Introduction
Nasopharyngeal carcinoma (NPC) differs from other
head and neck carcinomas by its specific geographic
and ethnic distribution, its association with Epstein-
Barr virus (EBV) infection, and predisposition of distant
metastases.[]
NPC is also chemotherapy and radiotherapy (RT)
sensitive disease with distinct demographic, clinical, staging, and treatment options as compared to non-nasopharyngeal
head and neck cancer.[] RT is the fundamental
treatment modality and concurrent chemo-
RT is recommended for locoregionally advanced NPC
according to the National Comprehensive Cancer Network
(NCCN) Guidelines.[] However, distant metastasis
remains a key challenge.
Both synchronous and metachronous distant metastases
are more common among NPC compared to other head and neck cancers.[-] For synchronous distant
metastasis of NPC, this rate ranges between 6 and 15%.
[,] Most of the current oncological treatment guidelines
suggest chemotherapy as the only treatment option
for metastatic disease in NPC.[,] This might be seen
as a reflection of the old perspective which limits RT
role with cancer palliation, mostly for symptom control.
Only the NCCN guidelines regard post-chemotherapy
locoregional RT (LR-RT) as a treatment option without
any suggestion on treatment or follow-up.[]
In recent years, the interest in LR-RT of primary
tumors with distant metastases has increased. The survival
benefit of local treatment directed at all metastasis
in oligometastatic disease has been demonstrated in an
early randomized study.[] The effectiveness of local
therapies to the primary tumor in metastatic disease is
evolving for some specific cancer types.
According to the "seed and soil" hypothesis, the soluble
growth factors secreted from the primary tumor
causes the clustering of hematopoietic progenitor cells
and macrophages, creating an environment conducive
to the spread of malignant clones and the formation
of metastasis.[,] This emphasizes the importance
of the local tumor stage and the possible contribution
of local therapies to survival in patients with distant
metastases.[] In accordance with this thesis, the survival
benefit of local therapy in metastatic renal cell
cancers and transitional cell bladder cancer has been
demonstrated.[,] Similarly, the role of radical LRRT
in metastatic NPC has been investigated in several
retrospective studies[-] and in a very recent
a prospective randomized trial.[] They conclude
LRRT infer a positive effect on OS.
Following induction chemotherapy, we deliver radical
LR RT in de novo metastatic NPC (unless obvious
progression under chemotherapy) for more than two
decades due to the survival advantage observed in our
clinical practice. We aimed to share our retrospectively
evaluated data of patients with nasopharyngeal cancer
who had distant metastases at the time of diagnosis and
were treated with LR RT in terms of clinical features
and survival.
Methods
589 cases of patients who had biopsy-proven nasopharyngeal
cancer referred to our clinic between 2000 and
2018 were assessed and 36 patients who had distant
metastases at diagnosis and also received radical dose
RT to the head and neck region were identified. After
excluding one patient who had previously received chemotherapy for 12 courses in another clinic, the remaining
35 patients were included in the analysis.
Pretreatment Evaluation
All patients received pre-treatment evaluation consisting
of a complete history and physical examination,
endoscopic examination, complete blood counts, blood
chemistries, computed tomography (CT), or magnetic
resonance imaging (MRI) of the nasopharynx and neck.
Until 2006, all patients were screened for distant
metastases, using chest radiography, Technetium-99m
bone scintigraphy, and abdominal ultrasonography
(USG). After 2006, (18F-fluorodeoxyglucose positron
emission tomography-CT [PET-CT]) superseded these
methods. Tumors were staged according to the 7th edition
of the American Joint Cancer Committee (AJCC)
TNM staging system.
Treatment
De novo metastatic NPC patients eligible for combined
modality chemotherapy received 3-6 courses
of 33 of the 35 patients. The chemotherapy responses
were evaluated by CT or MRI. The metastases were
screened by abdominal USG, chest radiography, bone
scintigraphy, or PET-CT. The patients with partial/
complete chemotherapy response were assessed for
RT. A total of 60-74 Gy of RT were administered with
daily fractions of 1.8-2 Gy. In patients under the age
of 16, the RT dose was reduced (60-63 Gy) and concurrent
chemotherapy was not used. For the patients
older than 16 years of age, the decisions for the concurrent
chemotherapy were made on a patient basis.
Side effects during RT were monitored weekly.
Follow-up Evaluations
The periods for follow-up exams were 1 month-3 months
for the first 2 years after RT, 4-6 months for the 3rd, 4th,
and 5th years and annually thereafter. Complete blood
count, blood biochemistry, and endoscopic examination
were performed at each control. Head and neck region
evaluation was performed annually by CT or MRI. PETCT
evaluation was held 3 months after the end of LR
treatment and else when there is clinical indication.
Statistical Analysis
OS was calculated from the date of diagnosis to the day
of death for any reason or date of the last follow up.
Survival was estimated by the Kaplan-Meier method.
Potential prognostic factors for OS, including age, sex,
radiation dose, chemotherapy, and site of metastases,
number of metastatic disease, and liver metastasis were evaluated using log-rank comparisons. P<0.05 was
considered statistically significant. All statistical analyses
were performed using SPSS version 26.
Results
The median age of the patients was 49 (9-85 years)
and 85.7% (n=30) of them were male. Overwhelming
majority of the patients had either undifferentiated
carcinoma 65.7% (n=23) or non-keratinized carcinoma
28.6% (n=10) only 2 (5.7%) of the 35 patients
and keratinized carcinoma. PET-CT was used in 82.9%
(n=29) of the patients at diagnosis. Eight (22.9) patients
had a single metastasis. Furthermore, 17.1% of
patients were oligometastatic. The remaining 60% was
multiple metastatic. Thirteen (37.1%) of the patients
had multiple organ metastases. Bone metastasis was
present in 71.4% of patients, liver metastasis in 22.9%,
and lung metastasis in 20%. Three patients had mediastinal
lymph node metastasis, three patients had bone
marrow involvement, one patient had axillary lymph
nodes, one patient had adrenal, and one patient had
para-aortic lymph node metastasis (Table 1).
Table 1: Patient and treatment characteristic
Except for two patients with insufficient renal function,
all patients first received 3-6 cycles of chemotherapy.
While the median dose of RT was 7000 cGy
(6000-7400), a reduced dose of 6000-63.00 cGy RT
was applied to patient's ≤16 years of age for treatment
(Table 2). Eighteen patients received RT concurrently
with chemotherapy (one patient, carboplatin; 17 patients,
cisplatin). Palliative bone irradiation was performed
in 19 patients after LR RT, and one patient received
radioembolization for liver metastasis (Table 2).
Table 2: Summary of clinical characteristics and treatments of 35 patients
The median follow-up time was 25 months (5-196
months). During the follow-up period, 24 patients
died, one surviving patient with active disease continues
to be treated with chemotherapy. Ten patients were
on follow-up without disease (48-196 months). Six of
the ten patients are alive for more than 5 years without
disease. 4-year-survival was calculated as 34% (Fig.
1). In univariate analysis, none of the factors (age ≤40
years, gender, oligometastatic disease, presence of liver
metastasis, and RT dose) effected survival.
Fig 1: Overall survival of all patients.
Discussion
It has been reported that 6-15% of NPC patients are
diagnosed with de novo metastatic cancer before any
treatment has begun.[,] By the development of PETCT
at the end of the 1990s, its sensitivity and specificity
in cancer staging have begun to be investigated. In their trial comparing four different staging methods (n=78),
Chua et al.[] found PET-CT superior in the terms of
sensitivity, specificity, and accuracy to the conventional
methods (chest radiography, abdominal USG, and
bone scan) (Also the conventional methods performed
poorly in this trial, missing four of six metastases). Ng
et al.[] reported a false positivity rate of 18% with
PET-CT for their prospective trial (n=115). Tang et
al.[] (n=583) showed that PET-CT detects more distant
metastases than conventional staging in patients
with NPC and the largest benefit in terms of cost and
patient management was observed in the subgroup with N2-3 disease and EBV DNA ≥4000 copies/mL. In
our clinic, we have been staging the NPC patients using
PET-CT, irrespective of their local stage since 2006. Six
of the patients (17%) analyzed in this study were staged
previously with conventional methods. All patients in
the study were stage N2-3 in regional staging, except
one patient with T4N0 disease.
In the last 18 years, 589 NPC patients have been
referred to our clinic, 6.1% of them had distant metastases
at the time of diagnosis. In this current study of
35 de novo metastatic NPC patients with a median follow-
up time of 25 months, the 4-year-survival was 34%
and no significant prognostic factor on survival could
be identified.
Local therapy has been used for metastatic disease
with the intent of reducing primary tumor burden, relieving
symptoms, or propagation of metastases. Some
cancer studies have demonstrated that intensive local
therapy could prolong overall survival (OS) in untreated
de novo metastatic cancer patients.[,,,] This
concept of LR treatment is supported by a randomized
clinical trial reporting the OS benefit of high dose RT
to the primary tumor (STAMPEDE).[] The number
of clinical studies researching the effect of LR RT in
de novo metastatic NPC is limited. It should, however,
be cleared since treatment of de novo metastatic NPC
patients must consider the control of primary tumors,
which is different from metastatic NPC after treatment.
Several retrospective analyses suggested that additional
LR RT could improve survival of these patients in addition
to palliative chemotherapy.[-] In accordance
with these emerging data, the NCCN Guidelines recommend
concurrent chemoradiation as an option in
de novo metastatic NPC.
NPC usually metastasize to bones, lungs, and liver.
[,] Among them, the primary metastasis site is
the bones. The solitary bone metastasis is alleged to
be related to a better prognosis than the others.[]
The liver, the third common metastasis site after the
lungs, has the worst survival rates according to Zou
et al. study.[] They separated the M stage into three
subgroups, according to the number of metastatic lesions
and the existence of liver metastasis in their classification.
While the oligometastatic disease subgroup
had the best survival rates, the subgroup with the liver
metastasis, which was named M1c, had the worst. In
their study using five different prognostic factors (age,
N stage, number of metastases, organ involvement,
and EBV DNA levels), Sun et al.[] found the existence
of multiple metastases and liver involvements,
negative prognostic factors. In our serial, there were
eight patients with liver metastases (one patient under
16 years of age, one single-metastatic-patient, and two
oligometastatic-patients) and three of them are alive
with no evidence of disease for 77, 83 and 196 months.
In their retrospective data Lin et al.[] evaluated
105 patients with de novo metastatic NPC and stated
better survival rates for single metastatic patients
treated with RT doses higher than 65 Gy. Among the
eight single-metastatic-patients in our serial, three of
them are alive, continuing their life disease-free.
In 2020, You et al.[] published a two-armed, Phase
III randomized trial, investigating the effectiveness of
LR RT in de novo metastatic NPC patients with partial
or complete response to three cycles of cisplatin, and
5-fluorouracil (PF) treatment. While the control group
(who had only taken chemo) had a 2-year-survival rate
of 54%, and the 2-year-survival rate of the CT+RT group
was 76% (p=0.004). In this trial, 30.9% of patients had
one or two metastases, and this group had longer OS.
It is the first and sole Phase III trial showing the contribution
of LRRT in de novo metastatic NPC patients
with good response to PF chemotherapy. The exclusion
of the unresponsive patients to PF chemotherapy limits
the generalizability of the results, the results are still
important since they point out the value of LR RT in
de novo metastatic NPC treatment. In this trial, the RT
dose following PF was 7000 cGy and the irradiated RT
volumes were designated according to pre-chemotherapy
imaging. In the same issue with article invited
commentators suggested limiting irradiation with postchemotherapy
volumes and the dose of 60 Gy in the patients
with complete response.[] However, yet there
is no convincing proof for the dose decrement in this
group with a long survival (You et al., 2-year-survival >50%). In our clinical practice, we use pre-chemotherapy
imaging and apply 70 Gy for adult patients.
Limitations of the Study
This is a retrospective study with a limited sample size.
Although it reflects the two decades of experience of
a single center in de novo metastatic disease treated
with a considerably homogenous program the patient
group consisted of various age groups (9-85), had different
chemotherapy regimens, their number and sites
of metastases varied. This complicates the investigation
of survival related factors.
Conclusion
The LR treatment in de novo metastatic diseases is gaining
prominence since the related patient group can have
long survival depending on the count of their metastases
and organ involvement. De novo metastatic NPC patients
had highly prolonged survival with the use of LR
RT and this treatment approach should be validated by
further multi-centric clinical studies. In our clinic, postchemotherapy
LR RT constitutes the primary treatment
option for de novo metastatic NPC.
Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors have no conflicts of interest
to declare.
Ethics Committee Approval: The study was approved by
the Local Ethics Committee of Istanbul University Oncology
Instıtute (No: 70973125-604.01.01, Date: 09/12/2020).
Financial Support: The authors declared that this study has
received no financial support.
Authorship contributions: Concept - M.A.; Design -
Y.D., K.Ö.T.; Supervision - M.A.; Funding - None; Materials
- K.Ö.T., Y.D.; Data collection and/or processing - K.Ö.T.,
Y.D.; Data analysis and/or interpretation - K.Ö.T., Y.D.; Literature
search - K.Ö.T., Y.D.; Writing - K.Ö.T., Y.D., MA.;
Critical review - M.A.
References
Lee A, Lin J, Ng W. Current management of nasopharyngeal
cancer. Semin Radiat Oncol 2012;22(3):233-44.
Fandi A, Altun M, Azli N, Armand JP, Cvitkovic E.
Nasopharyngeal cancer: epidemiology, staging, and
treatment. Semin Oncol 1994;21(3):382-97.
National Comprehensive Cancer Network. Available
at: https://www.nccn.org/professionals/physician_gls/
pdf/head-and-neck.pdf. Accessed Mar 10, 2021.
Chen WZ, Zhou DL, Luo KS. Long-term observation
after radiotherapy for nasopharyngeal carcinoma
(NPC). Int J Radiat Oncol Biol Phys 1989;16(2):311-4.
Frezza G, Barbieri E, Emiliani E, Silvano M, Babini L.
Patterns of failure in nasopharyngeal cancer treated
with megavoltage irradiation. Radiother Oncol
1986;5(4):287-94.
Ho JH. An epidemiologic and clinical study of nasopharyngeal
carcinoma. Int J Radiat Oncol Biol Phys
1978;4(3?4):182-98.
Lee AW, Poon YF, Foo W, Law SC, Cheung FK, Chan
DK, et al. Retrospective analysis of 5037 patients with
nasopharyngeal carcinoma treated during 1976-1985:
overall survival and patterns of failure. Int J Radiat
Oncol Biol Phys 1992;23(2):261-70.
Tang LQ, Chen QY, Fan W, Liu H, Zhang L, Guo L,
et al. Prospective study of tailoring whole-body dualmodality
[18f] fluorodeoxyglucose positron emission
tomography/computed tomography with plasma Epstein-
Barr virus DNA for detecting distant metastasis
in endemic nasopharyngeal carcinoma at initial staging.
J Clin Oncol 2013;31(23):2861-9.
Chan AT, Grégoire V, Lefebvre JL, Licitra L, Hui EP, Leung
SF, et al; EHNS-ESMO-ESTRO Guidelines Working
Group. Nasopharyngeal cancer: EHNS-ESMOESTRO
Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol 2012;23(Suppl
7):vii83-5.
Lang J, Hu C, Lu T, Pan J, Lin T. Chinese expert consensus
on diagnosis and treatment of nasopharyngeal
carcinoma: evidence from current practice and future
perspectives. Cancer Manag Res 2019;11:6365-76.
Palma DA, Olson R, Harrow S, Gaede S, Louie AV,
Haasbeek C, et al. Stereotactic ablative radiotherapy
versus standard of care palliative treatment in patients
with oligometastatic cancers (SABR-COMET):
a randomised, phase 2, open-label trial. Lancet
2019;393(10185):2051-8.
Kaplan RN, Psaila B, Lyden D. Bone marrow cells in
the "pre-metastatic niche": within bone and beyond.
Cancer Metastasis Rev 2006;25(4):521-9.
Hiratsuka S, Watanabe A, Aburatani H, Maru Y. Tumour-
mediated upregulation of chemoattractants
and recruitment of myeloid cells predetermines lung
metastasis. Nat Cell Biol 2006;8(12):1369-75.
Seisen T, Sun M, Leow JJ, Preston MA, Cole AP, Gelpi-
Hammerschmidt F, et al. Efficacy of high-intensity
local treatment for metastatic urothelial carcinoma
of the bladder: a propensity score-weighted analysis
from the national cancer data base. J Clin Oncol
2016;34(29):3529-36.
Flanigan RC, Salmon SE, Blumenstein BA, Bearman
SI, Roy V, McGrath PC, et al. Nephrectomy followed
by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med
2001;345(23):1655-9.
Lin S, Tham IW, Pan J, Han L, Chen Q, Lu JJ. Combined
high-dose radiation therapy and systemic chemotherapy
improves survival in patients with newly diagnosed
metastatic nasopharyngeal cancer. Am J Clin
Oncol 2012;35(5):474-9.
Chen MY, Jiang R, Guo L, Zou X, Liu Q, Sun R, et al.
Locoregional radiotherapy in patients with distant
metastases of nasopharyngeal carcinoma at diagnosis.
Chin J Cancer 2013;32(11):604-13.
Rusthoven CG, Lanning RM, Jones BL, Amini A,
Koshy M, Sher DJ, et al. Metastatic nasopharyngeal
carcinoma: patterns of care and survival for patients
receiving chemotherapy with and without local radiotherapy.
Radiother Oncol 2017;124(1):139-146.
Zou X, You R, Liu H, He YX, Xie GF, Xie ZH, et al.
Establishment and validation of M1 stage subdivisions
for de novo metastatic nasopharyngeal carcinoma to
better predict prognosis and guide treatment. Eur J
Cancer 2017;77:117-26.
You R, Liu YP, Huang PY, Zou X, Sun R, He YX, et
al. Efficacy and safety of locoregional radiotherapy
with chemotherapy vs chemotherapy alone in de novo
metastatic nasopharyngeal carcinoma: a multicenter
phase 3 randomized clinical trial. JAMA Oncol
2020;6(9):1345-52.
Chua ML, Ong SC, Wee JT, Ng DC, Gao F, Tan TW, et
al. Comparison of 4 modalities for distant metastasis
staging in endemic nasopharyngeal carcinoma. Head
Neck 2009;31(3):346-54.
Ng SH, Chan SC, Yen TC, Chang J, Liao CT, Ko SF,
et al. Staging of untreated nasopharyngeal carcinoma
with PET/CT: comparison with conventional imaging
work-up. Eur J Nucl Med Mol Imaging 2009;36(1):12-22.
Mickisch GH, Garin A, van Poppel H, de Prijck L,
Sylvester R, et al. radical nephrectomy plus interferonalfa-
based immunotherapy compared with interferon
alfa alone in metastatic renal-cell carcinoma: a randomised
trial. Lancet 2001;358(9286):966-70.
Gomez DR, Blumenschein GR Jr., Lee JJ, Hernandez
M, Ye R, Camidge DR, et al. Local consolidative therapy
versus maintenance therapy or observation for patients
with oligometastatic non-small-cell lung cancer
without progression after first-line systemic therapy:
a multicentre, randomised, controlled, phase 2 study.
Lancet Oncol 2016;17(12):1672-82.
Parker CC, James ND, Brawley CD, Clarke NW,
Hoyle AP, Ali A, et al; evaluation of drug efficacy
(STAMPEDE) investigators. Radiotherapy to the primary
tumour for newly diagnosed, metastatic prostate
cancer (STAMPEDE): a randomised controlled phase
3 trial. Lancet 2018;392(10162):2353-66.
Kumar A, Kumar H, Dhanushkodi M, Ganesharajah S.
Metastatic nasopharyngeal carcinoma: outcome from
Cancer Institute, Chennai. Indian J Med Paediatr Oncol
2020;41:198-201.
Sun XS, Liang YJ, Liu SL, Li XY, Chen QY, Guo SS,
et al. Establishment and validation of a nomogram for
predicting survival in patients with de novo metastatic
nasopharyngeal carcinoma. Oral Oncol 2019;94:73?9.
Riaz N, Sherman E, Lee N. The importance of locoregional
therapy in metastatic nasopharyngeal cancer.
JAMA Oncol 2020;6(9):1353-4.
