 |
|
Nasopharyngeal Cancer: Current Status of Management
A New York Head and Neck Society Lecture
William I. Wei, MS, FRCS, FRCSE, FACS, FHKAM
Arch Otolaryngol Head Neck Surg. 2001;127:766-769.
ABSTRACT
Over the last decade, we have made significant progress in treating
nasopharyngeal cancer. We have achieved a better tumor control rate with conformal
radiotherapy and chemotherapy. Surgical salvage treatment has also contributed
to helping patients with localized disease in the neck or in the nasopharynx.
INTRODUCTION
To manage nasopharyngeal cancer successfully requires the joint efforts
of radiation oncologists, medical oncologists, and otolaryngologists/head
and neck surgeons. In the last decade, have we made any progress in understanding
the pathogenesis, diagnosis, therapy, and salvage of nasopharyngeal cancer?
This article presents the current status of managing this disease.
Nasopharyngeal cancer is a squamous cell carcinoma originating in the
fossa of Rosenmüller; it has a high prevalence rate in the southern Chinese
population. After years of immigration, this disease has spread to Southeast
Asia, the West Coast of North America, and the rest of the world.
DIAGNOSIS
In a 1941 article by Digby et al1 (Digby
was at that time professor of surgery at the University of Hong Kong), the
authors noted that patients with nasopharyngeal cancer frequently presented
with cranial nerve palsies and cervical lymph node metastases. Currently,
patients still frequently present with enlarged cervical lymph nodes. The
diagnosis of nasopharyngeal cancer is usually suspected when a Chinese patient
presents with one of the clinical features frequently associated with this
cancer. The diagnosis is confirmed by biopsy of the primary tumor or by cytologic
examination of fine needle aspirates of enlarged neck nodes.
In Hong Kong, serological tests for immunoglobulin A against Epstein-Barr
virus (EBV) are performed as a screening procedure for high-risk patients.
For patients with elevated EBV antiters, an endoscopic examination and biopsy
of the nasopharynx are then indicated to detect the cancer in its early stages.2 Flexible endoscopic examination is useful to assess
tumor size and to obtain a biopsy specimen at the designated site.3 Rigid endoscopic examination provides a better view,
to the extent that even submucosal bulges (common in nasopharyngeal cancer)
can be seen. Computed tomography and magnetic resonance imaging are performed
on patients with a confirmed diagnosis. The former delineates the extent of
tumor in the nasopharynx and whether it has affected surrounding bony structures.4 Magnetic resonance imaging, aside from providing better
images of soft tissue, also shows tumor size and penetration in other dimensions
because of its multiplanar ability. These imaging studies are important for
accurate planning of radiotherapy, which is essential for successful treatment.
TREATMENT
Radiotherapy
External radiotherapy is still the primary treatment for nasopharyngeal
cancer. The radiation field normally covers the nasopharynx and both sides
of the neck. Recently, with more patients surviving for longer periods, there
have been more long-term sequelae of radiotherapy. These include hearing problems
related to the inner ear, endocrine manifestations following radiation of
the pituitary gland, and cranial nerve palsies. Current advances in radiotherapy
are aimed at improving the rate of tumor control and reducing such complications.
The results of radiation treatment for nasopharyngeal cancer in different
centers have improved over the years.5-6
The use of computed tomography and magnetic resonance imaging provides better
imaging of the tumor and thus allows better administration of radiotherapy.7 Delivering radiation that conforms to the shape of
the tumor in the area of the nasopharynx while sparing important surrounding
structures is more effective. This conformal radiotherapy also delivers an
escalating dose of radiation to the bulky tumor.8
Shielding the pituitary gland during radiotherapy reduces endocrine functional
disturbances without compromising tumor control.9
In recent years, with the development of stereotatic radiosurgery (another
form of conformal radiotherapy), a large dose of radiation can be delivered
to a focal area. This may be used as a salvage treatment for recurrent nasopharyngeal
cancer following the administration of external radiation. Another application
of this technique is to give booster treatment following conventional radiotherapy.
The number of patients treated with this technique is small, and the efficacy,
especially long term, needs to be evaluated.10
Chemotherapy
Chemotherapy has also been used in recent years to manage nasopharyngeal
cancer, frequently in conjunction with radiotherapy. Nasopharyngeal carcinoma
is sensitive to cisplatin-based chemotherapeutic agents. As 30% of patients
with nasopharyngeal cancer have distant metastases or large cervical lymph
nodes on presentation to their physician, chemotherapy is a logical option.
Phase 2 studies on the use of induction chemotherapy show improved outcomes.
A prospective study of 339 patients with N2, N3 disease showed that at 3 years
there was improvement in disease-free survival but not overall survival.11 The Asian-Oceanian Clinical Oncology Association
carried out a prospective, randomized study on 334 patients with stage III
or IV nasopharyngeal cancer with cervical lymph nodes larger than 3 cm in
diameter. Patients were treated with radiotherapy and chemotherapy or radiotherapy
alone. The median follow-up time was 41 months. There was no difference in
3-year overall survival, disease-free survival, or the incidence of distant
metastasis.12
An intergroup randomized study13 showed
that concomitant chemotherapy was useful. This prospective randomized study
was of 185 patients with stage III and stage IV nasopharyngeal carcinoma treated
with cisplatin and fluorouracil along with radiotherapy or radiotherapy alone.
The 3-year progression-free survival rate was 69% in the group that received
concomitant therapies compared with 24% in the group that received only radiation
(P<.001). The 3-year overall survival was 78%
in the group that received concomitant therapies compared with a 47% survival
rate in the group that received radiation alone (P
= .005).13 The median follow-up time was 31
months. This study is the only prospective randomized study with a positive
outcome; however, this is now the standard treatment in the United States.
In regions where nasopharyngeal cancer is endemic and where the ethnic population
is different, the incidence rates of different types of tumor histology have
to be taken into consideration. The sensitivity of undifferentiated carcinoma
to radiotherapy without chemotherapy is high in Southeast Asia.14
Studies are now being carried out in Hong Kong and Singapore to verify the
results of this study.
EBV AND NASOPHARYNGEAL CANCER
Suggested causes of nasopharyngeal cancer are the consumption of salted
fish, EBV infection, and genetic factors. Cytogenetic studies have shown that
there are multiple aberrations in chromosomes 1, 3, 11, 12, and 17 in nasopharyngeal
cancer. Loss of genetic material has been seen at defined loci in 3p, 9p,
11q, 13q, and 14q.15 In contrast with other
head and neck cancers, mutations of the p53 and retinoblastoma
(Rb) genes were uncommon, and overexpression of the c-myc and Int-2 genes was frequent.16 The findings of molecular biology studies have some
clinical applications. First, the targeted immune response is applicable in
nasopharyngeal cancer. Tumor cells express EBV proteins EBNA1, LMP1, and LMP2.
Adoptive immunotherapy has been used, employing EBV-specific cytotoxic T cells
to kill the EBV, and, because of the association of EBV with nasopharyngeal
cancer cells, this therapy also kills cancer cells.17
On the diagnostic side, molecular biology studies contribute to the identification
of tumor markers. Polymerase chain reaction testing can now detect the DNA
of EBV in the serum of patients with nasopharyngeal cancer, and the levels
of DNA detected have been shown to correlate with stage, recurrence, and metastasis
of nasopharyngeal cancer.18 Because of the
cost of polymerase chain reaction testing, its application in clinical situations
is still being studied.
Salvage Therapy
Radiation oncologists, medical oncologists, molecular biologists, and
surgeons all have a role in managing nasopharyngeal cancer. The role of otolaryngologists/head
and neck surgeons is to manage persistent or recurrent tumors after radiotherapy,
either in the nasopharynx or in the cervical lymph nodes.
Management of Metastatic Neck Nodes
In our previous study, radical neck dissection controlled neck disease
in 66% of patients,19 which has been confirmed
in other studies.20-21 Radical
neck dissection has to be performed because step serial section studies of
radical neck dissection specimens have shown that there are more metastatic
lymph nodes in the neck than clinically evident. Tumors in the neck nodes
also show extensive infiltration outside the nodes, affecting neck muscle;
in roughly one third of patients, tumor was seen lying close to the spinal
accessory nerve.22 As a result, radical neck
dissection is recommended as the salvage treatment for localized neck disease.
When disease in the neck is extensive (such as when tumor has infiltrated
the skin of the neck or the floor of the neck), further brachytherapy following
radical neck dissection has been employed as the salvage procedure.23 The neck skin over the tumor is removed during the
radical neck dissection, and hollow nylon tubes are placed precisely at the
site of the surgery. The cutaneous neck defect is then covered with a flap,
such as a deltopectoral flap or a pectoralis major myocutaneous flap. Brachytherapy
is then administered through an iridium wire inserted through hollow nylon
tubes. Between 1993 and 1996, we performed this procedure in 13 patients with
extensive neck disease after radiotherapy. The 3-year actuarial control of
neck disease was 60%. All patients survived the operation, and the associated
morbidity was low.23
Salvage for Tumor in the Nasopharynx
If the tumor recurs or persists in the nasopharynx after radiotherapy,
then salvage procedures are still an option if there is no metastasis. Further
radiation treatment or chemotherapy is not effective in eradicating the disease,
and the associated adverse effects are significant. Stereotatic radiosurgery
is a possible treatment, but its efficacy and long-term complications are
not documented. Brachytherapy is another salvage option. Intubating the nasopharynx
with cesium is not an easy method of dosimetric evaluation for tumor eradication.
For salvage, we have used the insertion of radioactive gold grains as brachytherapy.
The procedure was performed under general anesthesia with a mouth gag. The
soft palate was split in the midline, and the mucoperiosteum over the hard
palate was then elevated and retracted, exposing a recurrent or persistent
tumor in the nasopharynx. Radioactive gold grains could then be inserted into
the tumor under direct visual contact. With the help of a template, the gold
grains could be inserted accurately at desired positions.24
To reduce the exposure to radiation of the operating room staff, lead shields
were placed in the nasopharynx and around the patient while the palatal wound
was closed in layers.
Between 1986 and 1998, we used gold grain implantation for 109 patients,
with follow-up of 8 months to 8 years (median, 4.5 years.) The 5-year actuarial
control of tumor for persistent disease after radiotherapy was 80%; for recurrent
disease, 65%.25 All patients had external radiotherapy
followed by brachytherapy; the incidence of palatal fistula formation was
around 20%. These fistulas can usually be managed conservatively with a dental
plate. A palatal flap can also be used to close the fistula in some patients.
Our early experience revealed that in some patients, the gold grains fell
off early in the postoperative period and were swallowed by the patients:
fortunately, there were no serious consequences as the gold grains moved along
the bowel.
Since many of the patients who underwent gold grain implantation survive
longer after implantation, we have recently noted some long-term adverse effects.
One patient developed severe epistaxis: an arteriogram showed a false aneurysm
of the internal carotid artery. This was successfully controlled with embolization.
Overall, the morbidity associated with gold grain brachytherapy was low. When
a persistent or recurrent tumor in the nasopharynx was detected early and
was small, split-palate insertion of gold grains was a good means of salvage.
If on presentation the recurrent or persistent tumor is already too
large or too bulky for brachytherapy, surgical salvage is another option.
Tumor in the nasopharynx can be exposed with the anterior approach, but even
with the Le Fort I approach, the tumor is still far from the surface. The
lateral approach through the infratemporal fossa passes through many vital
structures and results in only limited access. From the inferior approach,
the tumor can be seen and exposed, but it is difficult to carry out an oncological
resection to remove all the tissue around the tumor.
The anterolateral approach to the nasopharynx exposes the entire nasopharynx
and the surrounding area adequately for extirpation of tumor. This approach
derived from the fact that after total maxillectomy for carcinoma of the maxilla
the nasopharynx is widely exposed. We wondered whether it was possible to
swing the maxilla laterally and at the same time keep it attached to the anterior
cheek flap. After the tumor in the nasopharynx was removed, the maxilla could
be swung back and fixed to the facial skeleton.26
We have tried the procedure in preserved and in fresh cadavers, and found
that it was feasible. The first nasopharyngectomy with this anterolateral
approach was performed in 1989 on a 35-year-old man who had recurrent nasopharyngeal
carcinoma after external radiotherapy and brachytherapy. From 1989 to 2000,
we performed 78 salvage nasopharyngectomies. Although presurgical examinations
showed that curative resection was possible, a clear tumor margin was achieved
in only 60 patients. The remaining 18 patients continued to have microscopic
tumor either on the internal carotid artery or spilling through the musculoskeletal
crevasse. All patients survived the operation and were discharged from the
hospital. These patients were followed up for 6 months to 10 years (median,
3 years); in the 60 patients who had a curative resection, the 5-year actuarial
tumor control rate in the nasopharynx was 62%, while the 5-year actuarial
disease-free survival rate was only 49%.27
A frequent question is whether such a wide exposure is necessary for the salvage
procedure. Could the tumor be removed with laser or could cautery be applied
through the nose or transpalatally? Our step serial whole-organ section of
19 resected nasopharyngeal specimens showed that 90% of the tumor affected
the eustachian tube cartilage, and over 90% of the tumor showed extensive
submucosal infiltration.23 It is necessary
to remove all the related structures in the nasopharynx through a wide aperture
such as that used in the anterolateral approach.
This was a highly selected group of patients who had recurrent or persistent
tumor after radiotherapy with tumors that were localized enough to allow a
curative resection. Following surgery, over 80% of them had some degree of
trismus and 20% of them developed a palatal fistula, which may have been related
to their previous radiotherapy and salvage surgery. The palatal fistula can
be managed conservatively with a dental plate or closed with a palatal flap.
Two patients developed facial sinuses related to the titanium plate; both
of these healed after removal of the screws and plate.
Variations of the resection technique include removing the posterior
part of the nasal septum to allow resection of tumors that extend to the opposite
side. Removing the anterior wall of the sphenoid sinus also contributes to
improving the resection margin. With this wide exposure, the paranasopharyngeal
lymph nodes, if affected by the tumor, can be removed under direct visual
contact. Even a tumor situated close to the internal carotid artery can be
removed safely. As all these patients had large doses of radiation prior to
the salvage surgery, osteoradionecrosis was a risk when too much bare bone
was left exposed after surgery. The skull base may also undergo necrosis.
We treated this complication in one patient who underwent radical salvage
nasopharyngectomy at another institution. We used a microvascular free muscle
flap to fill the defect in the skull base, and the patient recovered.
The anterolateral approach for nasopharyngectomy provides a direct and
wide exposure of the entire nasopharynx and the surrounding area. The operation
is not difficult to perform, and the associated morbidity is low. It should
be considered for those patients in whom radiotherapy fails.
In conclusion, over the last decade, we have made progress in the diagnosis,
management, and salvage therapy of patients with nasopharyngeal cancer. Credit
is due to all the research workers, oncologists, surgeons, and other personnel
worldwide who work in this field.
AUTHOR INFORMATION
Accepted for publication April 2, 2000.
Presented as a keynote address at the annual meeting of the American
Head and Neck Society, Fifth International Conference on Head and Neck Cancer,
San Francisco, Calif, July 31, 2000.
Supported by grant 0200387.05078.21700.301.01 from the Committee on
Research and Conference Grants, University of Hong Kong; by grant 10200950.05078.21700.323.01
from the Research Grant Committee, Sun Yat Sen Foundation Fund; by grant 21378123.05078.21700.420.01
from the University of Hong Kong; and by grant 20375206.05078.21700.400.01
from the Simon K. Y. Lee Research Fund, University of Hong Kong.
Corresponding author and reprints: William I. Wei, MD, Department
of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong
Kong (e-mail: hrmswwi{at}hkucc.hku.hk).
From the Department of Surgery, Queen Mary Hospital, University of
Hong Kong Medical Center, Hong Kong.
REFERENCES
| |
1. Digby KH, Fook WL, Che YT. Nasopharyngeal carcinoma. Br J Surg. 1941;28:517-537.
FULL TEXT
|
ISI
2. Sham JST, Wei WI, Zong YS, et al. Detection of subclinical nasopharyngeal carcinoma by fibreoptic endoscopy
and multiple biopsy. Lancet. 1990;335:371-374.
FULL TEXT
|
ISI
| PUBMED
3. Wei WI, Sham JST, Zon YS, Choy D, Ng MH. The efficacy of fiberoptic endoscopic examination and biopsy in the
detection of early nasopharyngeal carcinoma. Cancer. 1991;67:3127-3130.
FULL TEXT
|
ISI
| PUBMED
4. Miura T, Hirabuki N, Nishiyama K, et al. Computed tomographic findings of nasopharyngeal carcinoma with skull
base and intracranial involvement. Cancer. 1990;65:29-37.
FULL TEXT
|
ISI
| PUBMED
5. Lee AWM, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma
treated during 1975-1985: overall survival and patterns of failure. Int J Radiat Oncol Biol Phys. 1992;23:261-270.
ISI
| PUBMED
6. Sham JST, Choy D. Prognostic factors of nasopharyngeal carcinoma: a review of 759 patients. Br J Radiol. 1990;63:51-58.
FREE FULL TEXT
7. Chong VFH, Fan YF, Mukherji SK. Carcinoma of the nasopharynx. Semin Ultrasound CT MR. 1998;19:449-462.
FULL TEXT
|
ISI
| PUBMED
8. Chao KS, Low DA, Perez CA, Purdy JA. Intensity-modulated radiation therapy in head and neck cancers: the
Mallinckrodt experience. Int J Cancer. 2000;90:92-103.
FULL TEXT
|
ISI
| PUBMED
9. Sham JST, Choy D, Kwong PW, et al. Radiotherapy for nasopharyngeal carcinoma: shielding the pituitary
may improve therapeutic ratio. Int J Radiat Oncol Biol Phys. 1994;29:699-704.
ISI
| PUBMED
10. Chua DT, Sham JST, Hung KN, Kwong DL, Kwong PW, Leung LH. Stereotactic radiosurgery as a salvage treatment for locally persistent
and recurrent nasopharyngeal carcinoma. Head Neck. 1999;21:620-626.
FULL TEXT
|
ISI
| PUBMED
11. International Nasopharynx Cancer Study Group. VUMCA I Trial: preliminary results of a randomized trial comparing
neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy
vs radiotherapy alone in stage IV ( N2, M0) undifferentiated nasopharyngeal
carcinoma: a positive effect on progression-free survival. Int J Radiat Oncol Biol Phys. 1996;35:463-469.
FULL TEXT
|
ISI
| PUBMED
12. Chua DTT, Sham JST, Choy D, et al. Preliminary report of the Asian-Oceanian Clinical Oncology Association
randomized trial comparing cisplatin and epirubicin followed by radiotherapy
versus radiotherapy alone in the treatment of patients with locoregionally
advanced nasopharyngeal carcinoma. Cancer. 1998;83:2270-2283.
FULL TEXT
|
ISI
| PUBMED
13. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal
cancer: phase III randomized intergroup study 0099. J Clin Oncol. 1998;16:1310-1317.
FREE FULL TEXT
14. Tan EH, Chua ET, Wee J, et al. Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian
patients with nasopharyngeal carcinoma: toxicities and preliminary results. Int J Radiat Oncol Biol Phys. 1999;45:597-601.
FULL TEXT
|
ISI
| PUBMED
15. Chen VJ, Ko JY, Chen PJ, et al. Chromosomal aberrations in nasopharyngeal carcinoma analyzed by comparative
genomic hybridization. Genes Chromosomes Cancer. 1999;25:169-175.
FULL TEXT
|
ISI
| PUBMED
16. Fan CS, Wong N, Leung SF, et al. Frequent c-myc and Int-2 overrepresentations in nasopharyngeal carcinoma. Hum Pathol. 2000;31:169-178.
FULL TEXT
|
ISI
| PUBMED
17. Khanna R, Busson P, Burrows SR, et al. Molecular characterization of antigen-processing function in nasopharyngeal
carcinoma (NPC): evidence for efficient presentation of Epstein-Barr virus
cytotoxic T-cell epitopes by NPC cells. Cancer Res. 1998;58:310-314.
FREE FULL TEXT
18. Lo YMD, Chan LYS, Lo KW, et al. Quantitiative analysis of cell-free Epstein-Barr virus DNA in plasma
of patients with nasopharyngeal carcinoma. Cancer Res. 1999;59:1188-1191.
FREE FULL TEXT
19. Wei WI, Lam KH, Ho CM, Sham JST, Lau SK. Efficacy of radical neck dissection for the control of cervical metastasis
after radiotherapy for nasopharyngeal carcinoma. Am J Surg. 1990;160:439-442.
FULL TEXT
|
ISI
| PUBMED
20. Khoo ML, Soo KC, Lim DT, et al. The pattern of nodal recurrence following definitive radiotherapy for
nasopharyngeal carcinoma. Aust N Z J Surg. 1999;69:354-356.
FULL TEXT
|
ISI
| PUBMED
21. Yen KL, Hsu LP, Sheen TS, Chang YL, Hsu MH. Salvage neck dissection for cervical recurrence of nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1997;123:725-729.
FREE FULL TEXT
22. Wei WI, Ho CM, Wong MP, et al. Pathological basis of surgery in the management of postradiotherapy
cervical metastasis in nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1992;118:923-930.
FREE FULL TEXT
23. Wei WI. Carcinoma of the nasopharynx. Adv Otolaryngol Head Neck Surg. 1998;12:119-132.
24. Wei WI, Sham JST, Choy D, Ho CM, Lam KH. Split-palate approach for gold grain implantation in nasopharyngeal
carcinoma. Arch Otolaryngol Head Neck Surg. 1990;116:578-582.
FREE FULL TEXT
25. Kwong DL, Wei WI, Cheng AC, et al. Long term results of radioactive gold grain implantation for the treatment
of persistent and recurrent nasopharyngeal carcinoma. Cancer. 2001;91:1105-1113.
FULL TEXT
|
ISI
| PUBMED
26. Wei WI, Lam KH, Sham JS. New approach to the nasopharynx: the maxillary swing approach. Head Neck. 1991;13:200-207.
ISI
| PUBMED
27. Wei WI. Salvage surgery for recurrent primary nasopharyngeal carcinoma. Crit Rev Oncol Hematol. 2000;33:91-98.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Nasopharyngectomy and Surgical Margin Status: A Survival Analysis
Vlantis et al.
Arch Otolaryngol Head Neck Surg 2007;133:1296-1301.
ABSTRACT
| FULL TEXT
Quality of life of patients with recurrent nasopharyngeal carcinoma treated with nasopharyngectomy using the maxillary swing approach.
Ng and Wei
Arch Otolaryngol Head Neck Surg 2006;132:309-316.
ABSTRACT
| FULL TEXT
|
