported improvement in relapse-free survi val,
but not improvement in overall survival, whereas two others reported no
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improvement in survival (78,79). The two prospective, randomized studies on
adjuvant chemotherapy reported no improvement, ei ther i n relapse-free survival
and overal l survival (80,81).
General agreement now is that, for advanced di seases, concurrent
chemoradiotherapy is useful, whereas other forms of combination therapy
require further evaluation. To i mprove the results of concurrent
chemoradiotherapy, a study on neoadjuvant chemotherapy foll owed by
concomitant chemoradi otherapy has reported excellent overal l survival and
acceptabl e toxicity (82). In view of the ototoxicity of cispl ati n, other
chemotherapeutic agents have been used. A study reports on the concurrent use
of ci spl ati n and radiotherapy, fol lowed by adjuvant ifosfamide, 5-fluorouraci l
(5FU), and l eucovori n in pati ents with stage IVb NPC. Although these pati ents
had more advanced disease, treatment outcome was comparable to other
platinum-based adjuvant chemotherapy studi es and the compliance rate was
acceptabl e (83).
Follow-Up
The health-related quali ty of life for those patients with NPC who survived, i n
general, i s i mpai red (84,85). Late compli cations appear i n the long-term
survivors and these are the resul ts of radiati on on the dose-limi ting organs
adjacent to the nasopharynx and neck nodes. These sequelae incl ude
neuroendocri ne (86) and auditory (87) complicati ons, xerostomia leading to poor
oral and dental hygi ene (88,89), radi ation-induced soft tissue fibrosi s (90), and
carotid artery stenosis (91). Debi litating neurologic compl ications include
temporal lobe necrosis (92), crani al nerve pal si es (93), and other l ess obvious
side effects such as memory (94), and cognitive (95) and neuropsychological
dysfunctions (96). Cispl ati n-based chemotherapy adds other otologi c side effects
(97).
Complete remission of NPC fol lowing treatment can be moni tored with cli nical
exami nation, endoscopi c examinati on with or without biopsy, and imaging
studies. Studi es comparing PET with MRI or CT to detect persistent and recurrent
tumor have reported PET to be superior (98,99). Early detecti on of l ocoregional
relapses is important because these tumors are still amenable to salvage when
detected earl y (100). In cases of persi stent disease, in either the nasopharynx
or neck 10 weeks after completion of the initi al therapy, then sal vage treatment
shoul d be considered (101).
Management of Persistentor Recurrent Disease
Although concomitant chemoradiation is effective in the management of NPC,
local or regional fail ure presenting as persi stent or recurrent tumor still occurs.
To attain a hi gh salvage rate, early detection and therapy are essential. PET is
superior to CT (99) and MRI (98) in detecting persistent or recurrent disease in
the nasopharynx, and any mal ignancy can usual ly be confi rmed with bi opsy
through endoscopic examination. Persi stent or recurrent tumor in the neck node
after chemoradiotherapy, however, is notori ously di fficul t to confi rm, because
only cl usters of tumor cells are present i n some l ymph nodes (102).
Aggressive treatment for locall y recurrent NPC is warranted because, although
survival after retreatment for extensi ve disease remains poor, it i s stil l longer
than for those managed wi th supportive treatment onl y. For pati ents with NPC,
even in cases of synchronous locoregional fai lures, aggressive treatment should
be considered for selected patients (103).
Persistent or Recurrent Tumor in Neck Lymph Nodes
Fol lowing combined chemoradiation for NPC, isolated fai lure i n the neck was
reported to be less than 5% (104). If cancer persi sts or recurs in the cervical
lymph nodes, as evidenced by fine-needle aspiration cytol ogy, i magi ng studies,
or progressive enl argement of the lymph nodes, salvage therapy i s i ndicated.
When managed with another course of external radiotherapy, the reported
overall 5-year survival rate was onl y 19.7% (105). Radical neck dissection as a
form of surgical sal vage has been reported to achieve a5-year tumor control rate
of 66% in the neck and a 5-year actuarial survival of 38% (106). For those
persi stent or recurrent tumors i n the neck nodes, pathologi c studies have shown
extensive disease involvement of the l ocal tissue. Mali gnant cells coul d be seen
to extend outside the capsule of the l ymph nodes and l ying cl ose to the
accessory nerve and the internal jugular vei n. Many lymph nodes that appeared
free of tumor were found to harbor malignant cel ls. Tumor clusters were seen in
the sternomastoi d muscle and other ti ssue in the neck. A radical neck dissecti on
was considered essential for salvage when mal ignant tumor were found i n the
neck nodes.
When tumor in the neck node extends beyond the confi nes of the l ymph node,
brachytherapy should be appli ed to the tumor bed in addition to radical neck
dissecti on. With this adjuvant therapy, a simi lar tumor control rate has been
reported when compared with radical neck dissecti on done for less extensive
neck di sease (107).
Persistent or Recurrent Tumor in the Nasopharynx
Persistent or recurrent disease in the nasopharynx after the initial radical dose
of radiation can still be managed with a second course of external radiotherapy
with a l arger radiation dose. A salvage rate of 32% has been reported, although
the cumul ati ve inci dence of l ate sequelae after repeated irradiation was 24%,
with a treatment mortali ty of 1.8% (108). The compli cations ari si ng from the
second dose of external radi otherapy affects signi ficantly the qual ity of li fe of
these pati ents. To al leviate this high incidence of compl ications resulting from
repeated irradiation, alternative salvage measures have been i ntroduced. These
include stereotactic radiotherapy, brachytherapy, and surgical resection. These
treatment options are useful only when the persistent or recurrent tumor is small
and l ocalized i n the nasopharynx.
Stereotactic Radiotherapy
The local tumor control rate achieved wi th stereotacti c radi otherapy for
management of persi stent or recurrent tumor was 72% at 2 years (62) and 86%
at 3 years (109). In general, fewer patients have been treated with this modal ity
(110) and long-term fol low-up i nformation on l ocal control rate, survi val rate,
and i ncidence of complication has to be documented before this method can be
applied widely for the management of these cases.
Brachytherapy
Wi th the appl ication of brachytherapy in the management of persi stent or
recurrent nasopharyngeal carcinoma, the radiation source i s i nserted directly
P.1665
into the tumor. The radiati on dose i s highest at the source and declines
gradually with increasi ng distance from the tumor. Thus this all ows the deli very
of a hi gh therapeutic radiation dose to the persistent or recurrent tumor in the
nasopharynx while the surrounding ti ssue was i rradi ated with a much smal ler
dose. The brachytherapy radiation source also delivers radiation at a conti nuous
rate and this gives radiobiological advantage over fractionated external
radiation. Intracavitary brachytherapy has been used for NPC, both as a boost of
the primary treatment and for persistent or recurrent disease (111). The
radiation source was pl aced either in a tube or a mould and then inserted i nto
the nasopharynx. Good results achieved with the intracavi tary brachytherapy
have been reported (112). In view of the i rregular contour of the primary tumor
within the nasopharynx, however, i t is difficult to apply the radi ati on source
accurately to provi de a tumoricidal dose to the whol e tumor. To ci rcumvent this
problem, radi oactive interstitial implants have been used to treat smal l local ized
persi stent or recurrent tumor in the nasopharynx (113).
Radioacti ve gold grai ns (
198
Au) are frequentl y used asa brachytherapy source.
Gol d grains can be impl anted ei ther transnasall y or using the split-palate
approach (114). The split-palate approach gives the surgeon a di rect view of the
tumor and enables the precise impl antation of the desired number of gol d grains
permanentl y i nto the tumor (Fi g. 117.9). Thus, the exact dosimetry of radiation
can be achieved for salvage. For tumors locali zed in the nasopharynx, without
bone invasion, this method has provi ded effective salvage with minimal
morbidity. The surgical procedure is simpl e and l ess than 10% of patients may
develop a small palatal fistula, which can be managed conservatively or repaired
later with a palatal flap (115). Lead shields, however, have to be used in the
Figure 117.9 A: The surgeon (l eft), after spl itti ng the pal ate, holds a
flexi ble endoscope placed in the nasopharynx to provide ill umi nati on and
guidance. The oncol ogist (right) uses the gold grain appl icator to insert the
radi oactive grains directl y into the tumor. B: Endoscopic vi ew showi ng the
ti p of the gold grai n appli cator (DUURZ) before inserti ng i nto the tumor
(7XPRU).
operati ng room to reduce the radiation hazards of health care workers. When
gold grain impl ants were used to treat persi stent and recurrent tumors after
radiotherapy, the reported 5-year local tumor
control rates were 87% and 63%, respectively, and the corresponding 5-year,
disease-free survi val rates were 68% and 60%, respectively (116).
Nasopharyngectomy
When the persi stent or recurrent tumor in the nasopharynx has extended to the
paranasopharyngeal space or i s too bul ky for brachytherapy to be successful, the
next salvage option is surgery. Nasopharyngectomy is effective in the eradication
of locali zed disease in selected patients.
The nasopharynx is located i n the central part of the head. It is difficult to
expose the regi on adequately to carry out an oncologic resection of a tumor
situated in the nasopharynx that has extended to its vicinity. Various approaches
have been used to expose the nasopharynx for salvage nasopharyngectomy. The
brain and the spinal cord render superior and posterior approaches not practi cal.
The transantral and mi dfacial degl ove procedures to reach the nasopharynx from
the front do not provide adequate exposure of the whol e nasopharynx. These
anterior approaches, even with the downfracture of the hard palate, expose onl y
the posterior wal l of the nasopharynx and not the lateral wal ls. Fisch described
an approach to the nasopharynx from the lateral aspect, through the
infratemporal fossa (117). This route of entry started with a radical
mastoidectomy and vari ous important structures have to be mobi lized, including
the internal caroti d artery, the fi fth crani al nerve, and the floor of the middle
crani al fossa. The resultant morbi dities are not negli gibl e and it mainl y exposes
the lateral wal l of the nasopharynx on the side of the surgery and not the entire
nasopharynx.
The nasopharynx can be approached from the inferior aspect using the
transpalatal , transmaxill ary, and transcervi cal approach (118,119). This
approach is useful for tumors l ocated in the central and posterior wall of the
nasopharynx (Fi g. 117.10). For more extensive tumors, especi al ly those situated
on the lateral wal l (Fig. 117.11), the di ssection of the paranasopharyngeal space
is diffi cult from the inferior aspect and the i nternal carotid artery has to be
protected. The anterol ateral approach to the nasopharynx or the maxil lary swing
procedure has al so been used for sal vage nasopharyngectomy. Following
osteotomies, the maxil la bone attached to the anterior cheek flap can be swung
laterall y as one osteocutaneous complex (120) (Fig. 117.12). Thi s exposes the
entire nasopharynx and the paranasopharyngeal space so that an oncol ogic
surgical procedure can be carried out. The operati ve procedure, which is simi lar
to a maxill ectomy (Fi g. 117.13), provides good control of the internal carotid
artery. The mortal ities associated with these salvage surgical procedures have
been general ly low and acceptable. As all these patients had previousl y had
radical radiotherapy; compl ete wound heali ng might take some ti me and many
patients developed trismus. In general, as long as the persi stent or recurrent
tumor can be resected with a clear margi n, the long-term resul ts have been
satisfactory. The 5-year actuarial control of tumors in the nasopharynx following
salvage nasopharyngectomy has been reported to be approximately 65%, and
the 5-year, disease-free survival rate is approximately 54% (121,122).
P.1666
External Radiotherapy and Concurrent Chemotherapy
For more advanced or extensi ve tumors localized in the nasopharynx, a second
course of external radiotherapy mi ght be required for sal vage (123). Based on
the experience
gained with the use of concurrent chemotherapy and radiotherapy as the primary
treatment modali ty for NPC, a second course of external radiotherapy
administered concurrently wi th chemotherapy has been tried. This treatment
reportedly has a 5-year actuarial overall survival rate of 26%, al though the risk
of major l ate toxi cities was signifi cant (124). The use of preci si on radi otherapy
(e.g., IMRT) might i mprove the therapeutic outcome without damagi ng the
surroundi ng normal tissue; the overall survi val rate, however, depends on the
incidence of distant metastasis, which is an issue i n patients with recurrent
disease after the initial therapy.
Figure 117.10 Endoscopic view showing recurrent tumor in the central
posteri or wal l (7XPRU). Opening of the eustachi an tube (DUURZ) and medi al
crura (&UXUD) can be seen.
P.1667
P.1668
Figure 117.11 Endoscopic view showing recurrent tumor (Tumor) i n the
posteri or wal l and fossa of Rosenmller encroaching onto the medi al crura
of the eustachian tube (Crura). The openi ng of the eustachi an tube (arrow)
is shown.
Figure 117.12 Schematic computed tomography. A: Planned osteotomies of
the maxi lla and the posterior part of the nasal septum (arrow and broken
li ne). B: The maxil la is swung l ateral ly whi le still attached to the cheek flap.
Figure 117.13 A: Faci al i ncision for maxil lary swing approach to the
nasopharynx. B: The left maxil la i s swung lateral ly to expose the
nasopharynx with recurrent tumor (T). The maxil la and the left central
incisor tooth (arrow) are shown. C: Nasopharyngectomy specimen showi ng
tumor (T). The eustachian tube openi ng is marked wi th a yell ow tube
(arrow).
Distant Metastasis
The most effective treatment for patients with NPC wi th distant metastasis is to
use cisplatin-based combinati on chemotherapy. Cisplatin and i nfusional 5FU is
currently the standard treatment, achi eving a 66% to 76% response rate (125).
The aim of thi s form of therapy is essentially palli ati ve, although long-term,
disease-free survi vors have been reported (126). A number of phase II studies
on the newer agents have been reported (127,128). More intensive combinati ons
give a higher response rate but are al so usuall y associ ated with i ncreased
toxicities (129).
For the few selected patients with l ocalized metastases to the lungs, resecti on of
the pulmonary metastases can result in prol onged tumor control (130). For
patients wi th localized metastasis to the medi astinal nodes, the appli cation of
radiotherapy and chemotherapy can also result in more prolonged tumor control
(131).
Future Therapeutic Possibilities
As nasopharyngeal carcinoma i s closely associated with Epstein-Barr virus, this
gives additional opportuni ties for other therapeuti c possi bili ties. Gene therapy,
usi ng a novel repli cation-defici ent adenovirus vector, has been reported to
increase cytotoxicity through apoptosis (132). Immunotherapy approaches
include the therapeutic augmentation of cytotoxic T l ymphocytes responses
(133), and adopti ve transfer of autol ogous EBV-specific cytotoxic T cells has al so
been reported (134). Further cl inical trials wi th longer follow-up periods are
required to document their efficacy.
Highlights
T Nasopharyngeal carcinoma is most commonly encoun-tered in ethnic
Chinese and Inuits of Al aska.
T Undifferenti ated carcinoma of the nasopharynx is associ -ated with elevated
anti bodies against Epstein-Barr vi rus.
T The most frequent presenti ng symptom i s a pai nless neck mass.
T For advanced tumor, concurrent chemoradiotherapy is often prescri bed.
T Nasopharyngectomy is effecti ve in treatment of some patients wi th
local ized persi stent or recurrent di sease after initi al therapy.
References
1. Jackson C. Primary carci noma of the nasopharynx. A table of cases. JAMA
1901;37:371C"377.
2. Di gby KH, Fook WL, Che YT. Nasopharyngeal carci noma. Br J Surg
1941;28:517C"537.
3. Parkin DM, Whelan SL, Ferl ay J, et al., eds. Cancer incidence in five
continents, Vol. VII. International Agency for Research on Cancer,
Publi cation No. 143, 1997;814C"815.
4. Niel sen NH, Mi kkel sen F, Hansen JP. Nasopharyngeal cancer i n
Greenl and. The inci dence i n an Arctic Eskimo popul ation. Acta Pathol
Microbi ol Scand [A] 1977;85:850C"858.
5. Di ckson RI, Flores AD. Nasopharyngeal carcinoma: an evaluati on of 134
patients treated between 1971C"1980. Laryngoscope 1985; 95:276C"283.
6. Buell P. The effect of migrati on on the risk of nasopharyngeal cancer
among Chi nese. Cancer Res 1974;34:1189C"1191.
7. Fong YY, Chan WC. Bacteri al production of di-methyl nitrosamine in sal ted
fi sh. Nature 1973;243:421C"422.
8. Yu MC, Ho JH, Lai SH, et al. Cantonese-style salted fish as a cause of
nasopharyngeal carcinoma: report of a case-control study in Hong Kong.
Cancer Res 1986;46:956C"961.
9. zur Hausen H, Schulte-Hol thausen H, Kl ein G, et al. EBV DNA in biopsies
of Burki tt tumors and anapl astic carcinomas of the nasopharynx. Nature
1970;228:1056C"1058.
10. Yu MC, Garabrant DH, Huang TB, et al. Occupational andother non-
dietary ri sk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J
Cancer 1990;45:1033C"1039.
11. Fang Y, Guan X, Guo Y, et al. Analysi s of genetic alterations i n primary
nasopharyngeal carcinoma by comparative genomic hybri dization. Genes
Chromosomes Cancer 2001;30:254C"260.
12. Chen YJ, Ko JY, Chen PJ, et al. Chromosomal aberrations in
nasopharyngeal carcinoma anal yzed by comparative genomic hybri dization.
Genes Chromosomes Cancer 1999;25:169C"175.
13. Cheng Y, Ko JM, Lung HL, et al . Monochromosome transfer provides
functional evidence for growth-suppressi ve genes on chromosome 14 in
nasopharyngeal carcinoma. Genes Chromosomes Cancer 2003;37:359C"368.
14. Godtfredsen E. On the hi stopathology of mal ignant nasopharyngeal
tumors. Acta Pathol Microbi ol Scand 1944;55 (Suppl): 38C"319.
15. Prasad U. Cel ls of origi n of nasopharyngeal carcinoma: an electron
mi croscopical study. J Laryngol Otol 1974;88:1087.
16. Shanmugaratnam K, Sobi n LH. Histological typing of upper respiratory
tract tumors. In: Shanmugaratnam K, Sobin LH, eds. International
hi stologi cal classi fication of tumours, No 19. Geneva: World Health
Organization, 1978:32C"33.
17. Nicholls JM. Nasopharyngeal carcinoma: classi ficati on and histological
appearances. Adv Anat Pathol 1997;4:71C"84.
18. Michaeu C, Ril ke F, Pilotti S. Proposal for a new hi stopathologi cal
classification of the carcinomas of the nasopharynx. Tumori
1978;64:513C"518.
19. Shanmugaratnam K, Sobi n LH. Histological typing of tumors of upper
respiratory tract and ear. In: Shanmugaratnam K, Sobi n LH, eds.
International hi stol ogical classi fication of tumours, 2nd ed. Geneva: Worl d
Health Organi zation, 1991:32C"33.
20. Reddy SP, Raslan WF, Gooneratne S, et al. Prognostic signi ficance of
kerati nizati on in nasopharyngeal carci noma. Am J Otolaryngol
1995;16:103C"108
21. Marks JE, Phil ips JL, Menck HR. The National Cancer Data Base report on
the relationship of race and national origi n to the histology of
nasopharyngeal carcinoma. Cancer 1998;83:582C"588.
22. Sham JS, Wei WI, Lau SK, et al. Serous otitis media. An opportunity for
early recogniti on of nasopharyngeal carcinoma. Arch Otol aryngol Head Neck
Surg 1992;118:794C"797.
23. Sham JS, Cheung YK, Choy D, et al. Cranial nerve i nvol vement and base
of the skull erosi on in nasopharyngeal carci noma. Cancer 1991;68
(2):422C"426.
24. Turgut M, Erturk O, Saygi S, et al. Importance of cranial nerve
i nvol vement in nasopharyngeal carci noma. A cli nical study comprising 124
cases wi th special reference to clinical presentation and prognosi s.
Neurosurg Rev 1998;21:243C"248.
25. AW Lee, W Foo, SC Law, et al . Nasopharyngeal carcinoma: presenti ng
symptoms and durati on before di agnosis. Hong Kong Med J
1997;3:355C"361.
26. Sham JS, Poon YF, Wei WI, et al. Nasopharyngeal carcinoma in young
patients. Cancer 1990;65:2606C"2610.
27. Ho HC, Ng MH, Kwan HC, et al. Epstein-Barr-virus-specifi c IgA and IgG
serum antibodies i n nasopharyngeal carci noma. Br J Cancer
1976;34:655C"660.
P.1669
28. Zeng Y, Zhang LG, Wu YC, et al . Prospecti ve studies on nasopharyngeal
carcinoma in Epstein-Barr virus IgA/VCA anti body-positive persons in
Wuzhou City, China. Int J Cancer 1985;36: 545C"547.
29. Sham JS, Wei WI, Zong YS, et al. Detecti on of subclinical nasopharyngeal
carcinoma by fibreopti c endoscopy and multipl e biopsy. Lancet
1990;335:371C"374.
30. Chien YC, Chen JY, Li u MY, et al. Serologic markers of Epstein-Barr virus
i nfecti on and nasopharyngeal carcinoma in Tai wanese men. N Engl J Med
2001;345:1877C"1882.
31. Cheng WM, Chan KH, Chen HL, et al. Assessing the risk of
nasopharyngeal carcinoma on the basis of EBV anti body spectrum. Int J
Cancer 2002;97:489C"492.
32. Henle W, Ho JH, Henle G, et al. Nasopharyngeal carcinoma: signifi cance
of changes in Epstein-Barr virus-rel ated antibody patterns foll owi ng therapy.
Int J Cancer 1977;20:663C"672.
33. Lynn TC, Tu SM, Kawamura A Jr. Long-term foll ow-up of IgG and IgA
antibodi es agai nst viral capsi d antigens of Epstein-Barr virus in
nasopharyngeal carcinoma. J Laryngol Otol 1985;99:567C"572.
34. Lo YM, Chan LY, Lo KW, et al . Quanti tati ve analysis of cel l-free Epstein-
Barr virus DNA in pl asma of patients wi th nasopharyngeal carci noma. Cancer
Res 1999;59:1188C"1191.
35. Wei WI, Yuen AP, Ng RW, et al. Quantitative analysi s of pl asma cell-free
Epstein-Barr virus DNA in nasopharyngeal carci noma after sal vage
nasopharyngectomy: a prospective study. Head Neck 2004;26:878C"883.
36. Chong VF, Mukherji SK, Ng SH, et al. Nasopharyngeal carcinoma: review
of how imaging affects staging. J Comput Assi st Tomogr 1999;23:984C"993.
37. Sham JS, Cheung YK, Choy D, et al. Nasopharyngeal carci noma: CT
evaluation of patterns of tumor spread. AJNR Am J Neuroradi ol
1991;12:265C"270.
38. Chong VF, Fan YF, Khoo JB. Nasopharyngeal carci noma with intracranial
spread: CT and MR characteristics. J Comput Assi st Tomogr
1996;20:563C"569.
39. Fang FM, Leung SW, Wang CJ, et al. Computed tomography findi ngs of
bony regeneration after radiotherapy for nasopharyngeal carcinoma wi th
skull base destruction: i mplicati ons for local control . Int J Radi at Oncol Biol
Phys 1999;44:305C"309.
40. Dillon WP, Mi lls CM, Kjos B, et al. Magnetic resonance imaging of the
nasopharynx. Radiology 1984;152:731C"738.
41. Cheng SH, Jian JJ, Tsai SY, et al. Prognostic features and treatment
outcome in locoregional ly advanced nasopharyngeal carcinoma fol lowing
concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Bi ol Phys
1998;41:755C"762.
42. Cel lai E, Olmi P, Chiavacci A, et al . Computed tomography in
nasopharyngeal carcinoma. Part II: Impact on survi val. Int J Radiat Oncol
Biol Phys 1990;19:1177C"1182.
43. Emami B, Sethi A, Petruzzelli GJ. Influence of MRI on target vol ume
delineation and IMRT planning in nasopharyngeal carcinoma. Int J Radiat
Oncol Biol Phys 2003;57:481C"488.
44. Chong VF, Fan YF. Detection of recurrent nasopharyngeal carcinoma: MR
i magi ng versus CT. Radi ology 1997;202:463C"470.
45. Ng SH, Chang JT, Ko SF, et al . MRI in recurrent nasopharyngeal
carcinoma. Neuroradiol ogy 1999;41:855C"862.
46. Yen RF, Hung RL, Pan MH, et al. 18-fluoro-2-deoxygl ucose posi tron
emission tomography in detecti ng residual/recurrent nasopharyngeal
carcinomas and comparison with magneti c resonance imaging. Cancer
2003;98:283C"287.
47. Kraiphibul P, Atichartakarn V, Cl ongsusuek P, et al. Nasopharyngeal
carcinoma: value of bone and liver scinti graphy i n the pre-treatment and
fol low-up period. J Med Assoc Thai 1991;74: 276C"279.
48. Sham JS, Chan LC, Loke SL, et al. Nasopharyngeal carci noma: role of
marrow biopsy at di agnosi s. Oncology 1991;48:480C"482.
49. Kumar MB, Lu JJ, Loh KS, et al. Tail oring di stant metastatic imaging for
patients with clinical ly locali zed undifferentiated nasopharyngeal carci noma.
Int J Radi at Oncol Biol Phys 2004;58: 688C"693.
50. Ho JHC. An epidemi ologic and clini cal study of nasopharyngeal
carcinoma. Int J Radiat Oncol Biol Phys 1978;4:182C"198.
51. Lee AW, Foo W, Law SC, et al . Staging of nasopharyngeal carcinoma:
from Ho's to the new UICC system. Int J Cancer 1999;84:179C"187.
52. Cooper JS, Cohen R, Stevens RE. A comparison of staging systems for
nasopharyngeal carcinoma. Cancer 1998;83, 213C"219.
53. -zyar E, Yil diz F, Akyol FH, et al. Comparison of AJCC 1988 and 1997
classifications for nasopharyngeal carci noma. Int J Radiat Oncol Bi ol Phys
1999;44:1079C"1087.
54. Lee AW, Sham JS, Poon YF, et al. Treatment of stage I nasopharyngeal
carcinoma: analysi s of the patterns of relapse and the results of wi thholding
elective neck irradiation. Int J Radiat Oncol Biol Phys 1989;17:1183C"1190.
55. Kwong D, Sham J, Choy D. The effect of loco-regional control on distant
metastati c di ssemination in carcinoma of the nasopharynx: an analysis of
1301 pati ents. Int J Radiat Oncol Biol Phys 1994;30:1029C"1036.
56. Mesic JB, Fl etcher GH, Goepfert H. Megavoltage irradiation of epithel ial
tumors of the nasopharynx. Int J Radiat Oncol Bi ol Phys 1981;7:447C"453.
57. Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx.
Ei ghteen years' experience wi th megavoltage radi ati on therapy. Cancer
1976;37:2605C"2612.
58. Chua DT, Sham JS, Wei WI, et al. The predictive value of the 1997
American Joint Committee on Cancer stage cl assi fication in determi ning
failure patterns in nasopharyngeal carcinoma. Cancer 2001;92:2845C"2855.
59. Lee AW, Poon YF, Foo W, et al . Retrospecti ve anal ysis of 5037 patients
with nasopharyngeal carcinoma treated during 1976C"1985: overal l survival
and patterns of fai lure. Int J Radiat Oncol Biol Phys 1992;23:261C"270.
60. Levendag PC, Lagerwaard FJ, de Pan C, et al. High-dose, high-preci sion
treatment options for boosting cancer of the nasopharynx. Radiother Oncol
2002;63:67C"74.
61. Le QT, Tate D, Koong A, et al . Improved l ocal control with stereotactic
radiosurgical boost i n patients with nasopharyngeal carcinoma. Int J Radiat
62. Chua DT, Sham JS, Kwong PW, et al. Linear accelerator-based
stereotactic radiosurgery for l imited, locall y persistent, and recurrent
nasopharyngeal carcinoma: effi cacy and compli cations. Int J Radi at Oncol
Biol Phys 2003;56:177C"183.
63. Waldron J, Tin MM, Kel ler A, et al. Li mitation of conventional two
dimensi onal radi ati on therapy planning i n nasopharyngeal carcinoma.
Radi other Oncol 2003;68:153C"161.
64. Cheng JC, Chao KS, Low D. Comparison of i ntensity modulated radiation
therapy (IMRT) treatment techni ques for nasopharyngeal carcinoma. Int J
Cancer 2001;96:126C"131.
65. Wu VW, Kwong DL, Sham JS. Target dose conformi ty i n 3-di mensi onal
conformal radi otherapy and intensity modulated radi otherapy. Radiother
Oncol 2004;71:201C"206.
66. Hsiung CY, Yorke ED, Chui CS, et al. Intensi ty-modul ated radiotherapy
versus conventional three-di mensi onal conformal radiotherapy for boost or
sal vage treatment of nasopharyngeal carci noma. Int J Radiat Oncol Bi ol Phys
2002;53:638C"647.
67. Lee N, Xia P, Qui vey JM, Sultanem K, et al. Intensity-modul ated
radiotherapy in the treatment of nasopharyngeal carci noma: an update of the
UCSF experience. Int J Radiat Oncol Bi ol Phys 2002;53:12C"22.
68. Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for
early-stage nasopharyngeal carci noma: a prospective study on disease
control and preservation of salivary functi on. Cancer 2004;101:1584C"1593.
69. Lu TX, Mai WY, Teh BS, et al . Initial experience using i ntensi ty-
modul ated radiotherapy for recurrent nasopharyngeal carci noma. Int J Radiat
70. Lee AW, Sze WM, Yau TK, et al . Retrospective analysis on treating
nasopharyngeal carcinoma wi th accel erated fractionati on (6 fractions per
week) in comparison with conventi onal fractionation (5 fractions per week):
report on 3-year tumor control and normal tissue toxi city. Radi other Oncol
2001;58:121C"130.
71. Franchi n G, Vaccher E, Tal ami ni R, et al. Nasopharyngeal cancer WHO
type II-III: monoi nsti tutional retrospecti ve anal ysis wi th standard and
accelerated hyperfractionated radiation therapy. Oral Oncol
2002;38:137C"144.
72. Wolden SL, Zelefsky MJ, Kraus DH, et al . Accel erated concomitant boost
radiotherapy and chemotherapy for advanced nasopharyn-geal carcinoma. J
Cli n Oncol 2001;19:1105C"1110.
73. Jian JJ, Cheng SH, Tsai SY, et al. Improvement of local control of T3 and
T4 nasopharyngeal carcinoma by hyperfracti onated radiotherapy and
concomi tant chemotherapy. Int J Radiat Oncol Biol Phys 2002;53:344C"352.
P.1670
74. Al-Sarraf M, Lebl anc M, Gi ri PG, et al . Chemoradi otherapy versus
radiotherapy in patients wi th advanced nasopharyngeal cancer: phase III
randomi zed intergroup study 0099. J Cl in Oncol 1998;16:1310C"1317.
75. Lin JC, Jan JS, Hsu CY, et al . Phase III study of concurrent
chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal
carcinoma: posi tive effect on overall and progressi on-free survival. J Clin
Oncol 2003;21:631C"637.
76. International Nasopharynx Cancer Study Group VUMCA I trial .
Prelimi nary results of a randomized trial comparing neoadjuvant
chemotherapy (cisplatin, epi rubicin, bl eomycin) plus radiotherapy vs.
radiotherapy al one in stage IV(> or = N2, M0) undifferentiated
nasopharyngeal carcinoma: a posi tive effect on progressi on-free survival. Int
J Radiat Oncol Biol Phys 1996;35:463C"469.
77. Ma J, Mai HQ, Hong MH, et al . Resul ts of a prospective randomi zed tri al
comparing neoadjuvant chemotherapy plus radiotherapy with radi otherapy
alone in patients with locoregi onall yadvanced nasopharyngeal carci noma. J
Cli n Oncol 2001;19:1350C"1357.
78. Chua DT, Sham JST, Choy D, et al. Prel iminary report of the Asian-
Oceanian Cli nical Oncology Association randomi zed tri al comparing cisplatin
and epirubicin foll owed by radi otherapy versus radi otherapy alone i n the
treatment of patients wi th locoregionally advanced nasopharyngeal
carcinoma. Cancer 1998;83: 2270C"2283.
79. Hareyama M, Sakata K, Shirato H, et al. A prospective, randomized trial
comparing neoadjuvant chemotherapy with radiotherapy alone in patients
with advanced nasopharyngeal carci noma. Cancer 2002;94:2217C"2223.
80. Rossi A, Mol inari R, Boracchi P, et al. Adjuvant chemotherapy wi th
vi ncristine, cyclophosphamide, and doxorubicin after radiotherapy in local -
regi onal nasopharyngeal cancer: resul ts of a4-year mul ticenter
randomi zed study. J Clin Oncol 1988;6:1401C"1410.
81. Chi KH, Chang YC, Guo WY, et al. A phase III study of adjuvant
chemotherapy in advanced nasopharyngeal carci noma patients. Int J Radi at
82. Oh JL, Vokes EE, Ki es MS, et al. Induction chemotherapy fol lowed by
concomi tant chemoradiotherapy in the treatment of locoregionall y advanced
nasopharyngeal cancer. Ann Oncol 2003; 14:564C"569.
83. Chua DT, Sham JS, Au GK. A concurrent chemoi rradiati on with cisplatin
fol lowed by adjuvant chemotherapy with i fosfamide, 5-fluorouracil, and
l eucovori n for stage IV nasopharyngeal carcinoma. Head Neck
2004;26:118C"126.
84. Fang FM, Chiu HC, Kuo WR, et al. Heal th-related qual ity of life for
nasopharyngeal carcinoma pati ents with cancer-free survival after treatment.
Int J Radi at Oncol Biol Phys 2002;53:959C"968.
85. McMill an AS, Pow EH, Leung WK, et al. Oral health-related quality of li fe
i n southern Chinese foll owing radiotherapy for nasopharyngeal carcinoma. J
Oral Rehabil 2004;31:600C"608
86. Lam KS, Tse VK, Wang C, et al. Effects of cranial irradiation
onhypothal ami c-pituitary functionCa 5-year l ongitudinal study i n pati ents
with nasopharyngeal carcinoma. Q J Med 1991;78:165C"176.
87. Ho WK, Wei WI, Kwong DL, et al . Long-term sensorineural hearing defici t
fol lowing radiotherapy i n patients sufferi ng from nasopharyngeal carcinoma:
a prospective study. Head Neck 1999;21: 547C"553.
88. Pow EH, McMi llan AS, Leung WK, et al. Sal ivary gland function and
xerostomia i n southern Chinese following radi otherapy for nasopharyngeal
carcinoma. Clin Oral Invest 2003;7: 230C"234.
89. Pow EH, McMi llan AS, Leung WK, et al. Oral health condi tion in southern
Chinese after radi otherapy for nasopharyngeal carcinoma: extent and nature
of the probl em. Oral Dis 2003;9:196C"202.
90. Leung SF, Zheng Y, Choi CY, et al. Quanti tati ve measurement of post-
i rradi ati on neck fibrosi s based on the young modulus: descri ption of a new
method and clinical results. Cancer 2002;95: 656C"662.
91. Cheng SW, Ting AC, Lam LK, et al. Carotid stenosis after radiotherapy for
nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg
2000;126:517C"521.
92. Lee AW, Kwong DL, Leung SF, et al. Factors affecting risk of symptomatic
temporal lobe necrosis: signi ficance of fracti onal dose and treatment time.
Int J Radi at Oncol Biol Phys 2002;53:75C"85.
93. Lin YS, Jen YM, Lin JC. Radiation-rel ated cranial nerve palsy in patients
with nasopharyngeal carcinoma. Cancer 2002;95:404C"409.
94. Lam LC, Leung SF, Chan YL. Progress of memory function after radi ati on
therapy i n pati ents with nasopharyngeal carcinoma. J Neuropsychiatry Clin
Neurosci 2003;15:90C"97.
95. Cheung M, Chan AS, Law SC, et al. Cogni tive function of pati ents with
nasopharyngeal carcinoma wi th and without temporal lobe radi onecrosis.
Arch Neurol 2000;57:1347C"1352.
96. Lee PW, Hung BK, Woo EK, et al. Effects of radiati on therapy on
neuropsychological functioning i n pati ents with nasopharyngeal carcinoma. J
Neurol Neurosurg Psychiatry 1989;52:488C"492.
97. Kwong DL, Sham JS, Au GK, et al . Concurrent and adjuvant
chemotherapy for nasopharyngeal carcinoma: a factori al study. J Cl in Oncol
2004;22:2643C"2653.
98. Yen RF, Hung RL, Pan MH, et al. 18-fluoro-2-deoxygl ucose posi tron
emission tomography in detecti ng residual/recurrent nasopharyngeal
carcinomas and comparison with magneti c resonance imaging. Cancer
2003;98:283C"287.
99. Kao CH, Tsai SC, Wang JJ, et al . Compari ng 18-fl uoro-2-deoxyglucose
positron emissi on tomography with a combinati on of technetium 99m
tetrofosmin single photon emi ssion computed tomography and computed
tomography to detect recurrent or persistent nasopharyngeal carcinomas
after radiotherapy. Cancer 2001;92:434C"439.
100. Chua DT, Sham JS, Kwong DL, et al. Local ly recurrent nasopharyngeal
carcinoma: treatment resul ts for patients wi th computed tomography
assessment. Int J Radiat Oncol Biol Phys 1998;41: 379C"386.
101. Kwong DL, Nicholls J, Wei WI, et al. The time course of histologic
remission after treatment of patients with nasopharyngeal carcinoma. Cancer
1999;85:1446C"1453.
102. Wei WI, Ho CM, Wong MP, et al. Pathol ogical basi s of surgery in the
management of postradi otherapy cervical metastasis in nasopharyngeal
carcinoma. Arch Otolaryngol Head Neck Surg 1992; 118:923C"929.
103. Chua DT, Wei WI, Sham JS, et al. Treatment outcome for synchronous
l ocoregional fai lures of nasopharyngeal carcinoma. Head Neck
2003;25:585C"594.
104. Huang SC, Lui LT, Lynn TC. Nasopharyngeal cancer: study III. A
review of 1206 patients treated with combined modali ties. Int J Radi at Oncol
Biol Phys 1985;11:1789C"1793.
105. Sham JS, Choy D. Nasopharyngeal carcinoma: treatment of neck node
recurrence by radi otherapy. Australas Radiol 1991;35: 370C"373
106. Wei WI, Lam KH, Ho CM, et al . Efficacy of radical neck di ssection for the
control of cervical metastasis after radiotherapy for nasopharyngeal
carcinoma. Am J Surg 1990;160:439C"442.
107. Wei WI, Ho WK, Cheng AC, et al. Management of extensi ve cervical
nodal metastasis i n nasopharyngeal carcinoma after radi otherapy: a
cli ni copathological study. Arch Otolaryngol Head Neck Surg
2001;127:1457C"1462.
108. Lee AW, Law SC, Foo W, et al . Retrospecti ve anal ysis of patients with
nasopharyngeal carcinoma treated during 1976C"1985: survi val after local
recurrence. Int J Radiat Oncol Biol Phys 1993;26: 773C"782.
109. Yau TK, Sze WM, Lee WM, et al. Effectiveness of brachytherapy and
fractionated stereotactic radiotherapy boost for persistent nasopharyngeal
carcinoma. Head Neck 2004;26:1024C"1030.
110. Xi ao J, Xu G, Miao Y. Fracti onated stereotactic radiosurgery for 50
patients with recurrent or residual nasopharyngeal carcinoma. Int J Radiat
111. Wang CC, Busse J, Gi tterman M. A simple afterloading appl ica tor for
i ntracavitary irradiation of carcinoma of the nasopharynx. Radiology
1975;115:737C"738.
112. Law SC, Lam WK, Ng MF, et al . Reirradiation of nasopharyngeal
carcinoma with intracavi tary mold brachytherapy: an effecti ve means of l ocal
sal vage. Int J Radiat Oncol Biol Phys 2002;54: 1095C"1113.
113. Harrison LB, Weissberg JB. A techni que for i nterstitial nasopharyngeal
brachytherapy. Int J Radiat Oncol Biol Phys 1987;13: 451C"453.
114. Wei WI, Sham JS, Choy D, et al. Split-palate approach for gol d grain
i mplantati on i n nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg
1990;116:578C"582.
115. Choy D, Sham JS, Wei WI, et al. Transpalatal insertion of radioacti ve
gol d grain for the treatment of persistent and recurrent nasopharyngeal
carcinoma. Int J Radiat Oncol Biol Phys 1993;25: 505C"512.
116. Kwong DL, Wei WI, Cheng AC, et al. Long term resul ts of radioactive
gol d grain i mplantation for the treatment of persistent and recurrent
nasopharyngeal carcinoma. Cancer 2001;91: 1105C"1113.
117. Fisch U. The infratemporal fossa approach for nasopharyngeal tumors.
Laryngoscope 1983;93:36C"44.
P.1671
118. Fee Jr WE, Roberson Jr JB, Goffinet DR. Long-term survi val after
surgical resection for recurrent nasopharyngeal cancer after radi otherapy
failure. Arch Otolaryngol Head Neck Surg 1991;117: 1233C"1236.
119. Morton RP, Liavaag PG, McLean M, et al. Transcervi co-mandibul o-palatal
approach for surgical salvage of recurrent nasopharyngeal cancer. Head
Neck 1996;18:352C"358.
120. Wei WI, Lam KH, Sham JS. New approach to the nasopharynx: the
maxill ary swing approach. Head Neck 1991;13:200C"207
121. Fee Jr WE, Moir MS, Choi EC, et al. Nasopharyngectomy for recurrent
nasopharyngeal cancer: a 2- to 17-year follow-up. Arch Otolaryngol Head
Neck Surg 2002;128:280C"284.
122. Wei WI. Nasopharyngeal cancer: current status of management.
Arch Otol aryngol Head Neck Surg 2001;127:766C"769.
123. Leung TW, Tung SY, Sze WK, et al. Salvage radiation therapy for locally
recurrent nasopharyngeal carci noma. Int J Radiat Oncol Bi ol Phys
2000;48:1331C"1338.
124. Poon D, Yap SP, Wong ZW, et al. Concurrent chemoradiotherapy i n
l ocoregionally recurrent nasopharyngeal carcinoma. Int J Radi at Oncol Biol
Phys 2004;59:1312C"1318.
125. Wang TL, Tan YO. Ci spl ati n and 5-fluorouracil continuous infusion for
metastati c nasopharyngeal carcinoma. Ann Acad Med Singapore
1991;20:601C"603.
126. Fandi A, Bachouchi M, Azl i N, et al. Long-term disease-free survivors i n
metastati c undifferenti ated carci noma of nasopharyngeal type. J Cli n Oncol
2000;18:1324C"1330.
127. Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients
with recurrent and metastatic nasopharyngeal carcinoma pretreated wi th
plati num-based chemotherapy. Oral Oncol 2003; 39:361C"366.
128. Ngan RK, Yiu HH, Lau WH, et al. Combination gemcitabine and cisplatin
chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report
of a phase II study. Ann Oncol 2002;13: 1252C"1258.
129. Taamma A, Fandi A, Azl i N, et al. Phase II trial of chemotherapy wi th 5-
fl uorouracil, bleomycin, epi rubicin, and cisplatin for pati ents with local ly
advanced, metastatic, or recurrent undi fferenti ated carcinoma of the
nasopharyngeal type. Cancer 1999;86: 1101C"1108.
130. Cheng LC, Sham JS, Chiu CS, et al. Surgi cal resection of pulmonary
metastases from nasopharyngeal carcinoma. Aust N Z J Surg
1996;66:71C"73.
131. Kwan WH, Teo PM, Chow LT, et al. Nasopharyngeal carci noma wi th
metastati c di sease to mediasti nal and hilar lymph nodes: an indication for
more aggressive treatment. Cli n Oncol (R Coll Radiol) 1996;8:55C"58.
132. Li JH, Chia M, Shi W, et al. Tumor-targeted gene therapy for
nasopharyngeal carcinoma. Cancer Res 2002;62:171C"178.
133. Durai swamy J, Sherritt M, Thomson S, et al. Therapeutic LMP1
pol yepitope vaccine for EBV-associ ated Hodgkin di sease and nasopharyngeal
carcinoma. Blood 2003;101(8):3150C"3156.
134. Chua D, Huang J, Zheng B, et al. Adoptive transfer of autologous
Epstein-Barr virus-speci fic cytotoxic T cell s for nasopharyngeal carci noma.
Int J Cancer 2001;94:73C"80.
135. Ho JH. Stage cl assifi cation of nasopharyngeal carcinoma: a revi ew.
International Agency for Research on Cancer, Publ icati on No.
20,1978;99C"113.
136. Fleming ID, Cooper JS, Henson DE, et al., eds. AJCC Cancerstaging
manual, 5th ed. Phil adel phia: Lippincott-Raven, 1997: 33C"35.

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Editors: Bailey, Byron J.; Johnson, Jonas T.; Newlands, Shawn D.

Title: Head & Neck Surgery - Otolaryngology, 4th Edition

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