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There is limited data regarding the role of 18F-Fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs.
[18F]-FDG PET/CT scans were performed at baseline and after six weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. Based on data from other solid tumors, metabolic response was defined as a reduction of [18F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions.
Fifty six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P <0.0001 to 0.0003): sensitivity and specificity for prediction of best response were 95% and 100% respectively. Metabolic responders had significantly longer progression-free survival (median 11.5 vs. 4.6 months, P = 0.044) and a trend towards longer overall survival (median 31.8 vs. 18.4 months, P = 0.14) than non-responders. [18F]-FDG uptake was significantly higher in thymic carcinoma compared with thymoma (P= 0.0004 to 0.0010).
In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [18F]-FDG PET may be used to monitor treatment efficacy and assess histological differences in patients with advanced TETs.
Thymic epithelial tumors (TETs) are the most common malignancies of the anterior mediastinum (1). Based on morphology and atypia of the neoplastic epithelial cells and their relative proportion compared with lymphocytes, the World Health Organization (WHO) classification groups TETs into a continuum of tumors with increasing degrees of aggressiveness: from type A, AB, B1, B2 and B3 to type C (thymic carcinoma) (2). The WHO classification along with the Masaoka staging system, which is based on the integrity of the thymic capsule, degree of local tumor invasion and presence of distant metastases (3), are used to predict the biologic behavior and prognosis of TETs (4, 5).
Types A, AB, and B1 thymoma have an excellent overall survival rate of more than 90% to 95% at 10 years (6). Five-year survival for types B2, B3, and thymic carcinoma are 75%, 70%, and 48%, respectively. Thymic carcinomas account for less than 1% of TETs and display a more aggressive phenotype with higher likelihood of distant metastases compared with thymomas (7).
Commonly used methods for response assessment using computed tomography (CT) and the Response Evaluation Criteria in Solid Tumors (RECIST) have several limitations in the evaluation of TETs (8). Functional response assessment using positron emission tomography (PET) scans with 18F-Fluorodeoxyglucose ([18F]-FDG) has been widely used in the diagnosis, staging, and prediction of response of many solid tumors (9, 10). Such assessments could provide an early, yet accurate assessment of the response to a multi-course therapy and could facilitate therapy modifications. However, given the low incidence of TETs, the utility of PET in these malignancies is not well defined and few clinical studies with [18F]-FDG PET have been conducted.
This study is a retrospective analysis of prospectively collected data, primarily aimed to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with anatomic imaging based response assessment. Other objectives were to evaluate the utility of baseline [18F]-FDG PET and early metabolic response to treatment as predictors of survival, and the association between [18F]-FDG PET assessment and histology.
As part of the clinical protocols, whole body [18F]-FDG PET/CT scans were performed at baseline and early post-treatment in 56 consecutive patients with histologically confirmed, unresectable advanced (Masaoka stage III or stage IV) TETs enrolled in clinical trials at the National Cancer Institute (NCI) between December 2007 and October 2011. Patients had no major surgery, radiation, chemotherapy and biologic or hormonal therapies within four weeks prior to study entry or between imaging sessions. Glucose levels within acceptable limits were reported in all patients without significant changes between [18F]-FDG-PET imaging sessions. All patients had measurable disease, which had a minimum diameter of >10 mm on helical CT scan. Following initial WHO pathological classification, patients with thymoma were stratified into two risk-groups: low-risk (types A, AB, and B1) and high-risk (types B2 and B3) (2, 11). All patients gave written informed consent in accordance with the NCI Institutional Review Board regulations.
Patients who were previously treated for advanced disease with at least one platinum-based chemotherapy were treated with cixutumumab, an insulin-like growth factor receptor 1 (IGF1R) inhibitor (NCT00965250) (12) or belinostat, an histone deacetylase (HDAC) inhibitor (NCT00589290) (13). Treatment was continued until disease progression or development of unacceptable toxicities. Patients untreated for advanced disease received belinostat, with cisplatin, doxorubicin and cyclophosphamide (PAC) (NCT01100944) for up to 6 cycles or until disease progression (14).
Baseline and early post-treatment [18F]-FDG PET/CT were obtained within 28 days prior to starting treatment and at six weeks (± 4.0 days) after starting treatment, respectively. [18F]-FDG PET/CT findings were considered exploratory and not used for treatment decisions. Methodological details of [18F]-FDG PET/CT image acquisition and analysis are provided in Supplementary appendix A.
We calculated four estimates of [18F]-FDG uptake for baseline and follow-up PET scans: a) SUVmax of the single most metabolically active lesion (SUVmax), b) average SUVmax of up to five most metabolically active lesions (SUVaverage), c) ratio of SUVmax of most metabolically active lesion to the mean SUV of the mediastinum (T/Mmax), and d) ratio of average SUVmax of up to five most metabolically active lesions to the mean SUV of the mediastinum (T/Maverage).
Contrast-enhanced helical CT scans of chest, abdomen and pelvis were obtained at baseline and every six weeks to evaluate tumor response based on the RECIST guidelines (15). Patients were followed up yearly for survival status. Progression-free survival (PFS) was defined as the time from treatment initiation to disease progression or death (whichever occurred first). Overall survival (OS) was defined as the time from treatment initiation until death resulting from any cause. For analysis of changes in [18F]-FDG uptake between baseline and early post-treatment scans, the starting times for PFS and OS were the time of the follow-up scan.
The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with anatomic imaging-based response assessment. Metabolic response was defined as a decrease of baseline SUVaverage by more than 30%, based on established guidelines (9). Lack of metabolic response was defined by an increase of SUVaverage or decline from baseline of less than 30%.
Two-group comparisons of quantitative outcomes were made using the exact Wilcoxon rank sum test, and comparisons of three or more categorical factors using the exact Kruskal-Wallis test. Trends in the outcomes across ordered groups were assessed using the exact Jonckheere-Terpstra test (16). Histology distributions and response rates over the treatment groups were tested by the Fisher-Freeman-Halton method (17). The diagnostic accuracy of changes in PET parameters to predict subsequent response was compared by receiver operating characteristic (ROC) curves. Estimation of PFS and OS were performed by the Kaplan-Meier method, and the log rank test of the proportional hazards model was applied to test possible associations with them. Results are from SAS version 9.3 statistical software (SAS Institute Inc., Cary, NC).
Between December 2007 and October 2011, 56 patients were evaluated. Patient characteristics are listed in Table 1. Thymic carcinoma accounted for 39% of cases. Low-risk and high-risk groups accounted for 26% and 67% of thymoma patients, respectively. Eighty seven percent of patients had received prior chemotherapy. The distribution of histologies in the three treatment groups was comparable: 65%, 57% and 60% of patients had thymoma in the cixutumumab, belinostat and PAC/belinostat trials, respectively.
All 56 patients underwent baseline imaging and had abnormal 18F-FDG uptake defined as having at least one lesion with an SUV of more than 2.5 (18). The number of lesions assessed in each patient ranged from 1 to 5 (mean 3.8 ± 1.1). All four of the baseline [18F]-FDG-PET measurements showed no association with the number of lesions assessed (P > 0.40), which demonstrated that the number of lesions could be disregarded in all analyses involving the measurements. Early post-treatment [18F]-FDG-PET was performed in 48 (86%) patients.
Objective response rate [ORR, complete response (CR) + partial response (PR)] in the entire study group was 18%: 26% for thymoma (PR, 8; CR, 1) and 5% for thymic carcinoma (PR, 1). Among the responders for whom baseline and early-post treatment [18F]-FDG PET were available, the duration of treatment prior to RECIST responses were variable (range 2–10 cycles; median 2). Table 2 shows quantitative measures of metabolic activity and overall best response according to RECIST criteria. The relative change in metabolic activity from baseline to early post-treatment [18F]-FDG PET predicted the subsequent best response by RECIST (P values ranging from <0.0001 to 0.0003, Table 2). Moreover, lower early post-treatment metabolic activity was associated with a higher likelihood of subsequent tumor response (P=0.0012 to 0.0037).
The established threshold of 30% for SUVaverage identified patients with eventual RECIST stable or progressive disease with a sensitivity and specificity of 95% and 100% respectively (Table 3). A higher proportion of patients treated with PAC/belinostat had a metabolic response compared with cixutumumab or belinostat: 6/9 (67%) vs. 2/18 (11%) vs. 1/21 (5%), respectively (P=0.0003). Furthermore, we estimated optimal threshold which were observed to have the highest sensitivity and specificity for RECIST response in this data set. All patients who had eventual responses to treatment by RECIST criteria had decreases of 35% or more in the SUVaverage, while only one of the non-responders had a decrease in this range. Using the optimal threshold, the estimated sensitivity and specificity in detecting stable or progressive disease were 97.5% and 100% respectively (Fig 1: area under ROC curve 0.98). Fig 2 shows representative PET images of responding and non-responding tumors.
The estimated median follow up time was 20.9 months (range, 1.4–48.6) for all patients, 19.3 (1.4–48.6) for patients with thymoma and 20.9 (4.3–20.9) for patients with thymic carcinoma. Tumor progression occurred in 30 (88%) patients with thymoma and 21 (95%) patients with thymic carcinoma. Deaths occurred in 11 (32%) patients with thymoma and 18 (82%) patients with thymic carcinoma during the follow up interval. The median PFS and OS were 5.9 and 19.8 months, respectively. Patients with thymic carcinoma had inferior PFS and OS (median PFS and OS 2.7 and 12.2 months) compared with patients with thymoma (7.8 and 35 months; P < 0.0001 for each). There was no difference in PFS or OS between high and low risk groups of thymoma (results not shown).
Compared with non-responders, metabolic responders had an increased PFS (median 11.5 months vs. 4.6 months, P = 0.044) and a trend toward improved OS (median 31.8 months vs. 18.4 months, P = 0.14) using the established SUVaverage threshold of 30% (Fig 3). Similar results were observed using the optimal SUVaverage threshold of 35% (median PFS, 11.5 months vs. 4.4 months, P = 0.024; median OS, 31.8 months vs. 16.5 months, P = 0.062). In the proportional hazards model for PFS including both metabolic response and treatment received as risk factors, treatment was found to have a nonsignificant p value and the association of metabolic response with PFS remained strong (results not shown).
Table 4 shows quantitative measures of metabolic activity at baseline in the histological subgroups. All estimates of baseline [18F]-FDG uptake were significantly higher in the thymic carcinoma compared with thymoma (P 0.0004 to 0.0010). Within the thymoma risk-groups, high risk thymoma had [18F]-FDG uptake similar to low risk thymoma (P > 0.40). A strong association was also found between early post-treatment [18F]-FDG uptake and histology (results not shown).
Survival analyses performed separately for the two histological subgroups and after stratifying for histology showed no association between baseline [18F]-FDG uptake and OS or PFS (P > 0.55 for each). Early-post treatment [18F]-FDG uptake and change in uptake between baseline and early-post treatment also had no association with OS or PFS (P > 0.50).
Despite the growing use of [18F]-FDG PET imaging in oncology (9, 10), limited data exist regarding its utility in monitoring treatment response and predicting survival in advanced TETs (11, 19–31). With a few exceptions (25, 27, 28, 30), most studies in this area have been retrospective, involving small sample sizes and inconsistent measures of [18F]-FDG uptake. Furthermore, the majority of the studies have an over-representation of thymoma compared with thymic carcinoma. There is limited information on its role in monitoring treatment response and as a predictor of survival (20, 23), and we are not aware of prospective systematic studies addressing these questions.
As a retrospective analysis of prospectively collected data, this study demonstrates that in patients with advanced or recurrent TET’s a) effective treatment with chemotherapy or targeted therapy causes rapid reduction in [18F]-FDG uptake, b) early metabolic response predicts eventual RECIST response and is associated with improved PFS, and c) baseline [18F]-FDG uptake correlates well with histology, but is not a predictor of survival after adjusting for histology and cannot differentiate between high and low-risk thymoma.
We observed rapid and significant reductions in metabolic activity with effective treatment in TETs. By contrast, no significant decrease in metabolic activity was seen with treatment that was ineffective. For all estimates of [18F]-FDG uptake, the relative decline in [18F]-FDG uptake with treatment and a lower early post-treatment metabolic activity were associated with higher likelihood of subsequent RECIST response. Our results suggest the utility of [18F]-FDG PET use in monitoring response to treatment in advanced TETs. These results are consistent with observations in several malignancies including breast, esophageal and gastric cancers that early metabolic response to chemotherapy or targeted agents correlated well with the eventual RECIST response (32–34). Decreases in T/M from baseline have been previously reported in a retrospective analysis of four patients with advanced TETs and RECIST partial responses (20). This study, however, was limited by the small number of patients (n=12) and heterogeneity in histology (10 thymic carcinoma, 2 thymoma) and treatment (10 systemic therapy, 2 radiotherapy).
In solid tumors, a decline of metabolic activity of 30% or more with treatment is thought to represent a medically relevant beneficial change (9). However in TETs there is no uniformly accepted treatment metabolic response metrics. Using the established SUVaverage threshold of 30%, we predicted eventual non-responders with a sensitivity and specificity exceeding 95%. Based on highest sensitivity and specificity to predict RECIST responses, we also identified an optimal SUVaverage threshold (35%) to identify metabolic response from our dataset. Notably, the optimal threshold identified for our dataset and the established threshold were remarkably close to each other. Moreover, independent of the treatment, metabolic responders identified using both thresholds had significantly improved PFS and a trend towards improved OS, compared with non-responders. Similar correlations between metabolic response to treatment and improved patient outcomes have been reported in several other malignancies (10).
After adjusting for histological differences, we found no association between tumor metabolic activity and survival. However, consistent with previous reports, our study found higher [18F]-FDG uptake in thymic carcinoma compared with thymoma (11, 22, 23, 28, 29), although, there were no significant differences in uptake among the high and low risk-groups of thymoma. Previous studies have found discordant results on [18F]-FDG uptake among the thymoma risk-groups. Whereas some investigators reported the usefulness of [18F]-FDG PET/CT (11, 23, 24, 28, 30), a marked overlap in uptake among high and low-risk thymomas was also observed (27, 29). Probable contributing factors to the wide range of reported associations include small number of patients in prior reports, difficulties in histological classification of thymomas and inconsistent definitions of risk-groups (19, 21, 24, 26).
In this study we demonstrate the utility of [18F]-FDG PET to monitor treatment efficacy and assess histological differences in patients with advanced or recurrent TETs. In addition to being the largest series of prospectively collected [18F]-FDG PET data, the strengths of our study include a uniform patient population, all having advanced TETs and receiving systemic therapy, even representation of all the major histological groups, availability of long-term follow-up data, and multi-parameter assessment of metabolic changes. Although early assessment of response to treatment can be potentially useful, for example to discontinue an ineffective treatment, it is not yet clear if it can alter treatment and result in beneficial effects on patient outcomes. Further studies are needed to clarify the role of [18F]-FDG PET in patients with TETs in other clinical settings. For example, using [18F]-FDG PET imaging for detection of residual tumor after primary therapy or earlier detection of recurrence in asymptomatic patients may improve outcomes. Achieving new imaging benchmarks in patients with TETs also requires establishment of [18F]-FDG PET protocols that include standardized methods for uptake measurements and thresholds of response.
Limited data exist regarding the role of 18F-Fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) in monitoring treatment and predicting outcomes in thymic epithelial tumors (TET). Studies in this area have been retrospective and have involved small sample sizes and inconsistent measures of [18F]-FDG uptake. In this retrospective analysis of prospectively collected data, we found that effective treatment with chemotherapy or targeted therapy causes rapid reduction in [18F]-FDG uptake in patients with advanced or recurrent TETs. We also observed that early metabolic response predicts eventual RECIST response and is associated with improved progression-free survival. The utility of an early assessment of metabolic response to treatment could be translated to clinical practice wherein patients who do not achieve an early metabolic response could be switched to alternative therapeutic approaches.
Financial Support: Intramural Program, National Cancer Institute, National Institutes of Health
Conflict of interest: None