The Value of 18F-FDG PET/CT in avoiding overtreatment of 131l Avidity Pulmonary Metastasis of Differentiated Thyroid Cancer

Background: We usually use 131 I whole body scan and serum thyroglobulin (Tg) values to determine whether differentiated thyroid cancer (DTC) patients need to receive 131 I treatment, but not all 131 I-avid (functioning) patients have good responses, which is more likely to cause the 131 I-avid patient to receive overtreatment. Our study aims to assess the date of 18 F-FDG PET/CT to avoid 131 I overtreatment and research the status of 131 I-avid pulmonary metastases (PMs) and the prognosis of the patients. Methods: The 131 I-avid PMs of DTC patients who underwent 18 F-FDG PET/CT scans were included. The SUVmax (maximum standardized uptake value), MTV (metabolic tumour volume) and TLG (total lesion glycolysis) were used to estimate 18 F-FDG uptake. The mean follow-up period was 34.14 ± 18.64months. Progression-free survival (PFS) was estimated by the Kaplan-Meier method.The study was based on per-patient and per-lesion analyses. Results: Among the 42 included patients, 34 (34/42, 81%) showed 18 F-FDG uptake, which was dened as abnormal foci (SUVmax >1.0) in the lungs. SUVmax, MTV and TLG and tumour size were the factors that inuenced the outcome of 131 I treatment based on Tg levels (p=0.000,0.016,0.000,0.000). The only independent factor was the size of the lesion. There was a signicant difference in response to 131 I therapy between PMs with F-I+ and F+/I+ according to both Tg levels and RECIST (version 1.1) (p= 0.044,0.001), according to the per-lesion analysis. When the changes in size or metabolism of some lesions are inconsistent with therapeutic ecacy of patients, it indicates that these patients have a poor prognosis (P=0.003). Conclusions: We concluded that higher 18 F-FDG uptake and larger tumour size predict poor therapeutic effects


Background
The lungs are the distant organs that most frequently have metastases from differentiated thyroid cancer (DTC), for these patients, 131 I therapy has become the main treatment, especially in patients with 131 I-avid (functioning) pulmonary metastases (PMs) [1] . The result of 131 I-whole body scan ( 131 I-WBS) and serum thyroglobulin (Tg) values are usually used to determine whether DTC patients need to receive 131 I treatment. However, not all 131 I-avid PMs have good responses to 131 I therapy, and more than 10% of them developed into refractory iodine diseases [2] . In this way, it is more likely to cause the 131 I-avid patient to receive overtreatment. Therefore, it is particularly important to screen out 131 I-avid patients who are not sensitive to 131 I treatment and nd new indicators that predict the e cacy. Nowadays, with the popularity of 18 F-uorodeoxyglucose (FDG) PET/CT, its application in DTC patients has also increased.
The accumulation of FDG in malignant tumours, to a certain extent, re ects the degree of differentiation of the tissue [3,4] , so 18 F-FDG PET/CT imaging can be used to predict the effect of 131 I treatment of patients with 131 I-avid PMs from DTC and the prognosis of them. Moreover, the status of FDG uptake in different metastatic lesions could be different even in an individual [5][6][7] , and these changes of morphology and metabolism are closely related to the e cacy of 131 I treatment and prognosis of patients. Therefore, in this study, we assessed the value of 18  PMs were positive for iodine uptake; (c) more than one course of 131 I treatment after the diagnosis of PMs; (d) only measurable soft tissue components on CT, as de ned by the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) [8] . The Shanghai Jiaotong University, Medical School A liated Xinhua Hospital Review Board approved this retrospective study.
The diagnosis of PMs was established according to one of the following criteria: (a) the lung lesion was histologically proven; (b) 131 I uptake on more than one 131 I-WBS with elevated thyroid stimulating hormone (TSH) and increased Tg levels.
Therapeutic approach and follow-up schedule All patients were instructed to follow a low-iodine diet for at least 3-4 weeks before 131 I treatment. TSH levels were 85.03±35.37 µIU/ml after stopping levothyroxine (L-T4) for 3-4 weeks. L-T4 therapy was administered 72 h after 131 I treatment.
Adult patients with 131 I-avid PMs of DTC were treated with a high activity dose of 131 I every 3-12 months. For children aged 10-18 years old, 4.625-7.4 GBq 131 I was administered, and for children aged 5-10 years old, 2.775-4.44 GBq 131 I was administered every 6-12 months. The cumulative activity of 131 I ranged from 3.70-75.85 GBq. The number of 131 I therapies ranged from 2-15 cycles (mean 4.5 cycles).
The mean follow-up period was 44.7±16.0 months.

Criteria of remission
Tumour size evaluation on anatomical imaging The CT images of 18 F-FDG PET/CT were obtained with a 3 mm slice thickness and reconstructed with a 1 mm slice thickness starting from the apex of the lungs. All CT images were obtained with the patient in Page 4/15 the supine position. The CT images were reviewed in consensus by two radiologists who were blinded to the 18 F-FDG PET results and clinical follow-up data.
The CT responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) as follows: (i) Complete response (CR), disappearance of all lesions; (ii) Partial response (PR), ≥30% decrease in the sum of lesion diameters, taking the baseline sum of diameters as the reference; (iii) Progressive disease (PD), ≥20% increase in the sum of lesion diameters or appearance of ≥1 new lesion; and (iv) Stable disease (SD), neither su cient shrinkage to qualify for PR nor su cient increase to qualify for PD. CR, PR, and SD were considered good responses to 131 I therapy in this study.

Tg evaluation
Tg and anti-thyroglobulin antibody (TgAb) levels were obtained before 131 I administration using a timeresolved immuno uorometric assay (Anytest, Symbio Lifescience Co., Ltd., Shanghai, China). After all courses of 131 I therapy were administered, we compared the Tg levels of each treatment and at the last follow-up were classi ed into three categories [9] : i) Effective: a reduction of >25% in Tg levels; ii); Stable: decreased or increased Tg by<25% and iii); Progression: Tg increased by >25%. Effective and stable were considered good responses to 131 I therapy in this study.
Images acquisition and analysis 18 F-FDG PET/CT imaging After 3-4 weeks of thyroid hormone withdrawal (THW), patients with PMs were admitted to our department. On the 1st day after admission, 18 F-FDG PET/CT scans together with other conventional assessments, including physical examination, serum TSH, serum-stimulated Tg, and serum TgAb, were performed. On average, the patients' TSH was 85.03±35.37 µIU/ml when the scans were performed. 131 I treatment was performed on the 2nd day after admission. A 131 I post-therapy scan was acquired 3 days after 131 I oral administration.

Per-lesion imaging analysis
For each patient, a maximum of ve lesions with 18 F-FDG uptake were studied. The lesions had to be measurable on the CT scan of the 18 F-FDG PET/CT. The SUVmax of each lesion (SUVmax/lesion) was measured by using a volume of interest with a standardized uptake value (SUV) expressed using the most commonly used de nition of SUV (g/mL) = (tissue activity (Bq/mL)/ [(injected activity (Bq)/ body weight (g))]. The 18 F-FDG metabolic tumour volume of each lesion (MTV/lesion), representing the volume measured in the volume of interest, was determined using margin thresholds set at 40% of the maximum SUV (SUVmax). Total lesion glycolysis (TLG/lesion) represents the 18 F-FDG metabolism in a given lesion and is obtained by multiplying the SUVmean by MTV.

Per-patient imaging analysis
The SUVmax/patient represents the highest SUVmax of all lesions in a given patient. The MTV of each patient (MTV/patient) represents the volume of all lesions with 18 F-FDG uptake for a given patient and is calculated by adding the metabolic tumour volumes of all lesions present in that patient. The TLG of each patient (TLG/patient) represents the sum of the 18 F-FDG metabolism of all lesions in a given patient.
Statistical analysis SPSS version 22.0 was used for statistical analyses. Continuous data are expressed as the mean ± standard deviation; categorical data are presented as frequency and percentage. Continuous data were analysed using independent samples t-tests and rank tests, and categorical data were analysed using Pearson`s chi-square test. All the factors that may have affected Tg and anatomical imaging of the PMs were analysed by univariate analysis and con rmed by the chi-square test. Logistic regression was performed for multifactor analysis. Spearman correlation and Pearson correlation were used to detect the correlations between categorical variables and continuous variables. Progression-free survival (PFS), as measured by the time between the date of the diagnosis of PMs and the date of disease progression according to RECIST, version 1.1, was the primary endpoint of this study. The effect of different variables on PFS was estimated by Kaplan-Meier survival analysis. A p value of less than 0.05 was considered statistically signi cant.

Patient characteristics
The patient characteristics are listed in Table 1 .217) and TLG/patient (1.74±0.67, P=0.109) were not the factors that in uenced the outcome of 131 I treatment, and the same results were found with CT response (P=0.493,0.128,0.113). We divided the PMs into 2 subgroups according to the 18 F-FDG and 131 I-avid results: (1) 18 F-FDG-negative and 131 I-positive PMs (F-I+, n =8); and (2) simultaneous accumulation of 18 F-FDG and 131 I (F+/I+, n =34); however, there was no signi cant difference in response to 131 I therapy between the two groups according to both the Tg levels and RECIST (version 1.1) (p= 0.306,1.000), see Table 2.  Table 3. In the subgroup analysis, a signi cant difference in response to 131 I therapy was found between PMs with F-I+ and F+/I+ (p= 0.044,0.001) according to RECIST (version 1.1) and Tg levels, see Table 2.

Per-lesion analysis
Because the status of different metastatic lesions, including size and 18 F-FDG uptake, could be different even in an individual, we observed changes in the lesions and then analysed the relationships between these changes and e cacy. According to RECIST, we usually used the sum of the diameters of all target lesions as the basis for evaluating patients' therapeutic e cacy, but in this study, we found that the changes in size or metabolism of individual lesion was not always consistent with therapeutic e cacy based on RECIST. For example, 131 I therapy showed good responses in a given patient, however, an increasing metabolism of the lesion could still be observed, see Figure 1. Accordingly, we further divided the patients into two groups: (1) the changes of size and metabolism in all lesions were consistent with patients' therapeutic e cacy (group consistency, n=31); and (2) the changes of size and metabolism in all lesions were inconsistent with patients' therapeutic e cacy (group inconsistency, n=11). In the consistency VS inconsistency comparison, we found a signi cant difference between the two groups in response to 131 I therapy (P=0.003).

Survival
The median progression-free interval (PFI) of these DTC patients with PMs was 62 months (ranging from 6 to 69 months). The Kaplan-Meier survival analysis showed that there was a signi cant difference in survival between the consistency and inconsistency groups (P=0.009), but no signi cantly differences were seen between the 18 F-FDG-positive and 18 F-FDG-negative groups (P=0.966), see Figure 2.

Discussion
According to our study, the effective rates of 131 I treatment for DTC with lung metastasis was 81% and 90%, based on Tg levels and RECIST respectively, which were higher than the levels reported in the literature [10,11] . This is related to the fact that we only included iodine-avid PMs' patients. Compared with those evaluated PD based on RECIST, slightly more patients were evaluated ine ciency based on Tg levels. This may show that factors about function of the lesion change earlier than the morphology, and it is important to nd markers predicting the status of 131 I uptake by metastatic lesions, which are desirable for timely changing therapeutic regimen. With the rapid growth of thyroid cancer morbidity [12] , 18 F-FDG PET/CT scans can provide a valuable diagnostic method about functional changing [13] . 18 F-FDG-avid tumours tend to be more aggressive in behaviour [14][15][16] . On the other hand, the reproducibility of CT measurements is known to be lower than the reproducibility of 18 F-FDG calculations. Therefore, 18 F-FDG PET/CT is a powerful tool for assessing DTC.
In the per-patient analysis, we evaluated 18 F-FDG avidity by SUVmax, MTV, TLG [9,16] , however, in our study, these factors had no clear signi cance for predicting the 131 I treatment effect of 131 I-avid PMs. We also did not nd a correlation between SUVmax/patient and PFS. This may be related to the limited number of patients or the shorter follow-up time. And as shown in our study, 81% (34/42) of patients showed simultaneous 18 F-FDG and 131 I uptake. The high proportion of 18 F-FDG-positive lesions demonstrated by our study may be due to all of the lung lesions that were measurable on chest CT. 18 F-FDG metabolism patterns are related to the size of the lesions [17] ; the larger the lesion is, the higher its 18 F-FDG uptake. Some of our patients also had extrapulmonary metastases, which may have more aggressive growth than PMs alone [18] . On the other hand, the high 18 F-FDG uptake maybe implicate that the clinical signi cance of this ip-op phenomenon has not been fully de ned [19,20] .
In the per-lesion analysis, 18 F-FDG uptake was related to age, sex, diameter of lesion and TSH level. 18 F-FDG PET/CT may be more useful in older patients, females, patients with larger PMs, or patients with high TSH values. The SUVmax, MTV, TLG and the size of the tumour were proven to be signi cant factors for the e ciency of 131 I treatment according to Tg levels. It is considered that 18 F-FDG-avid tumours tend to be less differentiated and more aggressive than those with low 18 F-FDG uptake [9] . In the subgroup analysis, the treatment for lesions with simultaneous 18 F-FDG and 131 I uptake had poor e ciency. Several reasons may account for this phenomenon: rstly, this may imply that the lesions are partially dedifferentiated, which is prone to happen during the process of metastasis or 131 I treatment [21,22] ; in addition, it may also be related to the diameter of the lesion, which is positively correlated with 18 F-FDG uptake. The longer the diameter of the lesion, the more 131 I treatment are required [11,23] . The above factors cause that the absorbed dose fails to eliminate the lesion completely. Some studies have shown that 18 F-FDG-avid metastases of DTC with or without 131 I uptake are resistant to 131 I therapy [10] , which is in line with our research. Therefore, FDG-avid lesions are seldomly eradicated by radioiodine therapy alone, it should be considered for close monitoring and other options, such as surgery or external radiation. However, the only independent in uencing factor was the size of the lesion. This may be related to interference from other factors.
Considering the multicentricity and polyclone of DTC, the status of different metastatic lesions could be different even in an individual [5][6][7] . In this study, we found that the changes in size or metabolism in some lesions were not consistent with the changes in therapeutic e cacy of some patients. Although some patients can achieve CR, PR or SD, they still have some lesions that show tendency to progression.
We can also conclude that these patients have poor prognosis through subgroup analyses. This phenomenon shows that some lesions exhibit different degrees of differentiation in a given patient.
These lesions may progress and affect the patient's response to 131 I treatment. Therefore, when we evaluate the therapeutic e ciency of patients, lesion-based analyses and quantitatively assessing the data of 18 F-FDG PET/CT using SUVmax, MTV, TLG to predict 131 I-avidity for metastatic DTC would be more reliable than qualitative per-patient evaluation only. The 18 F-FDG uptake PMs may show resistant to 131 I treatment, and these lesions may lead to a poor prognosis for the patient. Thus, tailored treatment modalities should be chosen for the lesions which have a malignant tendency, after balancing the toxicity of systemic treatment. This approach will effectively improve the patient's response to treatment and avoid the 131 I overtreatment of patients.
The limitations of our study are that it was a retrospective study with a relatively short follow-up period (less than 10 years). The number of patients was limited in the evaluation of 131 I therapeutic effects in the subgroup analysis. Moreover, the partial volume effect and respiratory motion can also signi cantly in uence the perception of 18 F-FDG uptake.    Abbreviations: SUVmax: maximum standardized uptake value; MTV: metabolic tumor volume; TLG: total lesion glycolysis. Figure 1 A 42 years old woman with 131I-avid metastases from papillary thyroid cancer (T4aN1M1). She was evaluated as PR based on RECIST (version 1.1) after 131I treatment. However, comparing the 18F-FDG PET-CT before (a) and after (b), we can still see the lesion in the lower lobe of the left lung, and its SUVmax is increasing than before (SUVmax=0.81, 2.81).