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© 2003 American Society for Clinical Oncology Whole Body 18FDG-PET and the Response of Esophageal Cancer to Induction Therapy: Results of a Prospective Trial
From the Thoracic Service and Gastric and Mixed Tumor Service, Department of Surgery, Division of Nuclear Medicine and Division of GI Radiology, Department of Radiology, Division of Gastrointestinal Oncology, Department of Medicine, Department of Epidemiology and Biostatistics, Department of Radiation Oncology, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; National Cancer Center, Singapore General Hospital, Singapore; and Division of Thoracic Surgery, Toronto General Hospital, Toronto, Ontario, Canada. Address reprint requests to Robert J Downey, MD, Division of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: downeyr{at}mskcc.org.
Purpose: Whole-body 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) imaging before and after induction therapy was prospectively evaluated in patients with esophageal cancer to determine whether changes in PET images could measure response to therapy. Patients and Methods: Between April 1997 and April 1999, 39 patients (34 men and five women; median age, 59 years; range, 36 to 76 years) with esophageal cancer were prospectively enrolled in a single-institution clinical trial of staging, including PET, induction therapy, restaging including PET, and esophagectomy. All patients undergoing esophagectomy after induction therapy (n = 17) were followed either to recurrence, to death, or through a disease-free interval of at least 24 months. Results: PET after standard staging studies and before therapy imaged undetected sites of metastatic disease in six patients (15%). Restaging (including PET) after induction therapy did not identify any patients with disease progression or any patients with loco-regionally unresectable disease at exploration. The median decrease in the standardized uptake value (SUV) during induction therapy was 59%. After R0 esophagectomy, the 2-year disease-free and overall survival was 38% and 63%, respectively, among patients who had a less than 60% decrease in SUV, and 67% and 89%, respectively, among patients who had a greater than 60% decrease in SUV (P = .055 and P = .088, respectively). Conclusion: Compared with conventional imaging, PET detects additional sites of metastatic disease at initial evaluation. After induction therapy, PET did not add to the estimation of loco-regional resectability and did not detect new distant metastases. However, changes in [18F]FDG PET may predict disease-free and overall survival after induction therapy and resection in patients with esophageal cancer. Further evaluation in larger trials is warranted.
HISTORICALLY, IN the United States, the overall 5-year survival of patients with newly diagnosed esophageal carcinoma is 12%, primarily because most patients present with advanced disease. Resection of stage II or III disease is associated with 5-year overall survival rates of 34% and 15%,1 respectively. Because of these poor survival figures, recent efforts have focused on developing effective combined-modality regimens, especially chemoradiotherapy followed by surgery. In phase II studies,2 a median survival rates of 29 months and a 5-year survival rates of 34% in treated patients has been reported. One randomized trial of induction chemoradiotherapy followed by surgery compared with surgery alone found that combined-modality therapy significantly improved overall survival (32% v 6%; P = .01).3 However, two other studies,4,5 did not show that preoperative chemoradiotherapy improved overall survival after esophagectomy. Taken together, these studies indicate that if an advantage to induction therapy and surgery exists, then patients who experience a significant pathologic response to treatment are those most likely to benefit,4,5 in that treatment response at the primary site implies treatment of occult micrometastases. Thus, a modality that accurately assessed response to treatment might allow stratification of patients according to the likelihood of benefiting from surgery. However, currently available noninvasive imaging modalities, such as computed tomography (CT) and endoscopic ultrasound, do not reliably correlate with pathologic response,6 and the most accurate method of determining treatment effect has been esophagectomy. 8F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET), an emerging imaging technology based on differences in glucose uptake between neoplastic and surrounding normal tissue, has improved the accuracy of clinical staging of untreated esophageal cancer by detecting otherwise occult metastases.7,8 The metabolism of FDG by both normal and malignant tissues is altered by cytotoxic treatment. It is not known, however, whether the changes in FDG uptake observed between studies performed before and after treatment will reflect true treatment effect. To assess the utility of PET in measuring the response of esophageal cancer to combined-modality treatment, a prospective single-institution clinical trial of staging including PET, induction therapy, restaging including PET, and esophagectomy was performed. The study objectives were, first, to determine whether whole-body [18F]FDG PET can quantitate response to induction therapy in patients with esophageal cancer by correlating changes in PET with disease-free and overall survival rates after esophagectomy and, second, to evaluate the ability of PET to uncover distant disease sites undetected by current imaging modalities before and after induction therapy.
Study Design This study was a single-arm, prospective, single-institution clinical trial approved by the institutional review board of Memorial Sloan-Kettering Cancer Center (MSKCC). Written informed consent was obtained from all patients. Patients were eligible for participation if they were 18 years of age or older, had a pathologic diagnosis of untreated carcinoma of the distal two thirds of the esophagus confirmed by the MSKCC Pathology Department, and were, by standard radiographic and endoscopic evaluation, felt to be acceptable candidates for induction therapy followed by resection. After conventional staging, patients underwent PET imaging, then induction therapy, followed by repeat CT and PET imaging. The choice of induction therapy regimen was at the discretion of the treating physician. Patients who had stable or responding disease were then explored for possible esophagectomy.
PET Imaging Methods
Data Review
Statistical Methods
Clinical Results Between April 1997 and April 1999, 184 patients underwent esophagectomy for esophageal cancer at MSKCC. During this time period, 39 patients (34 men and five women) with a median age of 59 years (range, 36 to 76 years) met the eligibility criteria and were enrolled onto the study. The protocol schema is shown in Fig 1  . The primary tumor was histologically classified as adenocarcinoma in 26 patients and squamous-cell carcinoma in 13 patients. Induction chemotherapy in 26 patients was concurrent paclitaxel/cisplatin (Bristol Meyers Squibb, Princeton, NJ) and 50.4-Gy radiation therapy (RT); two patients received paclitaxel/cisplatin alone. Seventeen patients (14 with adenocarcinoma and three with squamous-cell carcinoma) underwent R0 esophagectomies; all 17 had been treated with concurrent Taxol/CDDP and RT (50.4 Gy). Of these 17 patients, four were found to have pathologic complete responses at the primary site; the pathologic T stage in the other 13 patients was T1 in four patients, T2 in five patients, and T3 in four patients. The N stage was N0 in 12 patients and N1 in five patients. The sites of recurrence after R0 esophagectomies were the mediastinum in four patients; bone in two patients; lung and mediastinum in one; and one of each in the skin, brain, lung, and pleura. The median follow-up for all 39 patients was 27 months (range, 1 to 56 months), and it was 39 months (range, 26 to 56 months) for surviving patients. All patients who completed induction therapy and had an R0 esophagectomy were followed either to death or, if disease-free, for a median of 32 months (range, 25 to 45 months).
PET Results Preinduction Therapy There was no correlation between the initial SUV and survival in the entire group of 39 patients when they were considered together without regard to treatment (P = .5). Of the 39 study patients, six (15%) had distant M1 disease sites identified by preinduction PET that had not been detected by conventional imaging but that were confirmed either by biopsy or by other imaging techniques. The sites of M1 in these six patients were supraclavicular lymph node (one), liver (one), bone (one), retoperitoneal or pelvic lymph nodes (two), and liver and supraclavicular lymph node (one). Another patient who was found to have splenic lymphoma underwent splenectomy and esophagectomy without induction therapy. Four other patients either withdrew from the study at this point or opted for surgery without induction therapy.
PET Results Postinduction Therapy
Change in PET Imaging Results
The median decrease in SUV in patients undergoing R0 esophagectomy was 59% (range, 13% to 88%). Graphic representation of the disease-free and overall survival of patients undergoing esophagectomy stratified by percentage change in SUV above or below the median 60% decrease is displayed in Figs 2
The positron-emitting 18F-labeled analog of 2-deoxyglucose, 2-[18F]-FDG (FDG), is preferentially transported into tumor cells because of elevated levels of type I or type II hexose transporters.10 Once in the cell, FDG undergoes phosphorylation to FDG-6-phosphate and is selectively retained because of low levels of glucose-6-phosphatase, which degrades FDG-6-phosphate. The amount of FDG uptake into malignant cells has been shown to correlate with growth rate.11 The metabolism of FDG by both normal and malignant tissues is significantly altered by antineoplastic treatments. Malignant tissue may have reduced FDG activity because of both cell death and lowered metabolism. In contrast, the surrounding normal tissues can have increased FDG uptake because of inflammation, with both increased influx of metabolically active WBCs and increased vascular permeability to FDG. Given these confounding factors, there have been concerns that the changes in FDG uptake seen between PET images performed before and after treatment may not reflect true treatment effect. However, early studies in patients with glial12 or other13,14 brain tumors, locally advanced breast cancer,15–17 or colon cancer18 showed a significant correlation between changes in PET images and treatment effect by other imaging and pathologic measures. Other studies indicate that changes in PET images during treatment not only correlate with response but also may predict the risk of local recurrence and of death. Berlangieri et al19 described six patients undergoing chemoradiation for head and neck malignancies; all six patients had marked decreases in FDG uptake during treatment and all were without evidence of recurrent disease at 25 months of follow-up. Romer et al20 described 11 patients with lymphoma in whom the changes in the metabolic rates of FDG during treatment correlated with relapse rates over 16 months of follow-up. Three recent publications21,22,34 have explored the utility of FDG-PET in assessing the response of esophageal cancer to induction therapy. A recent abstract21 described 38 patients with esophageal cancer who were studied with whole-body PET before and after induction chemoradiation. PET "responders" were defined as patients having a greater than 80% decrease in FDG uptake in the primary site of disease during treatment. The median survival after esophagectomy was 16.3 months for responders and 8 months for nonresponders (log-rank test: P = .01). Subsequently, two closely related manuscripts from the same institution were published. In the first,22 the authors prospectively monitored 27 patients with squamous-cell carcinoma of the esophagus with PET during chemoradiation. This study was limited in that only PET imaging of the primary tumor was performed. Twenty-four of the patients underwent esophagectomy (including four incomplete resections). The median survival was 22.5 months in patients who had a greater than a 52% decrease in SUV and 6.7 months in patients with lesser decreases in SUV (P < .0001). In this group’s second article,23 the authors prospectively monitored 37 patients with adenocarcinoma of the esophagus with PET during chemoradiation, again imaging only the primary tumor site. Importantly, this article differed from the first in that PET imaging was performed 14 days after initiation of cisplatin-based chemotherapy, rather than at the completion of therapy. Response to treatment by PET was defined as having a greater than 35% decrease in SUV. Patients considered to have a response to treatment by PET had a median survival that was not reached during the study period (2-year survival, 60%), whereas nonresponders had a median survival of 13 months (2-year survival, 37%; P = .04). Although R0 esophagectomies were performed in 22 patients, the survival of this group was not separately analyzed. Our trial confirms and extends the results of these and other published studies. First, our prospective study confirms both retrospective24 and prospective7 studies, which indicate that 10% to 20% of patients with newly diagnosed esophageal cancer will have metastatic disease detected by PET that is not identified by other imaging modalities. This finding indicates that PET imaging should be a standard component of the initial evaluation of all esophageal cancer patients. However, the number of patients with new sites of M1 disease detected by PET after induction therapy appears to be few, if any. Our study found that after the completion of induction therapy, PET did not detect new sites of metastatic disease and did not define unresectable locoregional disease. Thus, the potential benefit of repeating PET scanning after induction therapy appears to be the assessment of the effectiveness of initial therapy. In our study, a comparison of the percentage decrease in SUV with the percentage of treatment effect by pathologic examination of esophagectomy specimens indicates a correlation between large decreases in SUV and pathologic measurements of treatment effect (data not shown). However, pathologic change is only an intermediate surrogate-marker for the clinical outcomes of disease-free and overall survival. As sufficiently long follow-up has become available, it appears that PET may be able to estimate the most important end points—that is, disease-free and overall survival. In our pilot study, patients with small decreases in FDG uptake following induction therapy were more likely to have disease recurrence than patients with larger changes in uptake (P = .055), and overall survival correlated less closely with percentage change in SUV (P = .089). These preliminary results warrant validation in larger trials, and if confirmed, several novel treatment strategies may be considered, including using PET to evaluate the effectiveness of induction therapy after only one cycle of induction therapy so that treatment could be altered or discontinued if necessary.
Supported in part by National Cancer Institute grant no. 40166913. Presented in part at the Thirty-seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, California, May 12–15, 2001.
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16. Schelling M, Avril N, Nahrig J, et al: Positron emission tomography using (18F)fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer. J Clin Oncol 18:1689–1695, 2000 17. Jansson T, Westlin JE, Ahlstrom H, et al: Positron emission tomography studies in patients locally advanced and/or metastatic breast cancer: A method for early therapy evaluation? J Clin Oncol 13:1470–1477, 1995[Abstract]
18. Findlay M, Young H, Cunnignham D, et al: Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: Correlation with tumor response to fluorouracil. J Clin Oncol 14:700–708, 1996 19. Berlangieri SU, Brizel DM, Sher RL, et al: Pilot study of positron emission tomography in patients with advanced head and neck cancer receiving radiotherapy and chemotherapy. Head Neck 16:340–346, 1994[Medline]
20. Romer W, Hanauske AR, Ziegler S, et al: Positron emission tomography in non-Hodgkin’s lymphoma: Assessment of chemotherapy with fluorodeoxyglucose. Blood 91:4464–4471, 1998 21. Flamen P, Van Cutsem E, Lerut T, et al: The utility of positron emission tomography with 18F-Fluorodeoxyglucose (FDG-PET) to predict the pathologic response and survival of esophageal cancer after preoperative chemoradiation therapy (CRT). Thirty-seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, California, May 12–15, 2001 (abstr 504) 22. Brucher BL, Weber W, Bauer M, et al: Neoadjuvant therapy of esophageal squamous cell carcinoma; response evaluation by positron tomography. Ann Surg 233:300–309, 2001[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
