Prediction of Response to Neoadjuvant Chemotherapy by Sequential F-18-Fluorodeoxyglucose Positron Emission Tomography in Patients With Advan
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《临床肿瘤学》
the Department of Nuclear Medicine, Pathology and Gynecology Technische Universit?t München, Munich, Germany
Division of Nuclear Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA
Department of Medical and Molecular Pharmacology, University of California, Los Angeles, CA
Department of Pathology, University of Freiburg, Freiburg
Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany
ABSTRACT
PURPOSE: The aim of this study was to evaluate sequential F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) to predict patient outcome after the first and third cycle of neoadjuvant chemotherapy in advanced-stage (International Federation of Gynecology and Obstetrics stages IIIC and IV) ovarian cancer.
PATIENTS AND METHODS: Thirty-three patients received three cycles of carboplatin-based chemotherapy, followed by cytoreductive surgery. Quantitative FDG-PET of the abdomen and pelvis was acquired before treatment and after the first and third cycle of chemotherapy. Changes in tumoral FDG uptake, expressed as standardized uptake values (SUV), were compared with clinical and histopathologic response; overall survival served as a reference.
RESULTS: A significant correlation was observed between FDG-PET metabolic response after the first (P = .008) and third (P = .005) cycle of chemotherapy and overall survival. By using a threshold for decrease in SUV from baseline of 20% after the first cycle, median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. At a threshold of 55% decrease in SUV after the third cycle median overall survival was 38.9 months in metabolic responders compared with 19.7 months in nonresponders. There was no correlation between clinical response criteria (P = .7) or CA125 response criteria (P = .5) and overall survival. There was only a weak correlation (P = .09) between histopathologic response criteria and overall survival.
CONCLUSION: Sequential FDG-PET predicted patient outcome as early as after the first cycle of neoadjuvant chemotherapy and was more accurate than clinical or histopathologic response criteria including changes in tumor marker CA125. FDG-PET appears to be a promising tool for early prediction of response to chemotherapy.
INTRODUCTION
The majority of ovarian cancer patients present with advanced stages of disease and tumor spread in the abdominal cavity.1 Standard treatment includes aggressive cytoreductive surgery followed by platinum/taxane-based chemotherapy.2 Numerous studies have shown that long-term survival greatly depends on the effectiveness of surgical procedures since cytoreduction increases the efficacy of additional adjuvant therapy. Women who fail to undergo optimum cytoreduction have a poorer prognosis3 and patients with International Federation of Gynecology and Obstetrics stages IIIC and IV have a 5-year survival of less than 15%.1
Neoadjuvant (preoperative) chemotherapy is under active investigation for the treatment of advanced stages of ovarian cancer and was initially introduced in patients who were unable to tolerate extensive cytoreduction.2 Preoperative chemotherapy is now being evaluated in clinical trials in patients unlikely to achieve primary successful surgery, and it has been shown to enhance cytoreduction, reduce blood loss, the duration of surgery, and the intensity of postoperative care.4-8 Few studies including a small series of patients have demonstrated that neoadjuvant chemotherapy followed by standard surgery is associated with a comparable progression-free interval and overall survival compared with conventional treatment.2,5,6,9,10 However, patients not responding to neoadjuvant chemotherapy seem to have a poorer prognosis and reduced overall survival compared with patients who are sensitive to chemotherapy.8
Imaging metabolic pathways offers an alternative to visualize therapeutic effects. Malignant transformation of cells is frequently associated with increased metabolic activity. Positron emission tomography (PET) using F-18-fluorodeoxyglucose (FDG) has been successfully employed to visualize enhanced glucose utilization in tumor tissue. The glucose analog FDG is phosphorylated by intracellular hexokinases after crossing the cell membrane via glucose transporters but not further metabolized and, therefore, trapped in the cells, reflecting exogenous glucose consumption.11 FDG-PET has been shown to identify primary tumors, regional lymph nodes, and distant metastases with high diagnostic accuracy for various tumor types, including primary and recurrent ovarian cancer.12-14
Several studies have shown that changes in tumor metabolism occur early in the course of therapy and precede the reduction of tumor size.15-22 These studies suggest that quantification of tumor glucose metabolism is highly accurate for monitoring effects of chemotherapy. In breast cancer, sequential FDG-PET imaging provided a sensitive means of early detection of response to therapy.15,17,18 In esophageal and gastric cancer the initial decrease of FDG uptake in tumor tissue correlated well with the results of histopathologic response evaluation after neoadjuvant treatment.19-22
However, no information is currently available describing the role of FDG-PET for the noninvasive prediction of response to neoadjuvant chemotherapy in ovarian cancer. This study evaluated the hypothesis that changes in FDG uptake early in the course of treatment allow predicting the effectiveness of chemotherapy and subsequent patient outcome. The aim of this study was to prospectively evaluate the use of sequential metabolic FDG-PET imaging at baseline, after the first and third cycle of chemotherapy and to compare changes in tumoral FDG uptake with overall survival serving as the gold standard.
PATIENTS AND METHODS
Patients
Women who presented with newly diagnosed, advanced ovarian cancer (International Federation of Gynecology and Obstetrics stages IIIC and IV) and large (> 500 mL) ascites volumes and participated in a prospective neoadjuvant treatment protocol were eligible for this study. Histologic diagnosis was confirmed by diagnostic laparoscopy in all patients before inclusion. Exclusion criteria were known diabetes, pregnancy, and younger than 18 years of age. Patients with chemotherapy or radiotherapy within the last 6 months or a second malignancy were also excluded. A physician explained details of the study and written informed consent was obtained from all patients. The institutional review board of the Technische Universit?t München approved the study protocol. Patient characteristics are given in Table 1.
Chemotherapy and Surgery
Standard neoadjuvant chemotherapy consisted of three cycles of carboplatin (AUC5) plus paclitaxel (175 mg/m2 body surface area), administered at intervals of 3 weeks. For patients in poor general state of health, single-agent carboplatin was administered alternatively. Twenty-three out of 33 patients (69.7%) received standard combination of carboplatin and paclitaxel and 10 patients (30.3%) received single-agent carboplatin. Cytoreductive surgery was performed after three cycles of chemotherapy in all patients, followed by another three cycles of platinum-based chemotherapy. The goal of all surgical procedures was to obtain tumor-free status or macroscopically-minimal residual tumor of less than 1 cm.
PET Imaging
Patients were fasted for at least 6 hours before PET imaging. The serum glucose level was measured preceding the intravenous administration of 240 to 400 MBq (approximately 10 mCi) F-18-FDG. The mean blood glucose level was 99.3 ± 15.9 mg/dL at baseline PET, 100.6 ± 12.7 mg/dL at PET after the first cycle of chemotherapy, and 107.0 ± 20.7 mg/dL at PET after the third cycle of chemotherapy. To reduce tracer retention in the urinary tract system and to minimize the FDG uptake in the bowel, 20 mg of furosemide and 20 mg N-butyl-scopolamine were administered intravenously at the time of FDG injection. Emission scans (two-dimensional mode) of the abdomen and pelvis, acquired in 3-4 bed positions (ECAT EXACT 47/921, Siemens, Knoxville, TN), were obtained 60 minutes after tracer injection followed by a transmission scan. Emission data obtained over 10 minutes per bed position, corrected for random events, dead time, and attenuation were reconstructed with filtered back-projection (Hanning filter with cutoff frequency of 0.4 cycles per bin). The image pixel counts were calibrated to activity-concentration (Bq/mL) and decay corrected using the time of tracer injection as reference.
Image Analysis
Between one and four tumor lesions per patient (mean, 2.2) were identified on the baseline PET scan. The criterion was a distinct area of increased FDG uptake. Regions of interest (ROI) were placed semi-automatically over the tumor lesions in attenuation-corrected images. The slice with the highest radioactivity concentration within a tumor lesion was identified and a circular ROI with a diameter of 1.5 cm was placed in this area as well as in the adjacent slices. The diameters of all tumor lesions were substantially larger than the size of the ROI. This method was chosen to reduce partial volume effects, which play a substantial role if a ROI is placed around the entire tumor and tumor size changes after the baseline study. Every lesion was also measured in both follow-up PET scans using the same ROI. Standardized uptake values were calculated using the average activity values within the ROIs of three adjacent slices normalized to injected dose and patient's body weight. The analysis of the PET scans was performed without knowledge of the results of other clinical studies.
Assessment of Therapy Response
CA125 response. CA125 response criteria were either a decrease of 75% from baseline or a complete normalization of CA125 levels (< 35 U/mL).
Clinical response. Clinical response criteria were defined before initiation of the study. CA125 was considered an important, objectively measurable criterion for assessment of response to therapy and, therefore, changes in CA125 were evaluated as single prognostic criterion (see above) and in combination with other clinical response criteria. Clinical evaluation of therapy response was accomplished after three cycles of neoadjuvant chemotherapy. All patients had presented with bulky tumors (> 4 cm) and extensive peritoneal carcinomatosis at initial diagnosis. Patients were classified as clinical responders when at least two of the following three criteria were present: intraoperative residual tumor less than 4 cm, regression of peritoneal carcinomatosis to small and single-standing implants, and/or decrease of CA125 levels of 75% or a normalization of CA125 levels (< 35 U/mL). We did not include computed tomography (CT) imaging in our study because of the inherent limitation to accurately determine the extent of disease in the peritoneal cavity.
Histopathologic response. For assessment of histopathologic response, specimens were cut in slices measuring 0.5 cm and evaluated for the presence or absence of macroscopic tumor. Specimens were fixed according to standard procedures in 4% neutral buffered formaldehyde and embedded in paraffin. Sections of 5 μm thickness were prepared and stained with hematoxylin and eosin (H&E staining) as well as periodic acid-schiff (PAS staining) on selected sections. All sections were microscopically analyzed by an experienced pathologist (J.N.) for signs of tumor regression, including low nucleocytoplasmic ratio, nuclear enlargement, decrease in mitotic activity, and stromal fibrosis or reactive inflammation.23 Specimens with no detectable residual tumor, residual tumor of less than 1 cm and marked signs of regression, or scattered foci of microscopic tumor were classified as histopathologic responders. Specimens with residual tumor greater than 1 cm or diffuse extensive infiltration on microscopic examination and no signs of regression were classified as nonresponders in histopathology.
Metabolic response. Evaluation of metabolic response was accomplished by comparing the relative changes in tumoral FDG uptake, expressed as standardized uptake values (SUV). The SUV from FDG-PET after the first and third cycle of chemotherapy was compared with the baseline study. If multiple metastatic tumors were present in a patient, the lesion with the lowest change in FDG uptake was used for analysis on the basis of the rationale that the metastatic tumor with the worst response would determine survival.
The criteria for metabolic response after the first cycle of chemotherapy have previously been defined as a decrease in SUV of more than two times the standard deviation (SD) of spontaneous changes, which is 20% or more for SUVs.24,25 In addition, various thresholds were retrospectively tested to determine the optimal threshold for prediction of response after the first and third cycle of chemotherapy on the basis of patient survival. Optimal was defined as the threshold that produced the most significant difference in overall survival of metabolic responders versus nonresponders.
Statistical Analysis
Linear regression and Spearman's rank correlation coefficient (rho) were used to describe the correlation between quantitative parameters. All quantitative values are expressed as mean value ± one SD. Changes in FDG uptake (metabolic response) were compared with subsequent overall survival of metabolic responders and nonresponders. The FDG-PET results after the first and third cycle were analyzed separately. Cumulative overall survival and survival probability was estimated by the Kaplan-Meier method. Survival of metabolic responders and nonresponders were compared by the log-rank test and differences with P < .01 were considered significant. In addition, the overall survival of metabolic responders and nonresponders was compared using increasing thresholds in increments of 5%, starting with a 20% decrease in SUV. The threshold that produced the most significant difference in overall survival of metabolic responders and nonresponders was identified as the optimal threshold. Statistical analysis was performed (N.A., S.S.) using Statistical Package for the Social Sciences (SPSS version 12.0 for Windows; SPSS Inc, Chicago, IL).
RESULTS
Patients
A total of 37 patients were enrolled in this study of which four were excluded because they did not undergo surgery (n = 2), had a secondary malignancy discovered at surgery (n = 1), or did not complete FDG-PET imaging (n = 1). In 33 patients the baseline FDG-PET was 5.0 ± 3.8 days before initiation of chemotherapy. Twenty-six patients underwent FDG-PET after the first cycle of chemotherapy at a mean interval of 16 ± 4.7 days (range, 8 to 24 days) following the initiation of chemotherapy and all 33 patients were studied after the third cycle at a mean of 23 ± 10 days after completion of chemotherapy. A total of 92 FDG-PET scans were performed.
Patient Follow-Up and Survival
Median follow-up time was 48.8 months (range, 38.3 to 70.6 months). During this period, 23 out of 33 patients have died. Median overall survival was 26.8 months. The overall 2-year and 3-year survival rates were 57.6% and 42.4%, respectively. Nineteen patients have died in a subset of 26 patients who had an FDG-PET scan after the first cycle of chemotherapy.
PET Monitoring of Therapy Response
Comparing SUVs calculated for maximum and average activity values within a tumor ROI showed an excellent correlation (rho = 0.98) after the first and third cycle of chemotherapy. We are presenting the SUV results for the average activity. FDG uptake after the first and third cycle of chemotherapy was compared to the baseline FDG-PET. Metastatic ovarian cancer showed high FDG uptake at baseline with a mean SUV of 6.8 ± 2.1 (n = 33). After the first cycle of chemotherapy the SUV decreased to 4.9 ± 2.8 (n = 26) and decreased further to 3.5 ± 2.8 (n = 33) after the third cycle of chemotherapy. By using a previously defined threshold of 20% decrease in SUV after the first cycle of chemotherapy, 15 out of 26 patients were classified as responders and had a mean decrease in SUV of 59.5% ± 19.0%. Eleven nonresponding patients (change in SUV < 20%) had a mean decrease of 4.0% ± 13.3% (Fig 1A). After the third cycle of chemotherapy, a threshold of 55% decrease in SUV was found to optimally differentiate between metabolic responders and nonresponders. Eighteen out of 33 patients were metabolic responders and had a mean decrease in SUV of 74.4% ± 9.1% compared to 15 nonresponders with a mean decrease in SUV of 23.9% ± 17.9% (Fig 1B).
There was a close relationship between the changes in FDG uptake after the first and third cycle of chemotherapy (rho = 0.81). FDG-PET was discordant regarding the metabolic response classification in only two out of 26 patients. These two patients were classified as nonresponders after the third cycle but had a decrease in SUV of more than 20% after the first cycle. The overall survival of these patients was 15.2 months and 19.7 months, respectively, compared with a median overall survival of 26.8 months. More important, no metabolic responder after the third cycle has been erroneously classified as nonresponder after the first cycle. In 26 patients who had three PET scans, the overall decrease in SUV in metabolic responders was 50.1% after the first cycle and 76.2% after the third cycle of chemotherapy. In metabolic responders, 65.7% of the metabolic changes occurred within the first 2 weeks (16 ± 4.7 days) after initiation of chemotherapy (Fig 1A and B).
Clinical and Histopathologic Response
Clinical response after chemotherapy was defined as response in at least two of the following three criteria: intraoperative residual tumor less than 4 cm, regression of peritoneal carcinomatosis, and/or decrease in CA125 tumor marker level 75% from baseline or complete normalization (< 35 U/mL). Twenty-one out of 33 patients (63.6%) had a clinical response and 12 patients (36.4%) did not show clinical response. CA125 response was defined as a decrease of 75% or a complete normalization (< 35 U/mL). In all 33 patients, the mean baseline CA125 serum level was 2,912 ± 7,404 U/mL (range, 94 to 42,160 U/mL) and the mean postchemotherapy level was 135 ± 255 U/mL (range, 15 to 1,120 U/mL). All patients, except one, had a decrease in CA125 of at least 50% after three cycles of chemotherapy, and 29 out of 33 patients had a decrease of 75%. In 13 patients (39.4%), CA125 levels were normal (< 35 U/mL) after chemotherapy. Histopathologic response was determined at surgery after three cycles of chemotherapy. Twenty-seven out of 33 patients (81.8%) did not respond and six patients (18.2%) responded in histopathology.
Metabolic Response and Survival
There was a significant correlation between metabolic response in FDG-PET after the first (P = .008) and after the third cycle (P = .005) of chemotherapy, respectively, and overall survival. Using a previously defined 20% threshold for decrease in SUV from baseline after the first cycle of chemotherapy, median overall survival was 38.3 months in metabolic responders (n = 15) compared with 23.1 months in metabolic nonresponders (n = 11; P = .008; Fig 2A). The corresponding 2-year survival rates were 73.3% and 45.5%, respectively. After the third cycle of chemotherapy, a threshold of 55% decrease in SUV was found to optimally differentiate between responders and nonresponders. Using this criterion, median overall survival was 38.9 months in metabolic responders (n = 18) compared with 19.7 months in metabolic nonresponders (n = 15; P = .005; Fig 2B). The corresponding 2-year survival rates were 72.2% and 40.0%, respectively (Table 2). It is important to note that the difference in overall survival between metabolic responders and nonresponders was the same using the SUVs calculated for maximum and average activity values within a tumor ROI.
Clinical and Histopathologic Response and Survival
Clinical response criteria did not correlate (P = .7) with overall survival, and histopathologic response criteria showed only a weak correlation (P = .09) with overall survival. Median overall survival was 27.8 months in clinical responders (n = 21) and 22.5 months in clinical nonresponders (n = 12). Patients with normal CA125 levels after chemotherapy (n = 13) had a median overall survival of 27.8 months compared with 24.4 months (P = .4) in patients with elevated CA125 (n = 20). Patients with a decrease in CA125 of 75% (n = 29) had a median overall survival of 27.8 months compared with 22.5 months (P = .5) in patients with a decrease in CA125 of less than 75% (n = 4). Patients who achieved histopathologic response (n = 6) had a median overall survival of 43.3 months compared with 25.6 months (P = .09) in patients with no histopathologic response (n = 27) after the third cycle of chemotherapy.
Residual Tumor after Surgery and Survival
It is generally accepted that optimal cytoreductive surgery is defined by residual tumor masses smaller than 1 cm. Out of 33 patients, 11 patients had residual tumor masses 1 cm, and 22 patients had tumor masses less than 1 cm. Optimal cytoreductive surgery was achieved in 15 out of 18 (83.3%) metabolic responders and in only seven out of 15 (46.6%) metabolic nonresponders. Macroscopically tumor-free surgery was achieved in six out of 18 (33.3%) metabolic responders compared with two out of 15 (13.3%) nonresponders. Patients with residual tumor masses less than 1 cm after surgery had a median overall survival of 37.9 months compared with 15.2 months in patients with residual tumor masses 1 cm (P = .002). Macroscopically tumor-free patients had a median overall survival of 41.4 months compared with 23.7 months in patients with residual tumor after surgery (P = .03).
DISCUSSION
Changes in tumor glucose metabolism predicted response to neoadjuvant chemotherapy in advanced-stage ovarian cancer better than histopathologic and clinical response criteria or the serum tumor marker CA125. Metabolic responders were identified by sequential FDG-PET imaging as early as after the first cycle of chemotherapy and had a significantly better overall survival than metabolic nonresponders.
Over the past few years, there is growing evidence that metabolic imaging by FDG-PET provides highly accurate information about response to treatment in various tumors.15-20,22,25-27 A decrease in FDG uptake by 60% to 67% from baseline to day seven was observed in successfully treated non-Hodgkin's lymphoma.16 Two thirds of the metabolic effect of chemotherapy occurred within the first week of treatment. Similar changes were found in solid tumors that varied depending on the chemotherapeutic regimen applied.17-19,22,25 In ovarian cancer, we observed an overall decrease in FDG uptake of 50.1% after the first cycle of chemotherapy and of 76.2% after the third cycle of chemotherapy in patients responding to treatment. In these metabolic responders, 65.7% of the metabolic changes occurred within the first 2 weeks after initiation of chemotherapy. Our study confirms a recently identified characteristic behavior of malignant tumors, namely the close correlation between the early decrease in glucose metabolism and patient survival. These findings establish the basis for the future clinical application of sequential FDG-PET imaging as in vivo test for chemosensitivity, predicting response to treatment early after onset of chemotherapy.
FDG-PET imaging has been shown to provide a highly reproducible measure of tumor glucose consumption.24,28 For clinical use, it is important to identify an optimal threshold for decrease in FDG uptake to differentiate metabolic responders from nonresponders. Weber et al24,25 recently defined metabolic response after the first cycle of chemotherapy as a decrease in FDG uptake larger than two times the SD of spontaneous changes, which is 20% or more for the semiquantitative SUV approach. By prospectively applying this criterion, we found a significant correlation between metabolic response after the first cycle of chemotherapy and overall survival (P = .008). The median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. In advanced non–small-cell lung cancer the same prospectively applied threshold demonstrated a close correlation between metabolic response and best response to therapy according to RECIST (Response Evaluation Criteria in Solid Tumors) in patients undergoing platinum-based chemotherapy.25 The median time to progression and the overall survival was significantly longer for metabolic responders than for nonresponding lung cancer patients.25 It is important to note that by using a threshold of 20% decrease in FDG uptake, not all metabolic nonresponders will be identified. In our study, two patients had a decrease in FDG uptake of more than 20% after the first cycle of chemotherapy but were classified as metabolic nonresponders after the third cycle (overall survival 15.2 months and 19.7 months, versus median overall survival of 26.8 months). However, for clinical application, it is preferable to choose a conservative threshold so that the treatment will not be changed in responders even at the cost of not identifying all nonresponders. Of note, no metabolic responder after the third cycle has been erroneously classified as nonresponder by FDG-PET after the first cycle.
FDG-PET after the third cycle of chemotherapy provided strong prognostic information and was significantly correlated with the overall survival (P = .005). In advanced stages of ovarian cancer, the patients' fate depends on both successful surgery and chemotherapy.1 Because it is virtually impossible to surgically remove all tumor deposits in the peritoneal cavity, survival is ultimately determined by the response to chemotherapy. Our study showed that sequential FDG-PET provided important prognostic information and could potentially be used for treatment stratification in the future. A French Multicenter Study concluded recently that aggressive surgery should be avoided in patients with initial resistance to chemotherapy.29 However, it is necessary to determine in a prospective study whether changes in treatment triggered by FDG-PET result in improved disease-free and overall survival. In our study, surgery in metabolic responders achieved a higher rate of complete tumor resections compared with nonresponding patients. Macroscopically tumor-free surgery was achieved in 33.3% of metabolic responders compared with only 13.3% in nonresponders. Patients with a metabolic response to chemotherapy could be optimally debulked (< 1 cm residual tumor) in 83.3% (15 out of 18 responders). In contrast, optimal cytoreduction could be achieved in only 46.6% of patients with no metabolic response (7 out of 15 nonresponders).
Clinical response criteria, including the serum tumor marker CA125, did not accurately reflect treatment response and did not provide prognostic information in the neoadjuvant chemotherapy setting. All patients had a decrease in CA125 levels after initiation of chemotherapy, but no absolute decrease or percentage of change predicted patient survival. The serum tumor marker CA125 is an early indicator of recurrence and has also been suggested for evaluation of response to chemotherapy.30 The Gynecological Cancer Intergroup defined response in recurrent ovarian cancer as a decrease in CA125 by at least 50%, and others have suggested a serial decrease over three samples of greater than 75%.31 In our study, all patients except one had a decrease in CA125 of at least 50%, and 29 out of 33 patients had a decrease of 75%. We found no correlation between the decrease in CA125 and overall survival (P = .5). Recent studies, including a meta-analysis of 19 phase II trials, indicated that CA125 response criteria tend to overestimate tumor response.32,33 Important differences between the palliative and neoadjuvant chemotherapy have to be considered. In our study, the CA125 level before treatment was on average 2,912 ± 7,404 U/mL and, in many cases, substantially higher than in the trials where the criteria were established. We also tested the normalization of CA125 (< 35 U/mL) as criterion and found no difference in survival in patients with normal or elevated CA125 levels after chemotherapy before surgery. The unexpected lack of changes in CA125 to predict response to neoadjuvant chemotherapy could have been potentially influenced by the relatively small number of patients studied and needs to be further evaluated. The decrease in ascites has not been used to determine clinical response since a previous study at our institution had demonstrated a substantial decrease in ascites after three cycles of neoadjuvant chemotherapy in almost all patients.6
Changes in tumor size are generally used as surrogate end points for assessment of treatment response. The RECIST criteria defined tumor response as a decrease of the maximum tumor diameter by at least 30%.34 Frequently, several cycles of chemotherapy need to be applied before treatment response can be assessed by current anatomic imaging modalities. Dissolving and shrinkage of a tumor mass is the final step in a complex cascade of cellular and sub-cellular changes after initiation of treatment. Several studies have shown that FDG-PET is more accurate than anatomic imaging in determining tumor response, the viability of residual masses, as well as for evaluation of new therapeutic agents.35,36 We did not include CT imaging in our study because of the difficulty in accurately determining the extent of disease in the peritoneal cavity.37 PET/CT is a new imaging modality that has recently become widely available in the United States, allowing the acquisition of spatially registered PET and CT data in one imaging procedure.38 Using a combined PET/CT scanner for monitoring therapeutic effects allows the assessment of tumor size (volume) and metabolic activity at the same time. An alternate method of response evaluation to RECIST combining CT measurements with FDG uptake is currently being discussed.39
Histopathologic tumor regression serves as a gold standard for response evaluation after neoadjuvant chemotherapy in several types of tumors. Initially developed for osteosarcomas40 various grades of response have been defined by the percentage of viable residual tumor after chemotherapy. Patients responding to neoadjuvant chemotherapy had a better overall survival compared with nonresponding patients, and histopathologic tumor regression provided important prognostic information.41,42 However, there is no generally accepted histopathologic classification of postchemotherapy changes established for ovarian cancer. McCluggage et al23 found a low nucleocytoplasmic ratio, nuclear enlargement, and a decrease in mitotic activity following chemotherapy. In contrast to other tumor types, the regression of ovarian cancer is characterized by tumor shrinkage without significant residual scar or fibrotic tissue. In our study, 27 out of 33 patients (81.8%) had no histopathologic response after three cycles of chemotherapy and six out of 33 patients (18.2%) responded in histopathology. However, there was only a weak correlation between histopathologic response and overall survival. It is necessary to develop more specific criteria for histopathologic tumor regression in ovarian cancer such as changes in proliferative activity, markers of apoptosis, as well as the genomic and proteomic expression profiles.
Recently, various molecular markers, genetic profiling, the presence of tumor cells in the blood, and in vitro testing for chemosensitivity have been suggested to be helpful in predicting response to treatment.43,44 Gene expression profiling with microarrays allows simultaneous assessment of thousands of genes potentially involved in the sensitivity or resistance of cancer cells to chemotherapy.45 Studies in various tumors, including ovarian cancer, have identified gene expression profiles that are linked to the response of cell lines to chemotherapeutic agents.46-48 Recently, Spentzos et al49 studied tumor tissues from 68 ovarian cancer patients and identified a gene expression signature comprising 115 genes with independent prognostic significance. Nevertheless, principal limitations of these approaches include the need for adequate tissue samples, tumor heterogeneity, as well as host factors such as drug delivery and metabolism that may not be reflected by gene expression profiles of the tumor cells.
In contrast, FDG-PET imaging allows evaluation of the net effect of chemotherapy on the tumor tissue. There is no simple explanation for FDG uptake in tumors. The expression of glucose transport proteins and cytoplasmatic hexokinase activity have been found to be key steps for intracellular tracer accumulation, but the overall FDG uptake in tumors is also affected by the variability in cellular density, macroscopic and microscopic blood supply, fraction of hypoxic tissue, cellular proliferation, and a myriad of enzyme systems determining the metabolic activity.11 Nevertheless, FDG-PET imaging has been shown to provide a stable and highly reproducible signal in metabolically active tumors, reflecting an integral over various factors contributing to chemosensitivity or resistance to chemotherapy. An invaluable advantage of imaging changes in tumoral metabolic activity by FDG-PET is the ability to monitor in vivo the overall result of therapeutic effects, not only in primary tumors but also in metastatic lesions throughout the body, in soft tissue, lymph nodes, liver, lungs, and in bones.
The limitations of this study include the relatively small number of patients and not all patients underwent FDG-PET after the first cycle of chemotherapy. This study focused on a subset of ovarian cancer with advanced stages of disease and the data may not be extrapolated to patients with less bulky disease. The metabolic response criteria discussed above need to be further validated in a larger group of patients. This study did not compare FDG-PET metabolic response with progression-free survival. Further palliative chemotherapies may have had an impact on overall survival. The substantial cost for applying sequential FDG-PET imaging for prediction of treatment response has to be considered, and a thorough examination of the cost-effectiveness of this approach is required. The hypothesis to test would be whether or not sequential FDG-PET would reduce the number of ineffective chemotherapies in nonresponding patients and, therefore, unnecessary cost.
In conclusion, we found that sequential FDG-PET was superior compared with clinical and histopathologic response criteria as well as the serum tumor marker CA125 in predicting response to neoadjuvant chemotherapy and, ultimately, patient survival. Prediction of response as early as after the first cycle of chemotherapy might be helpful in treatment stratification of ovarian cancer patients undergoing chemotherapy that needs to be validated in prospective studies.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank R. Busch, Department of Medical Statistics, Technische Universit?t München, for statistical consultation and the radiochemistry and PET staff for their help and support.
NOTES
Supported by the Department of Nuclear Medicine, Pathology and Gynecology of the Technische Universit?t München, Munich, Germany.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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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
Wieder HA, Brucher BL, Zimmermann F, et al: Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 22:900-908, 2004
McCluggage WG, Lyness RW, Atkinson RJ, et al: Morphological effects of chemotherapy on ovarian carcinoma. J Clin Pathol 55:27-31, 2002
Weber WA, Ziegler SI, Thodtmann R, et al: Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 40:1771-1777, 1999
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
Downey RJ, Akhurst T, Ilson D, et al: Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: Results of a prospective trial. J Clin Oncol 21:428-432, 2003
Mac Manus MP, Hicks RJ, Matthews JP, et al: Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non–small-cell lung cancer. J Clin Oncol 21:1285-1292, 2003
Minn H, Zasadny KR, Quint LE, et al: Lung cancer: Reproducibility of quantitative measurements for evaluating 2-[F-18]-fluoro-2-deoxy-D-glucose uptake at PET. Radiology 196:167-173, 1995
Ansquer Y, Leblanc E, Clough K, et al: Neoadjuvant chemotherapy for unresectable ovarian carcinoma: A French multicenter study. Cancer 91:2329-2334, 2001
Bridgewater JA, Nelstrop AE, Rustin GJ, et al: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 17:501-508, 1999
Rustin GJ: Use of CA-125 to Assess Response to New Agents in Ovarian Cancer Trials. J Clin Oncol 21:187-193, 2003
Rustin GJ, Nelstrop AE, Bentzen SM, et al: Selection of active drugs for ovarian cancer based on CA-125 and standard response rates in phase II trials. J Clin Oncol 18:1733-1739, 2000
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Division of Nuclear Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA
Department of Medical and Molecular Pharmacology, University of California, Los Angeles, CA
Department of Pathology, University of Freiburg, Freiburg
Department of Obstetrics and Gynecology, University of Bonn, Bonn, Germany
ABSTRACT
PURPOSE: The aim of this study was to evaluate sequential F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) to predict patient outcome after the first and third cycle of neoadjuvant chemotherapy in advanced-stage (International Federation of Gynecology and Obstetrics stages IIIC and IV) ovarian cancer.
PATIENTS AND METHODS: Thirty-three patients received three cycles of carboplatin-based chemotherapy, followed by cytoreductive surgery. Quantitative FDG-PET of the abdomen and pelvis was acquired before treatment and after the first and third cycle of chemotherapy. Changes in tumoral FDG uptake, expressed as standardized uptake values (SUV), were compared with clinical and histopathologic response; overall survival served as a reference.
RESULTS: A significant correlation was observed between FDG-PET metabolic response after the first (P = .008) and third (P = .005) cycle of chemotherapy and overall survival. By using a threshold for decrease in SUV from baseline of 20% after the first cycle, median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. At a threshold of 55% decrease in SUV after the third cycle median overall survival was 38.9 months in metabolic responders compared with 19.7 months in nonresponders. There was no correlation between clinical response criteria (P = .7) or CA125 response criteria (P = .5) and overall survival. There was only a weak correlation (P = .09) between histopathologic response criteria and overall survival.
CONCLUSION: Sequential FDG-PET predicted patient outcome as early as after the first cycle of neoadjuvant chemotherapy and was more accurate than clinical or histopathologic response criteria including changes in tumor marker CA125. FDG-PET appears to be a promising tool for early prediction of response to chemotherapy.
INTRODUCTION
The majority of ovarian cancer patients present with advanced stages of disease and tumor spread in the abdominal cavity.1 Standard treatment includes aggressive cytoreductive surgery followed by platinum/taxane-based chemotherapy.2 Numerous studies have shown that long-term survival greatly depends on the effectiveness of surgical procedures since cytoreduction increases the efficacy of additional adjuvant therapy. Women who fail to undergo optimum cytoreduction have a poorer prognosis3 and patients with International Federation of Gynecology and Obstetrics stages IIIC and IV have a 5-year survival of less than 15%.1
Neoadjuvant (preoperative) chemotherapy is under active investigation for the treatment of advanced stages of ovarian cancer and was initially introduced in patients who were unable to tolerate extensive cytoreduction.2 Preoperative chemotherapy is now being evaluated in clinical trials in patients unlikely to achieve primary successful surgery, and it has been shown to enhance cytoreduction, reduce blood loss, the duration of surgery, and the intensity of postoperative care.4-8 Few studies including a small series of patients have demonstrated that neoadjuvant chemotherapy followed by standard surgery is associated with a comparable progression-free interval and overall survival compared with conventional treatment.2,5,6,9,10 However, patients not responding to neoadjuvant chemotherapy seem to have a poorer prognosis and reduced overall survival compared with patients who are sensitive to chemotherapy.8
Imaging metabolic pathways offers an alternative to visualize therapeutic effects. Malignant transformation of cells is frequently associated with increased metabolic activity. Positron emission tomography (PET) using F-18-fluorodeoxyglucose (FDG) has been successfully employed to visualize enhanced glucose utilization in tumor tissue. The glucose analog FDG is phosphorylated by intracellular hexokinases after crossing the cell membrane via glucose transporters but not further metabolized and, therefore, trapped in the cells, reflecting exogenous glucose consumption.11 FDG-PET has been shown to identify primary tumors, regional lymph nodes, and distant metastases with high diagnostic accuracy for various tumor types, including primary and recurrent ovarian cancer.12-14
Several studies have shown that changes in tumor metabolism occur early in the course of therapy and precede the reduction of tumor size.15-22 These studies suggest that quantification of tumor glucose metabolism is highly accurate for monitoring effects of chemotherapy. In breast cancer, sequential FDG-PET imaging provided a sensitive means of early detection of response to therapy.15,17,18 In esophageal and gastric cancer the initial decrease of FDG uptake in tumor tissue correlated well with the results of histopathologic response evaluation after neoadjuvant treatment.19-22
However, no information is currently available describing the role of FDG-PET for the noninvasive prediction of response to neoadjuvant chemotherapy in ovarian cancer. This study evaluated the hypothesis that changes in FDG uptake early in the course of treatment allow predicting the effectiveness of chemotherapy and subsequent patient outcome. The aim of this study was to prospectively evaluate the use of sequential metabolic FDG-PET imaging at baseline, after the first and third cycle of chemotherapy and to compare changes in tumoral FDG uptake with overall survival serving as the gold standard.
PATIENTS AND METHODS
Patients
Women who presented with newly diagnosed, advanced ovarian cancer (International Federation of Gynecology and Obstetrics stages IIIC and IV) and large (> 500 mL) ascites volumes and participated in a prospective neoadjuvant treatment protocol were eligible for this study. Histologic diagnosis was confirmed by diagnostic laparoscopy in all patients before inclusion. Exclusion criteria were known diabetes, pregnancy, and younger than 18 years of age. Patients with chemotherapy or radiotherapy within the last 6 months or a second malignancy were also excluded. A physician explained details of the study and written informed consent was obtained from all patients. The institutional review board of the Technische Universit?t München approved the study protocol. Patient characteristics are given in Table 1.
Chemotherapy and Surgery
Standard neoadjuvant chemotherapy consisted of three cycles of carboplatin (AUC5) plus paclitaxel (175 mg/m2 body surface area), administered at intervals of 3 weeks. For patients in poor general state of health, single-agent carboplatin was administered alternatively. Twenty-three out of 33 patients (69.7%) received standard combination of carboplatin and paclitaxel and 10 patients (30.3%) received single-agent carboplatin. Cytoreductive surgery was performed after three cycles of chemotherapy in all patients, followed by another three cycles of platinum-based chemotherapy. The goal of all surgical procedures was to obtain tumor-free status or macroscopically-minimal residual tumor of less than 1 cm.
PET Imaging
Patients were fasted for at least 6 hours before PET imaging. The serum glucose level was measured preceding the intravenous administration of 240 to 400 MBq (approximately 10 mCi) F-18-FDG. The mean blood glucose level was 99.3 ± 15.9 mg/dL at baseline PET, 100.6 ± 12.7 mg/dL at PET after the first cycle of chemotherapy, and 107.0 ± 20.7 mg/dL at PET after the third cycle of chemotherapy. To reduce tracer retention in the urinary tract system and to minimize the FDG uptake in the bowel, 20 mg of furosemide and 20 mg N-butyl-scopolamine were administered intravenously at the time of FDG injection. Emission scans (two-dimensional mode) of the abdomen and pelvis, acquired in 3-4 bed positions (ECAT EXACT 47/921, Siemens, Knoxville, TN), were obtained 60 minutes after tracer injection followed by a transmission scan. Emission data obtained over 10 minutes per bed position, corrected for random events, dead time, and attenuation were reconstructed with filtered back-projection (Hanning filter with cutoff frequency of 0.4 cycles per bin). The image pixel counts were calibrated to activity-concentration (Bq/mL) and decay corrected using the time of tracer injection as reference.
Image Analysis
Between one and four tumor lesions per patient (mean, 2.2) were identified on the baseline PET scan. The criterion was a distinct area of increased FDG uptake. Regions of interest (ROI) were placed semi-automatically over the tumor lesions in attenuation-corrected images. The slice with the highest radioactivity concentration within a tumor lesion was identified and a circular ROI with a diameter of 1.5 cm was placed in this area as well as in the adjacent slices. The diameters of all tumor lesions were substantially larger than the size of the ROI. This method was chosen to reduce partial volume effects, which play a substantial role if a ROI is placed around the entire tumor and tumor size changes after the baseline study. Every lesion was also measured in both follow-up PET scans using the same ROI. Standardized uptake values were calculated using the average activity values within the ROIs of three adjacent slices normalized to injected dose and patient's body weight. The analysis of the PET scans was performed without knowledge of the results of other clinical studies.
Assessment of Therapy Response
CA125 response. CA125 response criteria were either a decrease of 75% from baseline or a complete normalization of CA125 levels (< 35 U/mL).
Clinical response. Clinical response criteria were defined before initiation of the study. CA125 was considered an important, objectively measurable criterion for assessment of response to therapy and, therefore, changes in CA125 were evaluated as single prognostic criterion (see above) and in combination with other clinical response criteria. Clinical evaluation of therapy response was accomplished after three cycles of neoadjuvant chemotherapy. All patients had presented with bulky tumors (> 4 cm) and extensive peritoneal carcinomatosis at initial diagnosis. Patients were classified as clinical responders when at least two of the following three criteria were present: intraoperative residual tumor less than 4 cm, regression of peritoneal carcinomatosis to small and single-standing implants, and/or decrease of CA125 levels of 75% or a normalization of CA125 levels (< 35 U/mL). We did not include computed tomography (CT) imaging in our study because of the inherent limitation to accurately determine the extent of disease in the peritoneal cavity.
Histopathologic response. For assessment of histopathologic response, specimens were cut in slices measuring 0.5 cm and evaluated for the presence or absence of macroscopic tumor. Specimens were fixed according to standard procedures in 4% neutral buffered formaldehyde and embedded in paraffin. Sections of 5 μm thickness were prepared and stained with hematoxylin and eosin (H&E staining) as well as periodic acid-schiff (PAS staining) on selected sections. All sections were microscopically analyzed by an experienced pathologist (J.N.) for signs of tumor regression, including low nucleocytoplasmic ratio, nuclear enlargement, decrease in mitotic activity, and stromal fibrosis or reactive inflammation.23 Specimens with no detectable residual tumor, residual tumor of less than 1 cm and marked signs of regression, or scattered foci of microscopic tumor were classified as histopathologic responders. Specimens with residual tumor greater than 1 cm or diffuse extensive infiltration on microscopic examination and no signs of regression were classified as nonresponders in histopathology.
Metabolic response. Evaluation of metabolic response was accomplished by comparing the relative changes in tumoral FDG uptake, expressed as standardized uptake values (SUV). The SUV from FDG-PET after the first and third cycle of chemotherapy was compared with the baseline study. If multiple metastatic tumors were present in a patient, the lesion with the lowest change in FDG uptake was used for analysis on the basis of the rationale that the metastatic tumor with the worst response would determine survival.
The criteria for metabolic response after the first cycle of chemotherapy have previously been defined as a decrease in SUV of more than two times the standard deviation (SD) of spontaneous changes, which is 20% or more for SUVs.24,25 In addition, various thresholds were retrospectively tested to determine the optimal threshold for prediction of response after the first and third cycle of chemotherapy on the basis of patient survival. Optimal was defined as the threshold that produced the most significant difference in overall survival of metabolic responders versus nonresponders.
Statistical Analysis
Linear regression and Spearman's rank correlation coefficient (rho) were used to describe the correlation between quantitative parameters. All quantitative values are expressed as mean value ± one SD. Changes in FDG uptake (metabolic response) were compared with subsequent overall survival of metabolic responders and nonresponders. The FDG-PET results after the first and third cycle were analyzed separately. Cumulative overall survival and survival probability was estimated by the Kaplan-Meier method. Survival of metabolic responders and nonresponders were compared by the log-rank test and differences with P < .01 were considered significant. In addition, the overall survival of metabolic responders and nonresponders was compared using increasing thresholds in increments of 5%, starting with a 20% decrease in SUV. The threshold that produced the most significant difference in overall survival of metabolic responders and nonresponders was identified as the optimal threshold. Statistical analysis was performed (N.A., S.S.) using Statistical Package for the Social Sciences (SPSS version 12.0 for Windows; SPSS Inc, Chicago, IL).
RESULTS
Patients
A total of 37 patients were enrolled in this study of which four were excluded because they did not undergo surgery (n = 2), had a secondary malignancy discovered at surgery (n = 1), or did not complete FDG-PET imaging (n = 1). In 33 patients the baseline FDG-PET was 5.0 ± 3.8 days before initiation of chemotherapy. Twenty-six patients underwent FDG-PET after the first cycle of chemotherapy at a mean interval of 16 ± 4.7 days (range, 8 to 24 days) following the initiation of chemotherapy and all 33 patients were studied after the third cycle at a mean of 23 ± 10 days after completion of chemotherapy. A total of 92 FDG-PET scans were performed.
Patient Follow-Up and Survival
Median follow-up time was 48.8 months (range, 38.3 to 70.6 months). During this period, 23 out of 33 patients have died. Median overall survival was 26.8 months. The overall 2-year and 3-year survival rates were 57.6% and 42.4%, respectively. Nineteen patients have died in a subset of 26 patients who had an FDG-PET scan after the first cycle of chemotherapy.
PET Monitoring of Therapy Response
Comparing SUVs calculated for maximum and average activity values within a tumor ROI showed an excellent correlation (rho = 0.98) after the first and third cycle of chemotherapy. We are presenting the SUV results for the average activity. FDG uptake after the first and third cycle of chemotherapy was compared to the baseline FDG-PET. Metastatic ovarian cancer showed high FDG uptake at baseline with a mean SUV of 6.8 ± 2.1 (n = 33). After the first cycle of chemotherapy the SUV decreased to 4.9 ± 2.8 (n = 26) and decreased further to 3.5 ± 2.8 (n = 33) after the third cycle of chemotherapy. By using a previously defined threshold of 20% decrease in SUV after the first cycle of chemotherapy, 15 out of 26 patients were classified as responders and had a mean decrease in SUV of 59.5% ± 19.0%. Eleven nonresponding patients (change in SUV < 20%) had a mean decrease of 4.0% ± 13.3% (Fig 1A). After the third cycle of chemotherapy, a threshold of 55% decrease in SUV was found to optimally differentiate between metabolic responders and nonresponders. Eighteen out of 33 patients were metabolic responders and had a mean decrease in SUV of 74.4% ± 9.1% compared to 15 nonresponders with a mean decrease in SUV of 23.9% ± 17.9% (Fig 1B).
There was a close relationship between the changes in FDG uptake after the first and third cycle of chemotherapy (rho = 0.81). FDG-PET was discordant regarding the metabolic response classification in only two out of 26 patients. These two patients were classified as nonresponders after the third cycle but had a decrease in SUV of more than 20% after the first cycle. The overall survival of these patients was 15.2 months and 19.7 months, respectively, compared with a median overall survival of 26.8 months. More important, no metabolic responder after the third cycle has been erroneously classified as nonresponder after the first cycle. In 26 patients who had three PET scans, the overall decrease in SUV in metabolic responders was 50.1% after the first cycle and 76.2% after the third cycle of chemotherapy. In metabolic responders, 65.7% of the metabolic changes occurred within the first 2 weeks (16 ± 4.7 days) after initiation of chemotherapy (Fig 1A and B).
Clinical and Histopathologic Response
Clinical response after chemotherapy was defined as response in at least two of the following three criteria: intraoperative residual tumor less than 4 cm, regression of peritoneal carcinomatosis, and/or decrease in CA125 tumor marker level 75% from baseline or complete normalization (< 35 U/mL). Twenty-one out of 33 patients (63.6%) had a clinical response and 12 patients (36.4%) did not show clinical response. CA125 response was defined as a decrease of 75% or a complete normalization (< 35 U/mL). In all 33 patients, the mean baseline CA125 serum level was 2,912 ± 7,404 U/mL (range, 94 to 42,160 U/mL) and the mean postchemotherapy level was 135 ± 255 U/mL (range, 15 to 1,120 U/mL). All patients, except one, had a decrease in CA125 of at least 50% after three cycles of chemotherapy, and 29 out of 33 patients had a decrease of 75%. In 13 patients (39.4%), CA125 levels were normal (< 35 U/mL) after chemotherapy. Histopathologic response was determined at surgery after three cycles of chemotherapy. Twenty-seven out of 33 patients (81.8%) did not respond and six patients (18.2%) responded in histopathology.
Metabolic Response and Survival
There was a significant correlation between metabolic response in FDG-PET after the first (P = .008) and after the third cycle (P = .005) of chemotherapy, respectively, and overall survival. Using a previously defined 20% threshold for decrease in SUV from baseline after the first cycle of chemotherapy, median overall survival was 38.3 months in metabolic responders (n = 15) compared with 23.1 months in metabolic nonresponders (n = 11; P = .008; Fig 2A). The corresponding 2-year survival rates were 73.3% and 45.5%, respectively. After the third cycle of chemotherapy, a threshold of 55% decrease in SUV was found to optimally differentiate between responders and nonresponders. Using this criterion, median overall survival was 38.9 months in metabolic responders (n = 18) compared with 19.7 months in metabolic nonresponders (n = 15; P = .005; Fig 2B). The corresponding 2-year survival rates were 72.2% and 40.0%, respectively (Table 2). It is important to note that the difference in overall survival between metabolic responders and nonresponders was the same using the SUVs calculated for maximum and average activity values within a tumor ROI.
Clinical and Histopathologic Response and Survival
Clinical response criteria did not correlate (P = .7) with overall survival, and histopathologic response criteria showed only a weak correlation (P = .09) with overall survival. Median overall survival was 27.8 months in clinical responders (n = 21) and 22.5 months in clinical nonresponders (n = 12). Patients with normal CA125 levels after chemotherapy (n = 13) had a median overall survival of 27.8 months compared with 24.4 months (P = .4) in patients with elevated CA125 (n = 20). Patients with a decrease in CA125 of 75% (n = 29) had a median overall survival of 27.8 months compared with 22.5 months (P = .5) in patients with a decrease in CA125 of less than 75% (n = 4). Patients who achieved histopathologic response (n = 6) had a median overall survival of 43.3 months compared with 25.6 months (P = .09) in patients with no histopathologic response (n = 27) after the third cycle of chemotherapy.
Residual Tumor after Surgery and Survival
It is generally accepted that optimal cytoreductive surgery is defined by residual tumor masses smaller than 1 cm. Out of 33 patients, 11 patients had residual tumor masses 1 cm, and 22 patients had tumor masses less than 1 cm. Optimal cytoreductive surgery was achieved in 15 out of 18 (83.3%) metabolic responders and in only seven out of 15 (46.6%) metabolic nonresponders. Macroscopically tumor-free surgery was achieved in six out of 18 (33.3%) metabolic responders compared with two out of 15 (13.3%) nonresponders. Patients with residual tumor masses less than 1 cm after surgery had a median overall survival of 37.9 months compared with 15.2 months in patients with residual tumor masses 1 cm (P = .002). Macroscopically tumor-free patients had a median overall survival of 41.4 months compared with 23.7 months in patients with residual tumor after surgery (P = .03).
DISCUSSION
Changes in tumor glucose metabolism predicted response to neoadjuvant chemotherapy in advanced-stage ovarian cancer better than histopathologic and clinical response criteria or the serum tumor marker CA125. Metabolic responders were identified by sequential FDG-PET imaging as early as after the first cycle of chemotherapy and had a significantly better overall survival than metabolic nonresponders.
Over the past few years, there is growing evidence that metabolic imaging by FDG-PET provides highly accurate information about response to treatment in various tumors.15-20,22,25-27 A decrease in FDG uptake by 60% to 67% from baseline to day seven was observed in successfully treated non-Hodgkin's lymphoma.16 Two thirds of the metabolic effect of chemotherapy occurred within the first week of treatment. Similar changes were found in solid tumors that varied depending on the chemotherapeutic regimen applied.17-19,22,25 In ovarian cancer, we observed an overall decrease in FDG uptake of 50.1% after the first cycle of chemotherapy and of 76.2% after the third cycle of chemotherapy in patients responding to treatment. In these metabolic responders, 65.7% of the metabolic changes occurred within the first 2 weeks after initiation of chemotherapy. Our study confirms a recently identified characteristic behavior of malignant tumors, namely the close correlation between the early decrease in glucose metabolism and patient survival. These findings establish the basis for the future clinical application of sequential FDG-PET imaging as in vivo test for chemosensitivity, predicting response to treatment early after onset of chemotherapy.
FDG-PET imaging has been shown to provide a highly reproducible measure of tumor glucose consumption.24,28 For clinical use, it is important to identify an optimal threshold for decrease in FDG uptake to differentiate metabolic responders from nonresponders. Weber et al24,25 recently defined metabolic response after the first cycle of chemotherapy as a decrease in FDG uptake larger than two times the SD of spontaneous changes, which is 20% or more for the semiquantitative SUV approach. By prospectively applying this criterion, we found a significant correlation between metabolic response after the first cycle of chemotherapy and overall survival (P = .008). The median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. In advanced non–small-cell lung cancer the same prospectively applied threshold demonstrated a close correlation between metabolic response and best response to therapy according to RECIST (Response Evaluation Criteria in Solid Tumors) in patients undergoing platinum-based chemotherapy.25 The median time to progression and the overall survival was significantly longer for metabolic responders than for nonresponding lung cancer patients.25 It is important to note that by using a threshold of 20% decrease in FDG uptake, not all metabolic nonresponders will be identified. In our study, two patients had a decrease in FDG uptake of more than 20% after the first cycle of chemotherapy but were classified as metabolic nonresponders after the third cycle (overall survival 15.2 months and 19.7 months, versus median overall survival of 26.8 months). However, for clinical application, it is preferable to choose a conservative threshold so that the treatment will not be changed in responders even at the cost of not identifying all nonresponders. Of note, no metabolic responder after the third cycle has been erroneously classified as nonresponder by FDG-PET after the first cycle.
FDG-PET after the third cycle of chemotherapy provided strong prognostic information and was significantly correlated with the overall survival (P = .005). In advanced stages of ovarian cancer, the patients' fate depends on both successful surgery and chemotherapy.1 Because it is virtually impossible to surgically remove all tumor deposits in the peritoneal cavity, survival is ultimately determined by the response to chemotherapy. Our study showed that sequential FDG-PET provided important prognostic information and could potentially be used for treatment stratification in the future. A French Multicenter Study concluded recently that aggressive surgery should be avoided in patients with initial resistance to chemotherapy.29 However, it is necessary to determine in a prospective study whether changes in treatment triggered by FDG-PET result in improved disease-free and overall survival. In our study, surgery in metabolic responders achieved a higher rate of complete tumor resections compared with nonresponding patients. Macroscopically tumor-free surgery was achieved in 33.3% of metabolic responders compared with only 13.3% in nonresponders. Patients with a metabolic response to chemotherapy could be optimally debulked (< 1 cm residual tumor) in 83.3% (15 out of 18 responders). In contrast, optimal cytoreduction could be achieved in only 46.6% of patients with no metabolic response (7 out of 15 nonresponders).
Clinical response criteria, including the serum tumor marker CA125, did not accurately reflect treatment response and did not provide prognostic information in the neoadjuvant chemotherapy setting. All patients had a decrease in CA125 levels after initiation of chemotherapy, but no absolute decrease or percentage of change predicted patient survival. The serum tumor marker CA125 is an early indicator of recurrence and has also been suggested for evaluation of response to chemotherapy.30 The Gynecological Cancer Intergroup defined response in recurrent ovarian cancer as a decrease in CA125 by at least 50%, and others have suggested a serial decrease over three samples of greater than 75%.31 In our study, all patients except one had a decrease in CA125 of at least 50%, and 29 out of 33 patients had a decrease of 75%. We found no correlation between the decrease in CA125 and overall survival (P = .5). Recent studies, including a meta-analysis of 19 phase II trials, indicated that CA125 response criteria tend to overestimate tumor response.32,33 Important differences between the palliative and neoadjuvant chemotherapy have to be considered. In our study, the CA125 level before treatment was on average 2,912 ± 7,404 U/mL and, in many cases, substantially higher than in the trials where the criteria were established. We also tested the normalization of CA125 (< 35 U/mL) as criterion and found no difference in survival in patients with normal or elevated CA125 levels after chemotherapy before surgery. The unexpected lack of changes in CA125 to predict response to neoadjuvant chemotherapy could have been potentially influenced by the relatively small number of patients studied and needs to be further evaluated. The decrease in ascites has not been used to determine clinical response since a previous study at our institution had demonstrated a substantial decrease in ascites after three cycles of neoadjuvant chemotherapy in almost all patients.6
Changes in tumor size are generally used as surrogate end points for assessment of treatment response. The RECIST criteria defined tumor response as a decrease of the maximum tumor diameter by at least 30%.34 Frequently, several cycles of chemotherapy need to be applied before treatment response can be assessed by current anatomic imaging modalities. Dissolving and shrinkage of a tumor mass is the final step in a complex cascade of cellular and sub-cellular changes after initiation of treatment. Several studies have shown that FDG-PET is more accurate than anatomic imaging in determining tumor response, the viability of residual masses, as well as for evaluation of new therapeutic agents.35,36 We did not include CT imaging in our study because of the difficulty in accurately determining the extent of disease in the peritoneal cavity.37 PET/CT is a new imaging modality that has recently become widely available in the United States, allowing the acquisition of spatially registered PET and CT data in one imaging procedure.38 Using a combined PET/CT scanner for monitoring therapeutic effects allows the assessment of tumor size (volume) and metabolic activity at the same time. An alternate method of response evaluation to RECIST combining CT measurements with FDG uptake is currently being discussed.39
Histopathologic tumor regression serves as a gold standard for response evaluation after neoadjuvant chemotherapy in several types of tumors. Initially developed for osteosarcomas40 various grades of response have been defined by the percentage of viable residual tumor after chemotherapy. Patients responding to neoadjuvant chemotherapy had a better overall survival compared with nonresponding patients, and histopathologic tumor regression provided important prognostic information.41,42 However, there is no generally accepted histopathologic classification of postchemotherapy changes established for ovarian cancer. McCluggage et al23 found a low nucleocytoplasmic ratio, nuclear enlargement, and a decrease in mitotic activity following chemotherapy. In contrast to other tumor types, the regression of ovarian cancer is characterized by tumor shrinkage without significant residual scar or fibrotic tissue. In our study, 27 out of 33 patients (81.8%) had no histopathologic response after three cycles of chemotherapy and six out of 33 patients (18.2%) responded in histopathology. However, there was only a weak correlation between histopathologic response and overall survival. It is necessary to develop more specific criteria for histopathologic tumor regression in ovarian cancer such as changes in proliferative activity, markers of apoptosis, as well as the genomic and proteomic expression profiles.
Recently, various molecular markers, genetic profiling, the presence of tumor cells in the blood, and in vitro testing for chemosensitivity have been suggested to be helpful in predicting response to treatment.43,44 Gene expression profiling with microarrays allows simultaneous assessment of thousands of genes potentially involved in the sensitivity or resistance of cancer cells to chemotherapy.45 Studies in various tumors, including ovarian cancer, have identified gene expression profiles that are linked to the response of cell lines to chemotherapeutic agents.46-48 Recently, Spentzos et al49 studied tumor tissues from 68 ovarian cancer patients and identified a gene expression signature comprising 115 genes with independent prognostic significance. Nevertheless, principal limitations of these approaches include the need for adequate tissue samples, tumor heterogeneity, as well as host factors such as drug delivery and metabolism that may not be reflected by gene expression profiles of the tumor cells.
In contrast, FDG-PET imaging allows evaluation of the net effect of chemotherapy on the tumor tissue. There is no simple explanation for FDG uptake in tumors. The expression of glucose transport proteins and cytoplasmatic hexokinase activity have been found to be key steps for intracellular tracer accumulation, but the overall FDG uptake in tumors is also affected by the variability in cellular density, macroscopic and microscopic blood supply, fraction of hypoxic tissue, cellular proliferation, and a myriad of enzyme systems determining the metabolic activity.11 Nevertheless, FDG-PET imaging has been shown to provide a stable and highly reproducible signal in metabolically active tumors, reflecting an integral over various factors contributing to chemosensitivity or resistance to chemotherapy. An invaluable advantage of imaging changes in tumoral metabolic activity by FDG-PET is the ability to monitor in vivo the overall result of therapeutic effects, not only in primary tumors but also in metastatic lesions throughout the body, in soft tissue, lymph nodes, liver, lungs, and in bones.
The limitations of this study include the relatively small number of patients and not all patients underwent FDG-PET after the first cycle of chemotherapy. This study focused on a subset of ovarian cancer with advanced stages of disease and the data may not be extrapolated to patients with less bulky disease. The metabolic response criteria discussed above need to be further validated in a larger group of patients. This study did not compare FDG-PET metabolic response with progression-free survival. Further palliative chemotherapies may have had an impact on overall survival. The substantial cost for applying sequential FDG-PET imaging for prediction of treatment response has to be considered, and a thorough examination of the cost-effectiveness of this approach is required. The hypothesis to test would be whether or not sequential FDG-PET would reduce the number of ineffective chemotherapies in nonresponding patients and, therefore, unnecessary cost.
In conclusion, we found that sequential FDG-PET was superior compared with clinical and histopathologic response criteria as well as the serum tumor marker CA125 in predicting response to neoadjuvant chemotherapy and, ultimately, patient survival. Prediction of response as early as after the first cycle of chemotherapy might be helpful in treatment stratification of ovarian cancer patients undergoing chemotherapy that needs to be validated in prospective studies.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank R. Busch, Department of Medical Statistics, Technische Universit?t München, for statistical consultation and the radiochemistry and PET staff for their help and support.
NOTES
Supported by the Department of Nuclear Medicine, Pathology and Gynecology of the Technische Universit?t München, Munich, Germany.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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