Concomi t ant Radi ot herapy and Chemot herapy f or Earl y-

St age Nasopharyngeal Carci noma

By Skye Hongiun Cheng, Stella Y.C. Tsai, K. Lawrence Yen, James Jer-Min Jian, Nei-Min Chu, Kwan-Yee Chan,
Tran-Der Tan, Jason C. Cheng, Cheng-Yee Hsieh, and Andrew T. Huang
Purpose: Early-stage nasopharyngeal carcinoma
(NPC) continues to carry a failure rate of 15% to 30%
when treated with radiotherapy alone; the benet of
concomitant radiotherapy and chemotherapy (CCRT) in
early-stage NPC is unclear. The purpose of this report is
to describe our efforts to improve treatment outcome in
early-stage NPC after CCRT.
Patients and Methods: Of 189 newly diagnosed
NPC patients without evidence of distant metastases
who were treated in our institution between 1990 and
1997, 44 presented with early-stage (stage I and II)
disease according to the American Joint Committee on
Cancer (AJCC) 1997 NPC staging system. Twelve of
these patients were treated with radiotherapy alone
and 32 with CCRT. Each patients head and neck area
was evaluated by magnetic resonance imaging or com-
puted tomography. Radiotherapy was administered at
2 Gy per fraction per day, Monday through Friday, for
35 fractions for a total dose of 70 Gy. Chemotherapy
consisting of cis-diamine-dichloroplatinumand uorou-
racil was delivered simultaneously with radiotherapy
in weeks 1 and 6 and sequentially for two monthly
cycles after radiotherapy.
Results: Patients who were treated with radiotherapy
alone primarily had stage I disease, whereas none of
those whowere treatedwithCCRT hadstage I disease (11
of 12 patients v none of 32 patients; P .001). The
locoregional control rate at 3 years for the radiotherapy
group was 91.7% (median follow-up period, 34 months)
and was 100% for the CCRT group (median follow-up
period, 44 months) (P .10). The 3-year disease-free
survival rate in the radiotherapy group was 91.7% and
was 96.9% in the CCRT group (P .66).
Conclusion: Our results reveal excellent prognosis
of AJCC 1997 stage II NPC treated with CCRT. Stage II
patients with a greater tumor burden treated with CCRT
showed an equal disease-free survival, compared with
stage I patients treated with radiotherapy alone. A
prospective randomized trial is underway to conrm
the role of CCRT in stage II NPC.
J Clin Oncol 18:2040-2045. 2000 by American
Society of Clinical Oncology.
E
ARLY-STAGE nasopharyngeal carcinoma (NPC) is
usually treated with radiotherapy alone. On the basis
of the American Joint Committee on Cancer (AJCC) 1997
staging system,
1
the 3-year survival rate of stage I patients
treated in Turkey was 100% and was 72% for stage II
patients.
2
For those patients with stage I disease who were
treated in New York, the 5-year survival rate was approxi-
mately 70% and was approximately 50% for stage II
patients.
3
The 5-year survival rate in a Hong Kong series,
based on Hos staging,
3
was 80.8% in stage I patients and
71.5% in stage II patients.
4
The 5-year local control rate for
T1 and T2 patients staged on the basis of the Ho system and
treated with or without sequential chemotherapy (CT)
ranged from 85% to 86%.
5
Even with brachytherapy incor-
porated into the treatment protocol, the 5-year disease-
specic survival rate for AJCC 1992 stage I and II (equal to
AJCC 1997 stage I) patients was only 85.8%, and the local
control was 83%.
6,7
Concomitant radiotherapy and chemotherapy (CCRT)
followed by adjuvant CT has been proved superior to
radiotherapy alone in the treatment of advanced-stage NPC
by a large prospective randomized trial.
8
The enhancement
of local control by adjunct CT in advanced-stage NPC has
also been observed in a retrospective large series in Hong
Kong
5
; however, its role in early-stage NPC is not clear. In
the study presented here, we retrospectively selected early-
stage NPC patients, as dened by the AJCC 1997 staging
system as stage I and II patients, and observed the treatment
outcome using radiotherapy alone or CCRT followed by
adjuvant CT during the period between 1990 and 1997 in
our institution.
PATIENTS AND METHODS
Between April 1990 and December 1997, 189 patients with histo-
logically proven NPC and without evidence of distant metastases were
given denitive radiotherapy with or without CT at the Koo Foundation
Sun Yat-Sen Cancer Center, Taipei, Taiwan. All patient clinical
information was collated in a comprehensive Nasopharyngeal Carci-
noma Data Base prospectively. Information collected in this database
consisted of (1) a general data form, which included patient demo-
From the Departments of Radiation Oncology, Research, Head and
Neck Surgery, Medical Oncology, and Radiology, Koo Foundation Sun
Yat-Sen Cancer Center, Taipei, Taiwan; and Department of Medicine,
Duke University Medical Center, Durham, NC.
Submitted October 12, 1999; accepted January 26, 2000.
Supported in part by grant no. NHRI-GT-EX89P930L from the
National Health Research Institutes of Taiwan, Taipei, Taiwan.
Address reprint requests to Skye H. Cheng, MD, Department of
Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, 125,
Lih-Der Rd, Pei-Tou, Taipei, Taiwan; email skye@mail.kfcc.org.tw.
2000 by American Society of Clinical Oncology.
0732-183X/00/1810-2040
2040 Journal of Clinical Oncology, Vol 18, No 10 (May), 2000: pp 2040-2045
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Copyright 2000 American Society of Clinical Oncology. All rights reserved.
graphic information, general medical and family history, as well as
specic, clinical, and treatment history; (2) an imaging review form,
which recorded imaging information regarding the head and neck
areas; (3) a CT form, which contained CT information and information
about CT-related complications; (4) a radiotherapy form, which con-
tained radiotherapy information and radiotherapy-related complica-
tions; (5) a follow-up form, which was submitted every 3 to 6 months
after the completion of all treatments or when tumor relapse was
observed; and (6) a late-complication form, which was submitted when
any late complications were observed.
After the publication of the revised AJCC staging system in 1997,
the head and neck images of all patients were reviewed and their
staging reclassied according to the new criteria. Forty-four patients
were identied as having AJCC 1997 stage I and II NPC. Twelve
patients (11 in stage I, one in stage II) had been treated with
radiotherapy alone, and 32 patients (all in stage II) with CCRT
followed by adjuvant CT. Pretreatment evaluations included a complete
history; physical examination; beroptic endoscopic examination of the
nasopharynx, oropharynx, and larynx; magnetic resonance imaging
(MRI) and/or computed tomography of the head and neck (37 patients
were evaluated by MRI, and seven by computed tomography); chest
radiographs; radionuclide bone scan; ultrasonography of the liver;
complete blood counts; and serum chemistry measurements. Patients
who were eligible for CCRT had to have a pretreatment peripheral
absolute granulocyte count of 2,000/L, platelet count of
100,000/L, and a creatinine concentration less than 1.5 mg/dL.
Informed consent was obtained from patients treated with CCRT in
accordance with the procedures of the Institutional Review Board of
the Koo Foundation Sun Yat-Sen Cancer Center.
Radiotherapy
Details of the radiotherapy technique have previously been report-
ed.
9,10
In brief, all patients had computed tomography of the head and
neck region for planning performed while they were in the treatment
position. This was used to delineate treatment volumes, which included
the primary tumor site and the neck nodes up to the clavicle. Computed
tomographyassisted radiation treatment planning was obtained before
the initiation of radiotherapy. An appropriate isodose line (usually 96%
to 98% of the central axis dose) was chosen to cover all gross tumor
volume shown on the computed tomographyassisted treatment-plan-
ning charts. The nasopharynx and upper neck were treated with 6-MV
photons through bilateral opposed elds and reserved 18-MV photons
for an off-cord boost and 9-MV electrons for a postneck boost. A
separate anterior low-neck eld with spinal-cord shielding was used for
the low neck and supraclavicular fossa.
Radiotherapy was administrated ve times a week at 2 Gy per day up
to a total dose of 70 Gy. The spinal cord was excluded from photon
elds after 44 Gy were administered. The accumulated dose given to
the primary tumor and involved neck lymph nodes was 70 Gy and was
50 to 60 Gy to uninvolved areas. There was a 1-week break after 44 Gy
had been delivered in the CCRT group.
Chemotherapy
Chemotherapy consisted of cis-diamine-dichloroplatinum (CDDP)
and uorouracil (5-FU). A CDDP 100 mg/m
2
bolus injection was
delivered on day 1, and FU 1,000 mg/m
2
was administered by 24-hour
continuous infusion daily on days 1 through 5 for 5 days. Sixty percent
of the drug doses were given to the patients when CT was administered
concomitantly with radiation. Four courses of chemotherapy were
delivered: two simultaneously with radiotherapy on weeks 1 and 6 and
an additional two courses monthly after the completion of radiotherapy.
Follow-Up
All patients were evaluated for disease control, complications, and
survival by a multidisciplinary team of physicians at 2-month intervals
for the rst 2 years, at 3- to 6-month intervals between the third and
fth years, and at 1-year intervals thereafter. Follow-up examination of
the primary tumor was assessed by beroptic endoscopy and MRI 3
months after the completion of radiotherapy. Fiberoptic endoscopy was
subsequently performed on every return visit. All patients underwent
MRI every 6 months for the rst 2 years and annually between the third
and fth years. Blood chemistry panels, whole-body bone scans, and
liver sonography were performed every 6 months in the rst 3 years
and every 12 months thereafter. Follow-up data were obtained as of
June 1999. For patients with recurring disease, the restaging work-up
was performed in the same manner as that in the initial evaluation.
Statistical Methods
The duration of the locoregional control, disease-free survival, and
overall survival were calculated from the rst day of treatment until the
day that tumor recurrence or patient death was observed. Survival and
recurrence estimates were calculated according to the methods of
Kaplan and Meier.
11
RESULTS
The patient characteristics in the radiotherapy and CCRT
groups are listed in Table 1. There were no signicant
differences in male-to-female ratio and age distribution in
the two groups of patients. The series presented here did not
Table 1. Patient Characteristics in Early-Stage NPC
Characteristic
Radiotherapy CCRT
P
No. of
Patients %
No. of
Patients %
Sex
Male 8 67 21 66 .95
Female 4 33 11 34
Age
30 years 0 2 6 .68
31-40 years 5 42 9 28
41-50 years 4 33 8 25
51-60 years 1 8 7 22
60 years 2 17 6 19
Histology
WHO type 2 3 25 9 28 .84
WHO type 3 9 75 23 72
Palpable neck lymph node 1 8 21 66 .001
Stage
I 11 92 0 .001
IIA (T2aN0) 0 2 6
IIB 1 8 30 94
T1N1 0 12
T2aN1 0 9
T2bN0 0 1
T2bN1 1 8
Abbreviation: WHO, World Health Organization.
2041 CCRT FOR EARLY-STAGE NPC
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Copyright 2000 American Society of Clinical Oncology. All rights reserved.
include patients with WHO type 1 histologies; WHO type 2
and 3 histologies were almost equally distributed in both
groups (three of nine v nine of 23, respectively; P .84).
However, the group with radiotherapy alone, compared with
the CCRT group, consisted of fewer patients with palpable
neck lymph nodes (one of 12 v 21 of 32, respectively; P
.001) and more patients having AJCC 1997 stage I disease
(11 of 12 v none of 32; P .001).
By the end of June 1999, with a minimum follow-up
period of 18 months and a median follow-up interval of 42
months (radiotherapy group: median, 34 months, range, 19
to 88 months; CCRT group: median, 44 months, range, 18
to 102 months), one of 12 patients in the radiotherapy group
who had T1N0 disease and no patients in the CCRT group
experienced local disease recurrence. In the CCRT group,
two of 32 patients developed distant metastases; both
patients were classied as having T2bN1M0 disease. There
were no distant metastases in the radiotherapy group. The
single patient who experienced local recurrence in the
radiotherapy group underwent salvage surgery and re-
mained disease-free for 34 months after surgery. Two
patients had persistent disease after receiving 70 Gy of
radiation (one in the radiotherapy group, the other in the
CCRT group); the radiation doses were increased in these
two patients to a total of 90 Gy and 82 Gy, respectively.
Both patients were not considered to have locoregional
recurrence. They remained disease-free for 19 and 43
months, respectively, after radiotherapy.
The locoregional control rate calculated by log-rank test
was better in the CCRT group than in the radiotherapy
group, although statistic signicance was not reached
(100% v 91.7%, respectively; P .10). At 3 years, the
disease-free survival rate was 91.7% (95% condence
interval [CI], 76.0% to 100%) in the radiotherapy group and
96.9% (95% CI, 90.8% to 100%; P .66) in the CCRT
group (Figs 1A and 1B). The overall survival rates at 3 years
in both groups were 100%.
Patient compliance in the CCRT group was excellent.
The radiation interval ranged from 48 to 65 days; 20 (63%)
of 32 patients completed radiotherapy within 8 weeks and
29 (91%) of 32 completed radiotherapy within 9 weeks.
Twenty-eight (88%) of 32 patients received four courses of
CT, and 31 (97%) of 32 received at least two cycles of
concurrent CT.
All patients were evaluated for toxicity from radiotherapy
and CT according to the National Cancer Institute Common
Toxicity Criteria. Acute toxicity of CCRT and postradiation
CT were reversible and tolerated by the patients (Table 2).
Mucositis, pharyngitis, and nausea and vomiting were the
major side effects during CCRT. Grade 3 mucositis and
pharyngitis occurred in 62.5% and 15.6% of patients,
respectively. Two patients (6%) experienced grade 4 toxic-
ity; both of them developed severe and persistent vomiting
and required parenteral support. No patient experienced
weight loss greater than grade 2 because 25% (eight of 32)
of our CCRT patients had feeding tubes inserted for
nutritional support. In contrast, 8% (one of 12) of patients in
the radiotherapy group were tube-fed. During postradiation
CT, grade 3 mucositis and nausea and vomiting occurred at
a much lower rate, in 17.2% and 10.3% of patients,
respectively. One patient (3%) experienced grade 4 infec-
tion and required hospitalization for infection control.
DISCUSSION
The 44 stage I and II patients in the series presented here
had had excellent locoregional disease control, disease-free
survival, and overall survival after radiotherapy alone or
CCRT. Of these early-stage patients, those in stage II who
had larger tumor volumes had a 3-year locoregional control
rate of 100% and a disease-free survival rate of 96.9% after
CCRT and adjuvant CT. However, patients who had smaller
tumor loads (primarily the AJCC 1997 stage I patients)
treated with radiotherapy alone had 3-year locoregional
control and a disease-free survival rate of 91.7% (Figs 1A
and 1B).
Patients with NPC in AJCC 1997 stage I are usually
treated with radiotherapy alone. Their 5-year survival rates
are approximately 85% to 100%.
2,7
Patients with AJCC
1997 stage II disease who are treated with radiotherapy
alone have had an approximately 5-year survival rate of
55% to 65%.
2,3
Similar survival results were observed on
the basis of Hos classication. Sham and Choy
4
reported
that in 759 patients treated in the Queen Mary Hospital in
Hong Kong, the actuarial survival rates at 5 years for
patients with stage I and II diseases (similar to AJCC 1997
stage I and II disease) were 80.8% and 71.5%, respectively.
The series presented here demonstrated that patients who
had AJCC 1997 stage II disease treated with CCRT had an
equal or better survival when compared with the results of
AJCC 1997 stage I patients treated with radiotherapy alone
as reported in the literature. The treatment result also
seemed to be much better than patients in AJCC 1997 stage
II treated with radiotherapy alone, as previously reported by
the investigators cited above.
2-4,7
The major dissimilarities between our study and the
series cited above are that their studies preceded our study
by a decade, and the image evaluation before treatment
(computed tomography versus MRI) and the treatment
modality (radiotherapy alone versus CCRT) are different.
Image evaluation before treatment by MRI may result in
2042 CHENG ET AL
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Copyright 2000 American Society of Clinical Oncology. All rights reserved.
patients being moved from an early-stage classication to a
more advanced stage. Therefore, our data demonstrate that
either stage II disease detected by MRI has an outcome
equally as good as stage I disease or that CCRT produces an
outcome for stage II disease equivalent to stage I disease
treated by radiotherapy alone, or both. In view of the fact
that more patients in the CCRT group had clinically
palpable lymph nodes (Table 1), which is not related with
staging migration by MRI, the impact of CCRT on the
survival benets of stage II patients cannot be dismissed.
The survival advantage of the CCRT group in the series
presented here is primarily attributed to excellent locore-
gional control and a far lower incidence of distant metasta-
ses. We demonstrated equal or better locoregional control
rate in stage II (AJCC 1997) NPC treated with CCRT,
compared with radiotherapy alone for stage I patients in our
Fig 1. (A) Locoregional control in early-stage NPC treated with radiotherapy (RT) alone or concomitant radiotherapy and chemotherapy (CCRT). The 3-year
locoregional control rate for the RT group is 91.7% (95% CI, 76% to 100%) and 100% for the CCRT group (P .10). (B) Disease-free survival rates in early-stage
NPC treated with radiotherapy (RT) alone or concomitant radiotherapy and chemotherapy (CCRT). The 3-year disease-free survival rate for the RT group is
91.7% (95% CI, 76% to 100%) and 96.9% for the CCRT group (95% CI, 90.8% to 100%) (P .66).
2043 CCRT FOR EARLY-STAGE NPC
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Copyright 2000 American Society of Clinical Oncology. All rights reserved.
own institution, using contemporary radiation therapy facil-
ities and techniques,
9,10
despite the fact that stage II patients
had a greater tumor burden.
We believe that the excellent locoregional control in our
series is attributable to a more precise delineation of the
tumor volume by MRI,
12-14
individualized radiation treat-
ment planning, and concomitant CT.
9,10
The improvement
of locoregional control rate due to stage migration by MRI
is less likely because, using same diagnostic and treatment
modalities, we have previously reported an excellent 3-year
primary tumor control rate of 92% for AJCC 1992 T4
patients.
15
More favorable histology types, such as nonke-
ratinizing carcinoma and poorly differentiated carcinoma,
are probably another reason for the improvement of locore-
gional control. These histology types are known to have
greater radiosensitivity and, hence, better local control when
compared with well-differentiated squamous histology.
16
Computed tomographyassisted treatment planning was
used routinely in the series presented here; its benet in the
locoregional control of NPC has been reported elsewhere.
10
We chose an appropriate isodose line (usually 96% to 98%
of the central axis dose) to cover all gross tumor volume
shown on the computed tomographyassisted treatment
planning charts. The relationship between 2% to 4% dose
escalation and the dramatic change of locoregional control
is unknown at present. We are now performing an analysis
of the relationship between tumor-dose nonhomogeneity
and local control in our institution; the results will be
reported soon.
Distant metastases in early-stage NPC are not common.
Geara et al
17
reported that the risk of distant metastases for
patients with N0-N1 or N2 (similar as AJCC 1997 N1)
classication was 11% to 13% and 37%, respectively, in a
long-term follow-up. With T1-T2 and N0 populations, the
risk of distant metastases will probably be less than 10%.
Therefore, postradiation adjuvant CT in this subset of
patients may not be necessary. However, for patients with
AJCC 1997 T1-T2 and N1 disease, whether adjuvant CT
after radiotherapy is benecial warrants further evaluation.
The study of the CCRT group presented here primarily
included T2N1 patients and included more patients with
WHO type 3 histologies; the distant metastasis rate at 3
years was only 3.2%. In a different series, by Teo et al,
18
in
which patients were evaluated by computed tomography
and treated with radiotherapy alone, the 3-year distant
metastasis rate in T2aN0 patients was 4% and in T2bN0
patients was 22%. Our series involved cases with more
advanced disease (more T2aN1 and T2bN1 patients; Table
1) but a far lower incidence of distant metastases. The
primary differences between the Teo et al study and our
study are that we used MRI evaluations before treatment
and a combination of radiotherapy and concomitant CT.
The study presented here also showed a good compliance
of our patients to the CCRT and adjuvant CT. The inter-
group study by Al-Sarraf et al
8
revealed that only 55% of
patients completed the combined modality treatment as
planned. Our data revealed that 88% of patients completed
CCRT as planned. Good compliance to CCRT was attrib-
uted to the immediate intervention of nasogastric tube-
feeding when patients developed 5% weight loss or grade
III mucositis.
15
Our concomitant treatment is better toler-
ated by patients because we administered two cycles of
Table 2. Toxicity of Concurrent Radiotherapy Plus Chemotherapy and Postradiation Chemotherapy
Toxicity
Toxicity Grade* Grade III or
Higher Toxicity
in the Entire
Course
CCRT (n 32) Postradiation Chemotherapy (n 29)
I II III IV I II III IV
Nausea 38 53 6 31 45 14 19
Vomiting 31 38 9 6 21 21 14 25
Diarrhea 19 6 24 0
Stomatitis/mucositis 13 25 63 17 24 17 66
Pharyngitis 31 53 16 16
Weight loss 34 16 0
Leukopenia 41 25 31 38 7 6
Hemoglobin 44 6 3 52 3 3 6
Platelet 13 6 13 3 3 3
Creatinine 6 3 0
Infection 13 14 3 0 3 3
Maximum grade of any
toxicity
3 31 59 6 10 59 24 3
*National Cancer Institute toxicity criteria.
Percentage of toxicity.
Weight loss was evaluated by Radiation Therapy Oncology Group criteria; eight (25%) of 32 patients had feeding tubes inserted.
Three patients did not undergo postradiation chemotherapy; their creatinine data are not available.
2044 CHENG ET AL
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Copyright 2000 American Society of Clinical Oncology. All rights reserved.
chemotherapy with CDDP and FU at a 60% dose reduction
during radiotherapy and two additional courses of CDDP
and FU in full doses after radiotherapy. Moreover, we
routinely allowed patients to have a 1-week break during
radiotherapy treatment. Still, our CCRT patients experi-
enced more severe mucositis and vomiting than did patients
undergoing radiotherapy alone (data not shown), and the
tube-feeding rate in the CCRT group was higher than in the
radiotherapy group (eight of 32 v one of 12).
The intergroup study concluded that CCRT is superior to
radiotherapy alone in patients with AJCC1992 stage III and IV
disease. However, they only included 13 patients with stage III
disease (equal to AJCC 1997 stage II) in their study popula-
tion.
8
As such, a conclusion that CCRT was better than
radiotherapy alone in this subset of patients seemed weak. Our
data presented here does offer additional support to the above
conclusion that patients with AJCC 1992 stage III (now AJCC
1997 stage II) can achieve a more favorable outcome with CCRT.
In summary, excellent locoregional control, fewer distant
metastases, and excellent survival have been obtained in
patients with AJCC 1997 stage II NPC who were evaluated
by MRI of the head and neck and who were treated with
CCRT. AJCC 1997 stage II patients, especially those with
T1N1, T2aN0, and T2aN1 classications, deserve to be
reviewed in the future as to whether this subset of patients
ought to remain in stage II or be reclassied to a lesser
stage. The benet of CCRT, compared with radiotherapy
alone, in early-stage NPC awaits conrmation by a prospec-
tively randomized trial.
ACKNOWLEDGMENT
The authors thank Yen-Chun Lin, Szu-Yun Sharon Leu, Yueh-Yun
Yu, Yi-Wen Chang, and Cheng-Fang Horng in the Clinical Protocol
Ofce for their thoughtful assistance with data collection, data entry,
data quality control, and outcome analysis.
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