Introduction

Nasopharyngeal carcinoma is a malignant tumor with unique features
that make it pathologically, epidemiologically, and clinically
distinct from other head and neck cancers. There is no clear
association with tobacco or alcohol use in most cases of
nasopharyngeal cancer (World Health Organization [WHO] grades II and
III). Patients with nasopharyngeal carcinoma have a higher incidence
of nodal involvement and bilateral nodal disease at presentation, and
overall (80% to 90%) nodal metastasis, as compared with patients with
other malignancies of the head and neck. In addition, patients with
nasopharyngeal carcinoma have a higher overall incidence of systemic
metastasis than patients with tumors in other head and neck sites.

In the United States and Europe, the incidence of nasopharyngeal
cancer ranges from 0.5 to 2 cases per 100,000 people.[1] In some
areas of the world, namely, southern China, Southeast Asia, North
Africa, the Middle East, Alaska, and Greenland,[1-5] nasopharyngeal
cancer is more common. In these areas, incidence may be as high as 25
to 50 per 100,000 people,[2] and the pathology is mostly of the
undifferentiated variety. The Epstein-Barr virus is more strongly
associated with nasopharyngeal carcinoma in areas of higher
prevalence and in patients whose tumors are WHO grades II and III
than in less aggressive grades and in areas of lower incidence.

Nasopharyngeal carcinoma affects men more often than women, with a
male-to-female ratio of 3–3.5:1.[1,6] The incidence of the
disease begins to rise at age 20 years and starts to decline at age
60 years, with a median age of incidence of 40 to 50 years.

Treatment Overview

Nasopharyngeal carcinomas respond to radiation therapy (Table
1[7-23]) as well as chemotherapy (Tables
2[24-38] and 3[25,28,30,39-50]).
Because nasopharyngeal cancer responds so well to radiotherapy, and
in light of the sensitive location of the primary disease and the
often advanced stage at presentation, surgery is often unnecessary or
impractical. However, for persistent or recurrent disease in regional
nodes, surgery is the treatment of choice in most cases.

Radiotherapy has been the traditional, standard form of therapy for
all patients with local and locoregional disease. Marcial et al[12]
reported complete local clearance of nasopharyngeal carcinoma in 96%
of patients with T1 disease treated with radiotherapy, 88% of those
with T2, 81% of those with T3, and 74% of those with T4. Complete
clearance rates in patients with N1-3 disease who received
irradiation ranged from 93% to 71%. The 5-year survival rate of these
patients with nodal involvement was only 40%; overall 5-year survival
rates of patients with all stages of nasopharyngeal carcinoma treated
with radiotherapy, reported by various investigators from all over
the world, have ranged from 24% to 62% (Table
1).

Qin et al[18] reviewed the survival rates of 1,379 patients with
advanced nasopharyngeal carcinoma treated with radiotherapy. The
majority of patients had either stage III (n = 417) or stage IV
cancer (n = 647). These investigators reported that the 5, 10-, and
20-year survival rates of patients with stage III cancers treated
with radiotherapy alone were 46%, 29%, and 17%, respectively. The 5-,
10-, and 20-year survival rates of stage IV patients treated with
irradiation were 29%, 21%, and 8%, respectively. Overall, the 5-year
survival rate of nasopharyngeal carcinoma patients with stage IV
disease treated with radiotherapy alone was less than 30%, regardless
of country of origin or histopathology.

Locoregional recurrences occur in 40% to 80% of patients, and distant
recurrences in 15% to 50% of patients. The usual radiation dose is 65
to 75 Gy in 1.8- to 2.0-Gy fractions, 5 days a week. This dose is
crucial for achieving complete locoregional control and 5-year survival.[18]

In a nonrandomized trial reported by Wang,[51] the local control rate
improved significantly with accelerated hyperfractionated
radiotherapy, as compared with once-daily radiotherapy. The improved
local control rates occurred in patients with N2-3 disease and among
both males and females.

Despite the high initial response rate and good local control
achieved with radiotherapy in patients with locally advanced stage
III and IV nasopharyngeal carcinoma, the 5- and 10-year survival
rates were poor and unacceptable. Options for patients who experience
local and/or regional failure include reirradiation and,
occasionally, surgical resection; the latter is especially
appropriate for patients with involvement of regional lymph nodes
only.[52] The majority of patients with recurrent disease, and all
patients with metastatic disease, should be treated with systemic
chemotherapy for palliation.

Chemotherapy

Nasopharyngeal carcinomas are highly sensitive to chemotherapy (Tables
2 and 3). Single agents
identified as being active in this disease include methotrexate,
bleomycin (Blenoxane), doxorubicin, cisplatin (Platinol), carboplatin
(Paraplatin), and, more recently, paclitaxel (Taxol), and to a lesser
extent, fluorouracil (5-FU) and the vinca alkaloids. For patients
with head and neck cancers in general, and especially for those with
nasopharyngeal carcinoma, combination chemotherapeutic regimens are
more active than single drugs, and cisplatin-based combinations are
more active than non–cisplatin-based combinations.[24-26]

The combination most widely used in these patients is cisplatin plus
a 5-FU infusion. The regimen is easy to administer and well tolerated
by most patients. Fluorouracil is given at a dose of 1,000
mg/m²/d as a 4- to 5-day continuous infusion, and cisplatin is
given at a dose of 80 to 100 mg/m² on the first day of
treatment.[53,54] The course is repeated every 3 to 4 weeks.

Chemotherapy for Recurrent or Metastatic Disease

Patients with nasopharyngeal carcinoma who present with metastatic
disease and those whose cancers recur after initial curative
treatment and who have received further local treatment with surgery
and/or reirradiation should be treated with systemic chemotherapy for
palliative purposes. Because of the rarity of this disease,
especially in western countries, all reported chemotherapy trials for
recurrent/metastatic nasopharyngeal carcinoma are phase II studies (Table
2). Since 1980, the success of cisplatin-based combinations in
patients with head and neck cancers has made these regimens the first
choice for the treatment of nasopharyngeal carcinoma (Table
2).[24,26]

As shown in Table 2, the majority
of the cisplatin-based combinations reported consist of cisplatin
plus a 5-FU infusion, with or without other agents, such as
leucovorin or bleomycin. The overall response rate is between 50% and
65%, but, more importantly, approximately 15% to 20% of treated
patients achieve a complete response. From the phase II trial data,
it does not seem that the addition of other agents to cis-

platin–5-FU infusion produces higher overall or complete
response rates. More recently, other active combinations have been
investigated using newer active agents, such as paclitaxel[35-37] and
ifosfamide (Ifex).[38]

The majority of patients who achieve a complete response to
chemotherapy remain alive for more than 2 years, or are even
considered cured. No standard duration of further treatment in
patients who have achieved a complete response has been reported. It
is our opinion that, if a biopsy confirms a complete response after
local recurrence, or a computed tomographic (CT) scan or bone scan
confirms complete response after nodal or systemic recurrence, an
additional four to six courses of chemotherapy may need to be
administered. Patients who achieve a complete response need to be
followed closely, especially for the first 2 years after completion
of chemotherapy.

The important prognostic factors that may influence overall and
complete response to chemotherapy in nasopharyngeal carcinoma
patients[53,54] are performance status, histopathology (WHO grades I,
II, and III), local vs systemic disease, site of the systemic
metastasis, bulk of recurrent or metastatic cancers being treated,
type of chemotherapy combinations used, and adequacy of treatment given.

Chemotherapy as Part of Combined-Modality Treatment for Primary Disease

Because of the high incidence of locoregional failure with
radiotherapy alone despite the initial high clearance rate, and
because of the high incidence of distant metastasis in nasopharyngeal
cancers, combined-modality therapy is a very attractive concept.
Chemotherapy can be given neoadjuvantly (induction chemotherapy
followed by radiation), concomitantly, or adjuvantly (radiotherapy
followed by chemotherapy). The use of more than one of these
approaches in sequence has also been investigated.

• Neoadjuvant (Induction) Chemotherapy—Neoadjuvant
chemotherapy was explored in the mid-1970s in patients with locally
advanced stage III and IV head and neck cancers of all sites. Most of
these patients, including those with nasopharyngeal carcinomas, had
inoperable or unresectable disease. High overall and clinical
complete response rates to induction chemotherapy were obtained, and
the feasibility of sequential induction chemotherapy followed by
radiotherapy was established. This led to many phase II studies using
the same treatments in patients with locally advanced nasopharyngeal
cancers (Table 3).

The factors that may influence response rate and overall survival are
stage of the nasopharyngeal carcinoma (especially the N stage),
performance status, histopathology, type of chemotherapeutic
combination used, number of courses, and adequacy of treatment given.
In addition, reports of complete response at the primary site may
differ from investigator to investigator, depending on whether the
response was evaluated clinically, by CT scan, or by magnetic
resonance imaging (MRI). Since the majority of patients initially
present with T3 or T4 disease, some abnormalities may still be
observed locally when a CT scan or MRI is performed; this can occur
even in patients who have repeated negative biopsies of these areas
and are considered cured without further treatment. Factors that may
affect survival are disease stage, type of response to chemotherapy
(partial vs complete), histopathology, and performance status.

The majority of the neoadjuvant chemotherapy trials mentioned here
used cisplatin-based combinations, especially cisplatin plus a 5-FU
infusion. In a few trials, leucovorin or bleomycin was added to this
combination. These studies demonstrated interesting results, with
overall response rates of 80% to 90%. In some trials, up to 66% of
the responses were complete. Because of the various prognostic
factors that may influence response rate, no determination could be
made as to the best possible chemotherapy combination.

Geara et al[46] and Teo et al[48] reported much higher complete
response rates to chemotherapy for nodal disease than for primary
tumors. Both these investigators used CT scans to evaluate responses.
In our experience, both in patients with nasopharyngeal carcinoma and
in patients with other head and neck cancers treated with
chemotherapy, the complete response rate is usually higher at the
primary site than the regional lymph nodes.

When the survival of patients treated with chemotherapy followed by
irradiation was compared to historical matched controls receiving
radiotherapy alone, the majority of investigators reported
significant improvement in overall survival for the combined
approach. This was especially true for the administration of adequate
doses of two to three courses of cisplatin and 5-FU infusion.

Recently, Teo et al[48] reported on the results of two courses of
cisplatin and 5-FU infusion followed by radiotherapy in 209 patients
with node-positive, locally advanced nasopharyngeal cancers, compared
to similar patients treated with radiotherapy alone during the same
period. The chemotherapy group had significantly more bulky nodes,
lower cervical and/or supraclavicular nodes, and more advanced
overall stages than the nonchemotherapy patients. Unfortunately, the
duration of the 5-FU infusion was 3 days, instead of the standard 5
days, and only two courses of chemotherapy were given instead of the
usual three courses.

Despite these facts, the addition of chemotherapy to radiation
treatment significantly enhanced local control in node-positive
nasopharyngeal cancer patients in general, and node-positive, T3 and
T4, stage IV patients in particular. The 5-year survival rate among
patients with stage IV cancers ranged from 50% to 55% in those who
underwent sequential radiotherapy, as compared to less than 30% in
those who received radiotherapy only. When evaluating survival in
patients with nasopharyngeal carcinoma, a minimum follow-up of 3
years is necessary before any conclusions can be drawn.

• Concomitant Chemoradiotherapy—This option is
attractive, with the possible advantages of synergy between
chemotherapy and radiotherapy, as well as additive effects.
Chemoradiotherapy has been investigated in many other solid
malignancies; improved disease-free and overall survival rates have
been reported for the combined approach, as opposed to radiotherapy alone.

Many phase II trials of concurrent chemoradiotherapy in patients with
locally advanced nasopharyngeal carcinoma have been reported.[55-65]
Several chemotherapeutic agents, especially cisplatin,[67-69] produce
synergistic and/or additive effects when used with radiotherapy. One
possible advantage of using concomitant cisplatin and radiotherapy in
patients with head and neck cancers, as opposed to other agents, such
as methotrexate, bleomycin, or 5-FU, is the lack of increased local
side effects (especially mucositis).

Most investigators gave standard one-fraction-per-day irradiation.
The radiation dose was the same as without chemotherapy, ie, >
6,400 cGy in most cases. When the results of concomitant
chemoradiotherapy were compared with those of historical matched
control patients, most investigators reported improvements in local
control, disease-free survival, and overall survival with the
combined treatment.

Other agents, such as the taxanes and gemcitabine (Gemzar), have been
shown to be radiation sensitizers and/or enhancers. These agents,
administered concomitantly with radiotherapy, may need to be
investigated in the future in patients with nasopharyngeal carcinoma.

In an early study published by the Radiation Therapy Oncology Group
(RTOG),[64-66] we reported the results of concomitant treatment with
single-agent cisplatin and radiotherapy in 124 patients with locally
advanced, inoperable or unresectable stage III (n = 24) or stage IV
(n = 100) head and neck cancers; this study population included 28
patients with nasopharyngeal cancers, 27 of whom had stage IV
disease. The cisplatin dose was 100 mg/m2, given intravenously with
hydration and mannitol diuresis, once every 3 weeks, concurrent with
standard radiation therapy to a total dose of up to 7,380 cGy.
Complete response rates were 70% for all patients and 89% for those
with nasopharyngeal cancers.

When the survival of patients with nasopharyngeal cancer was compared
with survival of those with tumors of other head and neck sites (all
were treated with the same chemoradiotherapy), a significantly higher
survival rate was observed in the nasopharyngeal carcinoma patients.
In addition, the survival of the nasopharyngeal carcinoma patients
treated with concurrent cisplatin and radiotherapy was significantly
better than the survival of historical matched controls treated with
the same dose of radiotherapy alone.

Even more interesting was the fact that approximately 55% of the
patients with cancers of the nasopharynx who had received
chemoradiotherapy were still alive 5 years later. No additive local
toxicities were observed with chemoradiotherapy when compared to
matched historical control patients with head and neck cancers
treated with the same dose of radiotherapy alone.

• Adjuvant Chemotherapy—In patients with locally
advanced nasopharyngeal carcinoma, the administration of systemic
chemotherapy after radiotherapy may help to consolidate the local
control achieved with radiation and reduce the incidence of
microscopic systemic metastasis. These beneficial effects of adjuvant
chemotherapy may result in improved disease-free and overall survival.

A prospective, randomized trial[70] of radiotherapy followed by
vincristine, cyclophosphamide (Cytoxan, Neosar), and doxorubicin that
did not show any benefit from the use of adjuvant chemotherapy is
discussed below. In another phase II trial,[71] the combination
chemotherapy used (5-FU and cisplatin) was too toxic, resulting in
high treatment-related mortality.

Other reports[72-76] of single-arm studies, however, did show
possible benefits of adjuvant chemotherapy in patients with
nasopharyngeal carcinoma. Many newer agents, and combinations
thereof, may have fewer local mucosal side effects; these may need to
be investigated in the future.