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Originally published as JCO Early Release 10.1200/JCO.2006.06.7801 on September 11 2006 © 2006 American Society of Clinical Oncology. Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction
From the Departments of Surgery, Nuclear Medicine, Pathology, Internal Medicine III, Medical Statistic, Technische Universität München, Munich, Germany; and the Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA Address reprint requests to Katja Ott, MD, Department of Surgery, Technische Universitaet Muenchen, Ismaningerstr 22, D-81675, Munich, Germany; e-mail: Katja.Ott{at}lrz.tum.de
PURPOSE: A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response. PATIENTS AND METHODS: Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET. RESULTS: Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients. CONCLUSION: This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.
It is known from several studies that the outcome of patients with adenocarcinomas of the esophagogastric junction (AEG) treated with preoperative chemotherapy is heterogeneous. Patients with a histopathologic response are characterized by a favorable prognosis.1,2 Two most recently presented phase III studies indicated that preoperative chemotherapy improves survival in patients with esophageal adenocarcinoma3 and in patients with tumors at the esophagogastric junction.4 However, a systematic review did show only marginal effects of preoperative chemotherapy for resectable intrathoracic esophageal cancer.5 Of note, in nonresponders survival seems to be similar or even worse than after surgical resection alone.6 Therefore, early identification of patients with an unfavorable outcome after preoperative therapy is highly important for the future use of neoadjuvant therapy in patients with tumors of the esophagogastric junction. We have previously studied early changes in tumor glucose utilization in patients with locally advanced AEG treated with cisplatinum-based chemotherapy followed by surgical resection. We found that a decrease of tumor metabolic activity by more than 35% after 2 weeks of therapy predicts a high histopathologic response rate (53%) and is associated with a favorable prognosis (median survival, > 50 months).7 However, this study used a posthoc definition of a metabolic response. Therefore, it might have overestimated the predictive value of early metabolic changes for tumor response and patient outcome. Furthermore, median patient follow-up was only 14 months and the long-term survival of metabolic responders and the patterns of recurrence could not be evaluated. Thus the aim of this study was to validate an a priori defined metabolic response in [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) as a predictor for response and patient survival in a larger patient population with longer follow-up. Such a prospective validation is necessary before preoperative treatment is changed for patients without a metabolic response early in the course of therapy.
Study Design Our previous study7 suggested that a metabolic response is achieved in approximately 40% of the treated patients, that the median survival of patients without a metabolic response is 19 months, and that the relative risk of death is approximately three times lower in patients with a metabolic response than in patients without a metabolic response. On the basis of these findings, an accrual time of 36 months and a follow-up time of 24 months, 53 patients have to be evaluated to detect with a power of 80% a three-fold higher risk of death in the group of metabolic nonresponders at a 5% significance level using a log-rank test.8 Our previous study has also suggested that in approximately 20% of the patients tumor metabolic activity will be too low for quantitative analysis. Therefore, a total of 65 patients were included in this study.
Patient Population Preoperative therapy consisted of two cycles of combination chemotherapy, each 49 days in duration. On day 1 cisplatinum, at a dose of 50 mg/m2 body surface area (BSA), was given as intravenous infusion over a period of 1 hour. Thereafter patients received leucovorin (500 mg/m2 BSA) over a period of 2 hours, followed by fluorouracil (2 g/m2 BSA) over a period of 24 hours. Treatment with cisplatinum was repeated on days 15 and 29. Infusion of leucovorin and fluorouracil was repeated on days 8, 15, 22, 29, and 36.11 AEG I tumors were additionally treated by paclitaxel (80 mg/m2 BSA) over a period of 3 hours, one day before infusion of cisplatinum.12 All patients were treated within ongoing phase II trials at our department. Surgical resection of the tumor was scheduled 3 to 4 weeks after completion of chemotherapy.7
Imaging Studies Patients fasted at least 6 hours before PET imaging to ensure standardized glucose metabolism. Static emission images of the tumor region of 20 minutes duration were acquired 40 minutes after intravenous injection of 250 to 370 MBq FDG as previously described. Blood glucose levels were measured before each PET study. Patients with a blood glucose level greater than 150 mg/dL were excluded. Images were reconstructed iteratively using an attenuation weighted ordered subset expectation maximization algorithm (eight iterations, four subsets) and then smoothed in 3D using a 4 mm Gauss filter. Image data were normalized for injected dose of FDG and patient's body weight.7,13 Normalization to body weight was used because this represents the most commonly used way to calculate standardized uptake values for the FDG uptake of tumor tissue. Because only short term changes of tumor metabolic activity were analyzed, other normalization procedures (BSA, lean body mass) yielded identical results (data not shown). Quantitative evaluation of tumor FDG uptake was otherwise performed as previously described.7,10
Surgical Therapy, Response Evaluation, and Patient Follow-Up
Statistical Analysis
Between January 1999 and July 2002, 65 patients were included in this study and underwent the baseline PET scan. This represents 65% of the patients with locally advanced AEG I and II tumors treated by preoperative chemotherapy at our institution during this time period. Results of 14 of the patients have already been reported previously.7 However, the cut off value for definition of a metabolic response (35% decrease of baseline FDG uptake) had already been defined on the basis of the results of the first 26 patients.16 The clinical stage as determined by endoscopic ultrasound was uT3 in all 65 patients. No significant difference between AEG I and II in the whole patient population could be found regarding Lauren classification (P = .60), grading (P = .30), N category (0 versus +; P = 1.0), overall survival (P = .77), and recurrence-free survival (P = .72). Significant differences could be found for sex (P = .014) and the ypT-category (P = .025) due to the ypT2b classification for proximal gastric cancer (AEG II). Demographic and histopathologic parameters of the AEG I and II tumors were in line with the published data.17 In eight patients FDG uptake of the tumor was too low for quantitative analysis,10,18 and in one additional patient the blood glucose level was markedly elevated at the time of the follow-up PET (175 mg/dL). These patients were excluded. Thus a total of 56 patients were assessable for this study. Thirty-five tumors were located above the cardia (AEG I tumors) and 21 tumors were located at the level of the cardia (AEG II tumors). Further patient characteristics are summarized in Table 1.
Baseline tumor FDG uptake in the assessable patients was 8.1 ± 3.4 standardized uptake value. FDG uptake significantly decreased to 5.4 ± 2.0 in the follow-up scan (P < .001). Eighteen patients were classified as metabolic responders and 38 as metabolic nonresponders. Figure 1 shows typical examples of FDG-PET scans in patients with and without a metabolic response.
Six patients showed disease progression during chemotherapy and were not resected. Five of these patients were metabolic nonresponders in FDG-PET. In 50 patients the tumor was resected after chemotherapy. The tumor stage was ypT0 in three patients, ypT1 in four patients, ypT2 in 21 patients, ypT3 in 20 patients, and ypT4 in two patients. In 19 patients no viable tumor was found in regional lymph nodes (ypN0), whereas lymph node metastases were present in 31 patients (27 ypN1, 3 ypN2, 1 ypN3). The tumor resection was histopathologically complete in 41 patients, whereas microscopic residual tumor tissue remained in nine patients. In a total of 10 patients, less than 10% viable tumor cells were present in the resected tumor bed. Thus, the overall histopathologic response rate was 10 (18%) of 56. A metabolic response was highly significantly correlated with a subsequent histopathologic response (P = .001; Table 2). A histopathologic response was achieved in 44% (8 of 18; 95% CI, 22% to 69%) of the patients with a metabolic response, but only in 5% of the patients without a metabolic response (2 of 38; 95% CI, 1% to 18%; Table 2). Metabolic response was significantly correlated with conventional methods for response evaluation as well (P < .001; Table 3).
Median follow-up time was 42 months (range, 26 to 67 months). During this time period 31 patients died. Median overall survival was 32 months. Overall median survival of metabolic nonresponders was 18 months, whereas median survival has not been reached for metabolic responders (P = .01). The corresponding 3-year survival rates were 35% and 70%, respectively (Fig 2A). In a proportional hazards model the risk of death for patients with a metabolic response was 34% of the patients without a metabolic response (P = .019). In contrast none of the other pretherapeutic charcteristics (sex, grading, Lauren classification, localization) showed a significant association with survival in the Cox regression analysis (P > .1). When limiting the analysis to the 50 patients who underwent tumor resection, metabolic response remained a significant prognostic factor (Table 4). As expected the ypT- and ypN-category and histopathologic response were significantly correlated with patient survival (Table 4). No significant correlation was found for baseline FDG-uptake or FDG-uptake after 14 days of therapy (Table 4). In a multivariate analysis including metabolic response, histopathologic response, and ypT-, ypN-category, only ypN-category remained significantly correlated with survival (Table 4).
In patients with complete tumor resection (n = 41), median overall survival was also significantly better for metabolic responders than for metabolic nonresponders (24 and > 55 months, respectively; P = .04). Univariate and multivariate analysis showed essentially the same results as in the group of the resected patients. Histopathologic (P = .04) and metabolic response (P = .05) as well as ypT- (P = .026) and ypN-category (P = .004) showed prognostic relevance in univariate analysis; ypN0-category was the only prognostic factor (P = .004; relative risk, 0.11; 95% CI, 0.03 to 0.50) in multivariate analysis. For the R0 patients median recurrence-free survival was 49 months. Recurrence-free survival was significantly better for metabolic responders as compared with metabolic nonresponders (Fig 2B). Median recurrence-free survival of metabolic nonresponders was only 10 months, while median recurrence-free survival has not been reached for metabolic responders (P = .009). The corresponding 3-year recurrence-free survival rates were 38% and 80%. Cox regression revealed metabolic response as the only independent prognostic factor for recurrence-free survival in the subgroup of R0 patients (Table 5).
This study prospectively demonstrates that FDG-PET identifies patients with a very low histopathologic response rate (5%) and a poor prognosis within 14 days after initiation of preoperative chemotherapy. Median survival of patients without a metabolic response in FDG-PET was only 18 months. Overall survival was chosen as the primary end point of this study because it can be applied to all included patients and not only to the subgroup of surgically resected patients. Even when the tumor was completely resected after preoperative chemotherapy, median overall survival of metabolic nonresponders was only 24 months and recurrence-free survival was only 10 months. In contrast, patients with a metabolic response in FDG-PET were characterized by high response rates and a favorable prognosis with a 3-year survival rate of 70%. After surgical resection alone, 3-year survival rates of only 10% to 40% are generally reported in the literature for patients with locally advanced AEG.5,19 Therefore, our data indicate that FDG-PET may allow an early identification of patients who benefit from preoperative chemotherapy. Interestingly, the ypN-category was the only prognostic factor in multivariate analysis predicting survival in the group of resected and completely resected patients. This is likely explained by the fact that the ypN-category integrates two important prognostic factors in AEG: the histopathologic response1,2 in neoadjuvantly treated patients and the nodal category, the strongest prognostic factor in completely resected patients undergoing primary tumor resection.20-22 However, ypT-, ypN-category, and histopathologic response are determined postoperatively, 3 to 4 months after initiation of preoperative chemotherapy. In contrast the metabolic response can already be assessed on day 14 of the first chemotherapy cycle. Although metabolic response in FDG-PET was not an independent prognostic factor in a multivariate model including ypT-, ypN-category, and histopathologic response as covariates for overall survival in the group of resected or completely resected patients, assessment of the tumor metabolic response may be used to adjust the treatment regimen early in the course of therapy, whereas this is not feasible for postoperative prognostic factors. Furthermore metabolic response was the only independent prognostic factor predicting recurrence after complete resection. Thus metabolic response appears to be the strongest factor predicting short-term outcome, whereas the ypN-category is a stronger predictor for long-term survival. Because metabolic response influences prognosis as well as recurrence in completely resected patients, it should be considered to offer PET-guided induction therapy even to patients with earlier tumor categories (for example, uT2) who have a high probability of complete resection. This consideration is based on the fact that there are subgroups of primary resected patients with early tumor stages, which present with dismal prognosis and early recurrence.23 The outcome of these patients may also be improved, if those patients are integrated in prospective PET-controlled trials. It has long been recognized that response to preoperative chemotherapy is a very strong prognostic factor for patients with gastric and esophageal cancer.1,2 Despite intensive efforts to identify molecular markers, which are predictive for tumor response and prognosis, the value of each of these markers is currently not sufficiently validated to use them for the selection of patients for preoperative chemotherapy.24-29 Our study indicates that patients, without a metabolic response after 2 weeks of therapy, may undergo salvage therapies after only a brief period of chemotherapy. Potential therapeutic options include the use of different chemotherapy regimens, chemoradiotherapy, or immediate surgical resection. Such an individualized approach could significantly reduce the adverse effects and costs of ineffective therapy in nonresponding patients. Based on the data of this prospective trial, we are currently evaluating such an approach in patients with locally advanced AEG. In this concept (MUNICON trial) patients with metabolic nonresponse are immediately referred to surgery after only 2 weeks of chemotherapy. Because disease progression during ineffective chemotherapy has been discussed as one reason for the poor survival of nonresponders, such a PET-controlled chemotherapy may even improve overall survival by reducing the time during which a patient receives ineffective therapy. However, this hypothesis can only be evaluated in randomized trials, because failure to respond to chemotherapy may also be a marker for a biologically aggressive tumor, which is associated with a poor prognosis irrespective of the applied therapy. A series of randomized studies will also be necessary to validate PET imaging as a surrogate end point for drug development. As pointed out by Prentice,30 a surrogate end point must correlate with the true clinical outcome and fully capture the net effect of treatment on the clinical outcome. The data presented indicate that a metabolic response in PET closely correlates with patient survival. However, close correlation does not guarantee surrogacy.31 It still needs to be established whether a metabolic response fully captures the net effect of treatment on the clinical outcome. For example, some new forms of preoperative therapy may result in a clinical benefit without causing a metabolic response early in the course of therapy, whereas others may cause a metabolic response without a clinical benefit. Only a series of randomized trial will be able to demonstrate whether treatment regimens with a higher metabolic response rate also lead to improved patient survival. In conclusion, this study confirms prospectively that quantitative assessment of tumor metabolism by FDG-PET is an efficient and clinically useful technique to monitor tumor response to chemotherapy early in the course of treatment. An a priori defined metabolic response predicted tumor response, overall survival, and recurrence-free survival. Furthermore the strong influence of metabolic response on overall survival as well as recurrence-free survival even in completely resected patients might justify the integration of earlier tumor stages in PET-controlled therapy strategies. Therefore we anticipate that FDG-PET will have a significant impact on patient management by allowing individualized therapy strategies in AEGs.
Although all authors completed the disclosure declaration, the following author or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C)
We thank the clinical staff for their excellent support and the technologists at the Departments of Nuclear Medicine and Surgery. Furthermore, we appreciate the efforts of the cyclotron and radiochemistry staff. The study was supported by internal funds of the Department of Nuclear Medicine, Technische Universitaet Muenchen.
published online ahead of print at www.jco.org on September 11, 2006 K.O. and W.A.W. contributed equally to the article. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Malthaner R, Fenlon D: Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev: CD001556, 2003 6. Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998 7. Weber WA, Ott K, Becker K, et al: Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 19:3058-3065, 2001 8. Dupont WD, Plummer WD Jr: Power and Sample size calculations: A review and computer program. Control Clin Trials 11:116-128, 1990[CrossRef][Medline] 9. Siewert JR, Stein HJ: Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg 85:1457-1459, 1998[CrossRef][Medline] 10. Ott K, Fink U, Becker K, et al: Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: Results of a prospective trial. J Clin Oncol 21:4604-4610, 2003 11. Ott K, Sendler A, Becker K, et al: Neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin (PLF) in locally advanced gastric cancer: A prospective phase II study. Gastric Cancer 6:159-167, 2003[CrossRef][Medline] 12. Ott K, Dittler HJ, Helmberger H: Preoperative chemotherapy of high dose 5-FU (HDFU) + folinic acid (HDFA) + biweekly cisplatin without (group A) or with paclitaxel (group B) in patients with locally advanced adenocarcinomas of the esophagus. Proc Am Soc Clin Oncol 19:287A, 2000 (abstr 1122) 13. Weber WA, Petersen V, Schmidt B, et al: Positron emission tomography in non-small-cell lung cancer: Prediction of response to chemotherapy by quantitative assessment of glucose use. J Clin Oncol 21:2651-2657, 2003 14. Siewert JR, Stein HJ, Sendler A, et al: Surgical resection for cancer of the cardia. Semin Surg Oncol 17:125-131, 1999[CrossRef][Medline] 15. Becker K, Mueller JD, Schulmacher C, et al: Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer 98:1521-1530, 2003[CrossRef][Medline] 16. Weber W, Ott K, Fink U, et al: FDG-PET for monitoring neo-adjuvant chemotherapy of adenocarcinomas of the distal esophagus. J Nucl Med 40:136P, 1999 (abstr 550) 17. Siewert JR, Feith M, Stein HJ: Biologic and clinical variations of adenocarcinoma at the esophago-gastric junction: Relevance of a topographic-anatomic subclassification. J Surg Oncol 90:139-146, 2005[CrossRef][Medline] 18. Stahl A, Ott K, Weber WA, et al: FDG PET imaging of locally advanced gastric carcinomas: Correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 30:288-295, 2003[Medline] 19. Enzinger PC, Mayer RJ: Esophageal cancer. N Engl J Med 349:2241-2252, 2003 20. Nakamura T, Ide H, Eguchi R, et al: Adenocarcinoma of the esophagogastric junction: A Summary of responses to a questionnaire on adenocarcinoma of the esophagus and the esophagogastric junction in Japan. Dis Esophagus 15:219-225, 2002[CrossRef][Medline] 21. de Manzoni G, Pedrazzani C, Pasini F, et al: Results of surgical treatment of adenocarcinoma of the gastric cardia. Ann Thorac Surg 73:1035-1040, 2002 22. Di Martino N, Izzo G, Cosenza A, et al: Surgical therapy of adenocarcinoma of the esophagogastric junction: Analysis of prognostic factors. Hepatogastroenterology 52:1110-1115, 2005[Medline] 23. Westerterp M, Koppert LB, Buskens CJ, et al: Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 446:497-504, 2005[CrossRef][Medline] 24. Nakashima S, Natsugoe S, Matsumoto M, et al: Expression of P53 and P21 is useful for the prediction of preoperative chemotherapeutic effects in esophageal carcinoma. Anticancer Res 20:1933-1937, 2000[Medline] 25. Shimada Y, Watanabe G, Yamasaki S, et al: Histological response of cisplatin predicts patients' survival in oesophageal cancer and P53 protein accumulation in pretreatment biopsy is associated with cisplatin sensitivity. Eur J Cancer 36:987-993, 2000[CrossRef][Medline] 26. Sarbia M, Stahl M, Fink U, et al: Expression of apoptosis-regulating proteins and outcome of esophageal cancer patients treated by combined therapy modalities. Clin Cancer Res 4:2991-2997, 1998[Abstract] 27. Langer R, Specht K, Becker K, et al: Association of pretherapeutic expression of chemotherapy-related genes with response to neoadjuvant chemotherapy in Barrett carcinoma. Clin Cancer Res 11:7462-7469, 2005 28. Warnecke-Eberz U, Metzger R, Miyazono F, et al: High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer. Clin Cancer Res 10:3794-3799, 2004 29. Harpole DH Jr, Moore MB, Herndon JE, et al: The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Clin Cancer Res 7:562-569, 2001 30. Prentice RL: Surrogate endpoints in clinical trials: Definition and operational criteria. Stat Med 8:431-440, 1989[Medline] 31. Fleming TR, DeMets DL: Surrogate end points in clinical trials: Are we being misled? Ann Intern Med 125:605-613, 1996 Submitted March 26, 2006; accepted June 19, 2006. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
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