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© 2003 American Society for Clinical Oncology Prediction of Response to Preoperative Chemotherapy in Gastric Carcinoma by Metabolic Imaging: Results of a Prospective Trial
From the Departments of Surgery, Nuclear Medicine, Pathology, Radiology, and Medical Statistics, Technische Universität München, Munich, Germany. Address reprint requests to Katja Ott, MD, Klinikum Rechts der Isar, Ismaningerstrasse 22, 81675 Munich, Germany; e-mail: katja.ott{at}lrz.tum.de.
Purpose: We prospectively evaluated the predictive value of therapy-induced reduction of tumor glucose use for subsequent response and patient survival in patients with gastric cancer treated by preoperative chemotherapy. Patients and Methods: Forty-four consecutive patients with locally advanced gastric carcinomas were studied by positron emission tomography with the glucose analog fluorine-18 fluorodeoxyglucose (FDG-PET) at baseline and 14 days after initiation of cisplatin-based polychemotherapy. On the basis of a previous study, a reduction of tumor FDG uptake by more than 35% was used as a criterion for a metabolic response. The metabolic response in FDG-PET was correlated with histopathologic response after completion of therapy (< 10% viable tumor cells in the resected specimen) and patient survival. Results: Thirty-five (80%) of the 44 tumors were visualized with sufficient contrast for quantitative analysis (two of 19 intestinal and seven of 25 nonintestinal tumors showed only low FDG uptake). In the 35 assessable patients, PET imaging after 14 days of therapy correctly predicted histopathologic response after 3 months of therapy in 10 (77%) of 13 responders and 19 (86%) of 22 nonresponders. Median overall survival for patients with a metabolic response has not been reached (2-year survival rate, 90%); for patients without a metabolic response, median survival was only 18.9 months (2-year survival rate, 25%; P = .002) Conclusion: This study prospectively demonstrates that in patients with gastric cancer, response to preoperative chemotherapy can be predicted by FDG-PET early during the course of therapy. By avoiding the morbidity and costs of ineffective therapy, FDG-PET imaging may markedly facilitate the use of preoperative chemotherapy.
POSITRON EMISSION tomography with the glucose analog fluorine-18 fluorodeoxyglucose (FDG-PET) allows noninvasive serial measurements of tumor glucose use. Previous studies have suggested that chemotherapy causes a measurable decrease in tumor glucose use within 1 to 3 weeks after the start of therapy. Furthermore, changes in tumor glucose use at this time point have been found to be correlated with patient survival. Thus, FDG-PET has the potential to predict patient outcome early in the course of therapy.1–5 Prediction of tumor response is particularly interesting in patients with locally advanced, but potentially curative resectable gastric cancer. Despite intense efforts, the prognosis of these patients has only minimally improved in the last 20 years. After primary resection, median survival ranges between 12 and 25 months.6–8 Preoperative chemotherapy is conceptually attractive to increase the rate of curative resections and improve patient survival.9–11 However, three randomized phase III trials published or presented at scientific meetings failed to demonstrate an improvement of survival by preoperative chemotherapy compared with surgery alone.12–14 Nevertheless, numerous studies have found that patients with an objective response to preoperative therapy are characterized by a favorable prognosis, which is significantly better than that achieved by surgical treatment alone.9–11 However, only 30% to 40% of the patients are responders, whereas 60% or even more are nonresponders; these patients undergo several months of toxic therapy without a survival benefit. Prognosis for patients with nonresponding tumors seems to be even worse than for patients treated with surgery alone. Therefore, a diagnostic test that allows prediction of response is considered to be crucial for the future use of preoperative chemotherapy in patients with gastric cancer. Recently, we found that a decrease of tumor FDG uptake by more than 35% of baseline value allowed accurate prediction of response in patients with locally advanced esophageal cancer as soon as 14 days after initiation of chemotherapy.5 At this time point patients had received the first complete course of chemotherapy. In this study we used a similar chemotherapy regimen for preoperative chemotherapy of gastric cancer and prospectively evaluated a decrease of 35% FDG uptake as a predictor of tumor response and patient survival.
Patients PET imaging was performed as part of a phase II study evaluating preoperative chemotherapy in patients with gastric carcinomas. Eligibility requirements included the presence of biopsy-proven gastric cancer with or without metastases in local lymph nodes (tumor stage T3–4, Nx, and M0 in the tumor-node-metastasis system classification).15 Staging procedures included endoscopy, endoscopic ultrasound, laparoscopy, and computed tomography (CT) of the chest, abdomen, and pelvis. Details of the applied techniques have been published.16–18 Eligible patients had to be fit for cisplatin-containing chemotherapy and consecutive surgical resection. Staging procedures except laparoscopy were repeated preoperatively for all patients and reduction of tumor size was evaluated as previously described.5 Patients with an Eastern Cooperative Oncology Group score worse than 1, previous or secondary malignancy, life expectancy of less than 3 months, uncontrolled bleeding from the tumor, pregnancy, diabetes, or age younger than 18 years were excluded. Patients were also ineligible if they had undergone previous chemotherapy, radiotherapy, or endoscopic laser therapy. The study protocol was approved by the Institutional Review Board at the Technische Universität München (Munich, Germany). Written informed consent was obtained from all patients.
Preoperative Chemotherapy
PET Imaging 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.5 Blood glucose levels were measured before each PET study (first PET scan, 109 ± 27 mg/dL; second PET scan, 106 ± 29 mg/dL). Images were reconstructed iteratively using an attenuation-weighted ordered subset expectation maximization algorithm (eight iterations, four subsets) and then smoothed in three dimensions using a 4-mm Gauss filter. Image data were normalized for injected dose of FDG and patients’ BSA20 using the following formula: standardized uptake value (SUV) = measured activity concentration/injected activity x BSA x 100. For quantitative evaluation, a circular region of interest (ROI; diameter 1.5 cm corresponding to 10 pixels) was placed over the tumor in the slice with maximum FDG uptake in the baseline scan. In addition, five circular ROIs of the same size were placed in the center of the liver to measure background activity. Patients were excluded from the study when SUVtumor was less than 1.35 x SUVliver + 2 x standard deviation (SUVliver). This definition was chosen to ensure that a decrease in tumor FDG uptake by 35% could be reliably measured in the PET scan. In the second PET scan the tumor ROI was placed at the same position as in the baseline study using the anatomic landmarks of the transmission image as a reference. To assess the reproducibility of the quantitative evaluation of FDG-PET studies, all PET scans were analyzed by two independent observers. For additional analysis the mean value of the two measurements was used.
Surgical Therapy and Response Evaluation
Patient Follow-Up
Statistical Analysis
FDG-PET Forty-four consecutive patients were studied by FDG-PET before preoperative therapy. Patient characteristics are summarized in Table 1  . In 35 patients (80%) the tumor could be visualized with sufficient contrast to allow quantitative analysis of changes in tumor FDG uptake. Twenty-three of these tumors (66%) were localized in the proximal third and 12 (34%) tumors were localized in the middle or distal third. Seven of the nine excluded patients (78%) had tumors of the nonintestinal subtype; five (56%) were localized in the distal third, seven (78%) showed Borrmann classification III/IV, and signet ring cells were found in six (66%). In the 35 assessable patients, mean FDG uptake was 17.1 ± 7.9 SUV (median, 14.0 SUV). In the second PET scan, mean FDG uptake decreased to 11.3 ± 5.4 SUV (median, 10.4 SUV; P < .001). Measurements of tumor FDG uptake by the two observers were closely correlated (r2 = 0.98, mean difference between the two observers, -0.2 ± 0.9 SUV for the first scan; r2 = 0.90, mean difference, -0.3 ± 1.5 SUV for the second scan).
Response Evaluation and Patient Survival In three patients (8.6%) newly developed distant lymph node metastases (n = 2) or liver metastases (n = 1) as detected by the follow-up CT did not allow surgical resection. Complete tumor resection (R0) was achieved in 26 of the assessable patients (81%; 95% CI, 64% to 93%). Histopathologically, less than 10% viable tumor cells at the site of the primary tumor were found in 13 patients (37%; 95% CI, 21% to 55%), and no patient showed a complete regression of the primary tumor and the lymph nodes (two patients showed complete regression of the primary tumor). Thus, 13 of the 35 assessable patients were classified as responders and 22 were classified as nonresponders (response rate, 37%; 95% CI, 21% to 55%).
In the nine patients who were not assessable because of low FDG uptake, all patients were resected. Histopathologically, four were responders and five were nonresponders (Table 2
The relative decrease in FDG uptake during therapy was markedly higher for responders than for nonresponders (-49% ± 24%, median, -50% in responders; -17% ± 21%, median, -18% in nonresponders; P = .0005). Thirteen patients (37%) were classified as metabolic responders (decrease of tumor FDG uptake by more than 35%) and 22 (63%) were classified as metabolic nonresponders. A metabolic response correctly predicted response after completion of chemotherapy in 10 of 13 responding and 19 of 22 nonresponding tumors (Table 2  ). This resulted in a sensitivity and specificity of 77% (95% CI, 46% to 95%) and 86% (95% CI, 65% to 97%), respectively. Positive and negative predictive value for final response was 77% (95% CI, 46% to 95%) and 86% (95% CI, 65% to 97%), respectively. The overall accuracy was 83% (95% CI, 66% to 93%). Figure 1 shows examples of typical PET scans in metabolic responders and nonresponders.
The clinical response rate as assessed by endoscopy, CT, and endoscopic ultrasound after completion of preoperative chemotherapy was 27% (12 of 44; 95% CI, 15% to 43%) in the whole group of patients and 26% (nine of 35; 95% CI, 12% to 43%) in patients with assessable PET scans. Disease progression was noted in three of 44 patients; the remaining 29 tumors were classified as stable disease. There was a significant correlation between a metabolic response in FDG-PET 14 days after initiation of chemotherapy and clinical response (P = .0002). Neither the whole group of patients (Table 1 ) nor the subgroups of assessable and nonassessable patients (P = .17 and .34, respectively) showed a significant correlation between baseline clinical stage and tumor response. Because of the relatively homogenous baseline clinical stage, this finding must be interpreted with caution. No other preoperative patient characteristics analyzed showed a significant correlation with tumor response (Table 1).
There was no statistically significant trend for a lower ypT category, negative nodal status, and complete resections (R0) in metabolic responders (Table 2
Median follow-up time for surviving patients was 18.7 months (9 to 58.2 months) for all included patients and 17.5 months (9 to 58.2 months) for the assessable patients. Fifteen of the assessable patients have died during the follow-up period. In 14 of these patients (93%), no metabolic response had been achieved during therapy. Median overall survival of the assessable patients was 20.8 months (2-year survival rate, 48%). In patients with a metabolic response, median overall survival has not been reached during the observation time (2-year survival rate, 90%). In contrast, patients without a metabolic response had a poor prognosis. Median survival for this group of patients was 18.9 months; the 2-year survival rate was 25% (P = .002; Fig 2A
The correlation between a metabolic response and patient survival remained significant when only the 26 completely resected patients were analyzed. Median survival after surgery was 35 months (2-year survival rate, 53%). In patients with a metabolic response, median survival has not been reached (2-year survival rate, 90%), whereas it was only 20.8 months for patients without a metabolic response (2-year survival rate, 29%; P = .023; Fig 2B ). When the survival data were analyzed for all 44 included patients there was no difference in overall survival between patients with assessable and nonassessable tumors in FDG-PET (P = .65). When the 44 patients were divided into groups with metabolic responder (n = 13), metabolic nonresponder (n = 22), and nonassessable tumors (n = 9), the median survival for these groups was more than 58, 18.9, and 35.2 months, respectively (2-year survival, 90%, 25%, and 53%, respectively; P = .006).
This prospective study demonstrates that metabolic measurements using FDG-PET allow early differentiation of responding and nonresponding tumors during preoperative chemotherapy of locally advanced gastric cancer. A metabolic response in FDG-PET was significantly correlated with subsequent histologic tumor regression as well as with patient survival. Several molecular markers have been investigated for their utility for response prediction in gastric cancer. Analysis of molecular markers would have the principle advantage over FDG-PET that chemotherapy may be obviated before a dose is administered. The expression of thymidylate synthase, the target enzyme for FU, has been shown to be significantly associated with response to FU-based therapy in gastric carcinoma.25 In addition, the expression of excision repair cross-complementing rodent repair deficiency complementation group 1, an enzyme involved in nucleotide excision repair, has been found to have a significant association with response in a neoadjuvant therapy regimen that is based on FU and cisplatin.26 Finally, chromosomal stable tumors (with a low rate of loss of heterozygosity) seem to respond less to cisplatin-based chemotherapy than patients with a high rate of loss of heterozygosity.27 However, the diagnostic accuracy for prediction of response reported in these studies is considerably lower than in the present study for FDG-PET. The sensitivities for prediction of response in these studies were 75%, 76%, and 46%, and the corresponding specificities were 65%, 75%, and 93%, respectively. In addition, it is important to note that the quantitative criteria used for prediction of response used in these studies have not been prospectively validated so far. Therefore, they are likely to overestimate the accuracy of the respective marker for prediction of response. In contrast, the strength of this study is the use of a prospectively defined quantitative criterion for a metabolic response, which was defined in an independent study.5 Other biologic markers tested for prediction of response include glutathione S-transferase, thymidine phosphorylase, vascular endothelial growth factor, bcl-2, bax, and p53. However, no conclusive results were obtained for these parameters.28–31 Furthermore, biopsies are generally restricted to the superficial, endoluminal parts of the tumor. It is therefore questionable whether analysis of biopsies can be representative for the whole tumor. Finally, prediction of response on the basis of molecular markers assumes that the expression remains stable during therapy. However, cytotoxic therapy may induce considerable changes in the expression of drug resistance–related proteins, which could only be detected by longitudinal analysis.32 In contrast to pretherapeutic biopsies used for molecular analyses, the whole tumor mass can be analyzed noninvasively by FDG-PET. Furthermore, FDG-PET can easily be repeated during preoperative therapy at certain time points. A specific limitation of FDG-PET in gastric cancer is that even in locally advanced stages, image contrast was insufficient for quantitative analysis in approximately 20% of the patients. Most of the nonassessable tumors in this study (78%) were of the nonintestinal subtype; 66% contained signet ring cells. This is in accordance with previous studies, which reported a sensitivity of 41% to 63% for detection of nonintestinal gastric cancer by FDG-PET.33,34 The low FDG uptake in this tumor type probably is due to the often diffuse growth pattern of nonintestinal gastric cancer and the lack of expression of the glucose transporter Glut-1.33,35 In contrast to other malignant tumors, such as non–small-cell lung cancer,36 pretherapeutic FDG uptake seems not to be correlated with patients’ prognosis in gastric cancer.33 In accordance with these previous data, survival of the nine PET-negative patients was not significantly different from that of the remaining patients. Evaluation of tumor response by morphologic imaging techniques has specific limitations in gastric cancer. According to strict WHO criteria gastric cancer is not bidimensionally measurable.37 Criteria from the Response Evaluation Criteria in Solid Tumors Group ratings, which use one-dimensional measurements, are in principle applicable for gastric cancer.38 However, the measured wall thickness is critically dependent on the distension of the stomach during the examination. Therefore, we used primarily histopathologic tumor regression as the gold standard for tumor response. However, only including patients who undergo tumor resection after preoperative chemotherapy in the analysis would cause a significant bias. Therefore, patients with tumor progression during therapy who were then considered as not curatively resectable were also considered as nonresponders in this study. Although similar criteria for response have been used in previous studies,9,10 these criteria are not standardized so far and may be investigator dependent. Therefore, it is important to note that FDG-PET not only allowed the prediction of tumor response but also was closely correlated with patient survival. The median survival for the metabolic responders was more than 58 months, whereas the median survival for the nonresponders was only 18.9 months. The correlation remained significant when only the 26 patients with complete resection were analyzed. In this subgroup the median survival for the nonresponders was also only 20.8 months. These findings suggest that the failure to achieve a metabolic response identifies a subgroup of patients with a poor prognosis despite successful surgical resection. A correlation between changes in FDG uptake and tumor response has previously been reported in experimental studies39 as well as in patients with upper gastrointestinal cancer.40–43 Three studies found that residual FDG uptake after preoperative chemoradiotherapy was associated with a poor prognosis in patients with esophageal cancer.41–43 However, in these studies PET imaging was performed after completion of preoperative therapy. In contrast, the aim of this study was to predict tumor response early during the course of chemotherapy. Furthermore, the previous studies did not use prospective, predefined quantitative criteria for definition of tumor response in FDG-PET. In this study we used so-called SUVs as a quantitative measure of tumor metabolic activity. This parameter has been criticized as being dependent on several parameters such as time after FDG injection, tumor size, blood glucose levels, spatial resolution of the reconstructed images, and so on.44 However, these limitations apply to the comparison of absolute SUVs measured at different institutions using different acquisition protocols. They do not apply to the measurement of changes in SUV when patients are examined under stable metabolic conditions according to a fixed protocol. The interstudy variability of repeated SUV measurements in untreated tumors has been shown to be less than 20% in previous studies.45,46 Furthermore, changes in tumor SUVs have been shown to be well correlated with more complex measurements of tumor glucose use, such as tracer kinetic analysis using compartment modeling.47 Currently, there are considerable efforts to change treatment of locally advanced gastric cancer by using a combination of chemotherapy with radiotherapy or postoperative treatment concepts as reported by MacDonald et al.48 Early identification of nonresponding tumors by FDG-PET may allow a significant optimization of preoperative regimes in locally advanced gastric cancer. We believe that nonresponding patients with potentially resectable tumors should primarily be referred to surgery after only 2 weeks of chemotherapy. Because preoperative chemotherapy with cisplatin, leucovorin, and FU is likely to fail in nonresponders to PET, these patients should be offered the standard form of treatment. Furthermore, disease progression or dissemination cannot be excluded during continued chemotherapy. Finally, gastrectomy also has a positive palliative effect in patients with advanced gastric cancer (eg, relief from dysphagia and bleeding). If the poor survival data for nonresponding patients are considered, even after curative tumor resection, a change of the chemotherapy regimen or use of chemoradiotherapy49 also should be discussed. Such an approach seems feasible because several new drug regimens with relatively high activity for treatment of gastric cancer have been described recently.50,51 In particular, nonresponding patients with locally advanced tumors that probably are not completely resectable are candidates for such salvage strategies. In these patients unnecessary surgery should be avoided except for palliation of symptoms. According to the data of our study, monitoring of chemotherapy by PET imaging may lead to a change in patient management in more than 60% of the patients. Thus, there is a considerable potential to avoid the side effects and costs of ineffective therapy by PET imaging. Whether this will lead to an overall improved patient prognosis needs to be evaluated in a randomized trial comparing PET-controlled preoperative therapy with conventional preoperative treatment.
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 gratefully acknowledge the efforts of the cyclotron and radiochemistry staff and the technologists for the excellent technical support. We thank J. Fessler, PhD, University of Michigan, for generously providing the software for the iterative reconstruction of the PET studies.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, 2002.
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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
2 test.
