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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 900-908 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.122 Time Course of Tumor Metabolic Activity During Chemoradiotherapy of Esophageal Squamous Cell Carcinoma and Response to TreatmentFrom the Departments of Nuclear Medicine, Surgery, Radiation Oncology, Pathology, Medicine III, and Diagnostic Radiology, Klinikum Rechts der Isar, Technische Universitaet Muenchen, Munich, Germany Address reprint requests to Hinrich Wieder, MD, Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universitaet Muenchen, Ismaningerstrasse 22, D-81675 Munich, Germany; e-mail: h{at}wieder.de
PURPOSE: To evaluate the time course of therapy-induced changes in tumor glucose use during chemoradiotherapy of esophageal squamous cell carcinoma (ESCC) and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival. PATIENTS AND METHODS: Thirty-eight patients with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) scheduled to undergo a 4-week course of preoperative simultaneous chemoradiotherapy followed by esophagectomy were included. Patients underwent positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) before therapy (n = 38), after 2 weeks of initiation of therapy (n = 27), and preoperatively (3 to 4 weeks after chemoradiotherapy; n = 38). Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUVs). RESULTS: Mean tumor FDG uptake before therapy was 9.3 ± 2.8 SUV and decreased to 5.7 ± 1.9 SUV 14 days after initiation of chemoradiotherapy (-38% ± 18%; P < .0001). The preoperative scan showed an additional decrease of metabolic activity to 3.3 ± 1.1 SUV (P < .0001). In histopathologic responders (< 10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% ± 15%, whereas it was only 21% ± 14% in nonresponders (P = .0055). Metabolic changes at this time point were also correlated with patient survival (P = .011). In the preoperative scan, tumor metabolic activity had decreased by 70% ± 11% in histopathologic responders and 51% ± 21% in histopathologic nonresponders. CONCLUSION: Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.
The prognosis of patients with locally advanced cancer of the esophagus remains poor [1,2]. Neoadjuvant therapy has been shown to improve the prognosis of patients in whom a complete or subtotal histopathologic tumor regression is achieved [3,4]. However, nonresponders appear to have an even poorer prognosis than patients treated with surgery alone [3,4]. Therefore, the need for a test that predicts response before therapy, or early in the course of therapy, is widely acknowledged. After chemoradiotherapy, morphologic imaging modalities (endoscopic ultrasonography [EUS] and computed tomography [CT]) do not reliably differentiate between viable tumor and inflammatory reaction, edema, and scar tissue [5,6]. Positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) has recently been introduced as a new technique for staging esophageal cancer [7,8]. Furthermore, tumor metabolic activity after preoperative chemotherapy or chemoradiotherapy has been shown to correlate well with histopathologic response and patient outcome [9-11]. For chemotherapy of esophageal adenocarcinoma, changes of metabolic activity 14 days after initiation of therapy also have been shown to provide a sensitive means to predict tumor response during therapy [12]. However, chemoradiotherapy generally causes local inflammatory reactions in the esophagus. Uptake of FDG in inflammatory lesions is a commonly known phenomenon [13-15]. Increased FDG uptake caused by radiation-induced inflammation may limit the use of FDG-PET for metabolic measurement in esophageal carcinomas during chemoradiotherapy. Therefore, it has been recommended that FDG-PET should be performed only several weeks or even months after completion of radiotherapy to assess tumor response. However, these recommendations are not based on systematic clinical data, but only on theoretical considerations and a few case reports [16]. Furthermore, there are no systematic studies that have evaluated quantitatively FDG uptake in radiation-induced inflammation. It is not known whether FDG uptake in radiation-induced inflammation is large enough to outweigh the decrease in FDG uptake caused by therapy-induced loss of viable tumor cells. The purpose of this study was to determine the time course of tumor FDG uptake during chemoradiotherapy in patients with esophageal cancer, and to correlate changes in FDG uptake during and shortly after chemoradiotherapy with histopathologic tumor response and patient survival.
Patient Population Thirty-eight consecutive patients (11 women, 27 men; mean age, 60.0 ± 6.8 years) with biopsy-proven, intrathoracic, locally advanced (cT3, cN0/+, cM0) esophageal squamous cell carcinoma scheduled to undergo neoadjuvant chemoradiotherapy at the Klinikum rechts der Isar (Munich, Germany) were included in this study (Table 1). All patients were recruited from a phase II trial of neoadjuvant chemoradiotherapy. The study protocol was approved by the Ethics Committee of the Technical University of Munich and all patients gave written informed consent. Pretherapeutic staging, including endoscopy, CT, EUS, and bronchoscopy, was performed as previously described [10].
Neoadjuvant Chemoradiotherapy External-beam radiotherapy was delivered by two opposed anteroposterior/posteroanterior fields using a 10- to 15-MeV photon beam. Single-dose fractions of 2.0 Gy were applied five times per week to a total dose of 40 Gy. The target volume of radiation therapy was the primary tumor with direct juxtaregional lymph nodes and a 1.5-cm margin in all directions. Concurrently, chemotherapy with fluorouracil was administered as a continuous intravenous infusion for 28 days at a daily dose of 300 mg/m2. Tumor resection was planned 4 to 6 weeks after completion of chemoradiotherapy. Preoperatively, tumor response was assessed by CT and EUS as previously described [12]. In three patients no follow-up CT and EUS studies were performed for response evaluation; these patients were not considered to be surgical candidates because of their poor general medical condition.
PET Imaging Patients fasted at least 6 hours before PET scanning to minimize the blood insulin level and ensure standardized metabolism in all patients. Blood glucose levels were measured before each PET examination. All measured values were less than 150 mg/dL and showed no significant changes during chemoradiotherapy. Emission images covering the area from the neck to the upper abdomen (four bed positions, 7 minutes duration each) were acquired 60 minutes after injection of 300 to 400 MBq using an ECAT EXACT PET scanner (Siemens CTI, Knoxville, TN). This was followed by a transmission scan for attenuation correction. Image data, corrected for dead time and random events, were reconstructed iteratively using attenuation-weighted, ordered-subset, expectation maximization algorithms (eight iterations, four subsets). Reconstructed images were smoothed in three dimensions with a 4-mm Gauss filter. Circular regions of interest with a diameter of 1.5 cm were manually placed over all tumors at the site of maximum FDG uptake in the baseline scan. Standardized uptake values (SUVs) normalized to patients' body weight were calculated from the average activity values in the regions of interest [17].
Surgical Therapy and Histopathologic Response Evaluation
Statistical Analysis
Response Evaluation and Histopathologic Work-Up After chemoradiotherapy, the T stage was unchanged in EUS in 35 of 38 patients. On the basis of a reduction of tumor length and wall thickness, 17 patients were classified as clinical responders and 18 patients were classified as nonresponders. In the 33 patients who underwent surgery, 19 tumors (57%) were classified as histopathologically responding. The T stage was pT3 in 12, pT2 in 11, pT1 in two patients. In eight patients (24%) no viable tumor cells were found at the site of the primary tumor (pT0). In two of these patients microscopic lymph node metastases were found in supraclavicular and infradiaphragmatic lymph nodes, which were well separated from the primary tumor. In one patient with subtotal tumor regression, peritumoral lymph node metastases showed similar regressive changes to those of the primary tumor. In all other patients with histopathologically responding tumors, no viable lymph node metastases were found. There was no significant correlation between clinical response and histopathologic response (P = .06). In particular, seven of 19 histopathologically responding tumors (37%) were classified as clinical nonresponders (Table 1).
Time Course of Tumor FDG Uptake
Diffuse esophageal FDG uptake suggesting esophagitis was only observed in a small number of patients (Fig 2). After 14 days of chemoradiotherapy, this phenomenon was seen in 15% of the patients (four of 27 patients). In addition, diffuse esophageal SUV uptake was low, with a mean SUV of 2.6 ± 0.3. In the preoperative scan diffuse FDG uptake in the esophagus was noted in five of 38 patients (13%). The intensity at this time was 2.8 ± 0.3 SUV.
Correlation of Findings in FDG-PET, Histopathologic Response, and Patient Survival Figure 3 shows typical examples of FDG-PET scans in histopathologically responding and nonresponding patients. The absolute SUV of the tumors at the time of the baseline PET and the PET after 2 weeks of therapy were not significantly different between histopathologic responders and nonresponders (Table 2). However, there was a highly significant correlation between the relative decrease in FDG uptake within 2 weeks after the initiation of chemoradiotherapy and histopathologic response (Table 2). Histopathologically responding tumors (n = 15) showed a decrease in mean SUV by 44% ± 15%, whereas nonresponding tumors (n = 8) showed a decrease by only 21% ± 14% (P = .0055; Table 2). There was little difference between patients with complete response (46% ± 14%; n = 6) and subtotal response (41% ± 15%; n = 9), as well as between those with partial response (22% ± 16%; n = 6) and minimal response (20% ± 3%; n = 2; Fig 4A).
The ROC curve demonstrated that the highest accuracy for differentiation of subsequently responding and nonresponding tumors was achieved by applying a cutoff value of a 30% decrease of baseline FDG uptake (Fig 5). Using this cutoff value, 14 of 15 responding and seven of eight nonresponding tumors were correctly identified, providing a sensitivity of 93% (95% CI, 68% to 100%) and a specificity of 88% (95% CI, 47% to 100%), respectively. Positive and negative predictive values were 93% (95% CI, 68% to 100%) and 88% (95% CI, 47% to 100%), respectively. Changes in metabolic activity after 14 days of therapy also were correlated with the rate of R0 resections. In all patients with a decrease of FDG uptake by more than 30%, an R0 resection was achieved. In contrast, resection was macroscopically or microscopically incomplete in three patients with a decrease in FDG uptake of less than 30% (P = .03).
After a median follow-up time of 33 months, median overall survival for patients with a decrease of FDG uptake by less than 30% was 18 months, whereas it was more than 38 months for patients with a decrease in FDG uptake by more than 30% (P = .011; Fig 6). The corresponding 2-year survival rates were 38% and 79%, respectively. Histopathologic response also was significantly correlated with overall survival. Median survival for patients with histopathologically responding and nonresponding tumors was 18 and more than 38 months, respectively (P = .0035).
There also was a significant correlation between the decrease in FDG uptake from the baseline to the preoperative scan and histopathologic response (P = .011; Table 2). Responders showed a decrease in SUV by 70% ± 11%, whereas nonresponders showed a decrease of 51% ± 21%. However, there was considerable overlap between the group of patients with subtotal response and partial response (Fig 4B). Optimum differentiation between responding and nonresponding tumors was obtained for a threshold value of 52% decrease of baseline FDG uptake (Fig 5). At this threshold value the sensitivity and specificity of FDG-PET was 89% (95% CI, 67% to 99%) and 57% (95% CI, 29% to 82%), respectively. The absolute tumor SUV in the preoperative scan also correlated with response (P = .017; Table 2). By using a threshold value of 3.8 SUV (Fig 5), histopathologically responding and nonresponding tumors could be differentiated with a sensitivity of 95% (95% CI, 74% to 99%) at a corresponding specificity of 50% (95% CI, 23% to 77%). Changes in tumor FDG uptake between baseline and day 14 were a slightly better predictor for histopathologic tumor response than changes in FDG uptake between the baseline and the preoperative PET scan (area under the ROC curve, 0.78 v 0.88; Fig 5). However, this difference was not statistically significant (P = .40). Measurement of absolute FDG uptake at the time of the preoperative scan and changes in FDG uptake from the baseline to the preoperative scan provided a similar diagnostic accuracy for assessment of histopathologic response (area under the ROC curve, 0.80 v 0.78).
This study demonstrates that chemoradiotherapy of esophageal cancer causes a rapid and continuous decrease of tumor glucose use. FDG uptake in radiation-induced esophagitis was observed in less than 15% of the scans and its intensity was low compared with tumor FDG uptake. Early changes in tumor metabolic activity after 14 days of therapy allowed us to predict subsequent histopathologic tumor response with a sensitivity and specificity of 93% and 88%, respectively. Furthermore, the decrease of metabolic activity at this time point was significantly correlated with overall survival. Several studies have suggested that FDG-PET may provide new means to assess tumor response and to predict patients' prognosis during and after chemotherapy and radiotherapy [9-12,23-27]. However, there is no consensus relating to the time points FDG-PET should be performed to achieve a most accurate assessment of tumor response. Therefore, we performed FDG-PET at several time points during and after chemoradiotherapy and determined changes in FDG uptake by tumor and normal tissues. In a pilot phase of the study, six patients were examined before chemoradiotherapy, immediately after completion of chemoradiotherapy, and 3 to 4 weeks later (preoperatively). In these patients we observed a 59% decrease of baseline metabolic activity immediately after completion of chemoradiotherapy. However, in the following weeks, there was no additional decrease of FDG uptake. Therefore, the protocol was modified and the patients were scheduled to undergo the second PET examination 14 days after the beginning of therapy. Increased FDG uptake in radiation-induced inflammation has been observed in case reports and systematic studies in a small number of patients [28,29]. However, it has also been reported that focal FDG uptake after chemoradiotherapy is a specific sign of viable tumor tissue in patients with esophageal [9-11] as well as head and neck cancer [27]. These discrepant findings are probably related to the complex proinflammatory and anti-inflammatory effects of radiation, which are strongly dependent on time and dose. Therefore, it is conceivable that cytotoxic effects of radiotherapy on radiosensitive cells such as lymphocytes limit the intensity of inflammatory reactions in the tumor tissue during and early after completion of therapy. Irrespective of the underlying mechanism, our study indicates that chemoradiotherapy with a radiation dose of 40 Gy and fluorouracil as a continuous infusion only mildly affects FDG uptake in normal esophageal tissue during and early after completion of therapy. On the basis of in vitro experiments, it has been hypothesized that radiotherapy causes increased glucose use of tumor cells because of activation of repair mechanisms [30]. However, in our study tumor FDG uptake decreased in all patients during and after chemoradiotherapy. Therefore, in vivo stress reactions induced by chemoradiotherapy seem to be less relevant for tumor FDG uptake than the therapy-induced reduction of viable tumor cells. In accordance with previous data in head and neck and esophageal cancer [9,10,27], the specificity of FDG-PET to detect histopathologic response 3 to 4 weeks after completion of chemoradiotherapy was relatively low in our study. This suggests that there may be a so-called stunning of tumor cells after chemoradiotherapy that is not correlated with tumor cell viability. In addition, the number of viable tumor cells may be too small to be detected by FDG-PET even in some of the histopathologically nonresponding tumors. In accordance with several previous publications, histopathologic response was defined in our study as no viable tumor cells or less than 10% viable tumor cells in the resected specimen [10,18-20]. Thus, even in nonresponding tumors, the number of tumor cells may decrease by up to 90%, resulting in a corresponding decrease of FDG uptake. Nevertheless, the relatively small amount of residual tumor tissue may lead to recurrence and poor prognosis. In accordance with this hypothesis, we only observed false-positive findings in patients with partial tumor response, indicating significant therapy-induced fibrosis (Fig 4B). Remarkably, we observed a trend that changes in metabolic activity after 14 days of therapy were more specific for histopathologic response than were changes after completion of therapy. This unexpected finding may be related to the kinetics of radiation-induced cell death. It is generally assumed that cell killing during radiotherapy can be approximated by a first-order kinetic model, with a given radiation dose killing a fixed fraction of the tumor cells. According to this fractional kill hypothesis, large absolute changes in the number of viable tumor cells must occur early in the course of therapy to achieve a complete or subtotal tumor response. In tumors with only minimal or partial tumor response, the decrease in the absolute number of viable cells at the beginning of therapy should be markedly lower, making it feasible to differentiate between responding and nonresponding tumors on the basis of changes in FDG uptake. However, after completion of chemoradiotherapy the number of tumor cells may decrease by up to 90% even in histopathologically nonresponding tumors. Accordingly, the differences in the absolute number of viable tumor cells for histopathologically responding and nonresponding tumors may be relatively small at this time point, thereby limiting the accuracy of FDG-PET for assessment of response. Thus, PET imaging during therapy may be preferable to imaging after completion of therapy. Given the limited spatial resolution of FDG-PET, it is often not possible to differentiate peritumoral lymph node metastases from the primary tumor. However, viable peritumoral lymph node metastases were found at surgery in only one patient with a histopathologically responding tumor. These metastases showed regressive changes similar to those in the primary tumor. Therefore, FDG uptake by lymph node metastases did not interfere with the analysis of the primary tumor. In accordance with previous studies, the accuracy of routine EUS and CT to assess tumor response was low in our study [31]. Measurement of changes in tumor cross-sectional areas or volumes may allow a more accurate assessment of histopathologic response by these techniques. However, this study was not designed as a comparison of FDG-PET and morphologic imaging techniques for assessment of tumor response. Such a comparison will require studies in a larger number of patients and the use of more sophisticated techniques for the analysis of CT and EUS data sets [32]. In this study, only standard techniques for data acquisition and analysis were used to measure changes in tumor metabolic activity during chemoradiotherapy. Therefore, it seems feasible to use our protocol for data acquisition and analysis with almost every PET and PET-CT system [33]. Nevertheless, several factors (for example, the interval between FDG injection and data acquisition) are likely to influence the results of the quantitative data analysis. Standardization of image acquisition protocols, methods for data analysis, and criteria for definition of tumor response will be crucial to the clinical use of FDG-PET for monitoring chemoradiotherapy. The clinical use of FDG-PET for prediction of response to chemoradiotherapy also requires confirmation of the results of this study in a larger number of patients to narrow the CIs for the sensitivity and specificity of FDG-PET to predict tumor response. Nevertheless, the excellent correlation among early changes in tumor metabolic activity, subsequent histopathologic tumor regression, and patient survival suggests that FDG-PET may provide a new means to individualize chemoradiotherapy in patients with esophageal cancer.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the last 2 years: Markus Schwaiger, CTI/Siemens.
We acknowledge the effort of the cyclotron and radiochemistry staff. We appreciate the excellent technical support by the technologists at our institution. We thank J. Fessler, PhD, University of Michigan, for generously providing the software for the iterative reconstruction of the PET studies.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) Changes in FDG uptake from the baseline scan to the scan after 14 days of chemoradiotherapy; (•) changes in FDG uptake from the baseline to the preoperative scan; (
) preoperative FDG uptake.
