Clinical Application Value and Progress of PETCT in Nasopharyngeal Carcinoma
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
Review
Clinical application value and progress of PET/CT in nasopharyngeal carcinoma
Fengwei Zeng, Muhua Cheng
Department of Nuclear Medicine, The Third Hospital Affiliated Sun Yat-sen University, Guangdong, Guangzhou 510630, China
Corresponding author: Cheng Muhua, Professor, M.D.; E-mail: [email protected]
Citation: Zeng FW, Cheng MH. Clinical application value and progress of PET/CT in nasopharyngeal carcinoma. J
Nasopharyng Carcinoma, 2014, 1(2): e2. doi:10.15383/jnpc.2.
Competing interests: The authors have declared that no competing interests exist.
Conflict of interest: None.
Copyright: 2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-
access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are
credited.
Abstract: Nasopharyngeal carcinoma (NPC) is one of common head and neck cancers which mainly threaten
people in Southeast Asia. PET/CT plays an important role in radiotherapy for NPC. This article reviews the
PET/CT in the diagnosis, staging, guiding treatment, monitoring of therapy efficacy, focal residual and recurrence,
prognosis and progress of NPC.
Keywords: Nasopharyngeal carcinoma; Clinical application; PET/CT
Nasopharyngeal carcinoma (NPC) is one of the common head and
neck malignant tumors among southern China and Southeast
Asian countries, which often occur in the pharyngeal recess. There
is a close association between Epstein-Barr virus (EBV) and NPC
pathogenesis[1]
. The annual incidence per 100,000 persons ranged
from 10 to 30[2-3]
. At present, the main method of treatment for
NPC is radiotherapy, which treatment effect is very satisfactory
for early NPC, local recurrence and distant metastasis. The 5-year
overall survival rate is about 50%-70%[4-7]
. Therefore, early
diagnosis and staging of NPC patients is very important to
improve the survival rate. Positron Emission
Tomography/Computed Tomography (PET/CT) images could
have a significant impact on diagnosing and staging malignant
disease, monitoring of efficacy, prognostic and so on. A lot of
researches indicated that fluor-18-fluorodeoxyglucose positron
emission tomography with computed tomography (18
F-FDG
PET/CT) is superior to separate PET and conventional imaging
(CT, MRI, etc.) in the diagnosis, staging, guiding treatment,
prognosis and so on[8-13]
. In recent years, the 11
C-choline PET/CT
imaging in the diagnosis and staging of NPC patients have
obtained satisfactory results, especially in the T staging of
NPC[14]
.
This review is focused on the the value of PET/CT in the
diagnosis, staging, therapeutic evaluation, guiding radiotherapy
and prognosis of NPC, the diagnostic value of PET/CT in residual
and recurrence of NPC and complications after NPC radiotherapy.
1 The value of PET/CT in the diagnosis of NPC
The diagnostic performance of PET/CT is better than conventional
imaging examination such as PET, CT, MRI. Eighty-six cases of
NPC were analyzed retrospectively by Chen et al.[10]
, their result
showed that 18
F-FDG PET/CT, PET and CT accuracy in the
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
diagnosis of NPC were 95.4%, 82.6%, 73.3%, respectively.
Furthermore, the differences between 18
F-FDG PET/CT and either
PET alone or CT alone were statistically significant (P<0.05). The
sensitivity, specificity, accuracy, positive predictive value and
negative predictive value of PET/CT studies for diagnosis NPC
were 96%, 94.4%, 96% and 94.4%, respectively. Gordian et al.
reported that 18
F-FDG PET/CT had sensitivity, specificity,
positive predictive value, negative predictive value and accuracy
of 92%, 90%, 90%, 90%, and 91%, respectively, as compared
with 92%, 65%, 76%, 86%, and 80% for PET, and 92%, 15%,
60%, 60%, and 60% for conventional imaging (CT and MRI)[11]
.
The reports of whole body 18
F-FDG PET/CT scans, performed 43
NPC patients were analyzed retrospectively (Wang et al.), their
results demonstrated that the overall accuracy, specificity,
sensitivity, positive predictive value, negative predictive value of
18F-FDG PET/CT were 95.3%, 100.0%, 85.7%, 93.8%, and
100.0%, respectively, and those of conventional imaging (CT and
MRI) were 65.5%, 79.4%, 64.7%, 81.8%, and 57.9%,
respectively[13]
.
2 The value of PET/CT in the staging of NPC
2.1 The T staging of NPC
18F-FDG PET/CT is benefited in the T staging of NPC. Chen et
al.[10]
compared 18
F-FDG PET/CT, PET and CT in the detect of
primary site of NPC, the T stage was accurately determined in 18
cases out of 20 cases with 18
F-FDG PET/CT. Both PET alone and
CT alone correctly assessed the T stage 15 cases out of 20 cases.
Lin et al.[15]
in the diagnosis of 68 cases of NPC patients indicated
that coincidence rate of 18
F-FDG PET/CT with MR was 95.5%
(65 cases) on lesion. Three cases were clearly displayed by
PET/CT, but not by MRI. However, many studies showed 18
F-
FDG PET/CT in the diagnosis NPC with local invasion such as
skull base, intracranial area, orbital apex, parapharyngeal space
was not so well compared with MRI. Because the high
physiological metabolism of brain and eye muscle affected skull
base, intracranial area, orbital apex show. In addition, soft tissue
resolution and parapharyngeal space invasion of MRI was better
than that of PET/CT. Wu et al.[14]
used 11
C-choline as a imaging
agent in the PET/CT and compared with 18
F-FDG PET/CT. Ten
patients with newly diagnosed and 5 patients recurrent NPC were
enrolled in the study. All of the patients with 11
C-choline PET/CT
were positive, but 13 cases were showed positive and 2 cases of
skull base and intracranial recurrence of NPC patients were
showed negative. The sensitivity of 18
F-FDG PET/CT in detecting
NPC was 86.6%, compared with a 100% sensitivity for 11
C-
choline PET/CT (t=2.143, P=0.483). The SUVmax of lesions
detected was higher using 18
F-FDG than using 11
C-choline
(SUVmax: 6.84±2.76 vs. 12.81±5.00, t=6.416, P<0.001), but the
T/B ratio was much higher for 11
C-choline than for 18
F-FDG
(18.62±7.95 vs. 1.38±0.59, t=8.801, P<0.001). Because 11
C-
choline uptake in normal brain was lower than 18
F-FDG
(0.38±0.09 vs. 10.01±1.90, t=19.68, P<0.001). Compared with18
F-
FDG PET/CT, 11
C-choline PET/CT improved the delineation of
intracranial invasion in 6 of 12 patients, skull base invasion in 4 of
14 patients, and orbital invasion in 3 of 3 patients.
2.2 The N staging of NPC
Neck lymph node metastases was the common clinical symptoms
in patients with NPC. Lee et al.[20]
did a retrospective analysis of
4768 patients, 75.8% of patients were discovered neck lymph
node metastases at initial diagnosis. Chen et al.[10]
had compared
of 18
F-FDG PET/CT, PET and CT on detecting neck lymph node
metastases of the NPC patients, PET/CT was found to be accurate
in 100% (20/20), where PET alone and CT alone accurately
determined lymph node involvement in 20 out of 20 patients
(100%) and 18 out of 20 patients. Hu et al.[8]
conducted a study
which was to compare the diagnostic value of 18
F-FDG PET/CT
with that of MRI in detecting nodal metastasis of NPC. Among the
105 patients, nodal metastasis patterns shown on PET/CT and
MRI were diverse in 35 patients. Thirty cervical nodes were
positive on PET/CT, but negative on MRI. Twenty-five of them
were later confirmed positive by follow-up. Thirty-seven cervical
nodes were negative on PET/CT, but positive on MRI. Twenty-
one of them were confirmed negative by follow-up. Lin et al.[15]
analyzed 68 cases of NPC patients with lymph node metastases
and found
that 39 out of 138 positive lymph nodes whose
diameters were <1 cm and identified by 18
F-FDG PET/CT, which
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
were not assured of positive lymph nodes by MRI, accounting for
28.0% (39/138). Ten patients underwent biopsy on their neck
lymph nodes. Fourteen out of 16 positive lymph nodes detected by
PET/CT were confirmed by pathological examination, while MRI
was not certain about eight lymph nodes and found the other eight
lymph nodes negative. Two cases detected by PET/CT changed its
N staging because of the lock lymph node metastasis. The results
of follow-up a total of 614 lymph nodes in 116 patients were
analyzed by Zhang et al.[21]
showed that the sensitivity, specificity
and accuracy of 18
F-FDG PET/CT in diagnosing node metastasis
were 93.2%, 98.2% and 95.4%, while those of MRI were 88.8%,
91.2% and 89.9%, respectively. Based on above studies, 18
F-FDG
PET/CT was superior to MRI in diagnosing lymph node
metastasis. We should be alert to the false-positive and false-
negative assessment based on 18
F-FDG PET/CT scan findings that
may be caused by retropharyngeal nodes, inflammatory
hyperplastic, large area lymph nodes of necrosis and node in
diameter less than spatial resolution limitation of PET[17, 22-23]
.
2.3 The M staging of NPC
18F-FDG PET/CT had a better diagnostic efficiency in M staging
of NPC. Lin et al.[15]
discovered that 18
F-FDG PET/CT showed the
distant metastases to lung, bone, and liver occurred in eight
patients. The stage of 24 NPC patients was adjusted after PET/CT
scan, among which the stage of 12 patients was adjusted higher
and that of 12 patients was adjusted lower, with a total adjustment
rate of 35.3%, when he analyzed sixty-eight NPC patients. Ng et
al. [17]
found that PET/CT correctly modified M staging in eight
patients (7.2%) and disclosed a second primary lung malignancy
in one patient (0.9%) among the 111 NPC patients. Chua et al.[21]
thought 18
F-FDG PET/CT was superior to PET alone, CT of the
thorax and abdomen, skeletal scintigraphy and conventional
imaging examination comprising chest X-ray, abdomen ultrasound
and bone scanning. The sensitivities and specificities of PET
alone, CT of the thorax and abdomen, bone scanning and
conventional imaging examination were 83.3%, 83.3%, 66.7% and
33.3%, respectively. And the specificities of PET alone, CT of the
thorax and abdomen, bone scanning and conventional imaging
examination were 97.2%, 94.4%, 91.7% and 90.3%, respectively.
The corresponding accuracies were 96.2%, 93.6%, 89.7% and
85.9%. Tang et al.[25]
discovered that 86 cases of the 583 eligible
patients were found to have distant metastases. seventy-one
patients (82.6%) by 18
F-FDG PET/CT were superior to 31 patients
(36.0%) by conventional imaging examination, and 34 cases cases
detected by 18
F-FDG PET/CT accurately up-regulated its staging.
Four cases accurately down-regulated its staging. Recently, some
scholars applied the meta-analysis to evaluate the accuracy of 18
F-
FDG PEC/CT in distant metastases of NPS, the result showed 18
F-
FDG PET/CT had a better diagnostic efficiency than conventional
work-up on detecting distant metastases[26]
.
3 The role of PET/CT in guiding treatment of NPC
3.1 Generation of gross tumor volume (GTV)
Gross tumor volume and the determination scope of the tumor
invasion was the key to radiotherapy of the NPC patients. PET/CT
located biological target volume from metabolism, blood flow,
tissue proliferation, hypoxia, tumor specific receptor,
angiogenesis, apoptosis and so on. In addition, PET/CT had
obvious advantages over CT. It is difficult to generate GTV
according to the conventional imaging examination after
radiotherapy. Zheng et al.[9]
identified that for the remaining 29
patients, GTV based on PET/CT was smaller than GTV based on
CT in 24 (82.8%) cases and was greater in 5 (17.2%) cases. The
target volume had to be significantly modified in 9 of 29 patients,
as GTV based on 18
FDG-PET images failed to be enclosed by the
treated volume in the salvage treatment plan performed based on
GTV based on CT simulation images. But another research result
of Zheng et al.[27]
showed that 39 patients without distant
metastasis proceeded to three-dimensional conformal radiotherapy
planning. Inadequate coverage of the GTVPET/CT and PTVPET/CT by
the PTVCT occurred in 7 (18%) and 20 (51%) patients,
respectively. This resulted in < 95% of the GTVPET/CT and
PTVPET/CT receiving ≥ 95% of the prescribed dose in 4 (10%) and
13 (33%) patients, respectively. Xin et al.[28]
considered simulate
actual treatment in the detachable phantom, including clinical
treatment volume (CTV), tumor treatment volume (GTV), high
metabolic gross treatment volume (FGTV). Its size 10×7 cm, 4×4
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
cm, 2×2 cm, respectively. The CTV put 0.3 cm into PTV. The
radiation dose of PTV, GTV and FGTV were set to 1.8 Gy, 2.0Gy,
and 1.8 Gy, respectively, which would achieve good efficacy.
Therefore, 18
F-FDG PET/CT image-guided dynamic intensity-
modulated radiation therapy (IMRT) is feasible.
3.2 Guiding radiotherapy treatment modality and rescue
therapy
Some radiotherapy modality for NPC may be changed after 18
F-
FDG PET/CT examination. Law et al.[12]
found that forty-eight
patients underwent a staging PET/CT, in which 4 cases (8%) of
NPC changed the primary treatment modality, 12 cases (25%)
changed treatment modality or dose and 32 cases (66%) was no
change in treatment modality. Zheng et al.[9]
discovered that all 33
patients were referred for salvage treatment in the pre-FDG-PET
decision, after knowledge of the FDG-PET results, the decision to
offer salvage treatment was withdrawn in 4 of 33 patients (12.1%),
as no abnormal uptake of FDG was found at nasopharynx.
Spontaneous remission was observed in repeat biopsies and no
local recurrence was found in these 4 cases. Thirty-three patients
with NPC had 45 18
F-FDG PET/CT examinations were analyzed
retrospectively[11]
. In this study, Gordin et al. found that imaging
with PET/CT eliminated the need for previously planned
diagnostic procedures in 11 patients, induced a change in the
planned therapeutic approach in 5 patients, and guided biopsy to a
specifical metabolically active area inside an edematous region in
3 patients.
4 The value of PET/CT in NPC therapeutic evaluation
Assessment of early treatment effect helped to adjust therapy
method and reduce the complications. Lesions of metabolic
reduced before and after radiotherapy, namely the reduction of
18F-FDG uptake were consistent with the pathological changes of
tumor tissue. A study of Lin et al.[29]
was to evaluate the treatment
response of 18
F-FDG PET/CT. The medium SUVmax of primary
tumor lesion was 11.1 (range 3.4-26.9) in 61 NPC patients before
treatment, then, reduced to 3.5 (range 0-8.1) after radiotherapy
with a dose of 50 Gy, and decreased to 3.1 (range 0-8.2) after
radiotherapy. The medium SUVmax of primary tumor lesion was
2.5 (range 0-6.9) one month after radiotherapy (P<0.001). The
medium SUVmax of regional lymph node lesion was 9.3 (range 2.5-
31.5) before treatment, and reduced to 3.1 (range 0-15.8) after
radiotherapy with a dose of 50 Gy, then, decreased to 2.4 (range 0-
7.2) after radiotherapy. The medium SUVmax of regional lymph
node lesions was 1.5 (range 0-5.4) one month after radiotherapy
(P<0.01). The efficacy of 41 NPC patients who underwent 18
F-
FDG PET/CT scan were reported by Xie et al.[30]
. The mean
SUVmax was 7.3 (range 3.2-20.7) before treatment, and the
SUVmax<2.5 of 26 patients with metabolic complete remission
after treatment, the remaining 15 patients’ SUVmax≥2.5. Another
study of Xie et al. reported that the median SUVmax was 8.55
(range 2.8-24.6) in 62 NPC patients before treatment. Fifty-eight
of the 62 patients’ treatment responses were evaluated by 18
F-FDG
PET/CT scan. The post-treatment PET/CT scan did not show any
abnormal FDG uptake (SUVmax<2.5, metabolic complete
response, MCR) in 35 patients, and the remaining 23 patients with
SUVmax≥2.5[31]
. Law et al.[12]
found that PET/CT had higher
negative predictive value than conventional imaging examination
(CT or MRI) that were 93 %, 91%, respectively in 21 NPC
patients, and had fewer equivocal results than MRI.
5 The value of PET/CT in diagnosis of residual and
recurrence of NPC
Radiotherapy of NPC would cause regional tissue radioactive
damaging, mucosal thickening, soft tissue swelling, fibrosis or
scar tissue formation and so on, meanwhile, metastases maybe
occur in other tissues. Correct evaluation of regional and systemic
disease progression was of great significance to prolong survival
and improve life quality. The radiotherapy techniques in
continuous improvement, but the local residual NPC and
recurrence rate were still as high as 10%-30% after
radiotherapy[7,9,30]
, which mainly because NPC tumor cells were
resistant to radiation therapy in the GTV region[32]
. Chen et al. [10]
indicated that the cases of T stage detected by 18
F-FDG PET/CT,
PET, CT were 66, 64 and 62, respectively in sixty-six patients
with residual and recurrence NPC. The cases were 6, 63 and 58 in
N stage and 64, 60 and 60 in M stage, respectively. There are three
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
cases of false-positive lymph nodes, which mainly occurred in
jugular vein and submental lymph node hyperplasia. Thirty-eight
NPC patients with radiotherapy were reported by Yu et al. [33]
. 18
F-
FDG PET/CT scan was a better tool than CT alone for the
detection of recurrence or residue, a litter better than PET alone.
The sensitivity and specificity of 18
F-FDG PET/CT, CT and PET
were 100%, 77.8%, 100%, and 89.5%, 84.2%, 80.0%,
respectively. There are also false-negatives and false-positives
occurred. The false-negative was mainly muscle uptake, while
false-positive was mainly lymph nodes and lung lesions
inflammatory intake. However, some scholars believed that the
accuracy of MRI over PET/CT in detecting residual or recurrent
NPC at the primary site (accuracy rate 92.1% vs. 85.7%)[34]
.
6 The evaluation of PET/CT in prognosis of NPC
SUV was used to reflect glycometabolism of carcinoma, which is
the most common indicator of PET/CT and the most important
indicator of prognosis evaluation of NPC. Some studies indicated
the higher the T staging of NPC, the higher SUVmax[35-36]
. The
worst prognosis was found in patients with the greater SUVmax.
The prognosis would become worse, when SUVmax of lymph
nodes metastasis (SUVmax-N) was higher than SUVmax of primary
lesions(SUVmax-T)[31]
. Chan et al. believed that patients with
SUVmax-T<7.5 and SUVmax-N<6.5 (P=0.042 and P=0.019,
respectively) would have significantly better 2 year DFS[37]
. The
study of Hung et al. [38]
showed that 371 NPC patients with
SUVmax-T<9.3 and SUVmax-N<7.4 had a significantly better 5-
year distant metastasis-free survival (DMFS) (91.1% vs. 84.0%,
and 83.7% vs.78.0%, respectively). The 5-year DMFSs of
SUVmax-T≥9.3 and SUVmax-N≥7.4 group lower than other three
groups (84.3% vs. 94.6%-97.4%) in stage I-III NPC patients. The
5-year DMFSs of SUVmax-T<9.3 and SUVmax-N<7.4 group
higher than other three groups (91.6% vs. 68.5%-82.9%) in stage
IVA-B patients.
In recent years, some scholars found tumour volume (TV) were
positively correlated with T-stage in primary NPC[36]
. Metabolic
tumor volume (MTV) and metabolic index (MI,
MI=MTV×SUVmean) from PET/CT were the semi-quantitative
indicators in the evaluation of the prognosis of NPC[30,39-40]
. NPC
patients having tumors with an MTV< 30 cm3 had significantly
better 5-year overall survival (OS) (84.6% vs. 46.7%, P=0.006)
and disease-free survival (DFS) (73.1% vs. 40.0%, P=0.014) than
patients with an MTV≥30 cm3 were reported by Xie et al.
[30]. And
the patients with MI <130 had significantly higher 5-year OS
(88.0% vs. 43.8%, P=0.002) and DFS (76.0% vs. 37.5%,
P=0.005) than other patients. A study of 196 patients with primary
stage III-IV NPC showed that MI values greater than 330
independently predicted OS (P=0.0014) and DFS (P=0.0005) as
independent predictors of local failure-free survival[39]
. Tang et
al.[25]
analysed that pretreatment N staging and EBV DNA level
were significant risk factors for distant metastases. 18
F-FDG
PET/CT was not superior to conventional imaging examination for
detecting distant metastases in very low-risk patients (N 0-1 and
EBV DNA<4 000 copies/mL, P=0.062), but was superior for the
low-risk patients (N 0-1 and EBV DNA≥4 000 copies/mL, N 2-3
and EBV DNA<4 000 copies/mL, P=0.039) and intermediate-risk
patients (N 2-3 and EBV DNA≥4 000 copies/mL, P<0.001). Fifty-
six NPC transferred patients were reported by Chen et al. [40]
. The
research found that EBV DNA titre>5000 copies/mL (P=0.001),
and MTV>110 mL (P=0.013) were independent risk factors for
progression-free survival (PFS) and OS.
7 The diagnostic value of PET/CT in complications after NPC
radiotherapy
Radiotherapy was the main therapeutic method for NPC.
Meanwhile, temporal lobe, brain stem and cerebellum were
inevitably exposed to radiation field in the treatment, which would
lead to some patients occurred radiation encephalopathy (RE).
Wang et al.[41-42]
found that 18
F-FDG PET/CT demonstrated
anteromedial temporal lobes metabolic significantly decreased in
35 of the 53 NPC patients receiving radical radiotherapy (namely
70 lobes). However, CT displayed normal density in the 25
temporal lobes lesions of the 35 delayed RE patients. And
metabolism of unilateral temporal lobe obviously reduced in 18
cases (18 lobes). The incidence of brain stem metabolic reductions
was 24.5% (13/53) in the investigated patients, including 4
patients with hypometabolic changes shown by PET and negative
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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2014-02 -27 ★ DOI:10.15383/jnpc.2
finding shown by CT. According to the PET/CT imaging finding,
the lesions could be classified as oedema type (56 temporal lobes),
liquefactive necrosis type (10 temporal lobes) and atrophic
calcification type (22 temporal lobe), and the former two types of
lesions may progress into the third type [42]
.
8 Conclusion
In summary, PET/CT play an important role in radiotherapy for
NPC. Correct diagnosis and accurate staging are a prerequisite for
radiotherapy, and target delineation and radiation dose
determination are the key to radiation therapy. The efficacy of
radiotherapy, recurrence and residue of NPC, prognosis judgment
have an important impact on the long-term quality of life and
survival of patients. 11
C-choline PET/CT in the diagnosis of skull
base and intracranial invasion of NPC patients are significantly
better than 18
F-FDG PET/CT. However, there was no good
solution to identify lymph node metastases, inflammatory lymph
nodes, lung micrometastases and inflammatory lesions. The
application of new imaging agents for PET/CT is to be further
researched.
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