Clinical Application Value and Progress of PETCT in Nasopharyngeal Carcinoma

1

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

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

3


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

4


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

5


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

6


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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Clinical Application Value and Progress of PETCT in Nasopharyngeal Carcinoma

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