Keywords
Chemoradiation - metastatic nasopharyngeal cancer - survival
Introduction
Nasopharyngeal carcinoma (NPC) is a rare malignancy with the highest incidence in
patients from northeast India.[1] The majority of patients in India present with locally advanced stage or with distant
metastasis.[2]
[3] NPC is a chemotherapy and radiosensitive disease with distinct demographic, clinical,
staging, and treatment options as compared to nonnasopharyngeal head-and-neck cancer.[4] In view of the paucity of randomized controlled trials in metastatic NPC, the optimal
treatment is unknown. The usual practice is first-line platinum-based therapy and
second-line gemcitabine- or taxane-based chemotherapy.[5] There is ongoing research with Epstein–Barr virus (EBV) such as vaccination or administration
of cytotoxic T cells targeting EBV[6] and immunotherapy.[7] There is a lack of long-term outcomes of metastatic NPC from India. This study was
done to compare the outcomes of patients with NPC treated with chemoradiation or radiation
alone and to assess factors that correlated with the outcome.
Methods
This was a retrospective study of patients with metastatic NPC treated in Cancer Institute,
Chennai, from 1996 to 2015. The diagnosis was established by biopsy of the nasopharyngeal
mass. The staging investigations were contrast-enhanced computerized tomography of
head and neck, chest X-ray, ultrasound of abdomen/pelvis, and bone scan. Patients
were treated with palliative intent either with chemoradiation or only radiation.
The chemotherapy regimen concurrent with radiation was either cisplatin and 5-fluorouracil
or only cisplatin. Patients were reassessed after completion of chemoradiation or
only radiation. Zoledronic acid 4 mg intravenously every month for 2 years was administered
for patients with bone metastasis. After completion of treatment, patients were evaluated
monthly for the first 6 months, 2 monthly until 2nd year, 3 monthly in the 3rd year, and 6 monthly thereafter. During the first follow-up, patients underwent clinical
examination, nasopharyngoscopy, and biopsy, if any residual disease. Further investigations
during the follow-up were nasopharyngoscopy, chest X-ray, ultrasound abdomen/pelvis
every year, and bone scan, if symptomatic.
Progression-free survival (PFS) was calculated from the date of diagnosis to date
of progression or date of the last follow-up. Overall survival (OS) was calculated
from the date of diagnosis to date of death or date of the last follow-up. Survival
was estimated by the Kaplan–Meier method. The Cox regression model was used to assess
prognostic factors. P < 0.05 was considered statistically significant, and statistical analysis was performed
using SPSS version 20 (IBM corporation, New York, USA).
Results
A total of 74 patients were included in this analysis, with a median follow-up of
14 months. The median age was 42 years (range: 9–77 years). Fifty-five patients (74%)
were male and 19 (26%) were female. The most common symptom at presentation was a
lump in the neck (78%) followed by a nasal block (18%). The histology was the World
Health Organization (WHO) Type 2 in 93% and WHO Type 1 or 3 in 7%. T Stage was T1–T2
(57%) and T3–T4 (43%). N stage was N 0–1 (24%) and N 2–3 (76%). The sites of metastasis
were bone only in 95% (n = 70) and 5% (n = 4) had visceral metastasis [Table 1].
Table 1
Baseline characteristics
|
Variable
|
n (%)
|
|
Median age (years) (range)
|
42 (9-77)
|
|
Male
|
55(74)
|
|
Female
|
19 (26)
|
|
Symptom at presentation
|
|
|
Lump in the neck
|
58 (78)
|
|
Nasal block
|
13 (18)
|
|
Others
|
3 (4)
|
|
Histology
|
|
|
WHO Type 2
|
69 (93)
|
|
WHO Type (1 or 3)
|
5 (7)
|
|
T stage
|
|
|
T1-T2
|
42 (57)
|
|
T3-T4
|
32 (43)
|
|
N stage
|
|
|
N0-N1
|
18 (24)
|
|
N2-N3
|
56 (76)
|
|
Site of metastasis
|
|
|
Bone only
|
70 (95)
|
|
Visceral
|
4 (5)
|
A total of 72% (n = 53) were treated with concurrent chemoradiation. The radiation schedule was 2 Gy
per fraction per day to a total dose of 66–70 Gy. The chemotherapy schedule concurrent
with radiation was cisplatin 70 mg/m2 on day 1 and 5-fluorouracil 325 mg/m2/day from day 1 to day 3 every 3 weekly for 3 cycles (70%), cisplatin 70 mg/m2 every 3 weekly for 3 weeks (23%), and weekly cisplatin 40 mg/m2 for 6 cycles (7%). A total of 28% (n = 21) received only radiation to locoregional sites. Complete response in the locoregional
site was 87% in patients who received chemoradiation and 48% in those who received
only radiation.
The median PFS was 11 months (range 1–201 months), and the 3-year PFS was better in
patients who received chemoradiation (35%) as compared to only radiation (19%). The
median OS was 19 months (range 1–201 months), and the 3-year OS rate was 36%. The
median OS for patients with bony only metastasis and visceral metastasis was 23 months
and 4 months, respectively.
The factors included in the univariate analysis [Table 2] were age, sex, histology, stage, number of sites of bone metastasis, and treatment
modality. Univariate analysis showed that type of treatment (chemoradiation) and oligometastatic
bone-only disease correlated with improved outcome. Multivariate analysis [Table 3] showed that patients with extensive bone metastasis >3 correlated with poor outcome
(hazard ratio-2.03, confidence interval 1.10–3.74, P = 0.022). [Figure 1] and [Figure 2] show the Kaplan–Meier curve for type of treatment and bone metastasis, respectively.
Table 2
Univariate analysis
|
Variable
|
n
|
Median survival (months)
|
3-year OS (%)
|
HR
|
CI
|
P
|
|
HR – Hazard ratio; CI – Confidence interval; OS – Overall survival
|
|
Age
|
|
|
|
|
|
|
|
<42
|
36
|
26
|
44.4
|
1.00*
|
0.81-2.29
|
0.233
|
|
>42
|
38
|
18
|
34.2
|
1.36
|
|
|
|
Sex
|
|
|
|
|
|
|
|
Male
|
55
|
19
|
38.2
|
1.00*
|
0.59-1.87
|
0.857
|
|
Female
|
19
|
22
|
31.6
|
1.05
|
|
|
|
Histology
|
|
|
|
|
|
|
|
WHO Type 2
|
69
|
19
|
36.2
|
1.00*
|
0.17-1.75
|
0.309
|
|
WHO Type (1/3)
|
5
|
36
|
40
|
0.54
|
|
|
|
T stage
|
|
|
|
|
|
|
|
T1-T2
|
42
|
19
|
34.7
|
1.00*
|
0.45-1.30
|
0.332
|
|
T3-T4
|
32
|
23
|
38.7
|
0.76
|
|
|
|
N stage
|
|
|
|
|
|
|
|
N0-N1
|
18
|
23
|
50
|
1.00*
|
0.68-2.30
|
0.457
|
|
N2-N3
|
56
|
18
|
35.7
|
1.25
|
|
|
|
Treatment modality
|
|
|
|
|
|
|
|
Chemoradiation
|
53
|
25
|
39.5
|
1.00*
|
1.02-3.06
|
0.039
|
|
Radiation only
|
21
|
17
|
23.8
|
1.77
|
|
|
|
Type of metastasis
|
|
|
|
|
|
|
|
Oligometastasis
|
51
|
36
|
51
|
1.00*
|
1.30-4.14
|
0.004
|
|
Multiple metastasis
|
19
|
13
|
15.8
|
2.32
|
|
|
Table 3
Multivariate analysis
|
Variable
|
HR
|
CI
|
P
|
|
HR – Hazard ratio; CI – Confidence interval
|
|
Treatment modality
|
|
|
|
|
Chemoradiation
|
1.00*
|
0.84-2.77
|
0.161
|
|
Radiation only
|
1.53
|
|
|
|
Type of metastasis
|
|
|
|
|
Oligometastasis
|
1.00*
|
1.10-3.74
|
0.022
|
|
Extensive metastasis
|
2.03
|
|
|
Figure 1: Kaplan–Meier curve of treatment modality. Blue line - Chemoradiation; Red
line - Radiation only
Figure 2: Kaplan–Meier curve showing type of metastasis. Blue line - Oligometastasis;
Red line - Multiple metastasis
Discussion
Nasopharyngeal cancer has a higher incidence of metastasis at presentation than nonnasopharyngeal
head-and-neck cancers.[8]
[9]
[10]
[11] In our study, 14.3% of carcinoma of nasopharynx presented with metastasis at presentation.
Bone was the most common site (95%) of distant metastasis in our patients. A study
from China also reported bone (75%) as the most common site of metastasis.[12]
It is debatable to consider chemoradiation or radiation alone for the treatment of
metastatic NPC. A Japanese study[13] showed incorporating radiation in advanced NPC improved the outcome. The National
Comprehensive Cancer Network Guidelines recommend concurrent chemoradiation as an
option in metastatic NPC.
The median survival of bone-only metastasis was 23 months, whereas, in visceral metastasis,
it was 4 months. Consideration to participate in a clinical trial should be strongly
recommended in patients with NPC with visceral metastasis.
The majority (72%) of our patients were treated with concurrent chemoradiation with
5-fluorouracil and cisplatin. A meta-analysis of palliative chemotherapy in metastatic
NPC showed that the triplet regimen improved response but failed to improve survival
and had more toxicity.[14] Among the doublet regimens, the taxane–platinum combination had the best efficacy
followed by gemcitabine platinum and then 5-fluorouracil and platinum.[14] Patients who cannot tolerate cisplatin can be considered for carboplatin-based chemotherapy.[15]
In one study, Yeh et al.[13] showed that median and 2 years’ OS of metastatic NPC were 9.7 months and 14%, respectively.
In our study, the median survival and 2 years’ OS was 19 months and 45.9%, respectively,
and patients treated with concurrent chemoradiation had a better median OS (25 months).
Bouaouina et al.[16] showed that cisplatin-based chemoradiation with curative dose improved survival.
A case series from Memorial Sloan Kettering Cancer Center[17] also showed that patients treated with chemoradiation had a long-term survival.
A Chinese study[18] showed that patients with >3 metastatic bone lesions have poor OS as compared to
patients with <3 bone lesions. Our study also showed that patients with oligometastatic
bone disease (1–3 lesions) had a better survival rate as compared to those with multiple
bone metastases.
The limitations of this study are the retrospective nature, nonrandomized study, small
sample size, physician discretion on type of treatment, lack of EBV testing in tumor,
and plasma EBV for surveillance.
Conclusion
Chemoradiation can be an option to treat metastatic NPC. Patients with bone-only oligometastasis
(<3 bone lesions) had improved survival.
